Name Reactions: a Collection of Detailed Mechanisms And

Name Reactions

Fourth Expanded Edition

Jie Jack Li

Name Reactions

A Collection of Detailed Mechanisms and Synthetic Applications

Fourth Expanded Edition

123 Jie Jack Li, Ph.D. Discovery Chemistry Bristol-Myers Squibb Company 5 Research Parkway Wallingford, CT 06492 USA [email protected]

ISBN 978-3-642-01052-1 e-ISBN 978-3-642-01053-8 DOI 10.1007/978-3-642-01053-8 Springer Dordrecht Heidelberg London New York

Library of Congress Control Number: 2009931220

c Springer-Verlag Berlin Heidelberg 2009 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.

Cover design:KunkelLopka¬ GmbH

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com) To Vivien

Foreword

I don't have my name on anything that I don't really do. –Heidi Klum

Can the organic chemists associated with so-called “Named Reactions” make the same claim as supermodel Heidi Klum? Many scholars of chemistry do not hesitate to point out that the names associated with “name reactions” are often not the actual inventors. For instance, the Arndt–Eistert reaction has nothing to do with either Arndt or Eistert, Pummerer did not discover the “Pummerer” rearrangement, and even the famous Birch reduction owes its initial discovery to someone named Charles Wooster (first reported in a DuPont patent). The list goes on and on… But does that mean we should ignore, boycott, or outlaw “named reactions”? Absolutely not. The above examples are merely exceptions to the rule. In fact, the chemists associated with name reactions are typically the original discoverers, contribute greatly to its general use, and/or are the first to popularize the transformation. Regardless of the controversial history underlying certain named reactions, it is the students of organic chemistry who benefit the most from the cataloging of reactions by name. Indeed, it is with education in mind that Dr. Jack Li has masterfully brought the chemical community the latest edition of Name Reactions. It is clear why this beautiful treatise has rapidly become a bestseller within the chemical community. The quintessence of hundreds of named reactions is encapsulated in a concise format that is ideal for students and seasoned chemists alike. Detailed mechanistic and occasionally even historical details are given for hundreds of reactions along with key references. This “must- have” book will undoubtedly find a place on the bookshelves of all serious practitioners and students of the art and science of synthesis. Phil S. Baran May 2009 La Jolla, California

Preface

The first three editions of this book have been warmly embraced by the organic chemistry community. Many readers have indicated that while they like the detailed mechanisms, they prefer to have more real case applications in synthesis. For this edition, we have revolutionized the format, which finally liberated more space to accomodate many more synthetic examples. As a consequence, the subtitle of the book has been changed to A Collection of Detailed Mechanisms and Synthetic Applications. When putting together the 4th edition, I also strived to cap- ture the latest references, up to 2009 whenever possible. Coincidentally, my daughter Vivien, a sophomore at the University of Michigan, will take soon Or- ganic Chemistry. I hope she finds this book useful in preparing for her exams. I am very much indebted to the readers who have kindly written to me with suggestions, which helped transform this book into a useful reference book for senior undergrate and graduate students around the world—the second edition was translated to both Chinese and Russian. I am grateful to my good friend Derek A. Pflum at Ash Stevens Inc. who kindly proofead the entire manuscript and provided many invaluable suggestions. Prof. Derrick L. J. Clive at University of Alberta also proofread the first half of the manuscript and offered helpful comments. I also wish to thank Prof. Phil S. Baran at Scripps Research Institute and his students, Tanja Gulder, Yoshi Ishihara, Chad A. Lewis, Jonathan Lockner, Jun Cindy Shi, and Ian B. Seiple for proofreading the final draft of the manuscript. Their knowledge and time have tremendously enhanced the quality of this book. Any remaining errors are, of course, solely my own responsibility. As always, I welcome your critique!

Jie Jack Li May 2009 Killingworth, Connecticut

Table of Contents

Foreword...... VII Preface ...... IX.. Abbreviations ...... XIX

Alder ene reaction ...... 1 Aldol condensation...... 3 Algar–Flynn–Oyamada reaction...... 6 Allan–Robinson reaction...... 8 Arndt–Eistert homologation...... 10 Baeyer–Villiger oxidation...... 12 Baker–Venkataraman rearrangement...... 14 Bamford–Stevens reaction ...... 16 Barbier coupling reaction...... 18 Bartoli indole synthesis ...... 20 Barton radical decarboxylation ...... 22 Barton–McCombie deoxygenation ...... 24 Barton nitrite photolysis...... 26 Batcho–Leimgruber indole synthesis...... 28 Baylis–Hillman reaction...... 30 Beckmann rearrangement...... 33 Abnormal Beckmann rearrangement...... 34 Benzilic acid rearrangement...... 36 Benzoin condensation...... 38 Bergman cyclization...... 40 Biginelli pyrimidone synthesis...... 42 Birch reduction ...... 44 Bischler–Möhlau indole synthesis ...... 46 Bischler–Napieralski reaction ...... 48 Blaise reaction ...... 50 Blum–Ittah aziridine synthesis ...... 52 Boekelheide reaction ...... 54 Boger pyridine synthesis ...... 56 Borch reductive amination ...... 58 Borsche–Drechsel cyclization...... 60 Boulton–Katritzky rearrangement...... 62 Bouveault aldehyde synthesis ...... 64 Bouveault–Blanc reduction...... 65 Bradsher reaction...... 66 Brook rearrangement...... 68 Brown hydroboration ...... 70 Bucherer carbazole synthesis ...... 72 XII

Bucherer reaction...... 74 Bucherer–Bergs reaction...... 76 Büchner ring expansion...... 78 Buchwald–Hartwig amination ...... 80 Burgess dehydrating reagent...... 84 Burke boronates...... 87 Cadiot–Chodkiewicz coupling...... 90 Camps quinoline synthesis...... 92 Cannizzaro reaction...... 94 Carroll rearrangement ...... 96 Castro–Stephens coupling...... 98 Chan alkyne reduction...... 100 Chan–Lam C–X coupling reaction ...... 102 Chapman rearrangement ...... 105 Chichibabin pyridine synthesis...... 107 Chugaev reaction...... 110 Ciamician–Dennsted rearrangement...... 112 Claisen condensation...... 113 Claisen isoxazole synthesis...... 115 Claisen rearrangement...... 117 para-Claisen rearrangement ...... 119 Abnormal Claisen rearrangement...... 121 Eschenmoser–Claisen amide acetal rearrangement ...... 123 Ireland–Claisen (silyl ketene acetal) rearrangement ...... 125 Johnson–Claisen (orthoester) rearrangement ...... 127 Clemmensen reduction...... 129 Combes quinoline synthesis...... 131 Conrad–Limpach reaction...... 133 Cope elimination reaction ...... 135 Cope rearrangement ...... 137 Anionic oxy-Cope rearrangement...... 138 Oxy-Cope rearrangement...... 140 Siloxy-Cope rearrangement ...... 141 Corey–Bakshi–Shibata (CBS) reagent ...... 143 Corey−Chaykovsky reaction...... 146 Corey–Fuchs reaction...... 148 Corey–Kim oxidation...... 150 Corey–Nicolaou macrolactonization ...... 152 Corey–Seebach reaction...... 154 Corey–Winter olefin synthesis...... 156 Criegee glycol cleavage ...... 159 Criegee mechanism of ozonolysis ...... 161 Curtius rearrangement...... 162 Dakin oxidation ...... 165 Dakin–West reaction...... 167 Darzens condensation...... 169 XIII

Delépine amine synthesis...... 171 de Mayo reaction...... 173 Demjanov rearrangement...... 175 Tiffeneau–Demjanov rearrangement ...... 177 Dess–Martin periodinane oxidation ...... 179 Dieckmann condensation ...... 182 Diels–Alder reaction...... 184 Inverse electronic demand Diels–Alder reaction ...... 186 Hetero-Diels–Alder reaction ...... 187 Dienone–phenol rearrangement ...... 190 Di-π-methane rearrangement ...... 192 Doebner quinoline synthesis ...... 194 Doebner–von Miller reaction ...... 196 Dötz reaction...... 198 Dowd–Beckwith ring expansion...... 200 Dudley reagent...... 202 Erlenmeyer−Plöchl azlactone synthesis...... 204 Eschenmoser’s salt ...... 206 Eschenmoser–Tanabe fragmentation...... 208 Eschweiler–Clarke reductive alkylation of amines ...... 210 Evans aldol reaction ...... 212 Favorskii rearrangement...... 214 Quasi-Favorskii rearrangement...... 217 Feist–Bénary furan synthesis ...... 218 Ferrier carbocyclization...... 220 Ferrier glycal allylic rearrangement...... 222 Fiesselmann thiophene synthesis ...... 225 Fischer indole synthesis ...... 227 Fischer oxazole synthesis...... 229 Fleming–Kumada oxidation ...... 231 Tamao−Kumada oxidation...... 233 Friedel–Crafts reaction...... 234 Friedel–Crafts acylation reaction...... 234 Friedel–Crafts alkylation reaction...... 236 Friedländer quinoline synthesis ...... 238 Fries rearrangement...... 240 Fukuyama amine synthesis ...... 243 Fukuyama reduction...... 245 Gabriel synthesis ...... 246 Ing–Manske procedure...... 249 Gabriel–Colman rearrangement...... 250 Gassman indole synthesis...... 251 Gattermann–Koch reaction ...... 253 Gewald aminothiophene synthesis...... 254 Glaser coupling...... 257 Eglinton coupling ...... 259 XIV

Gomberg–Bachmann reaction...... 262 Gould–Jacobs reaction ...... 263 Grignard reaction...... 266 Grob fragmentation ...... 268 Guareschi–Thorpe condensation...... 270 Hajos–Wiechert reaction...... 271 Haller–Bauer reaction ...... 273 Hantzsch dihydropyridine synthesis ...... 274 Hantzsch pyrrole synthesis...... 276 Heck reaction...... 277 Heteroaryl Heck reaction ...... 280 Hegedus indole synthesis...... 281 Hell–Volhard–Zelinsky reaction...... 282 Henry nitroaldol reaction ...... 284 Hinsberg synthesis of thiophene derivatives ...... 286 Hiyama cross-coupling reaction ...... 288 Hofmann rearrangement ...... 290 Hofmann–Löffler–Freytag reaction...... 292 Horner–Wadsworth–Emmons reaction ...... 294 Houben–Hoesch synthesis ...... 296 Hunsdiecker–Borodin reaction ...... 298 Jacobsen–Katsuki epoxidation...... 300 Japp–Klingemann hydrazone synthesis...... 302 Jones oxidation...... 304 Collins–Sarett oxidation...... 305 PCC oxidation ...... 306 PDC oxidation...... 307 Julia–Kocienski olefination...... 309 Julia–Lythgoe olefination ...... 311 Kahne glycosidation...... 313 Knoevenagel condensation ...... 315 Knorr pyrazole synthesis...... 317 Koch–Haaf carbonylation ...... 319 Koenig–Knorr glycosidation...... 320 Kostanecki reaction...... 322 Kröhnke pyridine synthesis...... 323 Kumada cross-coupling reaction...... 325 Lawesson’s reagent ...... 328 Leuckart–Wallach reaction ...... 330 Lossen rearrangement ...... 332 McFadyen–Stevens reduction...... 334 McMurry coupling ...... 335 Mannich reaction...... 337 Martin’s sulfurane dehydrating reagent...... 339 Masamune–Roush conditions ...... 341 Meerwein’s salt ...... 343 XV

Meerwein–Ponndorf–Verley reduction ...... 345 Meisenheimer complex ...... 347 [1,2]-Meisenheimer rearrangement ...... 349 [2,3]-Meisenheimer rearrangement...... 350 Meyers oxazoline method ...... 351 Meyer–Schuster rearrangement ...... 353 Michael addition...... 355 Michaelis–Arbuzov phosphonate synthesis...... 357 Midland reduction ...... 359 Minisci reaction...... 361 Mislow–Evans rearrangement...... 363 Mitsunobu reaction...... 365 Miyaura borylation...... 368 Moffatt oxidation...... 370 Morgan–Walls reaction ...... 371 Mori–Ban indole synthesis...... 373 Mukaiyama aldol reaction...... 375 Mukaiyama Michael addition ...... 377 Mukaiyama reagent ...... 379 Myers−Saito cyclization...... 382 Nazarov cyclization...... 383 Neber rearrangement ...... 385 Nef reaction ...... 387 Negishi cross-coupling reaction...... 389 Nenitzescu indole synthesis ...... 391 Newman−Kwart reaction ...... 393 Nicholas reaction...... 395 Nicolaou dehydrogenation ...... 397 Noyori asymmetric hydrogenation...... 399 Nozaki–Hiyama–Kishi reaction...... 401 Nysted reagent...... 403 Oppenauer oxidation ...... 404 Overman rearrangement...... 406 Paal thiophene synthesis...... 408 Paal–Knorr furan synthesis ...... 409 Paal–Knorr pyrrole synthesis ...... 411 Parham cyclization ...... 413 Passerini reaction...... 415 Paternò–Büchi reaction ...... 417 Pauson–Khand reaction...... 419 Payne rearrangement ...... 421 Pechmann coumarin synthesis ...... 423 Perkin reaction...... 424 Petasis reaction ...... 426 Petasis reagent ...... 428 Peterson olefination...... 430 XVI

Pictet–Gams isoquinoline synthesis...... 432 Pictet–Spengler tetrahydroisoquinoline synthesis...... 434 Pinacol rearrangement...... 436 Pinner reaction...... 438 Polonovski reaction...... 440 Polonovski–Potier rearrangement...... 442 Pomeranz–Fritsch reaction...... 444 Schlittler–Müller modification ...... 446 Prévost trans-dihydroxylation ...... 447 Prins reaction...... 448 Pschorr cyclization ...... 450 Pummerer rearrangement...... 452 Ramberg–Bäcklund reaction...... 454 Reformatsky reaction ...... 456 Regitz diazo synthesis...... 458 Reimer–Tiemann reaction...... 460 Reissert reaction...... 461 Reissert indole synthesis ...... 463 Ring-closing metathesis (RCM)...... 465 Ritter reaction...... 468 Robinson annulation...... 470 Robinson–Gabriel synthesis...... 472 Robinson–Schöpf reaction ...... 474 Rosenmund reduction...... 476 Rubottom oxidation...... 478 Rupe rearrangement ...... 480 Saegusa oxidation...... 482 Sakurai allylation reaction ...... 484 Sandmeyer reaction...... 486 Schiemann reaction ...... 488 Schmidt rearrangement ...... 490 Schmidt’s trichloroacetimidate glycosidation reaction ...... 492 Shapiro reaction...... 494 Sharpless asymmetric amino hydroxylation...... 496 Sharpless asymmetric dihydroxylation...... 499 Sharpless asymmetric epoxidation ...... 502 Sharpless olefin synthesis ...... 505 Simmons–Smith reaction ...... 507 Skraup quinoline synthesis...... 509 Smiles rearrangement...... 511 Truce−Smile rearrangement ...... 513 Sommelet reaction...... 515 Sommelet–Hauser rearrangement...... 517 Sonogashira reaction ...... 519 Staudinger ketene cycloaddition...... 521 Staudinger reduction ...... 523 XVII

Stetter reaction...... 525 Still–Gennari phosphonate reaction...... 527 Stille coupling...... 529 Stille–Kelly reaction...... 531 Stobbe condensation...... 532 Strecker amino acid synthesis ...... 534 Suzuki–Miyaura coupling ...... 536 Swern oxidation...... 538 Takai reaction ...... 540 Tebbe olefination...... 542 TEMPO oxidation ...... 544 Thorpe−Ziegler reaction...... 546 Tsuji–Trost allylation ...... 548 Ugi reaction ...... 551 Ullmann coupling ...... 554 van Leusen oxazole synthesis ...... 556 Vilsmeier–Haack reaction...... 558 Vinylcyclopropane−cyclopentene rearrangement ...... 560 von Braun reaction ...... 562 Wacker oxidation ...... 564 Wagner–Meerwein rearrangement...... 566 Weiss–Cook reaction...... 568 Wharton reaction ...... 570 White reagent...... 572 Willgerodt–Kindler reaction ...... 576 Wittig reaction...... 578 Schlosser modification of the Wittig reaction ...... 580 [1,2]-Wittig rearrangement ...... 582 [2,3]-Wittig rearrangement ...... 584 Wohl–Ziegler reaction...... 586 Wolff rearrangement ...... 588 Wolff–Kishner reduction...... 590 Woodward cis-dihydroxylation...... 592 Yamaguchi esterification...... 594 Zincke reaction ...... 596

Subject Index ...... 599

Abbreviations and Acronyms

polymer support 3CC three-component condensation 4CC four-component condensation 9-BBN 9-borabicyclo[3.3.1]nonane A adenosine Ac acetyl ADDP 1,1'-(azodicarbonyl)dipiperidine AIBN 2,2ƍ-azobisisobutyronitrile Alpine-borane® B-isopinocampheyl-9-borabicyclo[3.3.1]-nonane AOM p-Anisyloxymethyl = p-MeOC6H4OCH2- Ar aryl B: generic base [bimim]Cl•2AlCl3 1-butyl-3-methylimidazolium chloroaluminuminate BINAP 2,2ƍ-bis(diphenylphosphino)-1,1ƍ-binaphthyl Bn benzyl Boc tert-butyloxycarbonyl BT benzothiazole Bz benzoyl Cbz benzyloxycarbonyl CuTC copper thiophene-2-carboxylate DABCO 1,4-diazabicyclo[2.2.2]octane dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC 1,3-dicyclohexylcarbodiimide DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone de diastereoselctive excess DEAD diethyl azodicarboxylate (DHQ)2-PHAL 1,4-bis(9-O-dihydroquinine)-phthalazine (DHQD)2-PHAL 1,4-bis(9-O-dihydroquinidine)-phthalazine DIAD diisopropyl azodidicarboxylate DIBAL diisobutylaluminum hydride DIPEA diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-N,N-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMFDMA N,N-dimethylformamide dimethyl acetal DMS dimethylsulfide DMSO dimethylsulfoxide DMSY dimethylsulfoxonium methylide DMT dimethoxytrityl DPPA diphenylphosphoryl azide dppb 1,4-bis(diphenylphosphino)butane XX dppe 1,2-bis(diphenylphosphino)ethane dppf 1,1ƍ-bis(diphenylphosphino)ferrocene dppp 1,3-bis(diphenylphosphino)propane dr diastereoselctive ratio DTBAD di-tert-butylazodicarbonate DTBMP 2,6-di-tert-butyl-4-methylpyridine E1 unimolecular elimination E1cB 2-step, base-induced β-elimination via carbanion E2 bimolecular elimination EAN ethylammonium nitrate EDDA ethylenediamine diacetate ee enantiomeric excess Ei two groups leave at about the same time and bond to each other as they are doing so. Eq equivalent Et ethyl EtOAc ethyl acetate HMDS hexamethyldisilazane HMPA hexamethylphosphoramide HMTTA 1,1,4,7,10,10-hexamethyltriethylenetetramine IBX o-iodoxybenzoic acid Imd imidazole KHMDS potassium hexamethyldisilazide LAH lithium aluminum hydride LDA lithium diisopropylamide LHMDS lithium hexamethyldisilazide LTMP lithium 2,2,6,6-tetramethylpiperidide M metal m-CPBA m-chloroperoxybenzoic acid MCRs multicomponent reactions Mes mesityl MPS morpholine-polysulfide Ms methanesulfonyl MWI microwave irradiation MVK methyl vinyl ketone NBS N-bromosuccinimide NCS N-chlorosuccinimide NIS N-iodosuccinimide NMP 1-methyl-2-pyrrolidinone Nos nosylate (4-nitrobenzenesulfonyl) N-PSP N-phenylselenophthalimide N-PSS N-phenylselenosuccinimide Nu nucleophile PCC pyridinium chlorochromate PDC pyridinium dichromate Piv pivaloyl XXI

PMB para-methoxybenzyl PPA polyphosphoric acid PPTS pyridinium p-toluenesulfonate PT phenyltetrazolyl PyPh2P diphenyl 2-pyridylphosphine Pyr pyridine Red-Al sodium bis(methoxy-ethoxy)aluminum hydride Red-Al sodium bis(methoxy-ethoxy)aluminum hydride (SMEAH) Salen N,N´-disalicylidene-ethylenediamine SET single electron transfer SIBX Stabilized IBX SM starting material SMEAH sodium bis(methoxy-ethoxy)aluminum hydride SN1 unimolecular nucleophilic substitution SN2 bimolecular nucleophilic substitution SNAr nucleophilic substitution on an aromatic ring TBABB tetra-n-butylammonium bibenzoate TBAF tetra-n-butylammonium fluoride TBAO 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane TBDMS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl t-Bu tert-butyl TDS thexyldimethylsilyl TEA triethylamine TEOC trimethysilylethoxycarbonyl Tf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid TFAA trifluoroacetic anhydride TFP tri-2-furylphosphine THF tetrahydrofuran TIPS triisopropylsilyl TMEDA N,N,Nƍ,Nƍ-tetramethylethylenediamine TMG 1,1,3,3-tetramethylguanidine TMP tetramethylpiperidine TMS trimethylsilyl TMSCl trimethylsilyl chloride TMSCN trimethylsilyl cyanide TMSI trimethylsilyl iodide TMSOTf trimethylsilyl triflate Tol toluene or tolyl Tol-BINAP 2,2ƍ-bis(di-p-tolylphosphino)-1,1ƍ-binaphthyl TosMIC (p-tolylsulfonyl)methyl isocyanide Ts tosyl TsO tosylate XXII

UHP urea-hydrogen peroxide Δ solvent heated under reflux 1

Alder ene reaction The Alder ene reaction, also known as the hydro-allyl addition, is addition of an enophile to an alkene (ene) via allylic transposition. The four-electron system including an alkene ʌ-bond and an allylic C–H ı-bond can participate in a pericyclic reaction in which the double bond shifts and new C–H and C–C ı-bonds are formed.

‡ HOMO X Δ ‡ , or X X Y Y H Lewis acid Y H H ene enophile H LUMO

X=Y: C=C, CŁC, C=O, C=N, N=N, N=O, S=O, etc.

Example 15

O ‡ O O xylene O 6-membered O reflux, 31% H transition state O

ene enophile

O ‡ O O O Alder ene O H reaction O

Example 27 O H H2N N O O O KOH, Pt/Clay, 35% O O O H O (Kishner reduction) 0 oC, CH Cl , 89% OH H 2 2 (Alder ene reaction)

Example 3, Intramolecular Alder-ene reaction8

O H O H toluene, reflux O N N 5 h, 95% O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_1, © Springer-Verlag Berlin Heidelberg 2009 2

Example 4, Cobalt-catalyzed Alder-ene reaction9

Et [Co(dppp)Br2], Zn, ZnI2, CH2Cl2 Et OTMS Ph OTMS 25 oC, 8 h, 95% (GC yield) Ph

Example 5, Nitrile-Alder-ene reaction10

NC CH3 CH3 CH 3 H sealed ampule CH3 CH3 CN CN CN NC NC CH3 CN 120−130 oC, 5 h H H C H CH3 70% 3 CN H3C CN Example 611

OAc OAc C6H13 C6H13 CpRu(CH3CN)3•PF6 acetone, rt, 81% SiEt SiEt3 3

References

1. Alder, K.; Pascher, F.; Schmitz, A. Ber. 1943, 76, 27−53. Kurt Alder (Germany, 1902−1958) shared the Nobel Prize in Chemistry in 1950 with his teacher Otto Diels (Germany, 1876−1954) for the development of the diene synthesis. 2. Oppolzer, W. Pure Appl. Chem. 1981, 53, 1181−1201. (Review). 3. Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325−335. (Review). 4. Mikami, K.; Nakai, T. In Catalytic Asymmetric Synthesis; 2nd edn.; Ojima, I., ed.; Wiley−VCH: New York, 2000, 543−568. (Review). 5. Sulikowski, G. A.; Sulikowski, M. M. e-EROS Encyclopedia of Reagents for Organic Synthesis (2001), John Wiley & Sons, Ltd., Chichester, UK. 6. Brummond, K. M.; McCabe, J. M. The Rhodium(I)-Catalyzed Alder-ene Reaction. In Modern Rhodium-Catalyzed Organic Reactions 2005, 151−172. (Review). 7. Miles, W. H.; Dethoff, E. A.; Tuson, H. H.; Ulas, G. J. Org. Chem. 2005, 70, 2862−2865. 8. Pedrosa, R.; Andres, C.; Martin, L.; Nieto, J.; Roson, C. J. Org. Chem. 2005, 70, 4332−4337. 9. Hilt, G.; Treutwein, J. Angew. Chem., Int. Ed. 2007, 46, 8500−8502. 10. Ashirov, R. V.; Shamov, G. A.; Lodochnikova, O. A.; Litvynov, I. A.; Appolonova, S. A.; Plemenkov, V. V. J. Org. Chem. 2008, 73, 5985−5988. 11. Cho, E. J.; Lee, D. Org. Lett. 2008, 10, 257−259. 12. Curran, T. T. Alder ene reaction. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 2−32. (Review). 3

Aldol condensation The Aldol condensation is the coupling of an enolate ion with a carbonyl compound to form a ȕ-hydroxycarbonyl, and sometimes, followed by dehydration to give a conjugated enone. A simple case is addition of an enolate to an aldehyde to afford an alcohol, thus the name aldol.

O 2 O 2 1. Base R OH Δ R O R 1 3 1 R O R R R3 R1 2. R R R2 R3

O O R deprotonation R condensation R1 R1 3 2 H R R

B: O

2 OR O acidic R2 OH O R3 R1 workup R3 R1 R R

Example 13

LDA, THF, then OH O O MgBr , −110 oC, then 2 OTMS OTMS BnO O CHO BnO O 85% yield

Example 28

LDA, THF, −78 to −40 oC, then aldehyde, 1 h, 43%, 3:2 dr 7 CO2H HO O OTBS 6 CO2H H O OTBS 22% of of 6S,7R-diastereomer O and 10% recovered SM

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_2, © Springer-Verlag Berlin Heidelberg 2009 4

Example 3, Enantioselective Mukaiyama-aldol reaction10

O O Ph N Ph N N cat. O OH OTMS O OSii-Pr3 OSii-Pr3 Ph CO2CHPh2 Ph CO2CHPh2 Sc(OTf) , 4 Å MS, CH Cl , −40 oC 83% yield, 98% ee 3 2 2

Example 4, Intermolecular aldol reaction using organocatalyst12

H O N H NH

O O N O OH H O DMSO, 10 equiv H O, rt Cl 2 Cl 72 h, 57%, 46% ee, 95% de

Example 5, Transannular aldol reaction13

OMe O OH O OMe OMe O 1. LiN(SiMe2Ph)2, THF o OH MeO −105 C, 74%, 10:1, dr MeO CH3 MeO MeO CH3 2. MgI2, Et2O, 57% O O OMe OMe OMe O OH O

References

1. Wurtz, C. A. Bull. Soc. Chim. Fr. 1872, 17, 436−442. Charles Adolphe Wurtz (1817−1884) was born in Strasbourg, France. After his doctoral training, he spent a year under Liebig in 1843. In 1874, Wurtz became the Chair of Organic Chemistry at the Sorbonne, where he educated many illustrous chemists such as Crafts, Fittig, Friedel, and van’t Hoff. The Wurtz reaction, where two alkyl halides are treacted with sodium to form a new carbon−carbon bond, is no longer considered synthetically useful, although the Aldol reaction that Wurtz discovered in 1872 has become a staple in organic synthesis. Alexander P. Borodin is also credited with the discovery of the Aldol reaction together with Wurtz. In 1872 he announced to the Russian Chemical Society the discovery of a new byproduct in aldehyde reactions with properties like that of an alcohol, and he noted similarities with compounds already discussed in publications by Wurtz from the same year. 2. Nielsen, A. T.; Houlihan, W. J. Org. React. 1968, 16, 1−438. (Review). 3. Still, W. C.; McDonald, J. H., III. Tetrahedron Lett. 1980, 21, 1031−1034. 5

4. Mukaiyama, T. Org. React. 1982, 28, 203−331. (Review). 5. Mukaiyama, T.; Kobayashi, S. Org. React. 1994, 46, 1−103. (Review on Tin(II) enolates). 6. Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325−335. (Review). 7. Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432−440. (Review). 8. (a) Borzilleri, R. M.; Zheng, X.; Schmidt, R. J.; Johnson, J. A.; Kim, S.-H.; DiMarco, J. D.; Fairchild, C. R.; Gougoutas, J. Z.; Lee, F. Y. F.; Long, B. H.; Vite, G. D. J. Am. Chem. Soc. 2000, 122, 8890–8897. (b) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K. C. Angew. Chem., Int. Ed. 1997, 36, 166−168. (c) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119, 7960–7973. 9. Mahrwald, R. (ed.) Modern Aldol Reactions, Wiley−VCH: Weinheim, Germany, 2004. (Book). 10. Desimoni, G.; Faita, G.; Piccinini, F.; Toscanini, M. Eur. J. Org. Chem. 2006, 5228−5230. 11. Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249−2293. (Review on enantioselective direct aldol reaction using organocatalysis.) 12. Doherty, S.; Knight, J. G.; McRae, A.; Harrington, R. W.; Clegg, W. Eur. J. Org. Chem. 2008, 1759−1766. 13. O’Brien, E. M.; Morgan, B. J.; Kozlowski, M. C. Angew. Chem., Int. Ed. 2008, 47, 6877−6880. 14. Trost, B. M.; Maulide, N.; Rudd, M. T. J. Am. Chem. Soc. 2009, 131, 420−421.

Algar−Flynn−Oyamada Reaction Conversion of 2ƍ-hydroxychalcones to 2-aryl-3-hydroxy-4H-1benzopyran-4-ones (flavonols) by an oxidative cyclization.

R1 O Ar R1 OH Ar R1 O Ar H2O2, NaOH OH OH R2 O R2 O R2 O

OH OH O HO α β H O O O O 2 2 O OOH OH O

O O O β-attack

OH OH O O flavonol A side reaction:

O α-attack O α β then dehydration O O aurone O

Example 15 OH O Ph 1. PhCHO, NaOH, EtOH, rt

o OH 2. H2O2, 15 to 50 C, 54% O O

Example 25

CHO

1. , aq. NaOH, EtOH OMe

O OH OMe O O

2. aq. NaOH, 30% H2O2 OH O 47% for two steps O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_3, © Springer-Verlag Berlin Heidelberg 2009 7

Example 3, The side reaction dominated to give the aurone derivative:9

MeO OH Ph MeO O OMe aq. NaOH Ph H OMe H2O2, 80% OMe O OH OMe O

Example 412

CHO BnO OH OMe BnO OH NaOH

EtOH, 54% O O OMe

OMe

H2O2, NaOH BnO O

EtOH, dioxane OH 76% O

References

1. Algar, J.; Flynn, J. P. Proc. Roy. Irish. Acad. 1934, B42, 1−8. 2. Oyamada, T. J. Chem. Soc. Jpn 1934, 55, 1256−1261. 3. Oyamada, T. Bull. Chem. Soc. Jpn. 1935, 10, 182−186. 4. Wheeler, T. S. Record Chem. Progr. 1957, 18, 133−161. (Review) 5. Smith, M. A.; Neumann, R. M.; Webb, R. A. J. Heterocycl. Chem. 1968, 5, 425−426. 6. Wagner, H.; Farkas, L. In The Flavonoids; Harborne, J. B.; Mabry, T. J.; Mabry H., Eds.; Academic Press: New York, 1975, 1, pp 127−213. (Review). 7. Wollenweber, E. In The Flavonoids: Advances in Research; Harborne, J. B.; Mabry, T. J., Eds; Chapman and Hall: New York, 1982; pp 189−259. (Review). 8. Wollenweber, E. In The Flavonoids: Advances in Research Since 1986; Harborne, J. B., Ed.; Chapman and Hall: New York, 1994, pp 259−335. (Review). 9. Bennett, M.; Burke, A. J.; O’Sullivan, W. I. Tetrahedron 1996, 52, 7163−7178. 10. Bohm, B. A.; Stuessy, T. F. Flavonoids of the Sunflower Family (Asteraceae); Springer-Verlag: New York, 2000. (Review). 11. Limberakis, C. Algar−Flynn−Oyamada Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 496−503. (Review). 12. Li, Z.; Ngojeh, G.; DeWitt, P.; Zheng, Z.; Chen, M.; Lainhart, B.; Li, V.; Felpo, P. Tetrahedron Lett. 2008, 49, 7243−7245.

Allan–Robinson reaction Synthesis of flavones or isoflavones by the treatment of of o-hydroxyaryl ketones with aromatic aldehydes. Cf. Kostanecki reaction on page 322.

O O OH O R1 R1 O R1

R 1 Δ R R CO2Na, O O

OH 1 OHR1 R O O OH − O CR1 acylation 2 enolization O O OCOR1 R R R O R1 O H O R1CO 2 R1 OH 1 H O R : 1 OH 1 O O R O R enolization O R H R R R O O 1 H O O2CR OH 1 O2CR

Example 16

OMe O O HO OH O

OMe MeO OMe OMe O

OMe OMe − o PhCO2Na, 170 180 C HO O

8 h, 45% OMe OMe O

Example 29

OH O O O O CO2H S S O N pyr., 40 oC, 72 h, 85% O N Me Me

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_4, © Springer-Verlag Berlin Heidelberg 2009 9

Example 310

O O OH OMe O OMe O

Et3N, reflux, 12 h, 87% O O O O

References

1. Allan, J.; Robinson, R. J. Chem. Soc. 1924, 125, 2192–2195. Robert Robinson (United Kingdom, 1886−1975) won the Nobel Prize in Chemistry in 1947 for his studies on alkaloids. However, Robinson himself considered his greatest contribution to science was that he founded the qualitative theory of electronic mechanisms in organic chemistry. Robinson, along with Lapworth (a friend) and Ingold (a rival), pioneered the arrow pushing approach to organic reaction mechanism. Robinson was also an accomplished pianist. James Allan, his student, also coauthored another important paper with Robinson on the relative directive powers of groups for aromatic substitution. 2. Széll, T.; Dózsai, L.; Zarándy, M.; Menyhárth, K. Tetrahedron 1969, 25, 715–724. 3. Wagner, H.; Maurer, I.; Farkas, L.; Strelisky, J. Tetrahedron 1977, 33, 1405–1409. 4. Dutta, P. K.; Bagchi, D.; Pakrashi, S. C. Indian J. Chem., Sect. B 1982, 21B, 1037– 1038. 5. Patwardhan, S. A.; Gupta, A. S. J. Chem. Res., (S) 1984, 395. 6. Horie, T.; Tsukayama, M.; Kawamura, Y.; Seno, M. J. Org. Chem. 1987, 52, 4702– 4709. 7. Horie, T.; Tsukayama, M.; Kawamura, Y.; Yamamoto, S. Chem. Pharm. Bull. 1987, 35, 4465–4472. 8. Horie, T.; Kawamura, Y.; Tsukayama, M.; Yoshizaki, S. Chem. Pharm. Bull. 1989, 37, 1216–1220. 9. Poyarkov, A. A.; Frasinyuk, M. S.; Kibirev, V. K.; Poyarkova, S. A. Russ. J. Bioorg. Chem. 2006, 32, 277–279. 10. Peng, C.-C.; Rushmore, T.; Crouch, G. J.; Jones, J. P. Bioorg. Med. Chem. Lett. 2008, 16, 4064–4074.

Arndt–Eistert homologation One-carbon homologation of carboxylic acids using diazomethane.

O O O SOCl2 1. CH2N2 R + ROH RCl2. Ag , H2O, hv OH

O N O N O R R Cl R Cl HH N H2CNN N Cl O − O − N ↑ CH3N2 N N 2 N N R R hv H H

O H H OH O : R CCO C R H R R OH OH : OH2 α-ketocarbene intermediate ketene intermediate

Example 17

O BnO CO2H − o N 1. ClCO2Et, Et3N, THF, 10 C, 15 min BnO 2 HN HN BnO Boc 2. CH N , Et O, 0 oC to rt, 18 h, 78% 2 2 2 BnO Boc

BnO PhCO2Ag, Et3N, MeOH/THF, dark CO2Me HN − o 25 C to rt, 3 h, 61% BnO Boc

Example 2, An interesting variation9

o 1. Fmoc-Cl, pyridine, 0 C O CO H 2. isobutylchloroformate, Et3N 2 N2 Ph Ph OH then CH N , 0 oC, 39% OFmoc 2 2 CONH Ph 2 Ph NH H 2 N Ph CONH PhCO2Ag, dioxane 2 o O 15 min., 50 C, 72%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_5, © Springer-Verlag Berlin Heidelberg 2009 11

Example 310

H H 1. LiOH, MeOH/H2O, reflux o 2. ClCO2Et, Et3N, THF, 0 C H H H H OTBDPS MeO2C OTBDPS MeO C N N 2 3. CH2N2, Et2O Cbz Cbz 4. PhCO2Ag, Et3N, MeOH, rt 69% for 4 steps

References

1. Arndt, F.; Eistert, B. Ber. 1935, 68, 200−208. Fritz Arndt (1885−1969) was born in Hamburg, Germany. He discovered the Arndt−Eistert homologation at the University of Breslau where he extensively investigated the synthesis of diazomethane and its reactions with aldehydes, ketones, and acid chlorides. Fritz Arndt’s chain-smoking of cigars ensured that his presence in the laboratories was always well advertised. Bernd Eistert (1902−1978), born in Ohlau, Silesia, was Arndt’s Ph.D. student. Eistert later joined I. G. Farbenindustrie, which became BASF after the Allies broke up the con- glomerate after WWII. 2. Podlech, J.; Seebach, D. Angew. Chem., Int. Ed. 1995, 34, 471−472. 3. Matthews, J. L.; Braun, C.; Guibourdenche, C.; Overhand, M.; Seebach, D. In Enanti- oselective Synthesis of β-Amino Acids Juaristi, E. ed.; Wiley-VCH: New York, N. Y. 1997, pp 105−126. (Review). 4. Katritzky, A. R.; Zhang, S.; Fang, Y. Org. Lett. 2000, 2, 3789−3791. 5. Vasanthakumar, G.-R.; Babu, V. V. S. Synth. Commun. 2002, 32, 651−657. 6. Chakravarty, P. K.; Shih, T. L.; Colletti, S. L.; Ayer, M. B.; Snedden, C.; Kuo, H.; Tyagarajan, S.; Gregory, L.; Zakson-Aiken, M.; Shoop, W. L.; Schmatz, D. M.; Wy- vratt, M. J.; Fisher, M. H.; Meinke, P. T. Bioorg. Med. Chem. Lett. 2003, 13, 147−150. 7. Gaucher, A.; Dutot, L.; Barbeau, O.; Hamchaoui, W.; Wakselman, M.; Mazaleyrat, J.- P. Tetrahedron: Asymmetry 2005, 16, 857−864. 8. Podlech, J. In Enantioselective Synthesis of β-Amino Acids (2nd Edn.) John Wiley & Sons: Hoboken, NJ, 2005, pp 93−106. (Review). 9. Spengler, J.; Ruiz-Rodriguez, J.; Burger, K.; Albericio, F. Tetrahedron Lett. 2006, 47, 4557−4560. 10. Toyooka, N.; Kobayashi, S.; Zhou, D.; Tsuneki, H.; Wada, T.; Sakai, H.; Nemoto, H.; Sasaoka, T.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. Bioorg. Med. Chem. Lett. 2007, 17, 5872−5875. 11. Fuchter, M. J. Arndt–Eistert Homologation. In Name Reactions for Homologations- Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 336−349. (Review). 12

Baeyer–Villiger oxidation General scheme:

O O O H O R3 O O 2 1 2 1 R R R or H2O2 R O HO R3

The most electron-rich alkyl group (more substituted carbon) migrates first. The general migration order: tertiary alkyl > cyclohexyl > secondary alkyl > benzyl > phenyl > primary alkyl > methyl >> H. For substituted aryls: p-MeO-Ar > p-Me-Ar > p-Cl-Ar > p-Br-Ar > p-MeOAr > p-O2N-Ar

Example 1: H O AcO O HOAc O : O Cl H O

Cl O O H O alkyl Cl O HO O migration O O

Example 24

O O UHP, Zr-salen (5 mol%) Zr-salen: O CH2Cl2, rt N Y N Ph 68%, 87% ee Ph Zr O Y O Ph Ph O UHP, O Zr-salen (5 mol%) O O O PhCl, rt normal product abnormal product 12%, > 99% ee 26%, 82% ee UHP = Urea-hydrogen peroxide complex

Example 35

OH O OH O OH m-CPBA O O O NH CH2Cl2, rt NH NH quant. O 100% O 0% O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_6, © Springer-Verlag Berlin Heidelberg 2009 13

Example 46 O AcO O O m-CPBA, NaHCO3 O O CH2Cl2, 0 °C, 4 h 60% O O H H

Example 58 O O O OAc m-CPBA, CF3SO3H OAc CH2Cl2, 45 min., 90%

References

1. v. Baeyer, A.; Villiger, V. Ber. 1899, 32, 3625−3633. Adolf von Baeyer (1835−1917) was one of the most illustrious organic chemists in history. He contributed to many areas of the field. The Baeyer−Drewson indigo synthesis made possible the commer- cialization of synthetic indigo. Another Baeyer’s claim of fame is his synthesis of barbituric acid, named after his then girlfriend, Barbara. Baeyer’s real joy was in his laboratory and he deplored any outside work that took him away from his bench. When a visitor expressed envy that fortune had blessed so much of Baeyer’s work with success, Baeyer retorted dryly: “Herr Kollege, I experiment more than you.” As a scientist, Baeyer was free of vanity. Unlike other scholastic masters of his time (Liebig for instance), he was always ready to acknowledge ungrudgingly the merits of others. Baeyer’s famous greenish-black hat was a part of his perpetual wardrobe and he had a ritual of tipping his hat when he admired novel compounds. Adolf von Baeyer received the Nobel Prize in Chemistry in 1905 at age seventy. His apprentice, Emil Fischer, won it in 1902 when he was fifty, three years before his teacher. Victor Villiger (1868−1934), born in Switzerland, went to Munich and worked with Adolf von Baeyer for eleven years. 2. Krow, G. R. Org. React. 1993, 43, 251−798. (Review). 3. Renz, M.; Meunier, B. Eur. J. Org. Chem. 1999, 4, 737−750. (Review). 4. Wantanabe, A.; Uchida, T.; Ito, K.; Katsuki, T. Tetrahedron Lett. 2002, 43, 4481−4485. 5. Laurent, M.; Ceresiat, M.; Marchand-Brynaert, J. J. Org. Chem. 2004, 69, 3194−3197. 6. Brady, T. P.; Kim, S. H.; Wen, K.; Kim, C.; Theodorakis, E. A. Chem. Eur. J. 2005, 11, 7175−7190. 7. Curran, T. T. Baeye−Villiger oxidation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 160−182. (Review). 8. Demir, A. S.; Aybey, A. Tetrahedron 2008, 64, 11256−11261. 9. Baj, S.; Chrobok, A. Synth. Commun. 2008, 38, 2385−2391. 10. Malkov, A. V.; Friscourt, F.; Bell, M.; Swarbrick, M. E.; Kocovsky, P. J. Org. Chem. 2008, 73, 3996−4003. 14

Baker–Venkataraman rearrangement Base-catalyzed acyl transfer reaction that converts α-acyloxyketones to β- diketones.

O OH O O Ph O O base Ph

O Ph Ph O :B Ph O O O O O H O O

O O O OH O O acyl H3O Ph Ph transfer workup

Example 1, Carbamoyl Baker−Venkataraman rearrangement5

O NEt2 OH O NaH, THF NEt reflux, 2 h, 84% 2 O O O

Example 2, Carbamoyl Baker−Venkataraman rearrangement6

O NEt2 O O O 2.5 eq. NaH, PhMe, reflux, 2 h

then 6 equiv TFA, reflux, 1 h, 93% MeO MeO OH O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_7, © Springer-Verlag Berlin Heidelberg 2009 15

Example 3, Ester Baker−Venkataraman rearrangement9

O O OH O O O O O LiH, THF CH 3 reflux, 12 h, 50% CH3 CH3 O O

Example 4, Ester Baker−Venkataraman rearrangement10

O O OH O O Cl 2 equiv DBU Cl Cl pyridine, 80 oC OH 90% OH Cl Cl

References

1. Baker, W. J. Chem. Soc. 1933, 1381−1389. Wilson Baker (1900−2002) was born in Runcorn, England. He studied chemistry at Manchester under Arthur Lapworth and at Oxford under Robinson. In 1943, Baker was the first one who confirmed that penicil- lin contained sulfur, of which Robinson commented: “This is a feather in your cap, Baker.” Baker began his independent academic career at University of Bristol. He retired in 1965 as the Head of the School of Chemistry. Baker was a well-known chemist centenarian, spending 47 years in retirement! 2. Mahal, H. S.; Venkataraman, K. J. Chem. Soc. 1934, 1767−1771. K. Venkataraman studied under Robert Robinson Manchester. He returned to India and later arose to be the Director of the National Chemical Laboratory at Poona. 3. Kraus, G. A.; Fulton, B. S.; Wood, S. H. J. Org. Chem. 1984, 49, 3212−3214. 4. Reddy, B. P.; Krupadanam, G. L. D. J. Heterocycl. Chem. 1996, 33, 1561−1565. 5. Kalinin, A. V.; da Silva, A. J. M.; Lopes, C. C.; Lopes, R. S. C.; Snieckus, V. Tetrahe- dron Lett. 1998, 39, 4995−4998. 6. Kalinin, A. V.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4999−5002. 7. Thasana, N.; Ruchirawat, S. Tetrahedron Lett. 2002, 43, 4515−4517. 8. Santos, C. M. M.; Silva, A. M. S.; Cavaleiro, J. A. S. Eur. J. Org. Chem. 2003, 4575– 4585. 9. Krohn, K.; Vidal, A.; Vitz, J.; Westermann, B.; Abbas, M.; Green, I. Tetrahedron: Asymmetry 2006, 17, 3051–3057. 10. Abdel Ghani, S. B.; Weaver, L.; Zidan, Z. H.; Ali, H. M.; Keevil, C. W.; Brown, R. C. D. Bioorg. Med. Chem. Lett. 2008, 18, 518–522.

Bamford–Stevens reaction The Bamford−Stevens reaction and the Shapiro reaction share a similar mechanistic pathway. The former uses a base such as Na, NaOMe, LiH, NaH, NaNH2, heat, etc., whereas the latter employs bases such as alkyllithiums and Grignard reagents. As a result, the Bamford−Stevens reaction furnishes more-substituted olefins as the thermodynamic products, while the Shapiro reaction generally affords less-substituted olefins as the kinetic products.

R1 R1 H NaOMe R2 N R2 N Ts H R3 R3

MeO R1 R1 1 R H R2 N R2

2 N: Ts N R N H H N N Ts R3 R3 H 3 R

In protic solvent (S–H):

HS R1 R1 H − N R2 R2 2 N N HN 3 HN3 R R 1 R1 R1 R 3 R2 R2 R SH H H H H 2 R3 R3 R S In aprotic solvent: R1 R1 − N R2 R2 2 N N HN HN 3 R3 R 1 1 R1 R R 1,2-hydride 2 3 2 : R R R H H shift H 3 R3 R2 R

Example 1, Tandem Bamford–Stevens/thermal aliphatic Claisen rearrangement sequence2

Ph Rh (OAc) 2 4 O Ph ClCH2CH2Cl N N H o O Ph 130 C Ph Ph 87% (> 20:1)

The starting material N-aziridinyl imine is also known as Eschenmoser hydrazone.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_8, © Springer-Verlag Berlin Heidelberg 2009 17

Example 2, Thermal Bamford–Stevens6

N Ph Tol., 145 oC N Me3Si Ph

Me Si Ph sealed tube, 65% E : Z = 90 : 10 3

Example 37

t-BuOK, t-BuOH N NHTs Ot-Bu O O reflux, 83%

Example 48

Rh2(OAc)4 O Na tetrahydrothiophene O R1 N R2 H + − R2 R1 N Ts BnEt3N Cl , MeCN, 40 oC, 3 h, 59−97%

References

1. Bamford, W. R.; Stevens, T. S. M. J. Chem. Soc. 1952, 4735−4740. Thomas Stevens (1900−2000), another chemist centenarian, was born in Renfrew, Scotland. He and his student W. R. Bamford published this paper at the University of Sheffield, UK. Ste- vens also contributed to another name reaction, the McFadyen−Stevens reaction (page 334). 2. Felix, D.; Müller, R. K.; Horn, U.; Joos, R.; Schreiber, J.; Eschenmoser, A. Helv. Chim. Acta 1972, 55, 1276−1319. 3. Shapiro, R. H. Org. React. 1976, 23, 405−507. (Review). 4. Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 55−59. (Review on the Shapiro reaction). 5. Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 1−83. (Review). 6. Sarkar, T. K.; Ghorai, B. K. J. Chem. Soc., Chem. Commun. 1992, 17, 1184−1185. 7. Chandrasekhar, S.; Rajaiah, G.; Chandraiah, L.; Swamy, D. N. Synlett 2001, 1779−1780. 8. Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer, M. J.; Porcelloni, M.; Studley, J. R. Angew. Chem., Int. Ed. 2001, 40, 1430−1433. 9. May, J. A.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 12426−12427. 10. Zhu, S.; Liao, Y.; Zhu, S. Org. Lett. 2004, 6, 377−380. 11. Baldwin, J. E.; Bogdan, A. R.; Leber, P. A.; Powers, D. C. Org. Lett. 2005, 7, 5195−5197. 12. Paul Humphries, P. Bamford−Stevens reaction. In Name Reactions for Homologa- tions-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 642−652. (Review).

Barbier coupling reaction In essence, the Barbier coupling reaction is a Grignard reaction carried out in situ although its discovery preceded that of the Grignard reaction by a year. Cf. Grig- nard reaction (Page 266).

OH O R3X, M RM R1 R2 R1 R2 R

According to conventional wisdom,3 the organometallic intermediate (M = Mg, Li, Sm, Zn, La, etc.) is generated in situ, which is intermediately trapped by the carbonyl compound. However, recent experimental and theoretical studies seem to suggest that the Barbier coupling reaction goes through a single electron transfer pathway.

Generation of the Grignard reagent,

SET-1 MX SET-2 R3 X RX M R RM RM

Ionic mechanism,

2 δ R δ 1 2 1 2 O R R H3O R R R1 RMgX R OMgX R OH δ δ

Single electron transfer mechanism,

R2 2 R 1 2 1 2 1 O O R R H3O R R R R1 MgX R OMgX R OH RMgX R

Example 16

O OH O Sm, THF, rt O Br 20 min., 70%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_9, © Springer-Verlag Berlin Heidelberg 2009 19

Example 29

O OH Zn, THF, aq. NH4Cl Ph Me Me Ph Br 0 oC, 82%, 95% de NHCO Et NHCO2Et 2

Example 310

Mg n-C H 20 mol% CuCN 4 9 n-C4H9Br H3C Cl H3C n-C4H9 H C THF, rt, 1.5 h, 86% 3 10 : 90

Example 411

n-BuLi, THF O O H O H OH −78 oC, 96% MeO OBn MeO OBn

References

1. Barbier, P. C. R. Hebd. Séances Acad. Sci. 1899, 128, 110–111. Phillippe Barbier (1848−1922) was born in Luzy, Nièvre, France. He studied terpenoids using zinc and magnesium. Barbier suggested the use of magnesium to his student, Victor Grignard, who later discovered the Grignard reagent and won the Nobel Prize in 1912. 2. Grignard, V. C. R. Hebd. Seanes Acad. Sci. 1900, 130, 1322–1324. 3. Moyano, A.; Pericás, M. A.; Riera, A.; Luche, J.-L. Tetrahedron Lett. 1990, 31, 7619– 7622. (Theoretical study). 4. Alonso, F.; Yus, M. Rec. Res. Dev. Org. Chem. 1997, 1, 397–436. (Review). 5. Russo, D. A. Chem. Ind. 1996, 64, 405–409. (Review). 6. Basu, M. K.; Banik, B. Tetrahedron Lett. 2001, 42, 187–189. 7. Sinha, P.; Roy, S. Chem. Commun. 2001, 1798–1799. 8. Lombardo, M.; Gianotti, K.; Licciulli, S.; Trombini, C. Tetrahedron 2004, 60, 11725– 11732. 9. Resende, G. O.; Aguiar, L. C. S.; Antunes, O. A. C. Synlett 2005, 119–120. 10. Erdik, E.; Kocoglu, M. Tetrahedron Lett. 2007, 48, 4211–4214. 11. Takeuchi, T.; Matsuhashi, M.; Nakata, T. Tetrahedron Lett. 2008, 49, 6462–6465.

Bartoli indole synthesis 7-Substituted indoles from the reaction of ortho-substituted nitroarenes and vinyl Grignard reagents.

1. MgBr N NO 2 2. H2O H R R

BrMg BrMg

O O OMgBr O N N N R O R OMgBr R

nitroso intermediate

O [3,3]-sigmatropic O H N rearrangement N R MgBr R MgBr

BrMg H H H O 3 OH OMgBr 2 N N N workup H H R R R

Example 13 1. MgBr (3 eq) −40 oC, THF NO N 2 2. aq. NH Cl, 67% H 4

Example 26

Me Me MgCl

THF, −40 oC N NO2 67% H Br Br

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_10, © Springer-Verlag Berlin Heidelberg 2009 21

Example 310

4 equiv MeO MeO MgCl N MeO NO MeO 2 THF, 66% H Br Br Br Br 4 equiv MeO MeO MgCl N MeO NO MeO 2 THF, 38% H Br Br

Example 411

2 equiv

MgCl

THF, −40 oC Br N Br NO2 H 52% Br Br

References

1. Bartoli, G.; Leardini, R.; Medici, A.; Rosini, G. J. Chem. Soc., Perkin Trans. 1 1978, 692−696. Giuseppe Bartoli is a professor at the Università di Bologna, Italy. 2. Bartoli, G.; Bosco, M.; Dalpozzo, R.; Todesco, P. E. J. Chem. Soc., Chem. Commun. 1988, 807−805. 3. Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30, 2129−2132. 4. Bosco, M.; Dalpozzo, R.; Bartoli, G.; Palmieri, G.; Petrini, M. J. Chem. Soc., Perkin Trans. 2 1991, 657−663. Mechanistic studies. 5. Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.; Marcantoni, E. J. Chem. Soc., Perkin Trans. 1 1991, 2757−2761. 6. Dobbs, A. J. Org. Chem. 2001, 66, 638−641. 7. Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 13179−13184. 8. Li, J.; Cook, J. M. Bartoli indole synthesis. In Name Reactions in Heterocyclic Chem- istry; Li, J. J., Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 100−103. (Re- view). 9. Dalpozzo, R.; Bartoli, G. Current Org. Chem. 2005, 9, 163−178. (Review). 10. Huleatt, P. B.; Choo, S. S.; Chua, S.; Chai, C. L. L. Tetrahedron Lett. 2008, 49, 5309−5311. 11. Buszek, K. R.; Brown, N.; Luo, D. Org. Lett. 2009, 11, 201−204.

Barton radical decarboxylation Radical decarboxylation via the corresponding thiocarbonyl derivatives of the carboxylic acids.

S O O HO n-Bu3SnH N N H R Cl R O AIBN, Δ R S

Barton ester

Δ ↑ N2 2 CN NC NN CN homolytic cleavage

AIBN = 2,2ƍ-azobisisobutyronitrile

n-Bu3Sn H CN n-Bu3Sn H CN

O N O RO N S RO S Bu Sn SnBu 3 3

CO ↑ H SnBu R H Bu3Sn 2 R 3

Example 13

OAc

1. (COCl)2 2. S H NaO O N H O N S CO2H

OAc OAc

− o Δ 1. m-CPBA, 78 C

98% H 2. 100 oC, 78% S N H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_11, © Springer-Verlag Berlin Heidelberg 2009 23

Example 26

S 2 Ph N O HO C OTBDPS 2 Bu P, THF, PhH 3 Ph Me3SiH, AIBN N O OTBDPS O PhH, 80 oC, 75% Ph OTBDPS S

Example 39 Ph O N O S O DCC, CH Cl 5 equiv HO 2 2 N CO2H N MeO C MeO2C O 2 rt, 2 h hv S 15 oC, 30 min, 82%

N S 1. m-CPBA, CH Cl , 0 oC 2 2 MeO2C O MeO2C O 2. toluene, 110 oC, 1 h, 90% NPh O O N Ph

References

1. Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1983, 939−941. Derek Barton (United Kingdom, 1918−1998) studied under Ian Heilbron at Imperial College in his youth. He taught in England, France and the US. Barton won the Nobel Prize in Chemistry in 1969 for development of the concept of conformation. He passed away in his office at the University of Texas A&M in 1998. 2. Barton, D. H. R.; Zard, S. Z. Pure Appl. Chem. 1986, 58, 675−684. (Review). 3. Cochane, E. J.; Lazer, S. W.; Pinhey, J. T.; Whitby, J. D. Tetrahedron Lett. 1989, 30, 7111−7114. 4. Barton, D. H. R. Aldrichimica Acta 1990, 23, 3. (Review). 5. Crich, D.; Hwang, J.-T.; Yuan, H. J. Org. Chem. 1996, 61, 6189−6198. 6. Yamaguchi, K.; Kazuta, Y.; Abe, H.; Matsuda, A.; Shuto, S. J. Org. Chem. 2003, 68, 9255−9262. 7. Zard, S. Z. Radical Reactions in Organic Synthesis Oxford University Press: Oxford, UK, 2003. (Book). 8. Carry, J.-C.; Evers, M.; Barriere, J.-C.; Bashiardes, G.; Bensoussan, C.; Gueguen, J.- C.; Dereu, N.; Filoche, B.; Sable, S.; Vuilhorgne, M.; Mignani, S. Synlett 2004, 316−320. 9. Brault, L.; Denance, M.; Banaszak, E.; El Maadidi, S.; Battaglia, E.; Bagrel, D.; Samadi, M. Eur. J. Org. Chem. 2007, 42, 243−247. 10. Guthrie, D. B.; Curran, D. P. Org. Lett. 2009, 11, 249−251. 24

Barton–McCombie deoxygenation

Deoxygenation of alcohols by means of radical scission of their corresponding thiocarbonyl derivatives.

R1 S n-Bu SnH, AIBN R1 3 ↑ n-Bu3SnSMe O CS R2 O S PhH, reflux R2 H

Δ ↑ N2 2 CN NC NN CN homolytic cleavage

AIBN = 2,2ƍ-azobisisobutyronitrile

n-Bu3Sn H CN n-Bu3Sn H CN

n-Bu3Sn SnBu3 1 R1 S β n-Bu3Sn R R1 S -scission S 2 R2 2 R O S O S R O S

R1 hydrogen atom R1 n-Bu3Sn H n-Bu3Sn 2 abstraction R2 H R

n-Bu3Sn S ↑ n-Bu3SnSMe O CS O S Example 12

H2 Si

Si H2 (1.5 equiv) S 10 mol% AIBN PhO O H nonane, 80 °C H 2 h, 85%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_12, © Springer-Verlag Berlin Heidelberg 2009 25

Example 26

O O O O O AIBN, Δ, 74% O O O O O (CH ) Bu SnH 2 4 2 O OPh S

Example 310

O OH O

O OBn O OBn 1. NaH, CS2, MeI, 80%

OO 2. Bu3SnH, AIBN, 70% OO

Example 411

S S Ts OH Ts N N Ts O H H NaH, CS2 N Bu3SnH, AIBN H MeI, THF Toluene, reflux MeO C MeO2C 2 N rt 72% 2 steps N O MeO2C O Boc N O Boc Boc

References

1. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574–1585. Stuart McCombie, a Barton student, now works at Schering−Plough. 2. Gimisis, T.; Ballestri, M.; Ferreri, C.; Chatgilialoglu, C.; Boukherroub, R.; Manuel, G. Tetrahedron Lett. 1995, 36, 3897–3900. 3. Zard, S. Z. Angew. Chem., Int. Ed. 1997, 36, 673–685. 4. Lopez, R. M.; Hays, D. S.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 6949–6950. 5. Hansen, H. I.; Kehler, J. Synthesis 1999, 1925–1930. 6. Boussaguet, P.; Delmond, B.; Dumartin, G.; Pereyre, M. Tetrahedron Lett. 2000, 41, 3377–3380. 7. Cai, Y.; Roberts, B. P. Tetrahedron Lett. 2001, 42, 763–766. 8. Clive, D. L. J.; Wang, J. J. Org. Chem. 2002, 67, 1192–1198. 9. Rhee, J. U.; Bliss, B. I.; RajanBabu, T. V. J. Am. Chem. Soc. 2003, 125, 1492–1493. 10. Gómez, A. M.; Moreno, E.; Valverde, S.; López, J. C. Eur. J. Org. Chem. 2004, 1830– 1840. 11. Deng, H.; Yang, X.; Tong, Z.; Li, Z.; Zhai, H. Org. Lett. 2008, 10, 1791–1793. 12. Mancuso, J. Barton–McCombie deoxygenation. In Name Reactions for Homologa- tions-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 614−632. (Review). 26

Barton nitrite photolysis Photolysis of a nitrite ester to a γ-oximino alcohol.

OAc OAc OAc NO O O O HO OH HO O hν H NOCl N

O O O

OAc OAc ONCl NO O O O HO ν − HCl h homolytic cleavage O − ON• O OAc OAc

ON O O HO O H 1,5-hydrogen abstraction

O O Nitric oxide radical is a stable and therefore, long-lived radical OAc OAc O O HO OH O H OH H N tautomerization N

O O nitroso intermediate

Example 12

O N H H OH O hυ Pyrex, 250-W Hg lamp NOH

PhH, reflux, 2 h, 67%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_13, © Springer-Verlag Berlin Heidelberg 2009 27

Example 26

O H N O O H H hν H H PhH, 6 oC N 46% OH

Example 37

HO HO HO − o N 1. NOCl, CH2Cl2, 20 C, 100% O O H 2. Irradiation at 350 nM H OAc 5 h, PhH, 0 oC, 50% OAc

References

1. (a) Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet, M. M. J. Am. Chem. Soc. 1960, 82, 2640−2641. In 1960, Derek Barton took a “vacation” in Cambridge, Massa- chusetts; he worked in a small research institute called the Research Institute for Medicine and Chemistry. In order to make the adrenocortical hormone aldosterol, Barton invented the Barton nitrite photolysis by simply writing down on a piece of paper what he thought would be an ideal process. His skilled collaborator, Dr. John Bea- ton, was able to reduce it to practice. They were able to make 40 to 50 g of aldosterol at a time when the total world supply was only about 10 mg. Barton considered it his most satisfying piece of work. (b) Barton, D. H. R.; Beaton, J. M. J. Am. Chem. Soc. 1960, 82, 2641−2641. (c) Barton, D. H. R.; Beaton, J. M. J. Am. Chem. Soc. 1961, 83, 4083−4089. (d) Barton, D. H. R.; Lier, E. F.; McGhie, J. M. J. Chem. Soc., (C) 1968, 1031−1040. 2. Nickon, A; Iwadare, T.; McGuire, F. J.; Mahajan, J. R; Narang, S. A.; Umezawa, B. J. Am. Chem. Soc. 1970 92, 1688–1696. 3. Barton, D. H. R.; Hesse, R. H.; Pechet, M. M.; Smith, L. C. J. Chem. Soc., Perkin Trans. 1 1979, 1159−1165. 4. Barton, D. H. R. Aldrichimica Acta 1990, 23, 3−10. (Review). 5. Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095−7129. (Review). 6. Sicinski, R. R.; Perlman, K. L.; Prahl, J.; Smith, C.; DeLuca, H. F. J. Med. Chem. 1996, 22, 4497–4506. 7. Anikin, A.; Maslov, M.; Sieler, J.; Blaurock, S.; Baldamus, J.; Hennig, L.; Findeisen, M.; Reinhardt, G.; Oehme, R.; Welzel, P. Tetrahedron 2003, 59, 5295−5305. 8. Suginome, H. CRC Handbook of Organic Photochemistry and Photobiology 2nd edn.; 2004, 102/1−102/16. (Review). 9. Hagan, T. J. Barton nitrite photolysis. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 633−647. (Review). 28

Batcho–Leimgruber indole synthesis Condensation of o-nitrotoluene derivatives with formamide acetals, followed by reduction of the trans-β-dimethylamino-2-nitrostyrene to furnish indole derivatives.

R OR3 1 R1 N C OR3 R H N R 1. Pd/C, H2 R 2 2 R R 2. 5% HCl NO2 DMF, 130 oC, 86% N NO2 82% H

Example 14

DMFDMA NMe2 Pd/C, H2 Δ N NO2 DMF, NO2 H DMFDMA = N,N-dimethylformamide dimethyl acetal, Me2NCH(OMe)2

MeO MeO N N OMe MeO

OMe

H MeO NMe2 MeO CH2 CH2 N O H N N O O NO2 O

: [H] MeOH NMe2 NMe2 reduction NO 2 NH2

H NMe2 − NHMe2

NH N NMe2 N H H

Example 24

CO2Me CO2H CO Me 1. MeI, NaHCO3 2 Pd/C, H2 NMe2 2. Me2NCH(OMe)2 DMF, Δ PhH, 82% N NO 2 80%, 2 steps NO2 H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_14, © Springer-Verlag Berlin Heidelberg 2009 29

Example 35

OBn OBn OBn Me2NCH(OMe)2 pyrrolidine NMe2

DMF, 110 oC NO NO2 NO2 2 3 h, 95% 15 : 1

OBn OBn

NMe2 Ra-Ni, NH2NH2 THF, MeOH NO N 2 96% H

Example 410

NO NO2 2 Me2NCH(OMe)2, CuI, DMF NMe2

o microwave, 180 C, 10 min. MeO C NO MeO2C NO2 2 2 76%

NH2 Pd/C, H2

MeOH, 3 d N 89% MeO2C H

References

1. Leimgruber, W.; Batcho, A. D. Third International Congress of Heterocyclic Chemis- try: Japan, 1971. Andrew D. Batcho and Willy Leimgruber were both chemists at HoffmannҟLa Roche in Nutley, NJ, USA. 2. Leimgruber, W.; Batcho, A. D. USP 3732245 1973. 3. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York & London, 1970. (Review). 4. Kozikowski, A. P.; Ishida, H.; Chen, Y.-Y. J. Org. Chem. 1980, 45, 3350–3352. 5. Batcho, A. D.; Leimgruber, W. Org. Synth. 1985, 63, 214–225. 6. Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195–221. (Review). 7. Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51, 5106–5110. 8. Siu, J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2004, 2, 160–167. 9. Li, J.; Cook, J. M. Batcho–Leimgruber Indole Synthesis. In Name Reactions in Het- erocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 104–109. (Review). 10. Braun, H. A.; Zall, A.; Brockhaus, M.; Schütz, M.; Meusinger, R.; Schmidt, B. Tetra- hedron Lett. 2007, 48, 7990–7993. 11. Leze, M.-P.; Palusczak, A.; Hartmann, R. W.; Le Borgne, M. Bioorg. Med. Chem. Lett. 2008, 18, 4713–4715. 30

Baylis–Hillman reaction Also known as Morita–Baylis–Hillman reaction. It is a carbon−carbon bond- forming transformation of an electron-poor alkene with a carbon electrophile. Electron-poor alkenes include acrylic esters, acrylonitriles, vinyl ketones, vinyl sulfones, and acroleins. On the other hand, carbon electrophiles may be aldehydes, α-alkoxycarbonyl ketones, aldimines, and Michael acceptors.

General scheme:

1 X EWG catalytic R XH EWG R2 R1 R2 tertiary amine

X = O, NR2, EWG = CO2R, COR, CHO, CN, SO2R, SO3R, PO(OEt)2, CONR2, CH2=CHCO2Me

Alternative catalytic tertiary amines:

N N N N

Example 1:

N O OH O O N Ph Ph H

O O O O Ph H O conjugate aldol Ph H : addition N N N N N N

OH O OH O Ph N Ph N N N

E2 (bimolecular elimination) mechanism is also operative here:

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_15, © Springer-Verlag Berlin Heidelberg 2009 31

OH O

Ph OH O H E2 2 N N Ph N : N N N

Example 2, Intramolecular Baylis–Hillman reaction6

PMB PMB PMB CO Me CO2Me CO Me N 2 N O N 2 N OBn O OBn OBn O OH DME, 0 oC, 7 d OH O 90% (dr = 9:1) major minor

Example 37

OEt O O O O O O DABCO OEt dioxane:water (1:1) CHO 24 h, 72%, de 80% HO

Example 48

O O

O O O O O2N O O , O H TiCl4, TBAI OCH(CH3)2 O O HO − − o H CH2Cl2, 78 to 30 C OCH(CH3)2 85%, dr > 99:1

NO 2 Example 59

O N OH O O N H OMe OMe MeOH, rt, 8 h, 79% Cl Cl

Example 610

N N

O NHTs OH R OH (10 mol%) O Ts N R = p-Cl-C6H5 R = p-OMe-C6H5 H R cyclopentyl methyl ether/toluene, −15 oC R = p-NO2-C6H5 R = 2-furyl 87−100%, 88−95% ee R = 2-naphthyl

References

1. Baylis, A. B.; Hillman, M. E. D. Ger. Pat. 2,155,113, (1972). Both Anthony B. Baylis and Melville E. D. Hillman were chemists at Celanese Corp. USA. 2. Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001−8062. (Review). 3. Ciganek, E. Org. React. 1997, 51, 201−350. (Review). 4. Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 2402−2403. 5. Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404−2405. 6. Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 6230−6231. 7. Krishna, P. R.; Narsingam, M.; Kannan, V. Tetrahedron Lett. 2004, 45, 4773−4775. 8. Sagar, R,; Pant, C. S.; Pathak, R.; Shaw, A. K. Tetrahedron 2004, 60, 11399−11406. 9. Mi, X.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2005, 70, 2338−2341. 10. Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680−3681. 11. Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T. Org. Lett. 2005, 7, 147−150. A novel mechanism involving a hemiacetal intermediate is proposed. 12. Limberakis, C. Morita–Baylis–Hillman reaction. In Name Reactions for Homologa- tions-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 350−380. (Review).

Beckmann rearrangement Acid-mediated isomerization of oximes to amides.

In protic acid:

OH O N H3O R1 N R2 R1 R2 H

R R1 OH OH : N H3O N 2 N N

R1 R2 1 2 R R R2 2 :OH R 2 the substituent trans to the leaving group migrates

R1 N R1 R1 − H N tautomerization HN H R2 O R2 OH R2 O H

With PCl5:

OH O N PCl5 R1 N R2 R1 R2 H

Cl 1

PCl4 R R1 − OPCl : : HCl 4 N N N O N H 1 2 2 : R R R R2 OH2 1 2 R R Again, the substituent trans to the leaving group migrates

1 R 1 N R R1 − H N tautomerization HN 2 H R O 2 R OH R2 O H

Example 1, Microwave (MW) reaction3

OH N O BiCl3 N MW, 90% H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_16, © Springer-Verlag Berlin Heidelberg 2009 34

Example 24 H NOH N FeCl3 O Solvent free 81%

Example 36

HO O OH H N N N O PPA PPA NH 21% 72%

PPA = polyphosphoric acid

Example 48

OH N O p-TsCl/Et3N HN OEt THF, 10% K2CO3 OEt 80% syn

Abnormal Beckmann rearrangement is when the migrating substituent fragment (e.g., R1) departs from the intermediate, leaving a nitrile as a stable product.

OH N H R2 N R1 R2 N R1 R1 R2

Example 19

H C NOH N OH2 3 H3C HC(OMe)3 H F3CCOOH H AcO AcO H THF, 60 oC H 40 min., 79% H H

H H H CN CN H H AcO AcO H H H H

References

1. Beckmann, E. Chem. Ber. 1886, 89, 988. Ernst Otto Beckmann (1853−1923) was born in Solingen, Germany. He studied chemistry and pharmacy at Leipzig. In addition to the Beckmann rearrangement of oximes to amides, his name is associated with the Beckmann thermometer, used to measure freezing and boiling point depressions to determine the molecular weights. 2. Gawley, R. E. Org. React. 1988, 35, 1−420. (Review). 3. Thakur, A. J.; Boruah, A.; Prajapati, D.; Sandhu, J. S. Synth. Commun. 2000, 30, 2105−2011. 4. Khodaei, M. M.; Meybodi, F. A.; Rezai, N.; Salehi, P. Synth. Commun. 2001, 31, 2047−2050. 5. Torisawa, Y.; Nishi, T.; Minamikawa, J.-i. Bioorg. Med. Chem. Lett. 2002, 12, 387−390. 6. Hilmey, D. G.; Paquette, L. A. Org. Lett. 2005, 7, 2067−2069. 7. Fernández, A. B.; Boronat, M.; Blasco, T.; Corma, A. Angew. Chem., Int. Ed. 2005, 44, 2370−2373. 8. Collison, C. G.; Chen, J.; Walvoord, R. Synthesis 2006, 2319−2322. 9. Wang, C.; Rath, N. P.; Covey, D. F. Tetrahedron 2007, 63, 7977−7984. 10. Kumar, R. R.; Vanitha, K. A.; Balasubramanian, M. Beckmann rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 274−292. (Review).

Benzilic acid rearrangement Rearrangement of benzil to benzylic acid via aryl migration.

O O KOH Ar Ar Ar OH Ar O OH benzil benzylic acid

O Ar O OH Ar Ar migration Ar O OH Ar Ar O O O OH

O O Ar workup O Ar Ar OH OH H OH Ar OH benzilate anion Final deprotonation of the carboxylic acid drives the reaction forward.

Example 13

O CO2H H3C H3C O OH KOH, MeOH/H2O H C H H3C H 3 o H H 130−140 C, 3 h, 32% H H O O

Example 26

KOH, dioxane

30 min., rt, 74% COOH O HO O

Example 3, Retro-benzilic acid rearrangement7

Boc Boc Boc N O OMe Boc N O OMe Boc Boc N O OH O OTBS K2CO3, MeOH

rt, 2 h, 98% H H H N O N O N O H H H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_17, © Springer-Verlag Berlin Heidelberg 2009 37

References

1. Liebig, J. Justus Liebigs Ann. Chem. 1838, 27. Justus von Liebig (1803−1873) pur- sued his Ph.D. In organic chemistry in Paris under the tutelage of Joseph Louis Gay- Lussac (1778−1850). He was appointed the Chair of Chemistry at Giessen University, which incited a furious jealousy amongst several of the professors already working there because he was so young. Fortunately, time would prove the choice was a wise one for the department. Liebig would soon transform Giessen from a sleepy university to the Mecca of organic chemistry in Europe. Liebig is now considered the father of organic chemistry. Many classic name reactions were published in the journal that still bears his name, Justus Liebigs Annalen der Chemie.2 2. Zinin, N. Justus Liebigs Ann. Chem. 1839, 31, 329. 3. Georgian, V.; Kundu, N. Tetrahedron 1963, 19, 1037−1049. 4. Robinson, J. M.; Flynn, E. T.; McMahan, T. L.; Simpson, S. L.; Trisler, J. C.; Conn, K. B. J. Org. Chem. 1991, 56, 6709−6712. 5. Fohlisch, B.; Radl, A.; Schwetzler-Raschke, R.; Henkel, S. Eur. J. Org. Chem. 2001, 4357−4365. 6. Patra, A.; Ghorai, S. K.; De, S. R.; Mal, D. Synthesis 2006, 15, 2556−2562. 7. Selig, P.; Bach, T. Angew. Chem., Int. Ed. 2008, 47, 5082−5084. 8. Kumar, R. R.; Balasubramanian, M. Benzilic Acid Rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 395−405. (Review).

Benzoin condensation Cyanide-catalyzed condensation of aryl aldehyde to benzoin. Now cyanide is mostly replaced by a thiazolium salt. Cf. Stetter reaction.

OH Ar H cat. CN Ar Ar O O

CN CN CN Ar H proton Ar O Ar H H O transfer OH Ar O

Ar Ar H proton H OH NC NC O OH Ar CN Ar transfer Ar Ar OH O O

Example 12

O Cl O O EtO NaCN, EtOH EtO H H 81% OH Cl MeO MeO

Example 27

CH3 N CHO O HO Br CH S 3 CH3 OH o Et3N, t-BuOH, 60 C, 24 h, 40% O

Example 37

H C O 3 CH3 O O N O OH O HO Br S O2 o Et3N, DMF, 60 C, 96 h, 69% (air)

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_18, © Springer-Verlag Berlin Heidelberg 2009 39

Example 49

Ar Ar Me O O O 5% P Me O H OMe O O O O Ar Ar H SiEt3 20% n-BuLi OMe OSiEt3 THF Ar = 2-FPh 87% yield; 91% ee

Example 510

Ph N N BF N 4 10 mol% O CHO OTMS Ph Ph OH 10 mol% KHMDS toluene, rt, 16 h 66% yield, 95% ee

References

1. Lapworth, A. J. J. Chem. Soc. 1903, 83, 995−1005. Arthur Lapworth (1872−1941) was born in Scotland. He was one of the great figures in the development of the modern view of the mechanism of organic reactions. Lapworth investigated the benzoin condensation at the Chemical Department, The Goldsmiths’ Institute, New Cross, UK. 2. Buck, J. S.; Ide, W. S. J. Am. Chem. Soc. 1932, 54, 3302−3309. 3. Ide, W. S.; Buck, J. S. Org. React. 1948, 4, 269−304. (Review). 4. Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407−496. (Review). 5. White, M. J.; Leeper, F. J. J. Org. Chem. 2001, 66, 5124−5131. 6. Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc. 2003, 125, 8432−8433. 7. Enders, D.; Niemeier, O. Synlett 2004, 2111−2114. 8. Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326−1328. (Review). 9. Linghu, X.; Potnick, J. R.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 3070−3071. 10. Enders, D.; Han, J. Tetrahedron: Asymmetry 2008, 19, 1367−1371. 11. Cee, V. J. Benzoin condensation. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp381−392. (Review).

Bergman cyclization 1,4-Benzenediyl diradical formation from enediyne via electrocyclization.

Δ or 2 hv hydrogen donor

electrocyclization H H reversible

enediyne 1,4-benzenediyl diradical

Example 16

S S Ph S S Ph

DMSO, 180 oC, 24 h, 60% S S Ph S S Ph

Example 27

H3C H3C N hv N THF, 45% N N

Example 3, Wolff rearrangement followed by the Bergman cyclization8

O OH CO R N2 2 CO2R OH O Δ hv or , ROH 7 : 4

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_19, © Springer-Verlag Berlin Heidelberg 2009 41

Example 410

O O TMS TMS

o 142 C, t1/2 = 14.4 h

References

1. Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660−661. Robert G. Berg- man (1942−) is a professor at the University of California, Berkeley. His discovery of the Bergman cyclization was completed far in advance of the discovery of ene-diyne’s anti-cancer properties. 2. Bergman, R. G. Acc. Chem. Res. 1973, 6, 25−31. (Review). 3. Myers, A. G.; Proteau, P. J.; Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212−7214. 4. Yus, M.; Foubelo, F. Rec. Res. Dev. Org. Chem. 2002, 6, 205−280. (Review). 5. Basak, A.; Mandal, S.; Bag, S. S. Chem. Rev. 2003, 103, 4077−4094. (Review). 6. Bhattacharyya, S.; Pink, M.; Baik, M.-H.; Zaleski, J. M. Angew. Chem., Int. Ed. 2005, 44, 592−595. 7. Zhao, Z.; Peacock, J. G.; Gubler, D. A.; Peterson, M. A. Tetrahedron Lett. 2005, 46, 1373−1375. 8. Karpov, G. V.; Popik, V. V. J. Am. Chem. Soc. 2007, 129, 3792−3793. 9. Kar, M.; Basak, A. Chem. Rev. 2007, 107, 2861−2890. (Review). 10. Lavy, S.; Pérez-Luna, A.; Kündig, E. P. Synlett 2008, 2621−2624. 11. Pandithavidana, D. R.; Poloukhtine, A.; Popik, V. V. J. Am. Chem. Soc. 2009, 131, 351−356.

Biginelli pyrimidone synthesis One-pot condensation of an aromatic aldehyde, urea, and β-dicarbonyl compound in the acidic ethanolic solution and expansion of such a condensation thereof. It belongs to a class of transformations called multicomponent reactions (MCRs).

O O

O O O Δ Ar Ar CHO O H2N NH2 HCl, EtOH NHHN O

H O O H H O O O O enolization O aldol H Ar O O addition H H Ar OH O H

H H H O O O O O O H O conjugate O O addition Ar : Ar OH Ar OH 2 H2N NH2 O

OH O H O O O O O HO H H O Ar

HN Ar H2N : N Ar HN NH H O NH2 O O

O O O O H O H 2 Ar H − H2O Ar HN NH NHHN O O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_20, © Springer-Verlag Berlin Heidelberg 2009 43

Example 14 F

O S O HCl F CHO NH H2N NH2 Δ O EtOH, 81% N S H

Example 25

OMe OMe

O O O CeCl3 •7H2O MeOOC NH MeO H2N NH2 EtOH, Δ, 2.5 h O H 95% N O H

Example 3, Microwave-induced Biginelli condensation (MWI = microwave irradiation)9

OMe OMe

O O O Bi(NO3)3, MWI EtOOC EtO H2N NH2 EtOH, Δ, 5 h NH 80% O H N O H

References

1. Biginelli, P. Ber. 1891, 24, 1317. Pietro Biginelli was at Lab. chim. della Sanita pubbl. In Roma, Italy. 2. Kappe, C. O. Tetrahedron 1993, 49, 6937−6963. (Review). 3. Kappe, C. O. Acc. Chem. Res. 2000, 33, 879−888. (Review). 4. Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043−1052. (Review). 5. Ghorab, M. M.; Abdel-Gawad, S. M.; El-Gaby, M. S. A. Farmaco 2000, 55, 249−255. 6. Bose, D. S.; Fatima, L.; Mereyala, H. B. J. Org. Chem. 2003, 68, 587−590. 7. Kappe, C. O.; Stadler, A. Org. React. 2004, 68, 1−116. (Review). 8. Limberakis, C. Biginelli Pyrimidone Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 509−520. (Review). 9. Banik, B. K.; Reddy, A. T.; Datta, A.; Mukhopadhyay, C. Tetrahedron Lett. 2007, 48, 7392−7394.

Birch reduction The Birch reduction is the 1,4-reduction of aromatics to their corresponding cyclohexadienes by alkali metals (Li, K, Na) dissolved in liquid ammonia in the presence of an alcohol.

Benzene ring bearing an electron-donating substituent:

O O Na, liq. NH3 ROH

O O O single electron H transfer (SET) HOR H radical anion

O O H O H e H H H H HOR

Benzene ring with an electron-withdrawing substituent:

CO2H CO2H Na, liq. NH3

CO2 CO2H CO2 e e

H radical anion

CO2 CO2 CO2H H

HH H HNH2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_21, © Springer-Verlag Berlin Heidelberg 2009 45

Example 14

OMe OMe

, − o 1. Na, NH3, THF 78 C N N O 2. MeI, 98%, 30:1 dr O O O OMe OMe

Example 27

Na, NH3, THF N N −78 oC, quant.

Example 38

Ph H Ph H H H Na, NH3 H H H THF, EtOH H Ph Ph Ph H H H H H − o H Ph 33 C, 1 h Ph Ph Ph H H 16.3% H H

References

1. Birch, A. J. J. Chem. Soc. 1944, 430−436. Arthur Birch (1915−1995), an Australian, developed the “Birch reduction” at Oxford University during WWII in Robert Robin- son’s laboratory. The Birch reduction was instrumental to the discovery of the birth control pill and many other drugs. 2. Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1−334. (Review). 3. Birch, A. J. Pure Appl. Chem. 1996, 68, 553−556. (Review). 4. Donohoe, T. J.; Guillermin, J.-B.; Calabrese, A. A.; Walter, D. S. Tetrahedron Lett. 2001, 42, 5841−5844. 5. Pellissier, H.; Santelli, M. Org. Prep. Proced. Int. 2002, 34, 611−642. (Review). 6. Subba Rao, G. S. R. Pure Appl. Chem. 2003, 75, 1443−1451. (Review). 7. Kim, J. T.; Gevorgyan, V. J. Org. Chem. 2005, 70, 2054−2059. 8. Gealis, J. P.; Müller-Bunz, H.; Ortin, Y.; Condell, M.; Casey, M.; McGlinchey, M. J. Chem. Eur. J. 2008, 14, 1552−1560.

Bischler–Möhlau indole synthesis The Bischler–Möhlau indole synthesis, also known as the Bischler indole synthesis, refers to the synthesis of 3-arylindoles from the cyclization of Ȧ- arylamino-ketones and excess anilines.

Δ Br H N N 2 H N O O H

H2N H : : SN2 N H HO O Br H N H H O

H dehydration

N N H H Example 15

O O NaHCO3, EtOH Br NH2 reflux, 4 h

230−250 oC O O − N silicone oil, 10 15 min N H 35−80% H O

Example 29

F OMe OMe OTBS DME, H2SO4 F reflux, 53% H2N N NH2 N N O H2N N H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_22, © Springer-Verlag Berlin Heidelberg 2009 47

Example 310

MeO OMe LiBr, NaHCO3 OMe EtOH, reflux Br H2N OMe 6 h, 74% N O H

Example 4, Microwave-assisted, solvent-free Bischler indole synthesis11

Cl neat Cl NaHCO3 Br N H N rt, 3 h H 2 O O

Br H3N

cat. DMF, microwave, 540 W 60 s, 52% N H

References

1. Möhlau, R. Ber. 1881, 14, 171–175. 2. Bischler, A.; Fireman, P. Ber. 1893, 26, 1346–1349. 3. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970, pp 164. (Book). 4. Buu-Hoï, N. P.; Saint-Ruf, G.; Deschamps, D.; Bigot, P. J. Chem. Soc. (C) 1971, 2606–2609. 5. Houlihan, W. J., Ed.; The Chemistry of Heterocyclic Compounds, Indoles (Part 1), Wiley & Sons: New York, 1972. (Book). 6. Bigot, P.; Saint-Ruf, G.; Buu-Hoï, N. P. J. Chem. Soc., Perkin 1 1972, 2573–2576. 7. Bancroft, K. C. C.; Ward, T. J. J. Chem. Soc., Perkin 1 1974, 1852–1858. 8. Coïc, J. P.; Saint-Ruf, G.; Brown, K. J. Heterocycl. Chem. 1978, 15, 1367–1371. 9. Henry, J. R.; Dodd, J. H. Tetrahedron Lett. 1998, 39, 8763–8764. 10. Pchalek, K.; Jones, A. W.; Wekking, M. M. T.; Black, D. S. C. Tetrahedron 2005, 61, 77–82. 11. Sridharan, V.; Perumal, S.; Avendaño, C.; Menéndez, J. C. Synlett 2006, 91–95.

Bischler–Napieralski reaction Dihydroisoquinolines from β-phenethylamides in refluxing phosphorus oxychloride.

POCl3 HN O N

R R

O Cl P Cl − Cl HN O Cl HN O NH POCl2 R R R OPOCl2

O N N H HCl H NH HCl PO H O ROPOCl ROP Cl 2 Cl R Cl Cl

Example 12

CO Me CO Me CO2Me 2 2 H H N N N O 1. POCl3 N N H N H H H H H 2. NaBH4 H 60% H 23% H

Example 24

Bn MeO POCl P O MeO N 3, 2 5 CO2Me N 96% Bn O

Example 36

H H H O H POCl3 O H H o N O N 80 C, 81% O MeO2C O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_23, © Springer-Verlag Berlin Heidelberg 2009 49

Example 47

O O

HN O N O POCl3 O

toluene, 95%

MeO OMe MeO OMe OMe OMe

Example 59

H N N O N POCl3, PhH, reflux, 3 h N H H H H H then LiAlH4, THF, 1.5 h H 64%

OH AcO OAc HO

References

1. Bischler, A.; Napieralski, B. Ber. 1893, 26, 1903–1908. Augustus Bischler (1865−1957) was born in Southern Russia. He studied in Zurich with Arthur Hantzsch. He discovered the Bischler–Napieralski reaction while studying alkaloids at Basel Chemical Works, Switzerland with his coworker, B. Napieralski. 2. Aubé, J.; Ghosh, S.; Tanol, M. J. Am. Chem. Soc. 1994, 116, 9009–9018. 3. Sotomayor, N.; Domínguez, E.; Lete, E. J. Org. Chem. 1996, 61, 4062–4072. 4. Wang, X.-j.; Tan, J.; Grozinger, K. Tetrahedron Lett. 1998, 39, 6609–6612. 5. Ishikawa, T.; Shimooka, K.; Narioka, T.; Noguchi, S.; Saito, T.; Ishikawa, A.; Yama- zaki, E.; Harayama, T.; Seki, H.; Yamaguchi, K. J. Org. Chem. 2000, 65, 9143–9151. 6. Banwell, M. G.; Harvey, J. E.; Hockless, D. C. R., Wu, A. W. J. Org. Chem. 2000, 65, 4241–4250. 7. Capilla, A. S.; Romero, M.; Pujol, M. D.; Caignard, D. H.; Renard, P. Tetrahedron 2001, 57, 8297–8303. 8. Wolfe, J. P. Bischler–Napieralski Reaction. In Name Reactions in Heterocyclic Chem- istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 376−385. (Review). 9. Ho, T.-L.; Lin, Q.-x. Tetrahedron 2008, 64, 10401–10405. 10. Csomós, P.; Fodor, L.; Bernáth, G.; Csámpai, A.; Sohár, P. Tetrahedron 2009, 65, 1475–1480.

Blaise reaction β-Ketoesters from nitriles, α-haloesters and Zn. Cf. Reformatsky reaction.

2 1. Zn, THF, reflux O Br CO2R RCN CO R2 R 2 R1 2. H O+ 3 R1

R N H2OH ZnBr 2 2 nucleophilic N workup Br CO2R Zn(0) OR 2 BrZn CO2R R1 O addition R 1 1 R R The Zn enolate itself is a C-enolate (in the crystal form), but for the reaction to occur, it equilibrates back into an O-enolate

H H N H2OH O 2 CO R N OH H 2 R 2 2 CO2R CO R2 R : 1 R 2 H2O R R1 1 R

Example 1, Preparation of the statin side chain5

OTMS 1. cat. Zn, THF, reflux OH O Cl CN Br CO2t-Bu Cl CO2t-Bu 2. H O+, 85% 3

Example 26 F CN Zn, MeSO3H Br CO2Et THF, reflux, 2.5 h Cl N Cl

Br Zn O O HN O HCl, 72% F F OEt OEt Cl N Cl Cl N Cl

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_24, © Springer-Verlag Berlin Heidelberg 2009 51

Example 37

O Me OMe O OH OH Br NC OBn MeO2C OBn 3 equiv Zn, 1 mol% MeSO3H THF, reflux, 78%

Example 4, The first chemoselective tandem acylation of the Blaise reaction in- termediate9

* Br Zn NH2 O BrCH CO Et Zn n-BuLi, Ac2O 2 2 HN O Ph CN Ph OEt rt, 3 h, 82% THF, reflux, 1 h Ph OEt O CH3

References

1. (a) Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 478–480. (b) Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 978–980. Blaise was at Institut Chimique de Nancy, France. 2. Beard, R. L.; Meyers, A. I. J. Org. Chem. 1991, 56, 2091–2096. 3. Deutsch, H. M.; Ye, X.; Shi, Q.; Liu, Z.; Schweri, M. M. Eur. J. Med. Chem. 2001, 36, 303–311. 4. Creemers, A. F. L.; Lugtenburg, J. J. Am. Chem. Soc. 2002, 124, 6324–6334. 5. Shin, H.; Choi, B. S.; Lee, K. K.; Choi, H.-w.; Chang, J. H.; Lee, K. W.; Nam, D. H.; Kim, N.-S. Synthesis 2004, 2629–2632. 6. Choi, B. S.; Chang, J. H.; Choi, H.-w.; Kim, Y. K.; Lee, K. K.; Lee, K. W.; Lee, J. H.; Heo, T.; Nam, D. H.; Shin, H. Org. Proc. Res. Dev. 2005, 9, 311–313. 7. Pospíšil, J.; Markó, I. E. J. Am. Chem. Soc. 2007, 129, 3516–3517. 8. Rao, H. S. P.; Rafi, S.; Padmavathy, K. Tetrahedron 2008, 64, 8037–8043. (Review). 9. Chun, Y. S.; Lee, S.-g.; Ko, Y. O.; Shin, H. Chem. Commun. 2008, 5098–5100.

Blum–Ittah aziridine synthesis

Ring opening of oxiranes using azide followed by PPh3-reduction of the intermediate azido-alcohol to give the corresponding aziridines.

N3 H O PPh NaN3 R1 3 N R2 R1 R2 OH R1 R2

O N3 1 SN2 R R2 R1 R2 OH N3 Regardless of the regioselectivity of the SN2 reaction of the azide, the ultimate stereochemical outcome for the aziridine is the same.

1 R1 R1 R HO HO HO NNN PR NNN PPh3 3 NNN :PPh 2 2 3 R2 R R

PR3 PR3 N PR3 N N 1 N N2 R HO N R2 R2 X 1 OH R

1 R P NH R NH H proton 3 N :O 2 transfer R O R2 1 2 1 PPh R R R 3

Example 13

1. NaN3, NH4Cl, MeOH, reflux, 4 h OTr O HN OTr 2. Ph3P, CH3CN, reflux, 30 min. 60−75%

Example 25

O NaN3, NH4Cl, MeOH OTBS reflux, 4 h, 50%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_25, © Springer-Verlag Berlin Heidelberg 2009 53

OH N3 OTBS OTBS N OH 3

Ph3P, CH3CN NH

OTBS reflux, 99%

Example 37

H H O H N N N o Cbz Cbz 1. NaN3, NH4Cl, MeOH, 3 h, 64 C

2. PPh3, MeCN, 1 h, reflux 66%

Example 48

OH NaN , NH Cl O 3 4 N3 microwave, 15 min. 93%

H N PPh3

CH3CN, reflux 2 h, 95%

References

1. Ittah, Y.; Sasson, Y.; Shahak, I.; Tsaroom, S.; Blum, J. J. Org. Chem. 1978, 43, 4271– 4273. Jochanan Blum is a professor at The Hebrew University in Jerusalem, Israel. 2. Tanner, D.; Somfai, P. Tetrahedron Lett. 1987, 28, 1211–1214. 3. Wipf, P.; Venkatraman, S.; Miller, C. P. Tetrahedron Lett. 1995, 36, 3639–3642. 4. Fürmeier, S.; Metzger, J. O. Eur. J. Org. Chem. 2003, 649–659. 5. Oh, K.; Parsons, P. J.; Cheshire, D. Synlett 2004, 2771–2775. 6. Serafin, S. V.; Zhang, K.; Aurelio, L.; Hughes, A. B.; Morton, T. H. Org. Lett. 2004, 6, 1561–1564. 7. Torrado, A. Tetrahedron Lett. 2006, 47, 7097–7100. 8. Pulipaka, A. B.; Bergmeier, S. C. J. Org. Chem. 2008, 73, 1462–1467.

Boekelheide reaction Treatment of 2-methylpyridine N-oxide with trifluoroacetic anhydride, or acetic, anhydride gives rise to 2-hydroxymethylpyridine.

TFAA N OH O N

TFAA, trifluoroacetic anhydride

O2CCF3 N acyl H O N N transfer O O O O F C O CF 3 3 CF CF3 3 O O

hydrolysis O CF N 3 OH N O Example 14

Ac2O, CH2Cl2

N N reflux, 1 h, 90% N N O OAc

Example 26 Ot-Bu Ot-Bu

1. TFAA, CH2Cl2

N 2. Na2CO3, 3 h N 89% O OH

Example 38

OTBDPS OTBDPS o 1. Ac2O, 100 C, 18 h

− N N N N 2. K2CO3, MeOH H2O, rt, 2 h HO OH OO 63%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_26, © Springer-Verlag Berlin Heidelberg 2009 55

Example 49

NO NO2 2 o Ac2O, HOAc, 90 C, 3 h

then HCl, 79% OH N N O

References

1. Boekelheide, V.; Linn, W. J. J. Am. Chem. Soc. 1954, 76, 1286−1291. Virgil Boekel- heide (1919−2003) was a professor at the University of Oregon. 2. Boekelheide, V.; Harrington, D. L. Chem. Ind. 1955, 1423−1424. 3. Katritzky, A. R.; Lagowski, J. M. Chemistry of the Heterocylic N-Oxides, Academic Press: NY, 1971. (Review). 4. Newkome, G. R.; Theriot, K. J.; Gupta, V. K.; Fronczek, F. R.; Baker, G. R. J. Org. Chem. 1989, 54, 1766−1769. 5. Katritzky, A. R.; Lam, J. N. Heterocycles 1992, 33, 1011−1049. (Review). 6. Fontenas, C.; Bejan, E.; Haddou, H. A.; Balavoine, G. G. A. Synth. Commun. 1995, 25, 629−633. 7. Galatsis, P. Boekelheide Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 340−349. (Review). 8. Havas, F.; Danel, M.; Galaup, C.; Tisnès, P.; Picard, C. Tetrahedron Lett. 2007, 48, 999−1002. 9. Dai, L.; Fan, D.; Wang, X.; Chen, Y. Synth. Commun. 2008, 38, 576−582.

Boger pyridine synthesis Pyridine synthesis via hetero-Diels−Alder reaction of 1,2,4-triazines and dienophiles (e.g., enamine) followed by extrusion of N2.

N N H NN O N

H N H O hetero-Diels-Alder 2 N N O OH N N reaction : HN

enamine

N :B N retro-Diels-Alder H N − N N reaction, N2 N N

Example 13

EtO C N CO Et o 2 2 CHCl3, 60 C EtO2C N CO2Et N N O EtO C N 26 h, 92% 2 EtO2C

Example 2, Intramolecular Boger pyridine synthesis8

Ph N Ph N Ph N Ph N triisopropylbenzene Ph N NN N Ph N Ph 232 oC, 36 h CH3 CH 70% 27% 3

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_27, © Springer-Verlag Berlin Heidelberg 2009 57

Example 310

O H3C

H N H H H3C HO N N N H N 1. pyrrolidine, xylene, Δ 10 h, sealed tube H H N 2. silica, 5 h, 67% HO

Example 411

N N N N N N N N o S S p-cumene, 30 h, 150 C S S 67%

References

1. Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179−2182. Dale Boger obtained his Ph.D. under Elias J. Corey at Harvard University in 1980. He started his independent career at the University of Kansas, moving onto Purdue University, and currently he is a professor at The Scripps Research Institute. 2. Boger, D. L. Tetrahedron 1983, 39, 2869−2939. (Review). 3. Boger, D. L.; Panek, J. S.; Yasuda, M. Org. Synth. 1988, 66, 142−150. 4. Boger, D. L. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 451−512. (Review). 5. Behforouz, M.; Ahmadian, M.Tetrahedron 2000, 56, 5259−5288. (Review). 6. Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099−6138. (Review). 7. Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379−471. (Review). 8. Lahue, B. R.; Lo, S.-M.; Wan, Z.-K.; Woo, G. H. C.; Snyder, J. K. J. Org. Chem. 2006, 69, 7171−7182. 9. Galatsis, P. Boger Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 323−339. (Review). 10. Catozzi, N.; Bromley, W. J.; Wasnaire, P.; Gibson, M.; Taylor, R. J. K. Synlett 2007, 2217−2221. 11. Lawecka, J.; Bujnicki, B.; Drabowicz, J.; Rykowski, A. Tetrahedron Lett. 2008, 49, 719−722.

Borch reductive amination

Reduction (often using NaCNBH3) of the imine, formed by an amine and a carbonyl, to afford the corresponding amine—basically, reductive amination.

O H H H R1 R2 N R R R1 R2 3 4 N R3 R4

O H OH H R R R1 R2 R1 R2 1 2 R R H 1 N: 2 N N R R R3 R4 N R3 3 4 R R R 3 4 4

Example 14

O 1. TiCl4, Et3N, CH2Cl2, rt, 18 h HN CH3 2. NaCNBH3, MeOH, rt, 15 min. CH3 NH2 94%

Example 25

NH2 5 N HCl, NaCNBH3 N MeOH, rt, 72 h, 75% O O

Example 38

O 0.3 equiv InCl3 N H N 2 equiv Et3SiH H •HCl MeOH, rt, 48 h, 66%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_28, © Springer-Verlag Berlin Heidelberg 2009 59

Example 49

OBn OBn O O − O 1. NaIO4, 8:2 acetone H2O, rt O N N 2. BnNH2, MeOH, HOAc O O − o NaCNBH3, 3 Å MS, 78 C to rt N OH 64% Bn OH

References

1. Borch, R. F., Durst, H. D. J. Am. Chem. Soc. 1969, 91, 3996–3997. Richard F. Borch, born in Cleveland, Ohio, was a professor at the University of Minnesota. 2. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897–2904. 3. Borch, R. F.; Ho, B. C. J. Org. Chem. 1977, 42, 1225–1227. 4. Barney, C. L.; Huber, E. W.; McCarthy, J. R. Tetrahedron Lett. 1990, 31, 5547–5550. 5. Mehta, G.; Prabhakar, C. J. Org. Chem. 1995, 60, 4638–4640. 6. Lewin, G.; Schaeffer, C. Heterocycles 1998, 48, 171–174. 7. Lewin, G.; Schaeffer, C.; Hocquemiller, R.; Jacoby, E.; Léonce, S.; Pierré, A.; Atassi, G. Heterocycles 2000, 53, 2353–2356. 8. Lee, O.-Y.; Law, K.-L.; Ho, C.-Y.; Yang, D. J. Org. Chem. 2008, 73, 8829–8837. 9. Sullivan, B.; Hudlicky, T. Tetrahedron Lett. 2008, 49, 5211–5213. 10. Koszelewski, D.; Lavandera, I.; Clay, D.; Guebitz, G. M.; Rozzell, D.; Kroutil, W. Angew. Chem., Int. Ed. 2008, 47, 9337–9340.

Borsche–Drechsel cyclization Tetrahydrocarbazole synthesis from cyclohexanone phenylhydrazone. Cf. Fischer indole synthesis.

HCl

N N N H H

H [3,3]-sigmatropic H N N NH rearrangement NH N NH H H H

H H

NH2 N NH2 N NH H H H

Example 16

CH3 H CO HCl, NaNO2, NaOAc 3 HO H2O, MeOH, 54% NH O 2

CH3 CH3

HOAc, HCl, reflux H3CO H CO 3 O 10 min., 44% N O N H N H

Example 210

O N O KOAc, H2O retro-Claisen condensation CO2Et − 4 oC to rt followed by Japp-Klingemann hydrazone synthesis N N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_29, © Springer-Verlag Berlin Heidelberg 2009 61

O N

CO2H H O , 100 oC 3 N NH CO Et N O 2 68% 2 steps N H EtO2C

CO H 2

Example 310

CO2Et CO2H

conc. HCl, EtOH N CO2Et N reflux, 85% N H CO Et H 2

References

1. Drechsel, E. J. Prakt. Chem. 1858, 38, 69. 2. Borsche, W.; Feise, M. Ann. 1908, 359, 49–80. Walther Borsche was a professor at Chemischen Institut, Universität Göttingen, Germany when this paper was published. Borsche was completely devoid of the arrogance shown by many of his contemporar- ies. Both Borsche and his colleague at Frankfurt, Julius von Braun, suffered under the Nazi regime for their independent minds. 3. Bruck, P. J. Org. Chem. 1970, 35, 2222–2227. 4. Gazengel, J.-M.; Lancelot, J.-C.; Rault, S.; Robba, M. J. Heterocycl. Chem. 1990, 27, 1947–1951. 5. Abramovitch, R. A.; Bulman, A. Synlett 1992, 795–796. 6. Lin, G.; Zhang, A. Tetrahedron 2000, 56, 7163–7171. 7. Ergun, Y.; Bayraktar, N.; Patir, S.; Okay, G. J. Heterocycl. Chem. 2000, 37, 11–14. 8. Rebeiro, G. L.; Khadilkar, B. M. Synthesis 2001, 370–372. 9. Takahashi, K.; Kasai, M.; Ohta, M.; Shoji, Y.; Kunishiro, K.; Kanda, M.; Kurahashi, K.; Shirahase, H. J. Med. Chem. 2008, 51, 4823–4833. 10. Pete, B. Tetrahedron Lett. 2008, 49, 2835–2838.

Boulton–Katritzky rearrangement Rearrangement of one five-membered heterocycle into another under thermolysis.

X A A Y B X B N Z D N Y D H H Z

Example 14

: N N 150 oC H H H N O N N N N N N Ph O O H Ph Ph

Example 2, Hydrazinolysis7

O Ph NH2NH2, DMF N Ph N N rt, 1 h N NH F C N F3C 2 3 O O

HO F3C N NH Ph Ph O N NN N N F3C N H H 5% 92%

Example 43

CF3 CH H3C O 3 O N NH t-BuOK, DMF CF3 N N reflux, 2 h, 75% H N N H O O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_30, © Springer-Verlag Berlin Heidelberg 2009 63

References

1. Boulton, A. J.; Katritzky, A. R.; Majid Hamid, A. J. Chem. Soc. (C) 1967, 2005–2007. Alan Katritzky, a professor at the University of Florida, is best known for his series Advances of Heterocyclic Chemistry, now in its 93rd volume. 2. Ruccia, M.; Vivona, N.; Spinelli, D. Adv. Heterocycl. Chem. 1981, 29, 141–169. (Re- view). 3. Vivona, N.; Buscemi, S.; Frenna, V.; Gusmano, C. Adv. Heterocyl. Chem. 1993, 56, 49–154. (Review). 4. Katayama, H.; Takatsu, N.; Sakurada, M.; Kawada, Y. Heterocycles 1993, 35, 453– 459. 5. Rauhut, G. J. Org. Chem. 2001, 66, 5444–5448. 6. Crampton, M. R.; Pearce, L. M.; Rabbitt, L. C. J. Chem. Soc., Perkin Trans. 2 2002, 257–261. 7. Buscemi, S.; Pace, A.; Piccionello, A. P.; Macaluso, G.; Vivona, N.; Spinelli, D.; Giorgi, G. J. Org. Chem. 2005, 70, 3288–3291. 8. Pace, A.; Pibiri, I.; Piccionello, A. P.; Buscemi, S.; Vivona, N.; Barone, G. J. Org. Chem. 2007, 64, 7656–7666. 9. Piccionello, A. P.; Pace, A.; Buscemi, S.; Vivona, N.; Pani, M. Tetrahedron 2008, 64, 4004–4010. 10. Pace, A.; Pierro, P.; Buscemi, S.; Vivona, N.; Barone, G. J. Org. Chem. 2009, 74, 351–358.

Bouveault aldehyde synthesis Formylation of an alkyl or aryl halide to the homologous aldehyde by transformation to the corresponding organometallic reagent then addition of DMF (M = Li, Mg, Na, and K).

1. M 2. DMF RX RCHO 3. H

O O M M Me2N H H RX Me2N RCHO RM R

Comins modification:4

O N LiO Li NN N H H

N O n-BuLi N 1. RX, X = Br, I H ortho-lithiation O 2. H3O Li R

Example3

Li, DMF, THF, 10 oC Br CHO ultrasound 5 min., 85%

References

1. Bouveault, L. Bull. Soc. Chim. Fr. 1904, 31, 1306−1322, 1322−1327. Louis Bou- veault (1864−1909) was born in Nevers, France. He devoted his short yet very pro- ductive life to teaching and to working in science. 2. Sicé, J. J. Am. Chem. Soc. 1953, 75, 3697−3700. 3. Pétrier, C.; Gemal, A. L.; Luche, J.-L. Tetrahedron Lett. 1982, 23, 3361−3364. 4. Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078−1083. 5. Einhorn, J.; Luche, J. L. Tetrahedron Lett. 1986, 27, 1793−1796. 6. Meier, H.; Aust, H. J. Prakt. Chem. 1999, 341, 466−471.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_31, © Springer-Verlag Berlin Heidelberg 2009 65

Bouveault–Blanc reduction Reduction of esters to the corresponding alcohols using sodium in an alcoholic solvent.

O Na, EtOH R OH R OEt

O single-electron OH O H OEt R OEt transfer (SET) R OEt ROEt e

ketyl (radical anion)

OH OEt H O O e e R OEt R H H OEt R OEt

OH O H OEt OH e R H R OH R H R H H OEt

Example2

O Na, Al2O3 t-BuOH, Tol. OH OEt reflux, 6 h, 66%

References

1. Bouveault, L.; Blanc, G. Compt. Rend. Hebd. Seances Acad. Sci. 1903, 136, 1676−1678. 2. Bouveault, L.; Blanc, G. Bull. Soc. Chim. 1904, 31, 666−672. 3. Rühlmann, K.; Seefluth, H.; Kiriakidis, T.; Michael, G.; Jancke, H.; Kriegsmann, H. J. Organomet. Chem. 1971, 27, 327−332. 4. Seo, B.-I.; Wall, L. K.; Lee, H.; Buttrum, J. W.; Lewis, D. E. Synth. Commun. 1993, 23, 15−22. 5. Singh, S.; Dev, S. Tetrahedron 1993, 49, 10959−10964. 6. Schopohl, M. C.; Bergander, K.; Kataeva, O.; Föehlich, R.; Waldvogel, S. R. Synthesis 2003, 2689−2694.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_32, © Springer-Verlag Berlin Heidelberg 2009 66

Bradsher reaction The intramolecular Bradsher cyclization refers to the acid-catalyzed aromatic cyclodehydration of ortho-acyl diarylmethanes to form anthracenes. On the other hand, the intermolecular Bradsher cycloaddition often involves the Diels–Alder reaction of a pyridium with a vinyl ether or vinyl sulfide.

HBr R CH3CO2H O R

anthracene

H R R H R O O O H H

− H H

R OH R OH2 R

Example 1, Intramolecular Bradsher reaction2

O HBr, CH3CO2H Br Br 150 oC, 7 h, 21%

Example 2, Intramolecular Bradsher reaction5

CH3 H3C

AcOH O Cl Cl Cl Cl PPA Cl Cl S S S S S S O CH 3

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_33, © Springer-Verlag Berlin Heidelberg 2009 67

Example 3, Intermolecular Bradsher cycloaddition (DNP = dinitrophenyl)8

CHO EtO OCO Et EtO2CO 2 OEt O H OEt CaCO3, MeOH

N rt, 2 d N DNP DNP 19% NHDNP 66% Cl

Example 4, Intermolecular Bradsher cycloaddition10

DNP DNP Cl N N CaCO , MeOH H SPh 3 PhS Cl

NHAc NHAc

DNPHN SPh

H3O OH 80% N Ac

References

1. (a) Bradsher, C. K. J. Am. Chem. Soc. 1940, 62, 486–488. Charles K. Bradsher was born in Petersburg, VA in 1912. After his Ph.D. under Louis F. Fieser at Harvard and postdoctoral training with R. C. Fuson, he became a professor at Duke University. (b) Bradsher, C. K.; Smith, E. S. J. Am. Chem. Soc. 1943, 65, 451–452. (c) Bradsher, C. K.; Vingiello, F. A. J. Org. Chem. 1948, 13, 786–789. (d) Bradsher, C. K.; Sinclair, E. F. J. Org. Chem. 1957, 22, 79–81. 2. Vingiello, F. A.; Spangler, M. O. L.; Bondurant, J. E. J. Org. Chem. 1960, 25, 2091– 2094. 3. Brice, L. K.; Katstra, R. D. J. Am. Chem. Soc. 1960, 82, 2669–2670. 4. Saraf, S. D.; Vingiello, F. A. Synthesis 1970, 655. 5. Ahmed, M.; Ashby, J.; Meth-Cohn, O. J. Chem. Soc., Chem. Commun. 1970, 1094– 1095. 6. Ashby, J.; Ayad, M.; Meth-Cohn, O. J. Chem. Soc., Perkin Trans. 1 1974, 1744–1747. 7. Bradsher, C. K. Chem. Rev. 1987, 87, 1277–1297. (Review). 8. Nicolas, T. E.; Franck, R. W. J. Org. Chem. 1995, 60, 6904–6911. 9. Magnier, E.; Langlois, Y. Tetrahedron Lett. 1998, 39, 837–840. 10. Soll, C. E.; Franck, R. W. Heterocycles 2006, 70, 531–540.

Brook rearrangement Rearrangement of α-silyl oxyanions to α-silyloxy carbanions via a reversible process involving a pentacoordinate silicon intermediate is known as the [1,2]- Brook rearrangement, or [1,2]-silyl migration.

[1,2]-Brook rearrangement

SiR OH RLi O 3 R 1 SiR R1 R 3 Li 2 R2

R O O H O R1 SiR3 R1 SiR3 R2 R1 R2 SiR3 R2 pentacoordinate silicon intermediate

SiPh 3 SiPh3 O workup O Ph Ph H Ph HOH Ph

[1,3]-Brook rearrangement

SiR3 OLi O O SiR3 SiR Li 3 R1 R1 R R R 1 2 R2 2

[1,4]-Brook rearrangement

R Si 3 O Li OLi SiR3 O SiR3

R R R1 R R1 R2 1 2 2

Example 16

O − o CN 1. 4 eq. NaHMDS, 30 to 15 C CN t-BuMe2Si t-BuMe2SiO Ph − o Ph Ph 2. PhCH2Br, 10 C, 75%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_34, © Springer-Verlag Berlin Heidelberg 2009 69

Example 2, [1,2]-Brook rearrangement followed by a retro-[1,5]-Brook rear- rangement8

O Ph O t-BuLi, Et2O Me3Si Ph Br Ph Li Ph Ph −78 oC to rt, 30 min. −78 oC SiMe then NH Cl, H O, 44% 3 4 2

Example 3, [1,5]-Brook rearrangement9

S S KHMDS, THF S S Bu Bu TMS H − 78 oC, 1 h, 93% OH OTMS

Example 4, Retro-[1,4]-Brook rearrangement10

n-BuLi, THF OH OTMS TESO OTMS TESO OH − 78 oC, 30 min. Me TMS Me TES Me SnBu3 91% 11% [1,2]-Brook 89% [1,4]- Brook

References

1. Brook, A. G. J. Am. Chem. Soc. 1958, 80, 1886−1889. Adrian G. Brook (1924−) was born in Toronto, Canada. He was a professor in Lash Miller Chemical Laboratories, University of Toronto, Canada. 2. Brook, A. G. Acc. Chem. Res. 1974, 7, 77−84. (Review). 3. Bulman Page, P. C.; Klair, S. S.; Rosenthal, S. Chem. Soc. Rev. 1990, 19, 147−195. (Review). 4. Fleming, I.; Ghosh, U. J. Chem. Soc., Perkin Trans. 1 1994, 257−262. 5. Moser, W. H. Tetrahedron 2001, 57, 2065−2084. (Review). 6. Okugawa, S.; Takeda, K. Org. Lett. 2004, 6, 2973−2975. 7. Matsumoto, T.; Masu, H.; Yamaguchi, K.; Takeda, K. Org. Lett. 2004, 6, 4367−4369. 8. Clayden, J.; Watson, D. W.; Chambers, M. Tetrahedron 2005, 61, 3195−3203. 9. Smith, A. B., III; Xian, M.; Kim, W.-S.; Kim, D.-S. J. Am. Chem. Soc. 2006, 128, 12368–12369. 10. Mori, Y.; Futamura, Y.; Horisaki, K. Angew. Chem., Int. Ed. 2008, 47, 1091–1093. 11. Greszler, S. N.; Johnson, J. S. Org. Lett. 2009, 11, 827–830.

Brown hydroboration Addition of boranes to olefins followed by alkalinic oxidation of the organoborane adducts to afford alcohols.

1. R' BH 2 OH R R 2. H2O2, NaOH

H R' H R' R' H R' H R' syn- B B B OH B R' R' R R' R O R R addition OOH

alkyl migration O R' OOH O OR' R B R B R' OR'

OH OH B(OH) R 3 Example 12

1. BH •SMe , LiAlH , Et O H 3 2 4 2 2. NaOOH H H H

H OH HO H H H H H H 35% 40% H

Example 27

OMe OMe

MeO MeO NO 2 BH3•SMe2, NaOOH NO2 OMe OMe Me THF, 85%, dr 8:1~11:1 Me OBn OBn HO

HO HO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_35, © Springer-Verlag Berlin Heidelberg 2009 71

Example 38

OH 1. Pyridine•BH3, I2, CH2Cl2, 2 h Ph Ph Ph OH 2. H2O2, NaOH, MeOH, 92% 15:1

Example 4, Asymmetric hydroboration10

O Ph N CH3 H 0.5 mol% Rh(nbd)2•BF4 O Ph O 1.1% cat., 2 equiv PinBH cat. = P N Ph N O CH3 H THF, 40 oC, 2 h CH 3 O OH O B(OCMe2)2 H2O2, aq. NaOH Ph Ph N CH3 N CH3 H H 80% 99% ee

Example 511 t-Bu OH t-Bu (t-Bu)2Si NH2 Si NH BH3•SM2, THF; Ph H Ph H NaOH, H2O2 85% Ph OH Ph H

References

1. Brown, H. C.; Tierney, P. A. J. Am. Chem. Soc. 1958, 80, 1552−1558. Herbert C. Brown (USA, 1912−2004) began his academic career at Wayne State University and moved on to Purdue University where he shared the Nobel Prize in Chemistry in 1981 with Georg Wittig (Germany, 1897−1987) for their development of organic boron and phosphorous compounds. 2. Nussim, M.; Mazur, Y.; Sondheimer, F. J. Org. Chem. 1964, 29, 1120−1131. 3. Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents, Academic Press: New York, 1972. (Book). 4. Brewster, J. H.; Negishi, E. Science 1980, 207, 44−46. (Review). 5. Fu, G. C.; Evans, D. A.; Muci, A. R. Advances in Catalytic Processes 1995, 1, 95−121. (Review). 6. Hayashi, T. Comprehensive Asymmetric Catalysis I−III 1995, 1, 351−364. (Review). 7. Carter K. D.; Panek J. S. Org. Lett. 2004, 6, 55−57. 8. Clay, J. M.; Vedejs, E. J. Am. Chem. Soc. 2005, 127, 5766−5767. 9. Clay, J. M. Brown hydroboration reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2007; pp 183−188. (Review). 10. Smith, S. M.; Thacker, N. C.; Takacs, J. M. J. Am. Chem. Soc. 2008, 130, 3734−3735. 11. Anderson, L. L.; Woerpel, K. A. Org. Lett. 2009, 11, 425−428. 72

Bucherer carbazole synthesis Carbazole formation from naphthols and aryl hydrazines promoted by sodium bisulfite. Another variant of the Fischer indole synthesis.

OH NaHSO3 NH NHNH2

HH H HH HH H H O OH O OH :NH2NHPh

OSO H OSO2H OSO2H 2

HH H OH NHNHPh NHNHPh :B NH H NH OSO H OSO H 2 2

[3,3]-sigmatropic NH H NH2 rearrangement H 2 H NH NH NH then H

Example 12

NaHSO , NaOH OH 3 Δ, 130 oC

CO2H NHNH2 several days, 46% N H

Example 23

OH Δ 1. aq. NaHSO3,

H NHN 2. H N 2 H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_36, © Springer-Verlag Berlin Heidelberg 2009 73

Example 37

Br OH Br Na2S2O5 HCl, Δ H2NHN N H

Example 34

NH HO OH HN Δ 1. NaHSO3, H NHN 2 2. H 0.5% yield!

References

1. Bucherer, H. T. J. Prakt. Chem. 1904, 69, 49−91. Hans Th. Bucherer (1869−1949) was born in Ehrenfeld, Germany. He shuttled between industry and academia all through his career. 2. Bucherer, H. T.; Schmidt, M. J. Prakt. Chem. 1909, 79, 369−417. 3. Bucherer, H. T.; Sonnenburg, E. F. J. Prakt. Chem. 1909, 81, 1−48. 4. Drake, N. L. Org. React. 1942, 1, 105−128. (Review). 5. Seeboth, H. Angew. Chem., Int. Ed. 1967, 6, 307−317. (Review). 6. Robinson, B. The Fischer Indole Synthesis, Wiley-Interscience, New York, 1982. (Book). 7. Hill, J. A.; Eaddy, J. F. J. Labelled Compd. Radiopharm. 1994, 34, 697−706. 8. Pischel, I.; Grimme, S.; Kotila, S.; Nieger, M.; Vögtle, F. Tetrahedron: Asymmetry 1996, 7, 109−116. 9. Moore, A. J. Bucherer carbazole synthesis. In Name Reactions in Heterocyclic Chem- istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 110−115. (Review).

Bucherer reaction Transformation of β-naphthols to β-naphthylamines using ammonium sulfite.

OH NH (NH4)2SO3•NH3 2

o H2O, 150 C

HH H HH H O O O H H

OSO2NH4 OSO2NH4

O OH tautomerization : NH2 NH3 H

OSO2NH4 OSO NH 2 4

H OH NH 2 2 NH NH 2 : 2 H OSO NH OSO NH 2 4 2 4

Example 1, Although the classic Bucherer reaction requires high temperatures, it may be carried out at room temperature with the aid of microwave (150 watts):7

OH NH2 NH3, (NH4)2SO3, H2O, rt

microwave 30 min. 93%

Example 2, Retro-Bucherer reaction7

OMe OMe O 5 mol% Na2S2O5 O H2O, reflux, 4 h; N N 10 mol% NaOH N reflux, 24 h N NH 46% 2 OH

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_37, © Springer-Verlag Berlin Heidelberg 2009 75

Example 38

(NH4)2SO3 NH3, H2O OH NH2 OH OH 200 oC, 5 d, 91%

References

1. Bucherer, H. T. J. Prakt. Chem. 1904, 69, 49−91. 2. Drake, N. L. Org. React. 1942, 1, 105−128. (Review). 3. Gilbert, E. E. Sulfonation and Related Reactions Wiley: New York, 1965, p 166. (Re- view). 4. Seeboth, H. Angew. Chem., Int. Ed. 1967, 6, 307−317. 5. Gruszecka, E.; Shine, H. J. J. Labelled Compd. Radiopharm. 1983, 20, 1257–1264. 6. Belica, P. S.; Manchand, P. S. Synthesis 1990, 539−540. 7. Deady, L. W.; Devine, S. M. Tetrahedron 2006, 62, 2313−2320. 8. Körber, K.; Tang, W.; Hu, X.; Zhang, X. Tetrahedron Lett. 2002, 43, 7163–7165. 9. Budzikiewicz, H. Mini-Reviews Org. Chem. 2006, 3, 93–97. (Review).

Bucherer–Bergs reaction Formation of hydantoins from carbonyl compounds with potassium cyanide (KCN) and ammonium carbonate [(NH4)2CO3] or from cyanohydrins and ammonium carbonate. It belongs to the category of multiple component reactions (MCRs).

H 1 R1 R KCN N O O 2 2 R NH R (NH4)2CO3 O

(NH4)2CO3 = 2 NH3 + CO2 + H2O

NH2 O CO 1 R OH : R1 R2 O H N R2 NH2 2 :

: 2 1 R R1 R N H3N NC 2 R

: OH H O 1 H R OH 1 H R N R1 N C R N O O R1 N 2 O 2 R 2 : R R O 2 NH R NH N HN 2 O O isocyanate intermediate

Example 15

CH O CH3O CH3O 3 KCN, (NH ) CO N N N 4 2 3 CH O CH3O CH3O 3 H H 48 h, 60 oC, 83% O HN O NH O HN NH O O

Example 26

O O HN H NH KCN, (NH4)2CO3 O O H CO2Et O o CO2Et O H EtOH/H2O, 70 C, 50% H O H H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_38, © Springer-Verlag Berlin Heidelberg 2009 77

Example 37

O O NH HN CH3 KCN, (NH4)2CO3 O CH3

EtOH/H2O (1:1) 60 oC, 4 h, 83% B(OH)2 B(OH)2

Example 49

1. 1 M NaOH, EtOH, rt, 30 min. HO2C H O EtO2C H O F H N F 2. KCN, (NH ) CO , 60 oC, 5 days O 4 2 3 O 77% N O H

References

1. Bergs, H. Ger. Pat. 566, 094, 1929. Hermann Bergs worked at I. G. Farben in Ger- many. 2. Bucherer, H. T., Steiner, W. J. Prakt. Chem. 1934, 140, 291–316. (Mechanism). 3. Ware, E. Chem. Rev. 1950, 46, 403–470. (Review). 4. Wieland, H. In Houben−Weyl’s Methoden der organischen Chemie, Vol. XI/2, 1958, p 371. (Review). 5. Menéndez, J. C.; Díaz, M. P.; Bellver, C.; Söllhuber, M. M. Eur. J. Med. Chem. 1992, 27, 61–66. 6. Domínguez, C.; Ezquerra, A.; Prieto, L.; Espada, M.; Pedregal, C. Tetrahedron: Asymmetry 1997, 8, 511–514. 7. Zaidlewicz, M.; Cytarska, J.; Dzielendziak, A.; Ziegler-Borowska, M. ARKIVOC 2004, iii, 11−21. 8. Li, J. J. Bucherer–Bergs Reaction. In Name Reactions in Heterocyclic Chemistry, Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 266−274. (Review). 9. Sakagami, K.; Yasuhara, A.; Chaki, S.; Yoshikawa, R.; Kawakita, Y.; Saito, A.; Ta- guchi, T.; Nakazato, A. Bioorg. Med. Chem. 2008, 16, 4359–4366. 10. Wuts, P. G. M.; Ashford, S. W.; Conway, B.; Havens, J. L.; Taylor, B.; Hritzko, B.; Xiang, Y.; Zakarias, P. S. Org. Proc. Res. Dev. 2009, 13, 331–335.

Büchner ring expansion Reaction of a phenyl ring with diazoacetic esters to give cyclohepta-2,4,6- trienecarboxylic acid esters. Intramolecular Büchner reaction is more useful in synthesis. Cf. Pfau−Platter azulene synthesis.

N2 CO2CH3 CO2CH3 [Rh]

[Rh] N CO CH N ↑ CO CH 2 2 3 2 [Rh] 2 3 rhodium carbenoid

CO CH CO2CH3 [2 + 2] 2 3 reductive

[Rh] cycloaddition [Rh] elimination

electrocyclic CO2CH3 CO2CH3 ring opening

Example 1, Intramolecular Büchner reaction7

O Rh (OAc) N2 2 4

CH2Cl2 H O

Example 2, Intramolecular Büchner reaction8

I Br I cat. Rh2(OCOt-Bu)4, DMAP Ac O, CH Cl , 73% O 2 2 2 OAc N 2

Example 3, An intramolecular Büchner reaction within the Grubbs’ catalyst!9

NN NN 1 atm CO Cl Cl CH Cl , 90% Ph Ru 2 2 OC Ru CO Cl Ph Cl PCy3 PCy 3

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_39, © Springer-Verlag Berlin Heidelberg 2009 79

Example 410

CPh3 CO2Et Ar [Rh] 0.5 mol% O O Rh Rh4 N2 Ar o CH2Cl2, −78 C, 49−66% EtO2C

Ar CO2Et Ar CO2Et Ar

[Rh] CO2Et

References

1. Büchner, E. Ber. 1896, 29, 106–109. 2. von E. Doering, W.; Knox, L. H. J. Am. Chem. Soc. 1957, 79, 352–356. 3. Marchard, A. P.; Brockway, N. M. Chem. Rev. 1974, 74, 431–469. (Review). 4. Anciaux, A. J.; Demoncean, A.; Noels, A. F.; Hubert, A. J.; Warin, R.; Teyssié, P. J. Org. Chem. 1981, 46, 873–876. 5. Duddeck, H.; Ferguson, G.; Kaitner, B.; Kennedy, M.; McKervey, M. A.; Maguire, A. R. J. Chem. Soc., Perkin Trans. 1 1990, 1055–1063. 6. Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001, 3, 933–935. 7. Manitto, P.; Monti, D.; Speranza, G. J. Org. Chem. 1995, 60, 484–485. 8. Crombie, A. L; Kane, J. L., Jr.; Shea, K. M.; Danheiser, R. L. J. Org. Chem. 2004, 69, 8652–8667. 9. Galan, B. R.; Gembicky, M.; Dominiak, P. M.; Keister, J. B.; Diver, S. T. J. Am. Chem. Soc. 2005, 127, 15702–15703. 10. Panne, P.; Fox, J. M. J. Am. Chem. Soc. 2007, 129, 22–23. 11. Gomes, A. T. P. C.; Leão, R. A. C.; Alonso, C. M. A.; Neves, M. G. P. M. S.; Faustino, M. A. F.; Tomé, A. C.; Silva, A.M. S.; Pinheiro, S.; de Souza, M. C. B. V.; Ferreira, V. F.; Cavaleiro, J. A. S. Helv. Chim. Acta 2008, 91, 2270–2283.

Buchwald–Hartwig amination The Buchwald–Hartwig amination is an exceedingly general method for generating an aromatic amine from an aryl halide or an aryl sulfonates. The key feature of this methodology is the use of catalytic palladium modulated by various electron- rich ligands. Strong bases, such as sodium tert-butoxide, are essential for catalyst turnover.

R2 X 2 R cat. LnPd(0) N R1 R3 + HN R1 R3 NaOt-Bu

X = I, Br, Cl, OSO2R

Mechanism:

Br N Pd(OAc)2, dppf N NaOt-Bu, Tol., Δ H

Br Pd(II) Br N Pd(0) H oxidative ligand addition exchange − HBr

Pd(II) N reductive N elimination − Pd(0)

The catalytic cycle is shown on the next page.

Example 13

0.5 mol% Pd2(dba)3 2 I 2 R R 2 mol% P(o-tol)3 R1 N + HN R3 R3 NaOt-Bu, dioxane R1 65–100 °C, 2–24 h 1 R = EWG or EDG 18–79% yield amine = 2° cyclic or acyclic 1 amine = 1° aliphatic: low yield, unless R ortho

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_40, © Springer-Verlag Berlin Heidelberg 2009 81

Catalytic cycle:

Ln+1Pd(0)

k-1 k1 2 R LnPd(0) Ar N ArX R3 Ar H

k4 k2 Ln-1Pd(0)

H NR2(R3) X LnPd LnPd LnPd Ar Ar Ar 2 NR k3

R3' H R2 NaX +HOt-Bu HN + NaOt-Bu 3 R

Pd(BINAP)2 catalyzed

–d[ArX] k1k2 = [ArX][Pd] dt k–1[L]

Example 24

R2 5 mol% (DPPF)PdCl2 X R2 15 mol% DPPF N 3 1 1 R R + HN R PPh2 R3 NaOt-Bu, THF Fe 100 °C (sealed), 3 h PPh2 X = Br or I 80–96% yield (11 examples) DPPF R1 = EWG or EDG amine = 2° acyclic (one example) amine = 1° aliphatic or aromatic

Example 3, Room temperature Buchwald–Hartwig amination9

R2 1–2 mol% Pd(dba)2 Br 2 0.8/1 N R (t-Bu)3P (P/Pd = ) 3 1 1 R R + HN R R3 NaOt-Bu, tol. 22 °C, 1–6 h 81–99% yield R1 = EDG or EWG amine = 2° cyclic or acyclic: aromatic, aliphatic, or azoles no aliphatic amine = 1° anilines:

Example 410

Me Me 0.25 mol% Pd2(dba)3 H Br 0.75 mol% rac-BINAP N n-Hex n-HexNH 2 NaOt-Bu (1.4 equiv) MeO tol., 80 °C, 18–23 h MeO 94%

Example 511

0.5 mol% Pd2(dba)2 1 mol% ligand O Cl HN O O N O 1.4 eq. NaOt-Bu, Tol. 100 oC, 24 h, 92%

i-Bu P N i-Bu i-Bu ligand = N N N

Example 612

NH2 MeO2C CO2Me Pd(OAc)2, Cs2CO3 H I N DPE-Phos, Tol., 95 oC 95% OCF3 OCF 3 PPh2 PPh2 O DPE-Phos =

Example 7, Amination of volatile amines14

5 equiv R1NHR2 O 5 mol% Pd(OAc)2 O O N 10 mol% dppp 2 equiv NaOt-Bu X N Br O N R1

o X N N 80 C, 14 h, sealed tube R2 X = N, CH2 55−98%

Example 815 O Ot-Bu O Ot-Bu 1 mol% Pd(OAc)2 2 mol% XPhos

1.4 equiv NaOt-Bu MeO NH2 Cl N Cl toluene, rt, 4 d, 67% MeO N N Cl H 83

XPhos = P

References

1. (a) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969−5970. John Hartwig earned his Ph.D. at the University of California-Berkeley in 1990 under the guidance of Robert Bergman and Richard Anderson. He moved from Yale University to the University of Illinois at Urbana-Champaign in 2006. Hartwig and Buchwald independently discovered this chemistry. (b) Mann, G.; Hartwig, J. F. J. Org. Chem. 1997, 62, 5413−5418. (c) Mann, G.; Hartwig, J. F. Tetrahedron Lett. 1997, 38, 8005−8008. 2. (a) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901−7902. Stephen Buchwald received his Ph.D. in 1982 under Jeremy Knowles at Harvard University. He is currently a professor at MIT. (b) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333−10334. 3. Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1996, 61, 1133−1135. 4. Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217−7218. 5. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805−818. (Review). 6. Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852−860. (Review). 7. Frost, C. G.; Mendonça, P. J. Chem. Soc., Perkin Trans. 1 1998, 2615−2624. (Re- view). 8. Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125−146. (Review). 9. Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575−5580. 10. Wolfe, J. P.; Buchwald, S. L. Org. Syn. 2002, 78, 23−30. 11. Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 9135−9142. 12. Csuk, R.; Barthel, A.; Raschke, C. Tetrahedron 2004, 60, 5737−5750. 13. Janey, J. M. Buchwald–Hartwig amination, In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2007; pp 564−609. (Review). 14. Li, J. J.; Wang, Z.; Mitchell, L. H. J. Org. Chem. 2007, 72, 3606−3607. 15. Lorimer, A. V.; O’Connor, P. D.; Brimble, M. A. Synthesis 2008, 2764−2770. 16. Nodwell, M.; Pereira, A.; Riffell, J. L.; Zimmerman, C.; Patrick, B. O.; Roberge, M.; Andersen, R. J. J. Org. Chem. 2009, 74, 995−1006.

Burgess reagent

CH3O2CNS NEt3 O

The Burgess reagent [(methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt], a neutral, white crystalline solid, is efficient at generating olefins from secondary and tertiary alcohols where the first-order thermolytic Ei (during the elimination takes place—the two groups leave at about the same time and bond to each other concurrently) mechanism prevails.

Preparation2

O O NEt , PhH O N S Cl MeOH, PhH CH3O2C 3 N S Cl O − rt, 88−92% H O rt, 84 86% H COH 3

CH3O2C O N S Cl O : NEt3 H O CH3O2CNS NEt3 O : NEt3

Mechanism5

O O CO Me MeO2CNS NEt3 O 2 O slow S N O D HNEt HO D 3 SN2 H Ph HPh Ph H Ph H

O CO Me O O 2 CO2Me S N fast H Ph O S N O D O D H Ph Ei Ph H HNEt Ph H HNEt3 3

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_41, © Springer-Verlag Berlin Heidelberg 2009 85

Example 1, On primary alcohols, the hydroxyl group does not eliminate but rather undergoes substitution3

OH OMe Burgess reagent O NH H THF, 21 oC, 9 h, 71% H

OMe O N H

Example 26

OH N 1.5 eq. Burgess, THF N Si Si O reflux, 1 h, 97% O

Example 37

NC NC H H O Burgess reagent O HO o OBn toluene, 50 C, 60% OBn

Example 48

OBn OBn CO2Me O O OH N O 2.5 equiv Burgess reagent S O BnO O BnO OH THF/CH2Cl2 (4:1) reflux, 6 h, 86% OBn OBn α/β = (8:1)

Example 510

O HN O NHBoc O S N 2.5 equiv Burgess reagent 2 THF, reflux, 30 min., 86% N NHBoc O

References

1 (a) Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744–4745. (b) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A., Jr. J. Am. Chem. Soc. 1970, 92, 5224–5226. (c) Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1972, 94, 6135– 6141. (d) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem. 1973, 38, 26– 31. 2 (a) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A.; Williams, W. M. Org. Synth. Coll. Edn. 1987, 6, 788–791. (b) Duncan, J. A.; Hendricks, R. T.; Kwong, K. S. J. Am. Chem. Soc. 1990, 112, 8433–8442. 3 Wipf, P.; Xu, W. J. Org. Chem. 1996, 61, 6556–6562. 4 Lamberth, C. J. Prakt. Chem. 2000, 342, 518–522. (Review). 5 Khapli, S.; Dey, S.; Mal, D. J. Indian Inst. Sci. 2001, 81, 461–476. (Review). 6 Miller, C. P.; Kaufman, D. H. Synlett 2000, 8, 1169–1171. 7 Keller, L.; Dumas, F.; D’Angelo, J. Eur. J. Org. Chem. 2003, 2488–2497. 8 Nicolaou, K. C.; Snyder, S. A.; Longbottom, D. A.; Nalbandian, A. Z.; Huang, X. Chem. Eur. J. 2004, 10, 5581–5606. 9 Holsworth, D. D. The Burgess Dehydrating Reagent. In Name Reactions for Func- tional Group Transformations; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2007; pp 189−206. (Review). 10 Li, J. J.; Li, J. J.; Li, J.; Trehan, A. K.; Wong, H. S.; Krishnananthan, S.; Kennedy, L. J.; Gao, Q.; Ng, A.; Robl, J. A.; Balasubramanian, B.; Chen, B.-C. Org. Lett. 2008, 10, 2897−2900.

Burke boronates

MeN MeN MeN MeN B O O Br S B O O B O O O O B O O O O O O Br O O HO

B-protected haloboronic acids Stable boronic acid surrogates

Burke boronates can serve as B-protected haloboronic acids for a wide variety of applications in iterative cross-coupling.1–6 The corresponding boronic acids can be 1–4 liberated using mild aqueous bases such as NaOH or NaHCO3. Burke boronates are also compatible with many synthetic reagents, enabling the synthesis of complex boronic acids from simple B-containing starting materials.3,6 They can also serve as stable building blocks for cross-coupling, i.e., under aqueous basic conditions, the corresponding boronic acid is released and coupled in situ.2,3,7 Moreover, Burke boronates are highly crystalline, monomeric, free-flowing solids that are indefinitely stable to benchtop storage under air and compatible with silica gel chromatography.1–3,6

Preparation:1,2,4,6

Me N MeN

HO2CCO2H Br S B O O Br S B(OH)2 O O PhH:DMSO 10:1 Dean-Stark Burke boronate 99%

Me N MeN NaO2CCO2Na BBr3 TMS BBr2 CH CN B O O CH2Cl2 3 O O 86% Burke boronate 30 mmol scale

Burke boronates can be conveniently prepared from the corresponding boronic acids via complexation with N-methyliminodiacetic acid (MIDA)1,4 or from 2− + 2,6 dibromoboranes via complexation with MIDA Na 2 Alternatively, many of these building blocks are now commercially available.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_42, © Springer-Verlag Berlin Heidelberg 2009 88

Example 12 A wide range of selective couplings can be performed at the halide terminus of a B-protected haloboronic acid.

B(OH)2 TMS MeN Ph MeN Pd(OAc)2 Pd(PPh3)4, CuI B O O piperidine B O O Ph O O SPhos, KF O O PhMe, 23°C THF ° TMS Suzuki coupling 92 % 23 C, 73% Sonogashira coupling

MeN MeN MeN PdCl2(CH3CN)2 O B SnBu3 B SPhos, KOAc Me O O B O O O O B O O Br O O O O Me Me O Pd2dba3, Fur3P Me O Me DMF, 45 °C, 91% B Me Miyaura coupling Stille coupling Me O 2 Me PhMe 45 °C, 71%

MeO MeN MeN Bu3Sn O ZnCl MeO B O O B O O O O Bu3Sn O O O Pd(OAc)2, PPh3 Pd(OAc)2, SPhos Et N, DMF, 45 °C THF, 0 °C Heck reaction 3 Negishi coupling 90% 66%

Example 22 Small molecule natural products can be prepared via iterative cross-coupling with B-protected haloboronic acids.

MeN

B O O MeN Br O O Me Me Me Me Me Me B(OH)2 B O O O O Pd(OAc)2, SPhos Me K3PO4,Toluene Me 23 °C, 78%

1. aq. NaOH, THF, 23 °C 2. Me H Me Me Me Me H Pd(OAc)2 Br O SPhos O ° Me K3PO4, THF, 23 C all-trans-retinal 66% over two steps

Example 33 Burke boronates are stable to a wide range of synthetic reagents, including acids, non-aqueous bases, oxidants, reductants, electrophiles, and soft nucleophiles. This reagent compatibility enables multistep synthesis of complex boranes from simple boron-containing starting materials.

Swern and then Bn MeN MeN Me n-BuOTf N O Et N, DCM CrO3, H2SO4 3 Bn B O O B O O − → ° Acetone O O 78 0 C, 2 h; Me O O O O O N HO 23 °C, 30 min H2O2, MeOH 90% pH 6.0 buffer, 79% O OH O O

MeN MeN MeN O O B O O TBSCl, Imid, THF B O O (EtO) P O O O O 23 °C, 9 h, 98% B O O 2 OEt O O EtO • NaH, DMF HF Py, THF 23 °C, 30 min, 71% O TBSO 23 °C, 20 min 83% HO

PMBOC(NH)CCl MeN 3 TfOH, THF morpholine MeN 0→23 °C , 5 h, 64% B O O NaBH(OAc)3 B O O O O O DCE, 23 °C, 8 h, 76% O O DDQ, DCM N 23 °C, 1.5 h, 79% PMBO

Example 42 Burke boronates can be hydrolyzed in situ under aqueous basic coupling conditions, as evidenced by this synthesis of the complex polyene skeleton of amphotericin B.

Me OAc

TESO Me Me OAc NMe Me Me Cl TESO Me Me O O B O O Pd(OAc)2, XPhos Me 5 1 N aq. NaOH THF, 45 °C, 48%

References

1. Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716–6717. 2. Lee, S. J., Gray, K. C., Paek, J. S., Burke, M. D. J. Am. Chem. Soc. 2008, 130, 466– 468. 3. Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084–14085. 4. Ballmer, S. G.; Gillis, E. P.; Burke, M. D. Org. Synth. 2009, in press. 5. Gillis, E. P.; Burke, M. D. Aldrichimica Acta 2009, in press. 6. Uno, B. E.; Gillis, E. P.; Burke, M. D. Tetrahedron 2009, 65, 3130–3138. 7. Knapp, D. M.; Gillis, E. P., Burke, M. D. J. Am. Chem. Soc. 2009, 131, ASAP. 90

Cadiot–Chodkiewicz coupling Bis-acetylene synthesis from alkynyl halides and alkynyl copper reagents. Cf. Castro−Stephens reaction.

R1 X Cu R2 R1 R2

oxidative X 2 R1 X Cu R R1 Cu R2 addition Cu(III) intermediate

reductive CuX R1 R2 elimination

Example 13

cat. CuCl, NH2OH•HCl Br OH EtNH2, MeOH OH 30−40 oC, 70−80%

Example 27

cat. CuCl, NH2OH•HCl TBS Br OH TBS OH 30% n-BuNH , H O, 92% 2 2

Example 39

MeO OMe MeO OMe n = 1 to 7

n = 1, 8% H H CuBr, NH2OH•HCl n = 2, 11% n = 3, 32% Br Br piperidine, MeOH n = 4, 8% rt, 3.5 h, 80% n = 5, 13% n = 6, 3% MeO OMe n = 7, 8% n MeO OMe

Example 4, Cadiot–Chodkiewicz active template synthesis of rotaxanes and switchable molecular shuttles with weak intercomponent interactions10

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_43, © Springer-Verlag Berlin Heidelberg 2009 91

1. 1 equiv n-BuLi THF, −78 oC H O 2. 1 equiv CuI, 0 oC 3. 1 equiv 3 1 equiv 2 1

N N

O O

O O O

N N

O O O Br trapping molecule 3 =

O O 2

References 1. Chodkiewicz, W.; Cadiot, P. C. R. Hebd. Seances Acad. Sci. 1955, 241, 1055−1057. Both Paul Cadiot (1923−) and Wladyslav Chodkiewicz (1921−) are French chemists. 2. Cadiot, P.; Chodkiewicz, W. In Chemistry of Acetylenes; Viehe, H. G., ed.; Dekker: New York, 1969, 597−647. (Review). 3. Gotteland, J.-P.; Brunel, I.; Gendre, F.; Désiré, J.; Delhon, A.; Junquéro, A.; Oms, P.; Halazy, S. J. Med. Chem. 1995, 38, 3207−3216. 4. Bartik, B.; Dembinski, R.; Bartik, T.; Arif, A. M.; Gladysz, J. A. New J. Chem. 1997, 21, 739−750. 5. Montierth, J. M.; DeMario, D. R.; Kurth, M. J.; Schore, N. E. Tetrahedron 1998, 54, 11741−11748. 6. Negishi, E.-i.; Hata, M.; Xu, C. Org. Lett. 2000, 2, 3687−3689. 7. Marino, J. P.; Nguyen, H. N. J. Org. Chem. 2002, 67, 6841−6844. 8. Utesch, N. F.; Diederich, F.; Boudon, C.; Gisselbrecht, J.-P.; Gross, M. Helv. Chim. Acta 2004, 87, 698−718. 9. Bandyopadhyay, A.; Varghese, B.; Sankararaman, S. J. Org. Chem. 2006, 71, 4544– 4548−4548. 10. Berna, J.; Goldup, S. M.; Lee, A.-L.; Leigh, D. A.; Symes, M. D.; Teobaldi, G.; Zer- betto, F. Angew. Chem., Int. Ed. 2008, 47, 4392−4396. 92

Camps quinoline synthesis Base-catalyzed intramolecular condensation of a 2-acetamido acetophenone (1) to a 2-(and possibly 3)-substituted-quinolin-4-ol (2), a 4-(and possibly 3)-substituted- quinolin-2-ol (3), or a mixture.

O R1 OH R1 R1 2 NaOR R NH R2 ROH N N OH R2 O 1 2 3

Pathway A:

O O O 1 OR 1 R R 1 R H H R2 2 NH R2 H O N N 2 2 H R 1 O H OH O

Pathway B:

O 1 1 R1 R R O HO R2 2 H NH R 3 2 H O R N O 2 O N O H H H 1 OR

Example 11

O OH

NaOH, H2O

NH 104 °C N OH N O 20% 69%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_44, © Springer-Verlag Berlin Heidelberg 2009 93

Example 26

O OH N Me N NaOH Me HN H2O, 90% N O Me Me

References

1. (a) Camps, R. Chem. Ber. 1899, 32, 3228−3234. Rudolf Camps worked under Profes- sor Engler from 1899 to 1902 at the Technische Hochschule in Karlsruhe, Germany. (b) Camps, R. Arch. Pharm. 1899, 237, 659−691. 2. Elderfield, R. C.; Todd, W. H.; Gerber, S. Heterocyclic Compounds Vol. 6, Elderfield, R. C., ed.; Wiley and Sons, New York, 1957, 576. (Review). 3. Clemence, F.; LeMartret, O.; Collard, J. J. Heterocycl. Chem. 1984, 21, 1345−1353. 4. Hino, K.; Kawashima, K.; Oka, M.; Nagai, Y.; Uno, H.; Matsumoto, J. Chem. Pharm. Bull. 1989, 37, 110−115. 5. Witkop, B.; Patrick, J. B.; Rosenblum, M. J. Am. Chem. Soc. 1951, 73, 2641−2647. 6. Barret, R.; Ortillon, S.; Mulamba, M.; Laronze, J. Y.; Trentesaux, C.; Lévy, J. J. Hete- rocycl. Chem. 2000, 37, 241−244. 7. Pflum, D. A. Camps Quinolinol Synthesis. In Name Reactions in Heterocyclic Chemis- try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 386−389. (Re- view).

Cannizzaro reaction Redox reaction between aromatic aldehydes, formaldehyde or other aliphatic aldehydes without α-hydrogen. Base is used to afford the corresponding alcohols and carboxylic acids.

O OH O 2 R OH R H R OH

O HO O OH OO R H R H R H OH Pathway A:

O hydride O O R H R O H R OH OH transfer R O R O R OH Final deprotonation of the carboxylic acid drives the reaction forward.

Pathway B:

O O acidic O R H hydride R O R OH OH transfer R O workup R OH R O

Example 14

OH CHO CO H KOH powder 2

100 oC, 5 min solvent-free 38% 41%

Example 26 H OH H O N CHO N Na THF, 0 oC, 5 h, 76% 76% 81%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_45, © Springer-Verlag Berlin Heidelberg 2009 95

Example 38

O N CHO 1 equiv TMG O2N O2N CO2H 2 OH

H2O, rt, 10 h 43% 42% TMG = 1,1,3,3-tetramethylguanidine

Example 4, Desymmetrization by intramolecular Cannizzaro reaction9

CHO CH2OH

O O

1 M BaCl O 2 O

H2O, reflux 2 quant. 2 O O

CHO CO H 2

References

1. Cannizzaro, S. Ann. 1853, 88, 129−130. Stanislao Cannizzaro (1826−1910) was born in Palermo, Sicily, Italy. In 1847, he had to escape to Paris for participating in the Si- cilian Rebellion. Upon his return to Italy, he discovered benzyl alcohol synthesis by the action of potassium hydroxide on benzaldehyde. Political interests brought Can- nizzaro to the Italian Senate and he later became its vice president. 2. Geissman, T. A. Org. React. 1944, 1, 94−113. (Review). 3. Russell, A. E.; Miller, S. P.; Morken, J. P. J. Org. Chem. 2000, 65, 8381−8383. 4. Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983−7985. 5. Reddy, B. V. S.; Srinvas, R.; Yadav, J. S.; Ramalingam, T. Synth. Commun. 2002, 32, 219−223. 6. Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983−1986. 7. Curini, M.; Epifano, F.; Genovese, S.; Marcotullio, M. C.; Rosati, O. Org. Lett. 2005, 7, 1331−1333. 8. Basavaiah, D.; Sharada, D. S.; Veerendhar, A. Tetrahedron Lett. 2006, 47, 5771−5774. 9. Ruiz-Sanchez, A. J.; Vida, Y.; Suau, R.; Perez-Inestrosa, E. Tetrahedron 2008, 64, 11661−11665. 10. Yamabe, S.; Yamazaki, S. Org. Biomol. Chem. 2009, 7, 951−961. 96

Carroll rearrangement Thermal rearrangement of β-ketoesters followed by decarboxylation to yield γ- unsaturated ketones via anion-assisted Claisen rearrangement. It is a variant of the Claisen rearrangement (page 117).

O O O Δ O

H H O O O O O O Δ [3,3]-sigmatropic O O O rearrangement

H O O keto–enol – CO2 α δ tautomerization β γ

Example 1, Asymmetric Carroll rearrangement4,5

OMe OMe OMe Li Li N N 2.4 equiv LiTMP N O N N O toluene O O –100 °C to rt CO H de > 96% 2

Example 2, Hetero-Carroll rearrangement6

O O O O O O OH H3C N H3C N H3C NH O 110 °C CH3 O toluene CH3 82% O CH3 CH CH CH 3 3 3

Example 37

H C H C H 3 H NaH, xylenes, 140 °C, 82% 3 H3C O O H3C SO2Ph H3C Me H S TESO H O OPh SO2Ph H ONa H TESO H O TESO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_46, © Springer-Verlag Berlin Heidelberg 2009 97

Example 4, Similar to Example 37

O O 2 eq. NaH, xylene O O reflux, 96% O O H H TESO TESO

CO2H Carroll CO2 O rearrangement O H H TESO TESO

Example 58

O O HO2C Me Me CCl O LDA, THF O 4 O − o reflux, 86% MeO 78 C to rt OMe MeO OMe MeO OMe

References

1. (a) Carroll, M. F. J. Chem. Soc. 1940, 704−706. Michael F. Carroll worked at A. Boake, Roberts and Co. Ltd., in London, UK. (b) Carroll, M. F. J. Chem. Soc. 1941, 507−511. 2. Ziegler, F. E. Chem. Rev. 1988, 88, 1423−1452. (Review). 3. Echavarren, A. M.; Mendosa, J.; Prados, P.; Zapata, A. Tetrahedron Lett. 1991, 32, 6421–6424. 4. Enders, D.; Knopp, M.; Runsink, J.; Raabe, G. Angew. Chem., Int. Ed. 1995, 34, 2278−2280. 5. Enders, D.; Knopp, M. Tetrahedron 1996, 52, 5805–5818. 6. Coates, R. M.; Said, I. M. J. Am. Chem. Soc. 1977, 99, 2355−2357. 7. Hatcher, M. A.; Posner, G. H. Tetrahedron Lett. 2002, 43, 5009−5012. 8. Jung, M. E.; Duclos, B. A. Tetrahedron Lett. 2004, 45, 107−109. 9. Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy, J. J. Org. Chem. 2004, 69, 4626−4647. 10. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 33−87. (Review). 98

Castro–Stephens coupling Aryl–acetylene synthesis, Cf. Cadiot–Chodkiewicz coupling and Sonogashira coupling. The Castro–Stephens coupling uses stoichiometric copper, whereas the Sonogashira variant uses catalytic palladium and copper.

pyridine, Δ 2 1 2 R1 Cu + X R R R or: 1: copper acetylide 2: sp2 halide DMF, base, Δ 3: disubstituted alkyne 1 R = alkyl or aryl R2 = aryl, vinyl, X = I, Br

L + ligands R2 (solvent) Cu I R1 C C Cu L C L C Cu R1 R2 L C L C I R1

L 1 Cu C R CuII R1 C C L C R2 I R2

An alternative mechanism similar to that of the Cadiot–Chodkiewicz coupling:

oxidative X reductive Ar X Cu R Ar Cu R CuX Ar R addition elimination Cu(III) intermediate

Example 1, A variant, also known as the Rosenmund–von Braun synthesis of aryl nitriles2 Br CuCN NC O 1-methyl-2-pyrrolininone O

N 170 oC, 3 h, 55% N N N

Example 24

CuSO4, NH2OH•HCl aq. NH3, EtOH H Cu ca. 95%

OH O N I pyridine, Δ N 75%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_47, © Springer-Verlag Berlin Heidelberg 2009 99

Example 35

O OMe OMe O pyridine, Δ O I O N N Cu 87% MeO N MeO N

Example 48

O O cat. CuI, Ph P, K CO 3 2 3 O O DMF, 120 oC, 37% I

Example 5, In situ Castro–Stephens reaction10

MeO2C MeO2C I

O OH CO2Me MeO C Cu O, pyridine 2 2 O O 100 oC, 43%

References

1. (a) Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28, 2163. Castro and Stephens worked in the Department of Nematology and Chemistry at University of California, Riverside. (b) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313–3315. 2. Clark, R. L.; Pessolano, A. A.; Witzel, B.; Lanza, T.; Shen, T. Y.; Van Arman, C. G.; Risley, E. A. J. Med. Chem. 1978, 21, 1158–1162. 3. Staab, H. A.; Neunhoeffer, K. Synthesis 1974, 424. 4. Owsley, D.; Castro, C. Org. Synth. 1988, 52, 128–131. 5. Kundu, N. G.; Chaudhuri, L. N. J. Chem. Soc., Perkin Trans 1 1991, 1677–1682. 6. Kabbara, J.; Hoffmann, C.; Schinzer, D. Synthesis 1995, 299–302. 7. White, J. D.; Carter, R. G.; Sundermann, K. F.; Wartmann, M. J. Am. Chem. Soc. 2001, 123, 5407–5413. 8. Coleman, R. S.; Garg, R. Org. Lett. 2001, 3, 3487–3490. 9. Rawat, D. S.; Zaleski, J. M. Synth. Commun. 2002, 32, 1489–1494. 10. Bakunova, A.; Bakunov, S.; Wenzler, T.; Barszcz, T.; Werbovetz, K.; Brun, R.; Hall, J.; Tidwell, R. J. Med. Chem. 2007, 50, 5807–5823. 11. Gray, D. L. Castro–Stephens coupling. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 212−235. (Review). 100

Chan alkyne reduction Stereoselective reduction of acetylenic alcohols to E-allylic alcohols using sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH, also known as Red-Al) or Li- AlH4.

OH OH NaAlH2(OCH2CH2OCH3)2 in PhH R1 Et O, heat R R1 R 2

RR OH H Al RR OH O AlH2R2 Al workup R H ↑ H O 1 2 R R1 R R1 R R R1

Example 13 OH OH LiAlH4 77%

Example 24

OH − o 1.5 eq. Red-Al, 72 C, 25 min. OH I Ph o then 5 eq. I2, −72 to −10 C, THF, 2 h Ph CO2Me CO2Me 78%

Example 36

1. Red-Al, THF/PhMe −78 oC to rt, 4 h OTBDPS OTBDPS 2. NCS, −78 oC to rt OH Cl OH 65%

Example 47 OMe OMe MeO OMe MeO OMe

Red-Al, Et O O O 2 O O Me o Me OH 0 C, 80% OH BnO BnO O O Me Me

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_48, © Springer-Verlag Berlin Heidelberg 2009 101

References

1. Chan, K.-K.; Cohen, N.; De Noble, J. P.; Specian, A. C., Jr.; Saucy, G. J. Org. Chem. 1976, 41, 3497−3505. Ka-Kong Chan was a chemist at Hoffmann−La Roche, Inc. in Nutley, NJ, USA. 2. Blunt, J. W.; Hartshorn, M. P.; Munro, M. H. G.; Soong, L. T.; Thompson, R. S.; Vaughan, J. J. Chem. Soc., Chem. Commun. 1980, 820−821. 3. Midland, M. M.; Gabriel, J. J. Org. Chem. 1985, 50, 1143−1144. 4. Meta, C. T.; Koide, K. Org. Lett. 2004, 6, 1785−1787. 5. Yamazaki, T.; Ichige, T.; Kitazume, T. Org. Lett. 2004, 6, 4073−4076. 6. Xu, S.; Arimoto, H.; Uemura, D. Angew. Chem., Int. Ed. 2007, 46, 5746−5749. 7. Chakraborty, T. K.; Reddy, V. R.; Gajula, P. K. Tetrahedron 2008, 64, 5162−5167.

102

Chan–Lam C–X coupling reaction Arylation of a wide range of NH/OH/SH substrates by oxidative cross-coupling with boronic acids in the presence of catalytic cupric acetate and either triethylamine or pyridine at room temperature in air. The reaction works for amides, amines, anilines, azides, hydantoins, hydrazines, imides, imines, nitroso, pyrazi- nones, pyridones, purines, pyrimidines, sulfonamides, sulfinates, sulfoximines, ureas, alcohols, phenols, and thiols. It is also the mildest method for N/O- vinylation. The boronic acids can be replaced with siloxanes or stannanes. The mild condition of this reaction is an advantage over Buchwald–Hartwig’s Pd- catalyzed cross-coupling. The Chan–Lam C–X bond cross-coupling reaction is complementary to Suzuki–Miyaura’s C–C bond cross-coupling reaction.

cat. Cu(AcO)2 Ar M HXR Ar XR air − − M = B(OH)2, B(OR)2, B(OR)3 , BF3 , SnMe3, Si(OMe)3. X = N, O, S, Se, Te.

N N cat. Cu(AcO) B(OH) 2 N 2 HN R air, > 90% R

Example 11a,d

H3C B(OH)2

NH N CH3 Cu(OAc)2, pyridine rt, 48 h, air 74% Mechanism:1c,d,17

L II L Cu(OAc) , pyridine Cu 2 N OAc NH coordination and pyridinium acetate deprotonation Ph

L II L H C B(OH) Cu 3 2 N + [CuII] AcOB(OH)2 I CH – [Cu ] transmetallation 3 Ph

L L CuIII N reductive N CH3 elimination CH3 Ph

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_49, © Springer-Verlag Berlin Heidelberg 2009 103

Example 24

O OH B(OH)2

1.1 eq Cu(OAc)2, TEA rt, 24 h, air 52%

Example 35 OH O B(OH)2 OMe OMe

Cu(OAc)2 O TEA, air O t-BuO C N CO Me t-BuO2C N CO2Me 54% 2 2 H H

Example 413 BnO O O BnO O (HO)2B N N O O N NH Cu(OAc)2/Et3N/Py α O 1eq/3 eq/ 3 eq 93% ( -ester assistance, acetal lower yield, 4 Å MS, air e.g., dimethyl acetal, 23%) Example 514 CO Me CO2Me 2 B(OH)2

N NaHMDS, Cu(AcO)2 N H DMAP, air, 95 oC 93% Example 615

0.1 eq Cu2O NH2 B(OH)2 MeOH, air, rt NH4OH 92%

References

1. (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933–2936. (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Win- ters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941–2949. Dominic Chan is a chemist at DuPont Crop Protection, Wilmington, DE, USA. He did his PhD research with Prof. Barry Trost at the University of Wisconson, Madison. Pat- rick Lam is a research director at Bristol–Myers Squibb, Princeton, NJ, USA. He was formerly with DuPont Pharmaceuticals Company. He did his PhD research with Prof. Louis Friedrich at the Univeristy of Rochester and Postdoc research with Prof. Mi- 104

chael Jung and the late Prof. Donald Cram at UCLA. (c) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937–2940. Prof. Evans’ group found out about the discovery of this reaction on a National Organic Symposium poster and became interested in the O-arylation because of his long interest in vancomycin total synthesis. (d) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett 2000, 674–676. (e) Lam, P. Y. S.; Bonne, D.; Vin- cent, G.; Clark, C. G.; Combs, A. P. Tetrahedron Lett. 2003, 44, 1691–1694. 2. Reviews: (a) Chan, D. M. T.; Lam, P. Y. S., Book chapter in Boronic Acids Hall, ed. 2005, Wiley–VCH, 205–240. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449. 3. Catalytic copper: (a) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415–3418. (b) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077–2079. (c) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397– 4400. (d) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236. (e) Lan, J.-B.; Zhang, G.-L.; Yu, X.-Q.; You, J.-S.; Chen, L.; Yan, M.; Xie, R.-G. Synlett 2004, 1095–1097. 4. Vinyl boronic acids: Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron Lett. 2003, 44, 4927–4931. 5. Intramolecular: Decicco, C. P.; Song, Y.; Evans, D.A. Org. Lett. 2001, 3, 1029–1032. 6. Solid phase: (a) Combs, A. P.; Saubern, S.; Rafalski, M.; Lam, P. Y. S. Tetrahedron Lett. 1999, 40, 1623–1626. (b) Combs, A. P.; Tadesse, S.; Rafalski, M.; Haque, T. S.; Lam, P. Y. S. J. Comb. Chem. 2002, 4, 179–182. 7. Boronates/borates: (a) Chan, D. M. T.; Monaco, K. L.; Li, R.; Bonne, D.; Clark, C. G.; Lam, P. Y. S. Tetrahedron Lett. 2003, 44, 3863–3865. (b) Yu, X. Q.; Yamamoto, Y.; Miyuara, N. Chem. Asian J. 2008, 3, 1517–1522. 8. Siloxanes: (a) Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.; DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600–7601. (b) Lam, P. Y. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett. 2001, 42, 2427–2429. 9. Stannanes: Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron Lett. 2002, 43, 3091–3094. 10. Thiols: (a) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2, 2019–2022. (b) Savarin, C.; Srogl, J.; Liebeskind, L. S. . Org. Lett. 2002, 4, 4309–4312. 11. Sulfinates: (a) Beaulieu, C.; Guay. D.; Wang, C.; Evans, D. A. Tetrahedron Lett. 2004, 45, 3233–3236. (b) Huang, H.; Batey, R. A. Tetrahedron. 2007, 63, 7667–7672. (c) Kar, A.; Sayyed, L. A.; Lo, W. F.; Kaiser, H. M.; Beller, M.; Tse, M. K. Org. Lett. 2007, 9, 3405–3408. 12. Sulfoximines: Moessner, C.; Bolm, C. Org. Lett. 2005, 7, 2667–2669. 13. β-Lactam: Wang, W.; Devsathale, P.; et al. Bio. Med. Chem. Lett. 2008, 18, 1939– 1944. 14. Cyclopropyl boronic acid: Tsuritani, T.; Strotman, N. A.; Yamamoto, Y.; Kawasaki, M.; Yasuda, N.; Mase, T. Org. Lett. 2008, 10, 1653–1655. 15. Ammonia: Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Ang. Chem., Int. Ed. 2009, 48, 1114– 1116. 16. Alcohol: Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 1381–1384. 17. Mechanism: (a) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 9196– 9197. (b) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131, 5044– 5045 105

Chapman rearrangement Thermal aryl rearrangement of O-aryliminoethers to amides.

1 O Ar Δ N Ar1 Ar N Ar OPh Ph

O Ar1 Ar1 : S Ar 1 N N N Ar Ar N O Ar O Ph Ar oxazete intermediate

Example 12

Cl Cl MeO C MeO NaOEt, EtOH/Et2O 2 MeO2C Cl o MeO N Ph 0 C to rt, 48 h O NaO N Ph

Cl MeO2C Cl MeO HO2C 210−215 oC, 70 min MeO

N 28% for 2 steps N H O Ph

Example 24

Ph O Ph Ph 300 oC Ph O N Ph N 30 min., 87% Ph

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_50, © Springer-Verlag Berlin Heidelberg 2009 106

Example 3, Double Chapman rearrangement10

C H C H C12H25 C12H25 12 25 12 25

110−140 oC

N O O N Me2N N N NMe2 70−74% O O Me2N NMe2 MeO C CO Me MeO2C CO2Me 2 2

Example 4, Chapman-like thermal rearrangement11

OR O Δ N NR S S O O O O

References

1. Chapman, A. W. J. Chem. Soc. 1925, 127, 1992−1998. Arthur William Chapman was born in 1898 in London, England. He was a Lecturer in Organic Chemistry and later became Registrar of the University of Sheffield from 1944 to 1963. 2. Dauben, W. G.; Hodgson, R. L. J. Am. Chem. Soc. 1950, 72, 3479−3480. 3. Schulenberg, J. W.; Archer, S. Org. React. 1965, 14, 1−51. (Review). 4. Relles, H. M. J. Org. Chem. 1968, 33, 2245−2253. 5. Shawali, A. S.; Hassaneen, H. M. Tetrahedron 1972, 28, 5903−5909. 6. Kimura, M.; Okabayashi, I.; Isogai, K. J. Heterocycl. Chem. 1988, 25, 315−320. 7. Farouz, F.; Miller, M. J. Tetrahedron Lett. 1991, 32, 3305−3308. 8. Dessolin, M.; Eisenstein, O.; Golfier, M.; Prange, T.; Sautet, P. J. Chem. Soc., Chem. Commun. 1992, 132−134. 9. Shohda, K.-I.; Wada, T.; Sekine, M. Nucleosides Nucleotides 1998, 17, 2199−2210. 10. Marsh, A.; Nolen, E. G.; Gardinier, K. M.; Lehn, J. M. Tetrahedron Lett. 1994, 35, 397−400. 11. Almeida, R.; Gomez-Zavaglia, A.; Kaczor, A.; Cristiano, M. L. S.; Eusebio, M. E. S.; Maria, T. M. R.; Fausto, R. Tetrahedron 2008, 64, 3296−3305.

107

Chichibabin pyridine synthesis Condensation of aldehydes with ammonia to afford pyridines.

R R NH 3 R CHO 3 R N

: H3N O H R NH2 NH OH R R H R H3N: H H NH2 enamine imine

: H NH3 H H R H H Aldol R − R O H2O O R O R O H R condensation R OH R H : H HN O

H NH 3 H OH R O Michael O H R R R R addition R H N R R R : N N H H

H OH H R R R R autoxidation R R H R [O] R R N N N H

Example 14

O CHO NH4OAc, HOAc

reflux, 1 h, 68% N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_51, © Springer-Verlag Berlin Heidelberg 2009 108

Example 28

HO 1. AcOH, rt, 1 d, 49%

N o Me N CH2 CHO 2. Zn, HCl, MeOH, 65 C, 72% Troc

Me N CH2 Troc 10 HO

N Me N CH2 10 Cl Troc

Example 39

O CH3CO2NH4, MeOH O2N O OHC CF3 reflux, 4 h, 45%

N O2N O O NO2

CF 3

Example 4, An abnormal Chichibabin reaction10

Ar Ar Br 1 equiv BnNH3Cl O 0.5 equiv Yb(OTf)3 N H H2O/dioxane, rt, 65% Bn TfO

dehydration [O] benzaldehyde

Ar Ar Ar Ar 6π N N Bn Ar Bn Ar

References

1. Chichibabin, A. E. J. Russ. Phys. Chem. Soc. 1906, 37, 1229. Alexei E. Chichibabin (1871−1945) was born in Kuzemino, Russia. He was Markovnikov’s favorite student. Markovnikov’s successor, Zelinsky (of Hell–Volhard–Zelinsky reaction fame) did not 109

want to cooperate with the pupil and gave Chichibabin a negative judgment on his Ph.D. work, earning Chichibabin the nickname “the self-educated man.” 2. Sprung, M. M. Chem. Rev. 1940, 40, 297−338. (Review). 3. Frank, R. L.; Riener, E. F. J. Am. Chem. Soc. 1950, 72, 4182−4183. 4. Weiss, M. J. Am. Chem. Soc. 1952, 74, 200−202. 5. Kessar, S. V.; Nadir, U. K.; Singh, M. Indian J. Chem. 1973, 11, 825−826. 6. Shimizu, S.; Abe, N.; Iguchi, A.; Dohba, M.; Sato, H.; Hirose, K.-I. Microporous Mesoporous Materials 1998, 21, 447−451. 7. Galatasis, P. Chichibabin (Tschitschibabin) Pyridine Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 308−309. (Review). 8. Snider, B. B.; Neubert, B. J. Org. Lett. 2005, 7, 2715−2718. 9. Wang, X.-L.; Li, Y.-F.; Gong, C.-L.; Ma, T.; Yang, F.-C. J. Fluorine Chem. 2008, 129, 56−63. 10. Burns, N. Z.; Baran, P. S. Angew. Chem., Int. Ed. 2008, 47, 205−208. 11. Liaw, D.-J.; Wang, K.-L.; Kang, E.-T.; Pujari, S. Pu.; Chen, M.-H.; Huang, Y.-C.; Tao, B.-C.; Lee, K.-R.; Lai, J.-Y. J. Polymer Sci., A: Polymer Chem. 2009, 47, 991−1002.

110

Chugaev elimination Thermal elimination of xanthates to olefins.

Δ 1. CS2, NaOH OS OH R OCS CH SH R R 3 2. CH3I S

xanthate R O S Δ R H O S S S O S ↑ ↑ R O CS CH3SH H S

Example 14

1. NaH, CS2; MeI, 90%

o OH OH 2. HMPA, 230 C, 90%

Example 25

O O O H H H H H H O O O dodecane CS2, MeI, NaH H H H THF, rt, 2 h, 51% reflux (216 oC) S 48 h, 74% O O O HO O S O O O

Example 3, Chugaev syn-elimination is followed by an intramolecular ene reac- tion6 S OH O S O CS2, MeI, NaH O O N THF, 92% O Cbz N Cbz

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_52, © Springer-Verlag Berlin Heidelberg 2009 111

NCbz

NaHCO3, Ph2O 72% O

280 oC, 25 min H O Alder ene N O Cbz Chugaev O

References

1. Chugaev, L. Ber. 1899, 32, 3332. Lev A. Chugaev (1873−1922) was born in Moscow, Russia. He was a Professor of Chemistry at Petrograd, a position once held by Dimitri Mendeleyev and Paul Walden. In addition to terpenoids, Chugaev also investigated nickel and platinum chemistry. He completely devoted his life to science. The light in Chugaev’s study would invariably burn until 4 or 5 a.m. 2. Harano, K.; Taguchi, T. Chem. Pharm. Bull. 1975, 23, 467−472. 3. Ho, T.-L.; Liu, S.-H. J. Chem. Soc., Perkin Trans. 1 1984, 615−617. 4. Fu, X.; Cook, J. M. Tetrahedron Lett. 1990, 31, 3409−3412. 5. Meulemans, T. M.; Stork, G. A.; Macaev, F. Z.; Jansen, B. J. M.; de Groot, A. J. Org. Chem. 1999, 64, 9178−9188. 6. Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 2, 3181−3183. 7. Nakagawa, H.; Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 2001, 42, 4523−4526. 8. Fuchter, M. J. Chugaev elimination. In Name Reactions for Functional Group Trans- formations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 334−342. (Review). 9. Ahmed, S.; Baker, L. A.; Grainger, R. S.; Innocenti, P.; Quevedo, C. E. J. Org. Chem. 2008, 73, 8116−8119.

112

Ciamician–Dennsted rearrangement

Cyclopropanation of a pyrrole with dichlorocarbene generated from CHCl3 and NaOH. Subsequent rearrangement takes place to give 3-chloropyridine.

Cl CHCl3

N NaOH H N

CCl − Cl Cl3CH 2 : H2O CCl2 OH Cl

carbene

Cl Cl CCl Cl 2 N N H H N HO Example 14

2 eq. PhHgCCl3 Cl PhH, Δ, 54% N N H Example 25 Cla Clb

b a Cl N Cl N H NaO2CCl3 N N NH HN 26% H Cla N Clb N

b a Cl Cl References

1. Ciamician, G. L.; Dennsted, M. Ber. 1881, 14, 1153. Giacomo Luigi Ciamician (1857−1922) was born in Trieste, Italy. Ciamician is considered the father of modern organic photochemistry. 2. Wynberg, H. Chem. Rev. 1960, 60, 169−184. (Review). 3. Wynberg, H. and Meijer, E. W. Org. React. 1982, 28, 1−36. (Review). 4. Parham, W. E.; Davenport, R. W.; Biasotti, J. B. J. Org. Chem. 1970, 35, 3775−3779. 5. Král, V.; Gale, P. A.; Anzenbacher, P. Jr.; K. Jursíková; Lynch, V.; Sessler, J. L. J. Chem. Soc., Chem. Comm. 1998, 9−10. 6. Pflum, D. A. Ciamician–Dennsted Rearrangement. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 350−354. (Review).

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_53, © Springer-Verlag Berlin Heidelberg 2009 113

Claisen condensation Base-catalyzed condensation of esters to afford β-keto esters.

O O O O R2 OR3 R 1 R2 OR1 OR base R

O O

R 1 deprotonation R OR OR1 condensation H R2 OR3

B: O

2 OR O O O R3O OR1 R2 OR1 R R

Example 14

O t-BuOK, solvent-free O O Ph Ph O Ph O Ph 90 oC, 20 min., 84% Ph

Example 26

3.5 eq. LDA, THF O O H o O −45 to −50 C H N CO2Me N t-Bu Cbz t-Bu Cbz O O then H+, 97% Ph Ph

Example 3, Retro-Claisen condensation9

5 equiv H O O O 2 5 mol% In(OTf)3 O O OH neat, 80 oC, 24 h 85%

In O O In H HO H2O: O O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_54, © Springer-Verlag Berlin Heidelberg 2009 114

Example 4, Solvent-free Claisen condensation10

O KOt-Bu, 100 oC, 30 min. O O = 13C OBn OBn solvent-free, 51%

References

1 Claisen, R. L.; Lowman, O. Ber. 1887, 20, 651. Rainer Ludwig Claisen (1851−1930), born in Cologne, Germany, probably had the best pedigree in the history of organic chemistry. He apprenticed under Kekulé, Wöhler, von Baeyer, and Fischer before embarking on his own independent research. 2 Hauser, C. R.; Hudson, B. E. Org. React. 1942, 1, 266−302. (Review). 3 Schäfer, J. P.; Bloomfield, J. J. Org. React. 1967, 15, 1−203. (Review). 4 Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983−7985. 5 Heath, R. J.; Rock, C. O. Nat. Prod. Rep. 2002, 19, 581−596. (Review). 6 Honda, Y.; Katayama, S.; Kojima, M.; Suzuki, T.; Izawa, K. Org. Lett. 2002, 4, 447−449. 7 Mogilaiah, K.; Reddy, N. V. Synth. Commun. 2003, 33, 73−78. 8 Linderberg, M. T.; Moge, M.; Sivadasan, S. Org. Pro. Res. Dev. 2004, 8, 838−845. 9 Kawata, A.; Takata, K.; Kuninobu, Y.; Takai, K. Angew. Chem., Int. Ed. 2007, 46, 7793−7795. 10 Iida, K.; Ohtaka, K.; Komatsu, T.; Makino, T.; Kajiwara, M. J. Labelled Compd. Ra- diopharm. 2008, 51, 167−169.

115

Claisen isoxazole synthesis Cyclization of β-keto esters with hydroxylamine to provide 3-hydroxy-isoxazoles (3-isoxazolols).

OO R2 NH2OH OH R R1 O − H O 2 R N R2 1 O

OO O O OR OO R OH OH R O R1 N 1 H R1 N R2 H R2 R2 :NH OH 2

R2 R O − 2 O R2 H2O OH R1 NH R NH N O 1 O R1 HO O 3-isoxazolol

A side reaction:

OO H : R HONOH O NH OH − H2O R1 O 2 R R O R2 1 R :NH OH 2 2

H O: N O NO ON O H R R R1 O R O 1 OR 1 R R R2 2 2 5-isoxazolone

Example 1, A thio-analog6

OO SH O

1. aqueous NH3, 67% OEt NH2 MeO N MeO N 2. H2S, HCl, EtOH, 53% O O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_55, © Springer-Verlag Berlin Heidelberg 2009 116

R OH

I , K CO , 59% N 2 2 3 S MeO N O

Example 27 O O OBoc O HN o HO O O R Cl, pyr., 0 C Boc − O 74 100% R O 53−91% O For R = Ph: O (PhCO) O, DMF 2 Meldrum’s acid

OO OH OBoc HCl R = Me, Et, i-Pr, cyclopropyl, R N N cyclohexyl, Ph, Bn, neopentyl 76−99% R O Boc

Example 38 OO

OMe NH2OH•HCl, NaOH OH MeOH, −50 oC, 2 h then 85 oC, 1 h, 65% N O

References

1. (a) Claisen, L; Lowman, O. E. Ber. 1888, 21, 784. (b) Claisen, L.; Zedel, W. Ber. 1891, 24, 140. (c) Hantzsch, A. Ber. 1891, 24, 495−506. 2. Barnes, R. A. In Heterocyclic Compounds; Elderfield, R. C., Ed.; Wiley: New York, 1957; Vol. 5, p 474ff. (Review). 3. Loudon, J. D. In Chemistry of Carbon Compounds; Rodd, E. H., Ed.; Elsevier: Am- sterdam, 1957; Vol. 4a, p. 345ff. (Review). 4. McNab, H. Chem. Soc. Rev. 1978, 7, 345−358. (Review). 5. Chen, B.-C. Heterocycles 1991, 32, 529−597. (Review). 6. Frølund, B.; Kristiansen, U.; Brehm, L.; Hansen, A. B.; Krogsgaard-Larsen, K.; Falch, E. J. Med. Chem. 1995, 38, 3287−3296. 7. Sorensen, U. S.; Falch, E.; Krogsgaard-Larsen, K. J. Org. Chem. 2000, 65, 1003−1007. 8. Madsen, U.; Bräuner-Osborne, H.; Frydenvang, K.; Hvene, L.; Johansen, T.N.; Niel- sen, B.; Sánchez, C.; Stensbøl, T.B.; Bischoff, F.; Krogsgaard-Larsen, K. J. Med. Chem. 2001, 44, 1051−1059. 9. Brooks, D. A. Claisen Isoxazole Synthesis. In Name Reactions in Heterocyclic Chem- istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 220−224. (Review). 117

Claisen rearrangements The Claisen, para-Claisen rearrangements, Belluš–Claisen rearrangement; Corey– Claisen, Eschenmoser–Claisen rearrangement, Ireland–Claisen, Kazmaier– Claisen, Saucy–Claisen; orthoester Johnson–Claisen, along with the Carroll rearrangement, belong to the category of [3,3]-sigmatropic rearrangements. The Claisen rearrangement is a concerted process and the arrow pushing here is merely illustrative.

2 1 2 R 3 Δ, [3,3]-sigmatropic R 1 3 R

O rearrangement O O 3 3 1 1 2 2

4 2 π2S 4 2 2 π2S σ2 1 1 1 S σ2S O O O 3 6 3 6 6 π2S 4 4 4 π2S 5 5 5 chair-like boat-like

Example 17

BnO OBn OBn BnO BnO O BnO O BnO O O n-decane/toluene 5:1 O BnO O 180 oC, 70% O O O O

Example 28

Et AlCl, hexanes O O 2

−78 oC, 81% OH O

Example 39

+ 1 mol% Ir(PCy3)3 OHC O SiMe3 SiMe3 Δ Et Ph PPh3, , 50% yield Et Ph syn:anti 95:85, 91% ee

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_56, © Springer-Verlag Berlin Heidelberg 2009 118

Example 4, Asymmetric Claisen rearrangement10

O CH O cat, 7.5 mol% 3 2+ O O MeO CH CF3CH2OH 3 OMe − O CH Cl , rt, 12 h NN 2 SbF6 2 2 O Cu BnO cat. t-Bu t-Bu = H2O OH2 OBn 98%, > 90% de, 99% ee

Example 5, Asymmetric Claisen rearrangement11

O 20 mol%, hexane, 8 days, 35 °C O CH3 CH3 MeO CH3 – MeO O NH2 CF3 O N N H H B N N H3C Ph Ph 4 73%, 96% ee CF 3

References

1. Claisen, L. Ber. 1912, 45, 3157−3166. 2. Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1−252. (Review). 3. Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Perga- mon, 1991, Vol. 5, 827−873. (Review). 4. Ganem, B. Angew. Chem., Int. Ed. 1996, 35, 937−945. (Review). 5. Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 43−50. (Review). 6. Castro, A. M. M. Chem. Rev. 2004, 104, 2939−3002. (Review). 7. Jürs, S.; Thiem, J. Tetrahedron: Asymmetry 2005, 16, 1631−1638. 8. Vyvyan, J. R.; Oaksmith, J. M.; Parks, B. W.; Peterson, E. M. Tetrahedron Lett. 2005, 46, 2457−2460. 9. Nelson, S. G.; Wang, K. J. Am. Chem. Soc. 2006, 128, 4232–4233. 10. Körner, M.; Hiersemann, M. Org. Lett. 2007, 9, 4979–4982. 11. Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 9228–9229. 12. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 33−43. (Review).

119

para-Claisen rearrangement Further rearrangement of the normal ortho-Claisen rearrangement product gives the para-Claisen rearrangement product.

OH O R R Δ R R

Mechanism 1:

OH O R R R O R Cope ortho- R R Claisen rearrangement dienone

Mechanism 2:

O OH O R R R R R R H2C CH2 Dewar intermediate

Mechanism 3:

O OH O O R R [3,3]-sigmatropic R R R R R R rearrangement H

120

Example 16 OH OH HO CHO OH HO CHO 160−170 oC HO O HO CHO CHO 4.6% 58% 25.5%

Example 27

CO2Me Me Me HO O PhNEt2 Me Me

reflux HO O O HO O O 12% Me Me 80%

Example 38

TBSO O TBSO 220 oC O O xylene, 70% O O OH Example 410

MOMO OMOM

PhNMe2, reflux MOMO OMOM o O O 200 C, 64%

OH O

References

1. Alexander, E. R.; Kluiber, R. W. J. Am. Chem. Soc. 1951, 73, 4304–4306. 2. Rhoads, S. J.; Raulins, R.; Reynolds, R. D. J. Am. Chem. Soc. 1953, 75, 2531–2532. 3. Dyer, A.; Jefferson, A.; Scheinmann, F. J. Org. Chem. 1968, 33, 1259–1261. 4. Murray, R. D. H.; Lawrie, K. W. M. Tetrahedron 1979, 35, 697–699. 5. Cairns, N.; Harwood, L. M.; Astles, D. P. J. Chem. Soc., Chem. Commun. 1986, 1264– 1266. 6. Kilényi, S. N.; Mahaux, J.-M.; van Durme, E. J. Org. Chem. 1991, 56, 2591–2594. 7. Cairns, N.; Harwood, L. M.; Astles, D. P. J. Chem. Soc., Perkin Trans. 1 1994, 3101– 3107. 8. Pettus, T. R. R.; Inoue, M.; Chen, X.-T.; Danishefsky, S. J. J. Am. Chem. Soc. 2000, 122, 6160–6168. 9. Al-Maharik, N.; Botting, N. P. Tetrahedron 2003, 59, 4177–4181. 10. Khupse, R. S.; Erhardt, P. W. J. Nat. Prod. 2007, 70, 1507–1509. 121

Abnormal Claisen rearrangement Further rearrangement of the normal Claisen rearrangement product with the β-carbon becoming attached to the ring.

α α β OH O Δ β δ δ

α α β β O [3,3]-sigmatropic O rearrangement δ tautomerization δ "normal Claisen" H

H α H α β β OH O ene O [1,5]-H-atom β δ reaction δ α shift δ

Example 13

O OH OH o PhNEt2, 230 C

5.5 h, 63% Me Me Me normal, 58% abnormal, 42%

O OH OH 10 equiv HSi(NMe2)2 o PhNEt2, 230 C

8.0 h, 70% Me Me Me normal, > 99% abnormal, < 1%

Example 2, Enantioselective aromatic Claisen rearrangement4

Ph Ph

S N N S O B O OH O 2 2 Br OH OH o Et3N, −23 C, 2 d 92%, 95% ee

122

Example 35 CHO MeO CHO PhNEt2 MeO O O 180 oC OMe MeO 40% MeO OMe kodsurenin M

Example 46

O O Tol., 180 oC O O 13 O O = C 24 h, 65%

Example 57

O AlM3, CH2Cl2

50% 50% OH

References

1. Hansen, H.-J. In Mechanisms of Molecular Migrations; vol. 3, Thyagarajan, B. S., ed.; Wiley-Interscience: New York, 1971, pp 177−236. (Review). 2. Kilényi, S. N.; Mahaux, J.-M.; van Durme, E. J. Org. Chem. 1991, 56, 2591−2594. 3. Fukuyama, T.; Li, T.; Peng, G. Tetrahedron Lett. 1994, 35, 2145−2148. 4. Ito, H.; Sato, A.; Taguchi, T. Tetrahedron Lett. 1997, 38, 4815−4818. 5. Yi, W. M.; Xin, W. A.; Fu, P. X. J. Chem. Soc., (S), 1998, 168. 6. Schobert, R.; Siegfried, S.; Gordon, G.; Mulholland, D.; Nieuwenhuyzen, M. Tet- rahedron Lett. 2001, 42, 4561−4564. 7. Wipf, P.; Rodriguez, S. Ad. Synth. Catal. 2002, 344, 434−440. 8. Puranik, R.; Rao, Y. J.; Krupadanam, G. L. D. Indian J. Chem., Sect. B 2002, 41B, 868−870. 9. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reac- tions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Ho- boken, NJ, 2009, pp 33−87. (Review). 123

Eschenmoser–Claisen amide acetal rearrangement [3,3]-Sigmatropic rearrangement of N,O-ketene acetals to yield γ,δ-unsaturated amides. Since Eschenmoser was inspired by Meerwein’s observations on the interchange of amide, the Eschenmoser–Claisen rearrangement is sometimes known as the Meerwein–Eschenmoser–Claisen rearrangement.

CONMe OH MeO OMe Δ 2

1 1 RR NMe2 R R

MeO OMe OMe OMe

NMe: 2 NMe2

OMe H : NMe2 OMe NMe Me2N OMe 2 H H : H O O O 1 RR1 1 RR RR

NMe2 [3,3]-sigmatropic CONMe2 O rearrangement 1 1 R R R R

Example 14

CH3C(OMe)2NMe2 CF3 O F3C O Ph Ph O NMe OH PhH, 100 oC, 2 h, 75% 2

Example 25

OMe CH CH3 3 O *ArHN LiNEt2, THF Li N O CH N –78 °C to rt 3 5 h, 78 % H O CH O 3 H (dr 97:3) CH3 H3C CH 3

124

Example 36

H OTBS H OTBS OTBS OTBS HO MeO OMe NMe2 TBS TBS H xylene, 150 °C O H O O 18 h, 91% NMe OPMB 2 OPMB

Example 48

NMe2 5 eq. CH3C(OMe)2NMe2 xylene, reflux, 48 h, 50% HO CO Me 2 CO Me 2

References

1. Meerwein, H.; Florian, W.; Schön, N.; Stopp, G. Ann. 1961, 641, 1−39. 2. Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. Helv. Chim. Acta 1964, 47, 2425−2429. Albert Eschenmoser (Switzerland, 1925−) is known for his work on, among many others, the monumental total synthesis of Vitamin B12 with R. B. Wood- ward in 1973. He now holds dual appointments at both ETH Zürich and the Scripps Research Institute in La Jolla, CA. 3. Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Perga- mon, 1991, Vol. 5, 827−873. (Review). 4. Konno, T.; Nakano, H.; Kitazume, T. J. Fluorine Chem. 1997, 86, 81−87. 5. Metz, P.; Hungerhoff, B. J. Org. Chem.1997, 62, 4442–4448. 6. Kwon, O. Y.; Su, D. S.; Meng, D. F.; Deng, W.; D’Amico, D. C.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37, 1877–1880. 7. Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 43−50. (Review). 8. Loh, T.-P.; Hu, Q.-Y. Org. Lett. 2001, 3, 279−281. 9. Castro, A. M. M. Chem. Rev. 2004, 104, 2939−3002. (Review). 10. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 60−68. (Review).

125

Ireland–Claisen (silyl ketene acetal) rearrangement Rearrangement of allyl trimethylsilyl ketene acetal, prepared by reaction of allylic ester enolates with trimethylsilyl chloride, to yield γ,δ-unsaturated carboxylic acids. The Ireland–Claisen rearrangement seems to be advantageous to the other variants of the Claisen rearrangement in terms of E/Z geometry control and mild conditions.

O LDA, then CO2H O Me3SiCl

O OSiMe OSiMe 3 3 CO H LDA, then Δ, [3,3]-sigmatropic H 2 O O O Me3SiCl rearrangement

Example 12

S O S SS H S LDA, TBSCl O S OTBS THF, reflux O H O O O H O O 77% O CO2TBS

Example 23

O O TIPSOTf, Et3N N CO2TIPS N PhH, rt, 62% Bn Bn

Example 3, Enantioselective ester enolate-Claisen Rearrangement6

F C CF 3 Ph Ph 3

CH 110 mol% H3C 3 N N H3C S B S O F C O2 O2 CF 3 Br 3 CO2H pentaisopropylguanidine, –94 to 4 °C O 86%, dr > 98:2, > 98% ee

126

Example 4, A modified Ireland–Claisen rearrangement8

F O BBr , Et N, PhMe F O 3 3 HO F chiral ligand O − F F 78 to rt, 63%, > 99% ee

F Example 59

OPMP PMPO KHMDS, TMSCl, THF CO2H O O o −78 to 25 C, 1 h, 81% O O

References

1. Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897−5898. Also J. Am. Chem. Soc. 1976, 98, 2868−2877. Robert E. Ireland obtained his Ph.D. from William S. Johnson before becoming a professor at the University of Virginia and later at the California Institute of Technology. He is now retired. 2. Begley, M. J.; Cameron, A. G.; Knight, D. W. J. Chem. Soc., Perkin Trans. 1 1986, 1933–1938. 3. Angle, S. R.; Breitenbucher, J. G. Tetrahedron Lett. 1993, 34, 3985−3988. 4. Pereira, S.; Srebnik, M. Aldrichimica Acta 1993, 26, 17−29. (Review). 5. Ganem, B. Angew. Chem., Int. Ed. 1996, 35, 936−945. (Review). 6. Corey, E.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 1229−1230. 7. Chai, Y.; Hong, S.-p.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron 2002, 58, 2905−2928. (Review). 8. Churcher, I.; Williams, S.; Kerrad, S.; Harrison, T.; Castro, J. L.; Shearman, M. S.; Lewis, H. D.; Clarke, E. E.; Wrigley, J. D. J.; Beher, D.; Tang, Y. S.; Liu, W. J. Med. Chem. 2003, 46, 2275−2278. 9. Fujiwara, K.; Goto, A.; Sato, D.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2005, 46, 3465−3468. 10. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 45−51. (Review).

127

Johnson–Claisen orthoester rearrangement Heating of an allylic alcohol with an excess of trialkyl orthoacetate in the presence of trace amounts of a weak acid gives a mixed orthoester. Mechanistically, the orthoester loses alcohol to generate the ketene acetal, which undergoes [3,3]- sigmatropic rearrangement to give a γ,δ-unsaturated ester.

2 2 CO2R OH CH(OR )3

1 1 R R H+ RR

H 2 2 2 : 2 OR :B OH CH(OR ) R O OR 3 H H O 1 O R R H+ 1 RR1 RR 2 OR 2 [3,3]-sigmatropic CO2R O rearrangement 1 1 RR R R

Example 12

CO Et OH 2 OEt CH3C(OEt)3 CH3 O EtCO2H (cat.) H xylene, Δ, 3 h 72% H3C

Example 23

TBSO TBSO H CH3C(OEt)3 CO Et MeCO2H (cat.) • 2 HO H THPO 170 °C, 30 min THPO 77% OPh OPh THPO THPO Example 34

OH Cl Cl O CH3C(OCH3)3, TsOH Cl OMe Cl 170 oC, 55% OTBS OTBS

128

Example 49

OMe OMe N CH C(OCH ) 3 3 3 N cat. CH3CH2CO2H

reflux, 77% O OMe OH

Example 510

TBS OTBS EtO2C OTBS OH O TBSO E (EtO)3CCH3 O O O H H O pivalic acid O H H O O O xylene, 140 °C O O 54%, E:Z > 95:5

References

1. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.-t.; Faulkner, D. J.; Peterson, M. R. J. Am. Chem. Soc. 1970, 92, 741–743. William S. Johnson (1913−1995) was born in New Rochelle, New York. He earned his Ph.D. in only two years at Harvard under Louis Fieser. He was a professor at the University of Wiscon- sin for 20 years before moving to Stanford University, where he was credited with building the modern-day Stanford Chemistry Department. 2. Paquette, L.; Ham, W. H. J. Am. Chem. Soc. 1987, 109, 3025–3036. 3. Cooper, G. F.; Wren, D. L.; Jackson, D. Y.; Beard, C. C.; Galeazzi, E.; Van Horn, A. R.; Li, T. T. J. Org. Chem. 1993, 58, 4280–4286. 4. Schlama, T.; Baati, R.; Gouverneur, V.; Valleix, A.; Falck, J. R.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2085–2087. 5. Giardiná, A.; Marcantoni, E.; Mecozzi, T.; Petrini, M. Eur. J. Org. Chem. 2001, 713– 718. 6. Funabiki, K.; Hara, N.; Nagamori, M.; Shibata, K.; Matsui, M. J. Fluorine Chem. 2003, 122, 237–242. 7. Montero, A.; Mann, E.; Herradón, B. Eur. J. Org. Chem. 2004, 3063–3073. 8. Scaglione, J. B.; Rath, N. P.; Covey, D. F. J. Org. Chem. 2005, 70, 1089–1092. 9. Zartman, A. E.; Duong, L. T.; Fernandez-Metzler, C.; Hartman, G. D.; Leu, C.-T.; Prueksaritanont, T.; Rodan, G. A.; Rodan, S. B.; Duggan, M. E.; Meissner, R. S. Bio- org. Med. Chem. Lett. 2005, 15, 1647–1650. 10. Hicks, J. D.; Roush, W. R. Org. Lett. 2008, 10, 681–684. 11. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 68−72. (Review).

129

Clemmensen reduction Reduction of aldehydes and ketones to the corresponding methylene compounds using amalgamated zinc in hydrochloric acid.

O Zn(Hg) HH

RR1 HCl RR1

The zinc-carbenoid mechanism:3

O Zn(Hg), HCl O ZnCl Ph CH SET 3 Ph CH 3 radical anion

OZnCl Zn H H Ph CH Ph CH3 Ph CH3 3 Zn H zinc-carbenoid

The radical anion mechanism:

H OZnCl O OZnCl Zn(Hg), HCl O ZnCl e ; H H Ph CH H 3 Ph CH SET Ph CH3 3 Ph CH3 H Cl radical anion

H H e ; H HH SN2 e Ph CH3 Ph CH3 Ph CH Cl 3

Example 15

Zn(Hg), HCl O OH O MeOH, reflux, 1 h OH OH OH 18% 67%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_57, © Springer-Verlag Berlin Heidelberg 2009 130

Example 26

H O H Zn(Hg), HCl

N − o N H Et2O, 5 C, 57% H O Ph O Ph

Example 38

H3C O H3C H C CH 3 Zn dust H 3 37% HCl, EtOH H3C H OH H C H O 3 OH reflux, 15 min. H H H H 50% diosgenin HO HO

References

1. Clemmensen, E. Ber. 1913, 46, 1837−1843. Erik C. Clemmensen (1876−1941) was born in Odense, Denmark. He received the M.S. degree from the Royal Polytechnic Institute in Copenhagen. In 1900, Clemmensen immigrated to the United States, and worked at Parke, Davis and Company in Detroit as a research chemist for 14 years, where he discovered the reduction of carbonyl compounds with amalgamated zinc. Clemmensen later founded a few chemical companies and was the president of one of them, the Clemmensen Chemical Corporation in Newark, New Jersey. 2. Martin, E. L. Org. React. 1942, 1, 155−209. (Review). 3. Vedejs, E. Org. React. 1975, 22, 401−422. (Review). 4. Talpatra, S. K.; Chakrabarti, S.; Mallik, A. K.; Talapatra, B. Tetrahedron 1990, 46, 6047−6052. 5. Martins, F. J. C.; Viljoen, A. M.; Coetzee, M.; Fourie, L.; Wessels, P. L. Tetrahedron 1991, 47, 9215−9224. 6. Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Chem. Soc., Perkin Trans. 1 1996, 1113−1124. 7. Kappe, T.; Aigner, R.; Roschger, P.; Schnell, B.; Stadlbauer, W. Tetrahedron 1995, 51, 12923−12928. 8. Alessandrini, L.; Ciuffreda, P.; Santaniello, E.; Terraneo, G. Steroids 2004, 69, 789−794. 9. Dey, S. P.; Dey, D. K.; Dhara, M. G.; Mallik, A. K. J. Indian Chem. Soc. 2008, 85, 717−720.

131

Combes quinoline synthesis Acid-catalyzed condensation of anilines and β-diketones to assemble quinolines. Cf. Conrad–Limpach reaction.

R2 OO H

NH R1 R2 Δ 2 NR1

O O NH : 2 2 R2 proton R

O R1 : transfer N OH N 1 OH2 2 1 R R O H2R H H

R2 O O O 2 H R H R2 1 N R1 1 N R N R H H imine enamine

H H 2 H R O 2 O 2 R O H R H H

: 1 N R1 N R1 N R H H H

H H R2 R2 O 2 R H

: 1 1 N R1 N R N R H H

An electrocyclization mechanism is also possible:

H R2 H R2 O O 6π-electrocyclization : N R1 N R1 H H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_58, © Springer-Verlag Berlin Heidelberg 2009 132

HO R2 2 OH R proton H 2 R2 H2O

1 transfer N R 1 N R1 N R H

Example 16

NH2 N PPA, 110 °C MeO MeO O O N N H H 35%

Example 27

O O CO2Et CO Et Ph 2 Ph N N H H cat. p-TsOH, 220 °C N NH 2 neat, 38%

References

1. Combes, A. Bull. Soc. Chim. Fr. 1888, 49, 89. Alphonse-Edmond Combes (1858−1896) was born in St. Hippolyte-du-Fort, France. He apprenticed with Wurtz at Paris. He also collaborated with Charles Friedel of the Friedel−Crafts reaction fame. He became the president of the French Chemical Society in 1893 at the age of 35. His sudden death shortly after his 38th birthday was a great loss to organic chemistry. 2. Roberts, E. and Turner, E. J. Chem Soc. 1927, 1832−1857. (Review). 3. Elderfield, R. C. In Heterocyclic Compounds, Elderfield, R. C., ed.; Wiley & Sons: New York, 1952, vol. 4, 36–38. (Review). 4. Popp, F. D. and McEwen, W. E. Chem. Rev. 1958, 58, 321–401. (Review). 5. Jones, G. In Chemistry of Heterocyclic Compounds, Jones, G., ed.; Wiley & Sons, New York, 1977, Quinolines Vol. 32, pp 119–125. (Review). 6. Alunni-Bistocchi, G.; Orvietani, P., Bittoun, P., Ricci, A.; Lescot, E. Pharmazie 1993, 48, 817−820. 7. El Ouar, M.; Knouzi, N.; Hamelin, J. J. Chem. Res. (S) 1998, 92−93. 8. Curran, T. T. Combes Quinoline Synthesis. In Name Reactions in Heterocyclic Chem- istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 390−397. (Review).

133

Conrad–Limpach reaction Thermal or acid-catalyzed condensation of anilines with β-ketoesters leads to quinolin-4-ones. Cf. Combes quinoline synthesis.

O Ph O O O 2 260 oC NH2 OEt N H

O proton CO2Et H2O

NH : : 2 transfer N OH EtO C H 2

H O OEt H OEt HO π CO2Et 6 electron tautomerize electrocyclization N N N Schiff base

O H O OH − HOEt proton transfer N N N HOEt H

Example 13

NH2 O O CHCl3, HCl (cat.) 60% N OEt

N HN Ph2O, reflux CO2Et 60% OH N N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_59, © Springer-Verlag Berlin Heidelberg 2009 134

Example 27

O PPA, + EtO C CO Et 2 2 N N 3 120 °C N NH2 25% CO2Et O 3 O paraffin,

280 °C CO2Et 75% N N H 3

Example 38

NH2 MeO C NHPhNO O N 2 2 HO CO2Me 2 2 HCl, MeOH

MeO C O 64% N CO2Me 2 H NO 2

O H Dowtherm A O2N N NO2

250 °C, 55% N CO2Me H

References

1. Conrad, M.; Limpach, L. Ber. 1887, 20, 944. Max Conrad (1848−1920), born in Mu- nich, Germany, was a professor of the University of Würzburg, where he collaborated with Leonhard Limpach (1852−1933) on the synthesis of quinoline derivatives. 2. Manske, R. F. Chem Rev. 1942, 30, 113–114. (Review). 3. Misani, F.; Bogert, M. T. J. Org. Chem. 1945, 10, 347–365 4. Reitsema, R. H. Chem. Rev. 1948, 43, 43–68. (Review). 5. Elderfield, R. C. In Chemistry of Heterocyclic Compounds, Elderfield, R. C., Wiley & Sons, New York, 1952, vol. 4, 31–36. (Review). 6. Jones, G. In Heterocyclic Compounds, Jones, G., ed.; John Wiley & Sons, New York, 1977, Quinolines, Vol 32, 137–151. (Review). 7. Deady, L. W.; Werden, D. M. Synth. Commun. 1987, 17, 319−328. 8. Kemp, D. S.; Bowen, B. R. Tetrahedron Lett. 1988, 29, 5077−5080. 9. Curran, T. T. Conrad–Limpach Reaction. In Name Reactions in Heterocyclic Chemis- try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 398−406. (Re- view). 10. Chan, B. K.; Ciufolini, M. A. J. Org. Chem. 2008, 72, 8489−8495. 135

Cope elimination reaction Thermal elimination of N-oxides to olefins and N-hydroxyl amines.

O Δ R R3 H N OH 1 2 N R R Ei R R R1 R2 3

Example 1, Solid-phase Cope elimination5

O O m-CPBA, CHCl N 3 rt, 67%

O O HO H O N O N O

OH OH

Example 26

OBn OBn OBn BnO m-CPBA BnO 145 oC BnO OTBDPS OTBDPS OTBDPS o CH2Cl2, 0 C BnO N(CH ) 63% BnO BnO N(CH3)2 3 2 83% O

Example 38

N N m-CPBA, CH Cl N O 2 2 O O OH O rt, 100% CN NC H CN

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_60, © Springer-Verlag Berlin Heidelberg 2009 136

Example 4, Retro-Cope elimination9

O O Me OTBDPS Me OTBDPS Ph m-CPBA, K2CO3 Ph Cope N N Me − o Me elimination 78 C, 3 h, then rt O NC H NC H

Δ, Ph O Ph O O MeOH, 5 d 67%, 2 steps Me OTBDPS 5 : 2 Ph N N retro-Cope Me Me N Me O Me O elimination OTBDPS HO Me OTBDPS

References

1. Cope, A. C.; Foster, T. T.; Towle, P. H. J. Am. Chem. Soc. 1949, 71, 3929−3934. Ar- thur Clay Cope (1909−1966) was born in Dunreith, Indiana. He was a professor at MIT when he discovered the Cope elimination reaction and the Cope rearrangement. The Arthur Cope Award is a prestigious award in organic chemistry from the Ameri- can Chemical Society. 2. Cope, A. C.; Trumbull, E. R. Org. React. 1960, 11, 317−493. (Review). 3. DePuy, C. H.; King, R. W. Chem. Rev. 1960, 60, 431−457. (Review). 4. Gallagher, B. M.; Pearson, W. H. Chemtracts: Org. Chem. 1996, 9, 126−130. (Re- view). 5. Sammelson, R. E.; Kurth, M. J. Tetrahedron Lett. 2001, 42, 3419−3422. 6. Vasella, A.; Remen, L. Helv. Chim. Acta. 2002, 85, 1118−1127. 7. Garcia Martinez, A.; Teso Vilar, E.; Garcia Fraile, A.; de la Moya Cerero, S.; Lora Maroto, B. Tetrahedron: Asymmetry 2002, 13, 17−19. 8. O’Neil, I. A.; Ramos, V. E.; Ellis, G. L.; Cleator, E.; Chorlton, A. P.; Tapolczay, D. J.; Kalindjian, S. B. Tetrahedron Lett. 2004, 45, 3659−3661. 9. Henry, N.; O’Meil, I. A. Tetrahedron Lett. 2007, 48, 1691−1694. 10. Fuchter, M. J. Cope elimination reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 342−353. (Review). 11. Bourgeois, J.; Dion, I.; Cebrowski, P. H.; Loiseau, F.; Bedard, A.-C.; Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131, 874−875.

137

Cope rearrangement The Cope, oxy-Cope, and anionic oxy-Cope rearrangements belong to the category of [3,3]-sigmatropic rearrangements. Since it is a concerted process, the arrow pushing here is only illustrative. This reaction is an equilibrium process. Cf. Claisen rearrangement.

R Δ, [3,3]-sigmatropic R R

rearrangement

Example 14 H H CO CH CO2CH3 2 3 NaCl Br 160 °C wet DMSO O toluene OTMS reflux Br OTMS Cope Br Krapcho 71%

Example 26 o CO2Me 100 C, 12 h CO2Me O O 84% TMS TMS

Example 39

o CO Me CO2Me dioxane, Et3N, 60 C 2 O O 22 h, 1 bar, 92% CO2Me CO2Me

Example 410

OH H H OH H H CO H3CO 140 °C 3 H benzene H OH 94% OH OH OH

Example 511

OMOM OTBDPS O OMOM MOMO 1,2-dichlorobenzene O TBDPSO O OMOM reflux, 95% O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_61, © Springer-Verlag Berlin Heidelberg 2009 138

Example 612

OCH 3 OCH3 H3CO H3CO 1. HCl, MeOH H CO H3CO O 3 O 2. 1,2-dichloro- N benzene N reflux, 80% OCH 3 O

References

1. Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441−444. 2. Frey, H. M.; Walsh, R. Chem. Rev. 1969, 69, 103−124. (Review). 3. Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1−252. (Review). 4. Wender, P. A.; Schaus, J. M. White, A. W. J. Am. Chem. Soc. 1980, 102, 6159–6161. 5. Hill, R. K. In Comprehensive Organic Synthesis Trost, B. M.; Fleming, I., Eds.; Per- gamon, 1991, Vol. 5, 785−826. (Review). 6. Chou, W.-N.; White, J. B.; Smith, W. B. J. Am. Chem. Soc. 1992, 114, 4658−4667. 7. Davies, H. M. L. Tetrahedron 1993, 49, 5203−5223. (Review). 8. Miyashi, T.; Ikeda, H.; Takahashi, Y. Acc. Chem. Res. 1999, 32, 815−824. (Review). 9. Von Zezschwitz, P.; Voigt, K.; Lansky, A.; Noltemeyer, M.; De Meijere, A. J. Org. Chem. 1999, 64, 3806–3812. 10. Lo, P. C.-K.; Snapper, M. L. Org. Lett. 2001, 3, 2819–2821. 11. Clive, D. L. J.; Ou, L. Tetrahedron Lett. 2002, 43, 4559–4563. 12. Malachowski, W. P.; Paul, T.; Phounsavath, S. J. Org. Chem. 2007, 72, 6792–6796. 13. Mullins, R. J.; McCracken, K. W. Cope and Related Rearrangements. In Name Reac- tions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 88−135. (Review).

Anionic oxy-Cope rearrangement

O OH KH R R THF

OK OH KH Δ, [3,3]-sigmatropic OK R R R THF rearrangement

O OK H2O OH tautomerize R R R

Example 11 OH O KH, THF, rt

then H2O, 88%

139

Example 24

OHC H C OH 3 H3C KH, THF OH CH O 3 70% H H

Example 35

CH CH H C 3 3 3 KHMDS H3C OMOM OTBS OMOM 18-crown-6, THF OH OPMB temperature; H BnO O OTBS then NH Cl, H O 4 2 H OPMB X BnO X OPMB OPMB

X = OCH2CH2TMS 0 °C; 71% X = SPh − 78 °C; 85%

Example 48

O NaH, THF, reflux OH 22 h, 88%

Example 59

MeO MeO

MeO KOt-Bu MeO 18-crown-6

THF, −10°C HO OMe 74% O OMe MeO OMe MeO OMe

References

1. Wender, P. A.; Sieburth, S. M.; Petraitis, J. J.; Singh, S. K. Tetrahedron 1981, 37, 3967–3975. 2. Wender, P. A.; Ternansky, R. J.; Sieburth, S. M. Tetrahedron Lett. 1985, 26, 4319– 4322. 3. Paquette, L. A. Tetrahedron 1997, 53, 13971−14020. (Review). 4. Corey, E. J.; Kania, R. S. Tetrahedron Lett. 1998, 39, 741–744. 5. Paquette, L. A.; Reddy, Y. R.; Haeffner, F.; Houk, K. N. J. Am. Chem. Soc. 2000, 122, 740–741. 6. Voigt, B.; Wartchow, R.; Butenschon, H. Eur. J. Org. Chem. 2001, 2519–2527. 140

7. Hashimoto, H.; Jin, T.; Karikomi, M.; Seki, K.; Haga, K.; Uyehara, T. Tetrahedron Lett. 2002, 43, 3633–3636. 8. Gentric, L.; Hanna, I.; Huboux, A.; Zaghdoudi, R. Org. Lett. 2003, 5, 3631–3634. 9. Jones, S. B.; He, L.; Castle, S. L. Org. Lett. 2006, 8, 3757–3760. 10. Mullins, R. J.; McCracken, K. W. Cope and Related Rearrangements. In Name Reac- tions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 88−135. (Review).

Oxy-Cope rearrangement While the anionic oxy-Cope rearrangements work at low temperature, the oxy- Cope rearrangements require high temperature but provide a thermodynamic sink.

OH Δ OH O , [3,3]-sigmatropic OH tautomerize R R R rearrangement R

Example 12

OPMB H TMS OPMB H H 1. 230−240 °C H O HO Me H O DMF, 19 h Me Me H Me O 2. CsF, DMF Me OMe 210 °C, 65% Me Me

Example 23

EtO2C EtO2C H CO2Et reflux ene o-dichlorobenzene OH OH H 90% O

Example 34 PhMe SiO O PhMe SiO O 2 t-Bu 1. 170 oC 2 t-Bu OHC PhMe2Si 2. p-TsOH•H O O 2 O − O O 65 75%

Example 46

OH xylene, Ace® tube O

225 oC, 24 h, 49%

141

References

1. Paquette, L. A. Angew. Chem., Int. Ed. 1990, 29, 609−626. (Review). 2. Paquette, L. A.; Backhaus, D.; Braun, R. J. Am. Chem. Soc. 1996, 118, 11990–11991. 3. Srinivasan, R.; Rajagopalan, K. Tetrahedron Lett. 1998, 39, 4133–4136. 4. Schneider, C.; Rehfeuter, M. Chem. Eur. J. 1999, 5, 2850−2858. 5. Schneider, C. Synlett 2001, 1079−1091. (Review on siloxy-Cope rearrangement). 6. DiMartino, G.; Hursthouse, M. B.; Light, M. E.; Percy, J. M.; Spencer, N. S.; Tolley, M. Org. Biomol. Chem. 2003, 1, 4423−4434. 7. Mullins, R. J.; McCracken, K. W. Cope and Related Rearrangements. In Name Reac- tions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 88−135. (Review).

Siloxy-Cope rearrangement

OSiR3 Δ, [3,3]-sigmatropic OSiR3 R' rearrangement R'

Example 11

CH3 OTMS sealed tube H H high vacuum OTBS H 310 °C, 1 h OTMS H3C OTBS > 79% OTMS OTMS

Example 22

TDSO O Bn TDSO O Bn 180 °C N N toluene, 3 h O 63% O O O > 97:3 dr TDS = thexyldimethylsilyl

Example 33

AOM O OTBDPS chlorobenzene OSiEt3 Et3SiO reflux, 3 h, 99% TBDPSO O O OAOM O AOM = p-Anisyloxymethyl = p-MeOC6H4OCH2-

142

Example 44

TBDPSO OTBDPS TESO TESO H3C H3C 4 4 115 °C O O O O toluene, reflux O O 95%

H3C OH H3C OH

References

1. Askin, D.; Angst, C.; Danishefsky, D. J. J. Org. Chem. 1987, 52, 622–635. 2. Schneider, C. Eur. J. Org. Chem. 1998, 1661–1663. 3. Clive, D. L. J.; Sun, S.; Gagliardini, V.; Sano, M. K. Tetrahedron Lett. 2000, 41, 6259–6263. 4. Bio, M. M.; Leighton, J. L. J. Org. Chem. 2003, 68, 1693–1700. 5. Mullins, R. J.; McCracken, K. W. Cope and Related Rearrangements. In Name Reac- tions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 88−135. (Review).

143

Corey–Bakshi–Shibata (CBS) reagent

Ph H Ph O N B Me

The CBS (Corey–Bakshi–Shibata) reagent is a chiral catalyst derived from proline. Also known as Corey’s oxazaborolidine, it is used in enantioselective borane reduction of ketones, asymmetric Diels–Alder reactions and [3 + 2] cycloadditions.

Preparation1,3 O O H H 1. PhMgCl MeOH 2. BH3•THF OH O NH NH 50% 3 steps H3O O O Ph Ph H H Ph Ph MeB(OH)2, toluene O OH N NH reflux, 3 h, 86% B Me The mechanism and catalytic cycle:1,3

Ph H Ph

O cat. O OH N B Me BH3, THF, rt, 97% ee

Ph Ph H Ph H Ph BH3•THF O O N B N B H3B R R H2BO H

CH3 : : Ph O H Ph O CH3 N B R H2B CH HCl, MeOH O 3 H B H Ph BH3 H H Ph HO H Ph R R CH O CH O 3 N B 3 B CH3 Ph O N B Ph H B O H H Ph 2 H 2 Ph

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_62, © Springer-Verlag Berlin Heidelberg 2009 144

Example 16

O 0.1 eq. (S)-CBS OH 1.0 eq. i-Pr(Et)NPh•BH3 SO C H CH -p SO2C6H4CH3-p 2 6 4 3 THF, rt, syringe pump O O 1.5 h, 98%, 97% ee

Ph H Ph (S)-Me-CBS = O N B CH3

Example 29

O BH •SMe O O 3 2 HO O cat. (R)-Me-CBS O

o O CH2Cl2, 30 C O 84%, > 99% ee

Example 311

H Ph Ph O N O Tf N O H B 2 N H Ac o-Tol OCH2CF3 H PO CO2CH2CF3 2 4 H3N CO2Et 10 mol%, neat > 97% ee 23 oC, 30 h, 97% ® oseltamivir (Tamiflu )

Example 4, Asymmetric [3 + 2]-cycloaddition10

H Ph OH Ph MeO N O Tf N O B 2 H H MeO o-Tol O H O O CH3CN−CH2Cl2 92% ee 65% 99% ee recryst. O

References

1. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551–5553. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925–7926. (c) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861–2863. 2. Reviews: (a) Corey, E. J. Pure Appl. Chem. 1990, 62, 1209–1216. (b) Wallbaum, S.; Martens, J. Tetrahedron: Asymm. 1992, 3, 1475–1504. (c) Singh, V. K. Synthesis 145

1992, 605–617. (d) Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763–784. (e) Taraba, M.; Palecek, J. Chem. Listy 1997, 91, 9–22. (f) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986–2012. g) Corey, E. J. Angew. Chem. Int. Ed. 2002, 41, 1650–1667. (h) Itsuno, S. Org. React. 1998, 52, 395–576. (i) Cho, B. T. Aldrichimica Acta 2002, 35, 3–16. (j) Glushkov, V. A.; Tolstikov, A. G. Russ. Chem. Rev. 2004, 73, 581–608. (k) Cho, B .T. Tetrahedron 2006, 62, 7621–7643. 3. (a) Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.; Carroll, J. D.; Corley, E. G.; Grabowski, E. J. J. J. Org. Chem. 1993, 58, 2880–2888. (b) Xavier, L. C.; Mohan, J. J.; Mathre, D. J.; Thompson, A. S.; Carroll, J. D.; Corley, E. G.; Des- mond, R. Org. Synth. 1997, 74, 50–71. 4. Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837–4840. 5. Clark, W. M.; Tickner-Eldridge, A. M.; Huang, G. K.; Pridgen, L. N.; Olsen, M. A.; Mills, R. J.; Lantos, I.; Baine, N. H. J. Am. Chem. Soc. 1998, 120, 4550–4551. 6. Cho, B. T.; Kim, D. J. Tetrahedron: Asymmetry 2001, 12, 2043–2047. 7. Price, M. D.; Sui, J. K.; Kurth, M. J.; Schore, N. E. J. Org. Chem. 2002, 67, 8086– 8089. 8. Degni, S.; Wilen, C.-E.; Rosling, A. Tetrahedron: Asymmetry 2004, 15, 1495–1499. 9. Watanabe, H.; Iwamoto, M.; Nakada, M. J. Org. Chem. 2005, 70, 4652–4658. 10. Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 11958–11959. 11. Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310–6311. 12. Patti, A.; Pedotti, S. Tetrahedron: Asymmetry 2008, 19, 1891–1897.

146

Corey−Chaykovsky reaction The Corey−Chaykovsky reaction entails the reaction of a sulfur ylide, either dimethylsulfoxonium methylide 1 (Corey’s ylide) or dimethylsulfonium methylide 2, with electrophile 3 such as carbonyl, olefin, imine, or thiocarbonyl, to offer 4 as the corresponding epoxide, cyclopropane, aziridine, or thiirane.

CH X 2 CH X 2 1 or 2 S O 1 H3C S R R1 R R CH3 H3C CH3 4 1 2 3

2 3 X = O, CH2, NR , S, CHCOR , CHCO R3, CHCONR , CHCN 2 2 Preparation1 O CH NaH 2 S I S H C CH H C O 3 CH 3 DMSO 3 CH 3 3 Mechanism1

O O R 1 R O O R R S R1 H C S 3 O O 1 H C CH S H C R 3 3 H3C CH2 3 CH3

Example 111 O O

+ − N Me3S(O) I N NaH, DMSO O O 60 oC, 3.5 h F F 79% Cl Cl

Example 29 OAc OAc Me SCOEt 2 2 O O PhH, rt, 8 h, 62% OEt OEt CO2Et Example 310

O O Me3SCl 50% aq. NaOH N N Bu4NHSO4 H H CH2Cl2, 84% O O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_63, © Springer-Verlag Berlin Heidelberg 2009 147

Example 414

H 2.5 equiv t-Bu3Ga O

Me2S CHO PhCl, rt, 3 h, 66% SiEt3 Z:E = 94:6 SiEt Br 3

Example 515

Ph O 4 equiv O Ph Ph (CH3)3SOI S Ph O O O OH n-BuLi, THF OH O 50% 20% 60 oC, 4 h

References

1 (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867−868. (b) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 3782. (c) Corey, E. J.; Chaykovsky, M. Tetrahedron Lett. 1963, 169−171. (d) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1964, 86, 1639−1640. (e) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353−1364. 2 Okazaki, R.; Tokitoh, N. In Encyclopedia of Reagents in Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995, pp 2139−2141. (Review). 3 Ng, J. S.; Liu, C. In Encyclopedia of Reagents in Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995, pp 2159−2165. (Review). 4 Trost, B. M.; Melvin, L. S., Jr. Sulfur Ylides; Academic Press: New York, 1975. (Re- view). 5 Block, E. Reactions of Organosulfur Compounds Academic Press: New York, 1978. (Review). 6 Gololobov, Y. G.; Nesmeyanov, A. N. Tetrahedron 1987, 43, 2609−2651. (Review). 7 Aubé, J. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Ed.; Perga- mon: Oxford, 1991, Vol. 1, pp 820−825. (Review). 8 Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341−2372. (Review). 9 Rosenberger, M.; Jackson, W.; Saucy, G. Helv. Chim. Acta 1980, 63, 1665−1674. 10 Tewari, R. S.; Awatsthi, A. K.; Awasthi, A. Synthesis 1983, 330−331. 11 Vacher, B.; Bonnaud, B. Funes, P.; Jubault, N.; Koek, W.; Assie, M.-B.; Cosi, C.; Kleven, M. J. Med. Chem. 1999, 42, 1648−1660. 12 Chandrasekhar, S.; Narasihmulu, Ch.; Jagadeshwar, V.; Reddy, K. V. Tetrahedron Lett. 2003, 44, 3629−3630. 13 Li, J. J. Corey−Chaykovsky Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 1−14. (Review). 14 Nishimura, Y.; Shiraishi, T.; Yamaguchi, M. Tetrahedron Lett. 2008, 49, 3492−3495. 15 Chittimalla, S. K.; Chang, T.-C.; Liu, T.-C.; Hsieh, H.-P.; Liao, C.-C. Tetrahedron 2008, 64, 2586−2595. 148

Corey−Fuchs reaction One-carbon homologation of an aldehyde to dibromoolefin, which is then treated with n-BuLi to produce a terminal alkyne.

R Br CBr4, PPh3 n-BuLi RCHO R H Zn H Br

SN2 Br CBr :PPh CBr 3 3 3 Br PPh3

Br Br SN2 Br PPh3 SN2 Br PPh3 CBr 3 Br

Br R H R Br Br2 PPh3 O PPh3 Br H Br Wittig reaction (see page 578 for the mechanism)

Br2 Zn ZnBr2

R Br R Br acidic H Br R R H Bu workup Bu

Example 13

OMe O Br OMe O O CBr4, Ph3P, CH2Cl2 O OHC Br rt, 35 min., 90% OTBS OTBS

OMe O 3.0 eq. n-BuLi/hexanes, THF O

−78 oC, 1 h; rt, 1 h, 99% OTBS OH

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_64, © Springer-Verlag Berlin Heidelberg 2009 149

Example 27

Br O Br n-BuLi H H CBr4, Zn Fe H Fe Fe 75% PPh3, quant.

Example 38

1. CBr4, Ph3P, Zn, CH2Cl2 CHO OTBS 2. n-BuLi, then NH Cl, 90% OTBS 4

Example 410

4 equiv CBr4 Br Br 8 equiv PPh H CHO 3 8 equiv Zn n-BuLi, n-hexane H CHO o H − o CH2Cl2, 0 C to rt 78 C to rt, 1 h, 96% 3 h, 94% H Br Br

References

1 Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769−3772. Phil Fuchs is a professor at Purdue University. 2 For the synthesis of 1-bromalkynes see Grandjean, D.; Pale, P.; Chuche, J. Tetrahe- dron Lett. 1994, 35, 3529−3530. 3 Gilbert, A. M.; Miller, R.; Wulff, W. D. Tetrahedron 1999, 55, 1607−1630. 4 Muller, T. J. J. Tetrahedron Lett. 1999, 40, 6563−6566. 5 Serrat, X.; Cabarrocas, G.; Rafel, S.; Ventura, M.; Linden, A.; Villalgordo, J. M. Tetrahedron: Asymmetry 1999, 10, 3417−3430. 6 Okamura, W. H.; Zhu, G.-D.; Hill, D. K.; Thomas, R. J.; Ringe, K.; Borchardt, D. B.; Norman, A. W.; Mueller, L. J. J. Org. Chem. 2002, 67, 1637−1650. 7 Tsuboya, N.; Hamasaki, R.; Ito, M.; Mitsuishi, M.; Miyashita, T. Yamamoto, Y. J. Mater. Chem. 2003, 13, 511–513 8 Zeng, X.; Zeng, F.; Negishi, E.-i. Org. Lett. 2004, 6, 3245−3248. 9 Quéron, E.; Lett, R. Tetrahedron Lett. 2004, 45, 4527−4531. 10 Sahu, B.; Muruganantham, R.; Namboothiri, I. N. N. Eur. J. Org. Chem. 2007, 2477– 2489. 11 Han, X. Corey−Fuchs reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 393−403. (Review). 150

Corey–Kim oxidation Oxidation of alcohol to the corresponding aldehyde or ketone using NCS/DMS, followed by treatment with a base. Cf. Swern oxidation.

OH NCS, DMS O

1 2 1 2 R R then NEt3 R R

NCS = N-Chlorosuccinimide; DMS = Dimethylsulfide.

O O O Cl O NH N Cl S Cl N S H :S N :O O O O R1 R2 O

Cl H S S :NEt Et N·HCl O O 3 3 O ↑ H (CH3)2S 1 2 1 2 1 R R R R R 2 H R

Example 1, Fluorous Corey−Kim reaction5

NO2 S NO2 C6F13 CHO OH NCS, toluene, −25 oC, 2 h then Et3N, 86%

Example 2, Odorless Corey−Kim reaction7

S N O OH − o 0.5 eq. NCS, CH2Cl2, 40 C, 2 h D − o then Et3N, 40 C to rt, 8 h

S D N O 86% O 45%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_65, © Springer-Verlag Berlin Heidelberg 2009 151

Example 39

OH CHO H H H H NCS, Me2S

N Et3N, CH2Cl2 N H H −78 oC to rt, 90% H H H H

Example 410

N N

O O H H N NCS, DMS O N O O N O N Et N, CH Cl O BzO 3 2 2 O O > 300 Kg scale BzO O O O O O

O OH O O

References

1 Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586−7587. Choung U. Kim now works at Gilead Sciences Inc., a company specialized in antiviral drugs in Foster City, California, where he co-discovered oseltamivir (Tamiflu). 2 Katayama, S.; Fukuda, K.; Watanabe, T.; Yamauchi, M. Synthesis 1988, 178−183. 3 Shapiro, G.; Lavi, Y. Heterocycles 1990, 31, 2099−2102. 4 Pulkkinen, J. T.; Vepsäläinen, J. J. J. Org. Chem. 1996, 61, 8604−8609. 5 Crich, D.; Neelamkavil, S. Tetrahedron 2002, 58, 3865−3870. 6 Ohsugi, S.-I.; Nishide, K.; Oono, K.; Okuyama, K.; Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron 2003, 59, 8393−8398. 7 Nishide, K.; Patra, P. K.; Matoba, M.; Shanmugasundaram, K.; Node, M. Green Chem. 2004, 6, 142−146. 8 Iula, D. M. Corey−Kim Oxidation. In Name Reactions for Functional Group Trans- formations; Li, J. J., Corey, E. J. (eds), John Wiley & Sons: Hoboken, NJ, 2007, pp 207−217. (Review). 9 Yin, W.; Ma, J.; Rivas, F. M.; Cook, M. Org. Lett. 2007, 9, 295−298. 10 Cink, R. D.; Chambournier, G.; Surjono, H.; Xiao, Z.; Richter, S.; Naris, M.; Bhatia, A. V. Org. Pro. Res. Dev. 2007, 11, 270−274.

152

Corey–Nicolaou macrolactonization Macrolactonization of ω-hydroxyl-acid using 2,2ƍ-dipyridyl disulfide. Also known as the Corey–Nicolaou double activation method.

O N S N O OH S n n O OH Ph3P

N H N PPh3 S S N S N S O H : H Ph3P O n OH N H N S PPh3 H O S O PPh3 OPPh N S O O 3 H n O n O OH n OH

O N S O H n N S O n H O 2-pyridinethione

Example 13 Ph Ph O O Ph OH Ph O H (2-pyr-S)2, PPh3 O O O HO2C Δ H CHCl3, , 75% N N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_66, © Springer-Verlag Berlin Heidelberg 2009 153

Example 26

OH OMOM O O O (2-pyr-S)2, PPh3 OH Δ HO O AgClO4, , 33% O O

Example 39

C5H11 O

O O (PyS) , PPh BnO O O O 2 3

HO OH toluene, reflux 7 d, 69%

HO2C

C5H11 C5H11 O O O O O O O O BnO O O O BnO O HO O OH O O 58% O 11%

References

1. Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614–5616. 2. Nicolaou, K. C. Tetrahedron 1977, 33, 683–710. (Review). 3. Devlin, J. A.; Robins, D. J.; Sakdarat, S. J. Chem. Soc., Perkin Trans. 1 1982, 1117– 1121. 4. Barbour, R. H.; Robins, D. J. J. Chem. Soc., Perkin Trans. 1 1985, 2475–2478. 5. Barbour, R. H.; Robins, D. J. J. Chem. Soc., Perkin Trans. 1 1988, 1169–1172. 6. Andrus, M. B.; Shih, T.-L. J. Org. Chem. 1996, 61, 8780–8785. 7. Lu, S.-F.; O’yang, Q. Q.; Guo, Z.-W.; Yu, B.; Hui, Y.-Z. J. Org. Chem. 1997, 62, 8400–8405. 8. Sasaki, T.; Inoue, M.; Hirama, M. Tetrahedron Lett. 2001, 42, 5299–5303. 9. Zhu, X.-M.; He, L.-L.; Yang, G.-L.; Lei, M.; Chen, S.-S.; Yang, J.-S. Synlett 2006, 3510–3512.

154

Corey–Seebach reaction Dithiane as a nucleophile, serving as a masked carbonyl equivalent. This is an example of umpolung.

SH CH2(OMe)2 S 1. BuLi

SH Et2O•BF3 S 2. Cl-(CH2)4-I 80%

S o HgCl2, 50 C OHC S 50% Cl Cl

I Bu Cl S S H S S H S Cl S Example 12 n-BuLi, THF CHO S S 0 oC, 30 min., 99% Ph

PhI(O CCCl ) HO O SS 2 3 2

HO Ph CH3CN, H2O, rt, 5 min., 95% Ph Ph Ph Example 24 OH Ph S S O CHO S O S n-BuLi, THF, −78 to 0 oC Ph

Example 3, Ethyl is infinitely different from methyl6

Me S S S OH O OMe Li S S S Me Me

O OMe S Et O Et S S S S

Et S n-BuLi, THF HO C rt, overnight 2 CO H 80−90% 2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_67, © Springer-Verlag Berlin Heidelberg 2009 155

S S O Et Et S O Et SET S S HO2C S HO C 2

O O Et Et S S S S S S S Et S Et HO C HO C 2 2

Example 48

HO SS BnO S OBn OBn S NHTfa n-BuLi, THF HO S BnO S O −10 oC, 78% BnO OBn NHTfa OBn NHTfa BnO OBn 54% 23% Tfa = Trifluoroacetyl HO HO BnO S BnO Ra-Ni, EtOH

BnO S reflux, 71% BnO NHTfa NHTfa BnO BnO

References

1. (a) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. 1965, 4, 1075–1077. Dieter See- bach is a professor at ETH in Zürich, Switzerland. (b) Corey, E. J.; Seebach, D. J. Org. Chem. 1966, 31, 4097–4099. (c) Seebach, D.; Jones, N. R.; Corey, E. J. J. Org. Chem. 1968, 33, 300–305. (d) Seebach, D.; Corey, E. J. Org. Synth. 1968, 50, 72. (e) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231–237. 2. Stowell, M. H. B.; Rock, R. S.; Rees, D. C.; Chan, S. I. Tetrahedron Lett. 1996, 37, 307–310. 3. Hassan, H. H. A. M.; Tamm, C. Helv. Chim. Acta 1996, 79, 518–526. 4. Lee, H. B.; Balasubramanian, S. J. Org. Chem. 1999, 64, 3454–3460. 5. Bräuer, M.; Weston, J.; Anders, E. J. Org. Chem. 2000, 65, 1193–1199. 6. Valiulin, R. A.; Kottani, R.; Kutateladze, A. G. J. Org. Chem. 2006, 71, 5047–5049. 7. Chen, Y.-L.; Leguijt, R.; Redlich, H. J. Carbohydrate Chem. 2007, 26, 279–303. 8. Chen, Y.-L.; Redlich, H.; Bergander, K.; Froehlich, R. Org. Biomol. Chem. 2007, 5, 3330–3339.

156

Corey–Winter olefin synthesis Transformation of diols to the corresponding olefins by sequential treatment with 1,1ƍ-thiocarbonyldiimidazole (TCDI) and trimethylphosphite. Also known as Corey–Winter reductive elimination, or Corey–Winter reductive olefination.

S R OH R R H O P(OMe)3 N N S 1 1 O R OH N N R R1 H

TCDI = Thiocarbonyldiimidazole

S N N N N N N R N S O H N S H R O S : R O Imd R OH Imd R1 O R1 OH 1 1 R OH R OH

R O : R O P(OMe)3 P(OMe)3 S S 1 O 1 O R R 1,3-dioxolane-2-thione (cyclic thiocarbonate)

: P(OMe)3 R R O S O SP(OMe)3 P(OMe)3 1 O P(OMe)3 1 O R R

R H O P(OMe)3 O CO↑ P(OMe)3 R1 H O

A mechanism involving a carbene intermediate can also be drawn and is supported by pyrolysis studies:

R R O : O P(OMe)3 S S P(OMe)3 1 O 1 O R R

R O R : O SP(OMe) P(OMe)3 3 P(OMe)3 1 O 1 O R R

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_68, © Springer-Verlag Berlin Heidelberg 2009 157

R H O : P(OMe)3 P(OMe)3 O CO↑ O R1 H

Example 12

S Ph O S H C P CH O O O O 3 N N 3 OH O Cl Cl O O O O CH Cl , DMAP O O O OH 2 2 40 °C, 88% 0 oC, 1 h, 93% O

Example 24

O O

N OMe Imd2CS, toluene N OMe HO O reflux, 79% S OMOM O OMOM HO CF CF3 3

P(OMe)3 N OMe 92% F3C OMOM Single olefin isomer

Example 38

OMe TBSO OMe H CSCl , DMAP TBSO HO OAc 2 H O OAc CH Cl , rt, 96% HO 2 2 S H O H

OMe TBSO H OAc P(OEt)3, reflux

76% H

158

Example 49

CH3 H3CO H3C OCH3 O O P(OMe)3 OCH S 3 CH3 O N O N O O CH O CH3 120 °C, 66% 3 O O

Example 510 Ph S OAc OAc H C P CH OAc 3 N N 3 OH Cl OAr(F)5 O S pyridine, DMAP O THF, 40 °C AcO AcO AcO OH 23 °C, 5 h, 78% 4 h, 65%

Example 611 S Ph OH Ph TCDI, THF O CbzHN NHCbz CbzHN NHCbz OH 70 oC Ph O Ph Ph

P(OEt) , 160 oC CbzHN 3 NHCbz 77%, 2 steps Ph References

1. Corey, E. J.; Winter, R. A. E. J. Am. Chem. Soc. 1963, 85, 2677−2678. Roland A. E. Winter works at Ciba Specialty Chemicals Corporation, USA. 2. Corey, E. J.; Carey, F. A.; Winter, R. A. E. J. Am. Chem. Soc. 1965, 87, 934−935. 3. Block, E. Org. React. 1984, 30, 457−566. (Review). 4. Kaneko, S.; Nakajima, N.; Shikano, M.; Katoh, T.; Terashima, S. Tetrahedron 1998, 54, 5485−5506. 5. Crich, D.; Pavlovic, A. B.; Wink, D. J. Synth. Commun. 1999, 29, 359−377. 6. Palomo, C.; Oiarbide, M.; Landa, A.; Esnal, A.; Linden, A. J. Org. Chem. 2001, 66, 4180−4186. 7. Saito, Y.; Zevaco, T. A.; Agrofoglio, L. A. Tetrahedron 2002, 58, 9593−9603. 8. Araki, H.; Inoue, M.; Katoh, T. Synlett 2003, 2401−2403. 9. Brüggermann, M.; McDonald, A. I.; Overman, L. E.; Rosen, M. D.; Schwink, L.; Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284−15285. 10. Freiría, M.; Whitehead, A. J.; Motherwell, W. B. Synthesis 2005, 3079−3084. 11. Mergott, D. J. Corey−Winter olefin synthesis. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 354−362. (Review). 12. Xu, L.; Desai, M. C.; Liu, H. Tetrahedron Lett. 2009, 50, 552−554. 159

Criegee glycol cleavage Vicinal diol is oxidized to the two corresponding carbonyl compounds using Pb(OAc)4, (lead tetraacetate, LTA).

HO OH Pb(OAc) O O 1 3 4 R R Pb(OAc)2 2 HOAc R2 R4 R1 R2 R3 R4

AcO Pb(OAc) 3 OAc

(AcO)2Pb HO OH HOAc O OH R1 R3 R1 R3 2 4 2 4 R R R R

AcO OAc Pb O O O O HOAc Pb(OAc)2 R1 R3 R1 R2 R3 R4 2 4 R R

An acyclic mechanism is possible as well. It is much slower than the cyclic mechanism, but is operative when the cyclic intermediate can not form:3

H O

O Pb(OAc) H 3 Pb(OAc) O: O O 2

O HOAc OH O H

AcO

II Pb (OAc)2 HOAc O

Example 17

CO2Et CO2Et OH N Pb(OAc)4, K2CO3 N H Ph O PhH, 0 oC, 80% O OH O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_69, © Springer-Verlag Berlin Heidelberg 2009 160

Example 29

H Pb(OAc)4, CH2Cl2, K2CO3 H OH −15 oC to rt, 1 h, then CO2Me HO Ph P=CHCO Me, CH CN, 80% H 3 2 3 H E:Z = 10:1 PhO S PhO2S 2

Example 310

HO O Ar Pb(OAc)4, PhH O Ar OHC O Ar HO rt, 1.5 h, quant. H H

Example 411

OMe OH OH OMe OH O Pb(OAc) , EtOAc Me 4 HO HO H 0 oC, 5 min., 99% Me Me Me MeMe OH Me Me Me Me

References

1 Criegee, R. Ber. 1931, 64, 260–266. Rudolf Criegee (1902−1975) was born in Düssel- dorf, Germany. He earned his Ph.D. at age 23 under K. Dimroth at Würzburg. Criegee became a professor at Technical Institute at Karlsruhe in 1937, a chair in 1947. He was known for his modesty, mater-of-factness, and his breadth of interests. 2 Mihailovici, M. L.; Cekovik, Z. Synthesis 1970, 209–224. (Review). 3 March, J. Advanced Organic Chemistry, 5th ed., Wiley & Sons: Hoboken, NJ, 2003. (Review). 4 Danielmeier, K.; Steckhan, E. Tetrahedron: Asymmetry 1995, 6, 1181–1190. 5 Masuda, T.; Osako, K.; Shimizu, T.; Nakata, T. Org. Lett. 1999, 1, 941–944. 6 Lautens, M.; Stammers, T. A. Synthesis 2002, 1993–2012. 7 Hartung, I. V.; Eggert, U.; Haustedt, L. O.; Niess, B.; Schäfer, P. M.; Hoffmann, H. M. R. Synthesis 2003, 1844–1850. 8 Gaul, C.; Njardarson, J. T.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 6042– 6043. 9 Gorobets, E.; Stepanenko, V.; Wicha, J. Eur. J. Org. Chem. 2004, 783–799. 10 Prasad, K. R.; Anbarasan, P. Tetrahedron 2006, 63, 1089–1092. 11 Perez, L. J.; Micalizio, G. C. Synthesis 2008, 627–648.

161

Criegee mechanism of ozonolysis

OO O3 O

O O 1,3-dipolar : O O O O cycloaddition

primary ozonide (1,2,3-trioxolane)

O O 1,3-dipolar OO O cycloaddition O

zwitterionic peroxide secondary ozonide (1,2,4-trioxolane) (Criegee zwitterion) also known as “carbonyl oxide”

Example 17

H HO − o O3, EtOAc, 78 C, then O O OAc HO Ac2O, Et3N, DMAP, O −78 oC to rt, 75% H

Example 28

O O O3, CH2Cl2 MeOH CO2Me O OMe − o quant. 70 C CO2Me O H

References

1. (a) Criegee, R.; Wenner, G. Ann. 1949, 564, 9−15. (b) Criegee, R. Rec. Chem. Prog. 1957, 18, 111−120. (c) Criegee, R. Angew. Chem. 1975, 87, 765−771. 2. Bunnelle, W. H. Chem. Rev. 1991, 91, 335−362. (Review). 3. Kuczkowski, R. L. Chem. Soc. Rev. 1992, 21, 79−83. (Review). 4. Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58, 3675−3680. 5. Ponec, R.; Yuzhakov, G.; Haas, Y.; Samuni, U. J. Org. Chem. 1997, 62, 2757−2762. 6. Dussault, P. H.; Raible, J. M. Org. Lett. 2000, 2, 3377−3379. 7. Jiang, L.; Martinelli, J. R.; Burke, S. D. J. Org. Chem. 2003, 68, 1150−1153. 8. Schank, K.; Beck, H.; Pistorius, S. Helv. Chim. Acta 2004, 87, 2025−2049.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_70, © Springer-Verlag Berlin Heidelberg 2009 162

Curtius rearrangement Alkyl-, vinyl-, and aryl-substituted acyl azides undergo thermal 1,2-carbon-to- nitrogen migration with extrusion of dinitrogen — the Curtius rearrangement — producing isocyantes. Reaction of the isocyanate products with nucleophiles, often in situ, provides carbamates, ureas, and other N-acyl derivatives. Alterna- tively, hydrolysis of the isocyanates leads to primary amines.

O Nu–H O R N Nu Heat O H C RN3 Curtius R N Rearrangement H2O R NH2 –CO2

The thermal rearrangement:

O NaN O Δ H2O 3 ↑ ↑ N2 RNC O RNH3 CO2 R Cl R N3

O O N3 O O O R Cl R Cl R N3 R N N N R N N N N3

H H Δ ↑ RNC O N O ↑ N2 R H RNH2 CO2 : O :B OH2 isocyanate intermediate

The photochemical rearrangement:

O hν O ↑ N2 R N N N R N:

Nitrene

O RNH ↑ : RNC O 2 CO2 R N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_71, © Springer-Verlag Berlin Heidelberg 2009 163

Example 1, The Shioiri–Ninomiya–Yamada modification2

O H NO2 H NO2 DPPA, Et3N Δ PhH, 21 HO 21 then MeOH, Δ O NH O 89% O OMe DPPA = diphenylphosphoryl azide

Example 23

O O CO2Me CO2Me DPPA, Et3N, t-BuOH BocHN HO2C O o O O 80 C, 16 h, 64% O

Example 34

EtO(CO)Cl, then NaN3 CO2H NHCO2Et OO OO EtOH, PhH, reflux, 55%

Example 4, The Weinstock variant of the Curtius rearrangement6

O O COOH HN OEt N H Cl OEt N H i-PrNEt2, acetone, 0 °C

NH then NaN3, rt, 12 h NH N H 75% N H Me Me

Example 57

O Ph Ph NHBoc Cl

1. n-Bu3SnN3 PhBr, 0 °C to RT 30 min., 97%

2. t-BuOH/o-xylene Δ, 6 h, 77%

164

Example 6, The Lebel modification8

OMPM OMPM O OMe 2 equiv DPPA H O OMe HO O N O O CO2H 0.1 equiv Ag2CO3 2 equivK2CO3 BnO OBn O OBn BnO BnO BnO OBn OBn PhH, Δ, 16 h, 81% OBn OBn OBn OBn (2 equiv)

References

1. Curtius, T. Ber. 1890, 23, 3033−3041. Theodor Curtius (1857−1928) was born in Du- isburg, Germany. He studied music before switching to chemistry under Bunsen, Kolbe, and von Baeyer before succeeding Victor Meyer as a Professor of Chemistry at Heidelberg. He discovered diazoacetic ester, hydrazine, pyrazoline derivatives, and many nitrogen-heterocycles. Curtius also sang in concerts and composed music. 2. Ng, F. W.; Lin, H.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9812–9824. 3. van Well, R. M.; Overkleeft, H. S.; van Boom, J. H.; Coop, A.; Wang, J. B.; Wang, H.; van der Marel, G. A.; Overhand, M. Eur. J. Org. Chem. 2003, 1704–1710. 4. Dussault, P. H.; Xu, C. Tetrahedron Lett. 2004, 45, 7455–7457. 5. Holt, J.; Andreassen, T.; Bakke, J. M.; Fiksdahl, A. J. Heterocycl. Chem. 2005, 42, 259–264. 6. Crawley, S. L.; Funk, R. L. Org. Lett. 2006, 8, 3995–3998. 7. Tada, T.; Ishida, Y.; Saigo, K. Synlett 2007, 235–238. 8. Sawada, D.; Sasayama, S.; Takahashi, H.; Ikegami, S. Eur. J. Org. Chem. 2007, 1064– 1068. 9. Rojas, C. M. Curtius Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 136−163. (Review).

165

Dakin oxidation Oxidation of aryl aldehydes or aryl ketones to phenols using basic hydrogen peroxide conditions. Cf. A variant of Baeyer–Villiger oxidation.

H2O2, NaOH

HO CHO HO OH HCO2 45−50 oC

O O H aryl HO HO H O migration HO O H O

OH HO O hydrolysis HO O O H OH O H

H workup HO OH HO O

Example 16

OBn OBn OBn CHO O OH CHO 2.5 eq. 30% H2O2 NH3, MeOH

4% (PhSe)2 1 h, 78% CO H CO2H CO H 2 CH2Cl2, 18 h 2 NHCO t-Bu NHCO t-Bu 2 2 NHCO2t-Bu

Example 27

CHO urea-hydrogen peroxide (UHP) OH

solvent-free, 55 oC, 3 h, 83% HO HO

Example 3, Improved solvent-free Dakin oxidation protocol9

MeO CHO 1.5 equiv m-CPBA, neat, 5 min. MeO OH

then10% aq. NaOH BnO 85% BnO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_72, © Springer-Verlag Berlin Heidelberg 2009 166

Example 410

OMe O

H2O2, HCl MeOH, THF MeO N MeO N H 50% H O CHO

References:

1. Dakin, H. D. Am. Chem. J. 1909, 42, 477−498. Henry D. Dakin (1880−1952) was born in London, England. During WWI, he invented his hypochlorite solution (Da- kin’s solution), which became a popular antiseptic for the treatment of wounds. After the Great War, he emmigrated to New York, where he investigated the B vitamins. 2. Hocking, M. B.; Bhandari, K.; Shell, B.; Smyth, T. A. J. Org. Chem. 1982, 47, 4208−4215. 3. Matsumoto, M.; Kobayashi, H.; Hotta, Y. J. Org. Chem. 1984, 49, 4740−4741. 4. Zhu, J.; Beugelmans, R.; Bigot, A.; Singh, G. P.; Bois-Choussy, M. Tetrahedron Lett. 1993, 34, 7401−7404. 5. Guzmán, J. A.; Mendoza, V.; García, E.; Garibay, C. F.; Olivares, L. Z.; Maldonado, L. A. Synth. Commun. 1995, 25, 2121−2133. 6. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553−1555. 7. Varma, R. S.; Naicker, K. P. Org. Lett. 1999, 1, 189−191. 8. Lawrence, N. J.; Rennison, D.; Woo, M.; McGown, A. T.; Hadfield, J. A. Bioorg. Med. Chem. Lett. 2001, 11, 51−54. 9. Teixeira da Silva, E.; Camara, C. A.; Antunes, O. A. C.; Barreiro, E. J.; Fraga, C. A. M. Synth. Commun. 2008, 38, 784−788. 10. Alamgir, M.; Mitchell, P. S. R.; Bowyer, P. K.; Kumar, N.; Black, D. St. C. Tetrahe- dron 2008, 64, 7136−7142.

167

Dakin−West reaction The direct conversion of an α-amino acid into the corresponding α-acetylamino- alkyl methyl ketone, via oxazoline (azalactone) intermediates. The reaction pro- ceeds in the presence of acetic anhydride and a base, such as pyridine, with the evolution of CO2.

O R CO H 2 Ac2O R ↑ CO2 NH2 NHAc

O RCO2H H R OH O

NH: 2 R HN OH O H O N O O O H OO AcO

H AcO O H H O O O O OH R R OH R O OH O O N N N H

oxazolone (azalactone) intermediate

H O O O O − R CO2 R tautomerization R O HN O H NOH NHAc

Example 16

O Me CO2H Ac2O, AcOH, Et3N Me Me NH2 DMAP, 50 oC, 14 h, > 90% NHAc

Example 27

Me HO O O O O Ac2O, pyr. O O

N OBn o N OBn H 90 C, 2 h, 58% H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_73, © Springer-Verlag Berlin Heidelberg 2009 168

Example 3, Green Dakin–West reaction using the heteropoly acid catalyst, acetonitrile is a reactant9

O CN CH3CN, H3PW12O40 Ph CHO Ph CH3COCl rt, 60 min., 75% NHAc O NC

Example 4, Acetonitrile is a reactant10

O CH3CN R1 R2 10 mol% Ln(OTf) CHO 3

CH3COCl, reflux R R 78−87% NHAc O 1 2

References:

1. Dakin, H. D.; West, R. J. Biol. Chem. 1928, 78, 91, 745, and 757. In 1928, Henry Da- kin and Rudolf West, a clinician, reported on the reaction of α-amino acids with acetic anhydride to give α-acetamido ketones via azalactone intermediates. Interestingly, one year before this paper by Dakin and West, Levene and Steiger had observed both tyrosine and α-phenylananine gave “abnormal” products when acetylated under these conditions.2,3 Unfortunately, they were slow to identify the products and lost an op- portunity to be immortalized by a name reaction. 2. Buchanan, G. L. Chem. Soc. Rev. 1988, 17, 91–109. (Review). 3. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553–1555. 4. Kawase, M.; Hirabayashi, M.; Koiwai, H.; Yamamoto, K.; Miyamae, H. Chem. Com- mun. 1998, 641–642. 5. Kawase, M.; Hirabayashi, M.; Saito, S. Recent Res. Dev. Org. Chem. 2001, 4, 283−293. (Review). 6. Fischer, R. W.; Misun, M. Org. Proc. Res. Dev. 2001, 5, 581–588. 7. Godfrey, A. G.; Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.; Mitchell, D. J. Org. Chem. 2003, 68, 2623–2632. 8. Khodaei, M. M.; Khosropour, A. R.; Fattahpour, P. Tetrahedron Lett. 2005, 46, 2105– 2108. 9. Rafiee, E.; Tork, F.; Joshaghani, M. Bioorg. Med. Chem. Lett. 2006, 16, 1221–1226. 10. Tiwari, A. K.; Kumbhare, R. M.; Agawane, S. B.; Ali, A. Z.; Kumar, K. V. Bioorg. Med. Chem. Lett. 2008, 18, 4130–4132.

169

Darzens condensation α,β-Epoxy esters (glycidic esters) from base-catalyzed condensation of α-haloesters with carbonyl compounds.

O X O OEt R1 R 1 2 2 R CO2Et R R R CO2Et

O O OEt 1 2 1 intramolecular O X R R R 1 H X 2 R R R OEt R 2 R OEt CO Et S 2 R CO2Et R X 2 N O O

Example 14

O O t-BuOK, t-BuOH CO2Et Cl CO2Et 10 °C, 85–95%

Example 26

O H O LDA, THF, O –78 °C then H3C Ph H3C Br PhCHO, –90 °C t-BuMe2Si H t-BuMe2Si 66%, 90% de

Example 39

Ar CONPh2 N N ee up to 50% Co O O O O O 2 mol% X MeO OMe Ar CONPh NPh Ar H 2 2 M M Solid OH, = Na, K, Rb ee up to 43% X = Cl, Br, I CH Cl , 4−24 h, rt 2 2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_74, © Springer-Verlag Berlin Heidelberg 2009 170

Example 4, the phenyl ring substituting for the carbonyl to acidify the protons10

O PO(OMe)2 MeO

DBU, CH3CN Br PO(OMe)2 6 h, 48% Br O OMe Br

References

1 Darzens, G. A. Compt. Rend. Acad. Sci. 1904, 139, 1214–1217. George Auguste Dar- zens (1867−1954), born in Moscow, Russia, studied at École Polytechnique in Paris and stayed there as a professor. 2 Newman, M. S.; Magerlein, B. J. Org. React. 1949, 5, 413–441. (Review). 3 Ballester, M. Chem. Rev. 1955, 55, 283–300. (Review). 4 Hunt, R. H.; Chinn, L. J.; Johnson, W. S. Org. Syn. Coll. IV, 1963, 459. 5 Rosen, T. Darzens Glycidic Ester Condensation In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 2, pp 409–439. (Re- view). 6 Enders, D.; Hett, R. Synlett 1998, 961−962. 7 Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad, K. R. J. Org. Chem. 2003, 68, 2410−2419. 8 Myers, B. J. Darzens Glycidic Ester Condensation. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 15−21. (Review). 9 Achard, T. J. R.; Belokon, Y. N.; Ilyin, M.; Moskalenko, M.; North, M.; Pizzato, F. Tetrahedron Lett. 2007, 48, 2965−2969. 10 Demir, A. S.; Emrullahoglu, M.; Pirkin, E.; Akca, N. J. Org. Chem. 2008, 73, 8992−8997. 171

Delépine amine synthesis The reaction between alkyl halides and hexamethylenetetramine, followed by cleavage of the resulting salt with ethanolic HCl to yield primary amines. Cf. Gabriel synthesis, where the product is also an amine and Sommelet reaction, where the product is an aldehyde. The Delépine works well for active halides such as benzyl, allyl halides, and α-halo-ketones.

N N X Ar Ar NH X Ar X N N N N 3 N N

hexamethylenetetramine

+ − [ArCH2C6H12N4] X + 3 HCl + 6 H2O

ArCH2NH2•HX + 6 CH2O + 3 NH4Cl

H O: N 2 : N N: N N SN2 Ar N N N Ar N N N Ar X X N

H H O N H N O Ar NH Ar Ar 3 N N N N CH2 X N N

Example 13

1. (CH ) N , NaHCO 2 6 4 3 O O 15 h, EtOH, H2O

Br OH 2. HCl, EtOH, reflux, 15 h, 85% H2N OH

Example 27

hexamethylenetetramine N Br N CH2Cl2, refux, 5 h, then Br − o 30 C

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_75, © Springer-Verlag Berlin Heidelberg 2009 172

conc. HCl, EtOH N Br N N reflux, 1 d Br N N C H +Br− 4 6 12 78%, 2 steps NH2

Example 38

Br NH2

O O O 1. hexamethylenetetramine O O O CHCl , reflux, 6 h O 3 O O O o O O O 2. 2 N HCl, EtOH, 100 C, 15 min. O O O O O O O O O

Example 49 N

Br N N Br N NH3 O 48% HBr O hexamethylenetetramine O CH3OH, rt, 5 d NO Br NO 2 NO 2 CHCl3, rt, 18 h 2 89% 2 steps

References

1. (a) Delépine, M. Bull. Soc. Chim. Paris 1895, 13, 352−355; (b) Delépine, M. Bull. Soc. Chim. Paris 1897, 17, 292−295. Stephe Marcel Delépine (1871−1965) was born in St. Martin le Gaillard, France. He was a professor at the Collège de France after working for M. Bertholet at that institute. Delépine’s long and fruitful career in science encompassed organic chemistry, inorganic chemistry, and pharmacy. 2. Galat, A.; Elion, G. J. Am. Chem. Soc. 1939, 61, 3585−3586. 3. Wendler, N. L. J. Am. Chem. Soc. 1949, 71, 375−384. 4. Quessy, S. N.; Williams, L. R.; Baddeley, V. G. J. Chem. Soc., Perkin Trans. 1 1979, 512−516. 5. Blažzeviü, N.; Kolnah, D.; Belin, B.; Šunjiü, V.; Kafjež, F. Synthesis 1979, 161−176. (Review). 6. Henry, R. A.; Hollins, R. A.; Lowe-Ma, C.; Moore, D. W.; Nissan, R. A. J. Org. Chem. 1990, 55, 1796−1801. 7. Charbonnière, L. J.; Weibel, N.; Ziessel, R. Synthesis 2002, 1101−1109. 8. Xie, L.; Yu, D.; Wild, C.; Allaway, G.; Turpin, J.; Smith, P. C.; Lee, K.-H. J. Med. Chem. 2004, 47, 756−760. 9. Loughlin, W. A.; Henderson, L. C.; Elson, K. E.; Murphy, M. E. Synthesis 2006, 1975−1980. 173 de Mayo reaction [2 + 2]-Photochemical cyclization of enones with olefins is followed by a retro- aldol reaction to give 1,5-diketones.

O O O CO2Me hν

OH OH CO2Me O CO2Me

Head-to-tail alignment gives the major product:

O O δ ν δ h , [2 + 2]

δ δ cycloaddition CO2Me CO2Me OH OH O H O O retro-aldol

cyclobutane cleavage CO Me O 2 O CO2Me O CO2Me H

Head-to-head alignment gives the minor regioisomer:

O O hν, [2 + 2] CO2Me CO2Me cycloaddition OH OH

H O O O CO Me 2 retro-aldol

cyclobutane cleavage CO2Me CO2Me O H O O

Example 13 O O

Ph O 1. hν, cyclohexane, 83%

2. H2 (3 atm), Pd/C (10%) HOAc, rt, 18 h, 83% O O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_76, © Springer-Verlag Berlin Heidelberg 2009 174

Example 26

O O O H H hν, MeOH

> 90% OH HO H H O

Example 39

O O O H H OH H O O hv, Pyrex filter

N N CH3CN, rt, 1.5 h, 72% N

O O O

Example 410

O R R O R O hv H O H O H H O Et2O O O O H H

R = H 70% 100 : 0 R = Me 58% 50 : 50 R = t-Bu 72% 0 : 100

References

1. (a) de Mayo, P.; Takeshita, H.; Sattar, A. B. M. A. Proc. Chem. Soc., London 1962, 119. Paul de Mayo received his doctorate from Sir Derek Barton at Birkbeck College, University of London. He later became a professor at the University of Western On- tario in London, Ontario, Canada, where he discovered the de Mayo reaction. (b) Challand, B. D.; Hikino, H.; Kornis, G.; Lange, G.; de Mayo, P. J. Org. Chem. 1969, 34, 794−806. 2. de Mayo, P. Acc. Chem. Res. 1971, 4, 41−48. (Review). 3. Oppolzer, W.; Godel, T. J. Am. Chem. Soc. 1978, 100, 2583−2584. 4. Oppolzer, W. Pure Appl. Chem. 1981, 53, 1181−1201. (Review). 5. Kaczmarek, R.; Blechert, S. Tetrahedron Lett. 1986, 27, 2845−2848. 6. Disanayaka, B. W.; Weedon, A. C. J. Org. Chem. 1987, 52, 2905−2910. 7. Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297−588. (Review). 8. Quevillon, T. M.; Weedon, A. C. Tetrahedron Lett. 1996, 37, 3939−3942. 9. Minter, D. E.; Winslow, C. D. J. Org. Chem. 2004, 69, 1603−1606. 10. Kemmler, M.; Herdtweck, E.; Bach, T. Eur. J. Org. Chem. 2004, 4582−4595. 175

Demjanov rearrangement Carbocation rearrangement of primary amines via diazotization to give alcohols through C−C bond migration.

HNO2 OH

NH2 OH

H N O O − N H H2O O O O 2 HO O N N N H2O O

O O O − N N HNO2

: N N O NH 2 H

− H H2O

N N OH N: N OH2 N N

H − N2 O: − H H OH N N

O: H − N2 or − H OH N N

Example 13

NaNO2, HOAc Ph N NH2 N N OH Ph 100 oC, 2 h Ph 30% 16%

Example 26 H NH H OH 2 NaNO2, AcOH/H2O

100−110 oC, 2 h, 61%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_77, © Springer-Verlag Berlin Heidelberg 2009 176

Example 37

O O o O NaNO2, 0−4 C

0.25 M H SO /H O 2 4 2 OH HO NH2

Example 48

O 5 equiv NaNO HO O 2 O 5 equiv AcOH H2N H H O H O/THF (1:1) H 2 MeO H 0 oC, 2 h, 61% MeO

References

1. Demjanov, N. J.; Lushnikov, M. J. Russ. Phys. Chem. Soc. 1903, 35, 26−42. Nikolai J. Demjanov (1861−1938) was a Russian chemist. 2. Smith, P. A. S.; Baer, D. R. Org. React. 1960, 11, 157−188. (Review). 3. Diamond, J.; Bruce, W. F.; Tyson, F. T. J. Org. Chem. 1965, 30, 1840−184. 4. Kotani, R. J. Org. Chem. 1965, 30, 350−354. 5. Diamond, J.; Bruce, W. F.; Tyson, F. T. J. Org. Chem. 1965, 30, 1840−1844. 6. Nakazaki, M.; Naemura, K.; Hashimoto, M. J. Org. Chem. 1983, 48, 2289−2291. 7. Fattori, D.; Henry, S.; Vogel, P. Tetrahedron 1993, 49, 1649−1664. 8. Kürti, L.; Czakó, B.; Corey, E. J. Org. Lett. 2008, 10, 5247−5250. 9. Curran, T. T. Demjanov and Tiffeneau–Demjanov Rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 2−32. (Review). 177

Tiffeneau–Demjanov rearrangement Carbocation rearrangement of β-aminoalcohols via diazotization to afford carbonyl compounds through C−C bond migration.

OH O NaNO2

NH2 H

Step 1, Generation of N2O3

H N O O − H O N H 2 O O O HO O N N N − H2O O H

Step 2, Transformation of amine to diazonium salt

OH O O O OH N N HONO

: N N O

NH2 H

OH OH OH − H O H 2 N N N OH N: N OH2 N

Step 3, Ring-expansion via rearrangement

: O N O OH − H − N N2 H

Example 15

NaNO2, H2O O HO AcOH, 0 oC, − o O then rt 60 C 76% yield 90 : 6 H2N

178

Example 26

AcOH•H2N CONEt2 OH O H NaNO , AcOH NEt2 2 O N2 − o H2O, 0 5 C O N 60% Me CONEt2 O

O N Me

Example 37

o NaNO2, AcOH/H2O, 0 C, 1 h OH then reflux 1 h, 98% O NH2

Example 49

O O HO NH2 NaNO2 SiMe3 AcOH SiMe 3 72% 28% SiMe3

References

1. Tiffeneau, M.; Weill, P.; Tehoubar, B. Compt. Rend. 1937, 205, 54−56. 2. Smith, P. A. S.; Baer, D. R. Org. React. 1960, 11, 157−188. (Review). 3. Parham, W. E.; Roosevelt, C. S. J. Org. Chem. 1972, 37, 1975−1979. 4. Jones, J. B.; Price, P. Tetrahedron 1973, 29, 1941−1947. 5. Miyashita, M.; Yoshikoshi, A. J. Am. Chem Soc. 1974, 96, 1917–1925. 6. Steinberg, N. G.; Rasmusson, G. H.; Reynolds, G. F.; Hirshfield, J. H.; Arison, B. H. J. Org. Chem. 1984, 49, 4731–4733. 7. Stern, A. G.; Nickon, A. J. Org. Chem. 1992, 57, 5342−5352. 8. Fattori, D.; Henry, S.; Vogel, P. Tetrahedron 1993, 49, 1649–1664. 9. Chow, L.; McClure, M.; White, J. Org. Biomol. Chem. 2004, 2, 648−650. 10. Curran, T. T. Demjanov and Tiffeneau–Demjanov Rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 293−304. (Review). 179

Dess−Martin periodinane oxidation Oxidation of alcohols to the corresponding carbonyl compounds using triacetoxyperiodinane. The Dess–Martin periodinane, 1,1,1-triacetoxy-1,1-dihydro-1,2- benziodoxol-3(1H)-one, is one of the most useful oxidant for the conversion of primary and secondary alcohols to their corresponding aldehyde or ketone products, respectively.

AcO OAc I OAc O OH O O R1 R2 R1 R2

1,2 Preparation, The oxone preparation is much safer and easier than KBrO3. The IBX intermediate that comes out of it has proven to be far less explosive12

OAc I KBrO H SO 93% AcO 3, 2 4, HO O Ac O, 0.5% TsOH I OAc CO H I 2 2 O or 1.3 equiv Oxone O 80 oC, 2 h, 91% H O, 70 oC, 3 h 2 IBX O 79-81% O

However, The Dess–Martin periodinane is hydrolyzed by moisture to o- iodoxybenzoic acid (IBX), which is a more powerful oxidating agent3

OAc HO O AcO H O I OAc 2 I O O CH2Cl2 IBX O O

Mechanism1

AcO OAc H AcO OAc OAc : O I O S 2 I H 2 N O R O 2 OAc 1 R R1 R O O

OAc O I O AcOH R1 R2 O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_78, © Springer-Verlag Berlin Heidelberg 2009 180

Example 16

AcO OAc I OAc O OH OO O OO O O O CH2Cl2, 2 h, 67% O O

Example 2, An atypical Dess–Martin periodinane reactivity7

AcO OAc I OAc O O CHO O N3 N NaN3, CH2Cl2 o N 0 C, 3 h, 86%

Example 310

S N H S OH O Dess−Martin periodinane H t-BuO2C N N N CH2Cl2, rt, 1 h, 70% H H O CO t-Bu NHBoc 2

S N H S O O H t-BuO C N 2 N N H H O CO t-Bu NHBoc 2

Example 411

PMBO BnO Dess−Martin periodinane O O O BnO OTDS BnO AllO CH2Cl2, rt, 2 h, 90% NHAc OH

BnO PMBO O O O BnO OTDS BnO AllO NHAc O TDS = Thexyldimethylsilyl 181

References

1. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155−4156. James Cullen (J. C.) Martin (1928−1999) had a distinguished career spanning 36 years both at the Uni- versity of Illinois at Urbana-Champaign and Vanderbilt University. J. C.’s formal training in physical organic chemistry with Don Pearson at Vanderbilt and P. D. Bart- lett at Harvard prepared him well for his early studies on carbocations and radicals. However, it was his interest in understanding the limits of chemical bonding that lead to his landmark investigations into hypervalent compounds of the main group ele- ments. Over a 20-year period the Martin laboratories successfully prepared unprece- dented chemical structures from sulfur, phosphorus, silicon and bromine while the ultimate “Holy Grail” of stable pentacoordinate carbon remained elusive. Although most of these studies were driven by J. C.’s fascination with unusual bonding schemes, they were not without practical value. Two hypervalent compounds, Martin’s sulfurane (for dehydration, page 365) and the Dess−Martin periodinane have found wide- spread application in synthetic organic chemistry. J. C. Martin and his student Daniel Dess developed this methodology at the University of Illinois at Urbana. (Martin’s bi- ography was kindly supplied by Prof. Scott E. Denmark). (b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277−7287. 2. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. 3. Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549−7552. 4. Speicher, A.; Bomm, V.; Eicher, T. J. Prakt. Chem. 1996, 338, 588−590. (Review). 5. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 622−625. 6. Bach, T.; Kirsch, S. Synlett 2001, 1974−1976. 7. Bose, D. S.; Reddy, A. V. N. Tetrahedron 2003, 44, 3543−3545. 8. Tohma, H.; Kita, Y. Adv. Synth. Cat. 2004, 346, 111−124. (Review). 9. Holsworth, D. D. Dess−Martin oxidation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ; 2007, pp 218−236. (Review). 10. More, S. S.; Vince, R. J. Med. Chem. 2008, 51, 4581−4588. 11. Crich, D.; Li, M.; Jayalath, P. Carbohydrate Res. 2009, 344, 140−144. 12. Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537−4538. 182

Dieckmann condensation The Dieckmann condensation is the intramolecular version of the Claisen condensation.

O CO2Et NaOEt CO2Et CO2Et

CO2Et O OEt O enolate 5-exo-trig O OEt OEt O H formation OEt ring closure CO Et O CO2Et 2 OEt

Example 16

OBn H OBn H NaHMDS, THF OTBS MeO C OTBS O 2 N N −78 oC, 58% MeO C MeO2C 2

Example 28

EtO2C

MeO2C O 1. t-BuOK, Tol., reflux, 5 min.

2. 18 N H2SO4, THF, 4 h N O N O 61% for two steps

Example 39

O OH 3 equiv KOt-Bu, DMF Ar1 OCH2CF3 Ar 1 Ar2 O o − − O Ar2 0 C, 30 90 min., 75 88% O O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_79, © Springer-Verlag Berlin Heidelberg 2009 183

Example 410

1. K CO , DMSO, 24 h O H 2 3 N N N 2. 60 oC, 48 h NH CO2Me O CO2Me 3. 5 oC, 2 M HCl, 1 h CO Me OMe 2 63% O

O H O H N N

N N HO CO Me O CO2Me 2

References

1. Dieckmann, W. Ber. 1894, 27, 102. Walter Dieckman (1869−1925), born in Ham- burg, Germany, studied with E. Bamberger at Munich. After serving as an assistant to von Baeyer in his private laboratory, he became a professor at Munich. At age 56, he died while working in his chemical laboratory at the Barvarian Academy of Science. 2. Davis, B. R.; Garratt, P. J. Comp. Org. Synth. 1991, 2, 795−863. (Review). 3. Shindo, M.; Sato, Y.; Shishido, K. J. Am. Chem. Soc. 1999, 121, 6507−6508. 4. Balo, C.; Fernández, F.; García-Mera, X.; López, C. Org. Prep. Proced. Int. 2000, 32, 563−566. 5. Deville, J. P.; Behar, V. Org. Lett. 2002, 4, 1403−1405. 6. Rabiczko, J.; UrbaĔczyk-Lipkowska, Z.; Chmielewski, M. Tetrahedron 2002, 58, 1433−1441. 7. Ho, J. Z.; Mohareb, R. M.; Ahn, J. H.; Sim, T. B.; Rapoport, H. J. Org. Chem. 2003, 68, 109-114. 8. de Sousa, A. L.; Pilli, R. A. Org. Lett. 2005, 7, 1617−1617. 9. Bernier, D.; Brueckner, R. Synthesis 2007, 2249−2272. 10. Koriatopoulou, K.; Karousis, N.; Varvounis, G. Tetrahedron 2008, 64, 10009−10013. 11. Takao, K.-i.; Kojima, Y.; Miyashita, T.; Yashiro, K.; Yamada, T.; Tadano, K.-i. Heterocycles 2009, 77, 167−172.

184

Diels–Alder reaction The Diels–Alder reaction, inverse electronic demand Diels–Alder reaction, as well as the hetero-Diels–Alder reaction, belong to the category of [4+2]-cycloaddition reactions, which are concerted processes. The arrow pushing here is merely illustrative.

‡ ‡ HOMO EDG EDG EDG EWG EWG Δ EWG LUMO

diene dienophile adduct EDG = electron-donating group; EWG = electron-withdrawing group

Example 16

‡ OMe OMe Me3SiO CO2Et hydroquinone

CO2Et AcO 180 oC, 1.5 h, 62% H Me3SiO OAc

The Danishefsky diene Alder’s endo rule

OMe OMe EtO2C CO2Et

AcO OSiMe3 Me3SiO AcO 4:1 α-OMe : β-OMe

Example 2, Intramolecular Diels–Alder reaction7

O O F Br4-BIPOL, AlMe3 O O F CH2Cl2, rt, 8 h, 65% H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_80, © Springer-Verlag Berlin Heidelberg 2009 185

Example 3, Asymmetric Diels–Alder reaction5,8

H Ph Ph N O B Br3Al O CH3 O OCH2CF3 O

CO2CH2CF3 4 mol%, CH2Cl2 94% ee − o 90:10 endo:exo 78 C, 12 h, 99%

Example 4, Retro-Diels–Alder reaction4,9

O H

MeO2C

H O

MeAlCl2, maleic anhydride MeO2C μ o CH2Cl2, -wave, 110 C 1 min., 74−84%

Example 5, Intramolecular Diels–Alder reaction11

O O Me AlCl, CH Cl O Me 2 2 2 O

−78 to −30 oC, 71% OH Me HO

References

1. Diels, O.; Alder, K. Ann. 1928, 460, 98−122. Otto Diels (Germany, 1876−1954) and his student, Kurt Alder (Germany, 1902−1958), shared the Nobel Prize in Chemistry in 1950 for development of the diene synthesis. In this article they claimed their terri- tory in applying the Diels–Alder reaction in total synthesis: “We explicitly reserve for ourselves the application of the reaction developed by us to the solution of such prob- lems.” 2. Oppolzer, W. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 315−399. (Review). 3. Weinreb, S. M. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 401−449. (Review). 4. (a) Rickborn, B. The retro-Diels−Alder reaction. Part I. C−C dienophiles in Org. Re- act. John Wiley & Sons, 1998, 52. (b) Rickborn, B. The retro-Diels−Alder reaction. Part II. Dienophiles with one or more heteroatom in Org. React. John Wiley & Sons, 1998, 53. 5. Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650−1667. (Review). 186

6. Wang, J.; Morral, J.; Hendrix, C.; Herdewijn, P. J. Org. Chem. 2001, 66, 8478−8482. 7. Saito, A.; Yanai, H.; Sakamoto, W.; Takahashi, K.; Taguchi, T. J. Fluorine Chem. 2005, 126, 709−714. 8. Liu, D.; Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 1498−1499. 9. Iqbal, M.; Duffy, P.; Evans, P.; Cloughley, G.; Allan, B.; Lledo, A.; Verdaguer, X.; Riera, A. Org. Biomol. Chem. 2008, 6, 4649−4661. 10. Ibrahim-Ouali, M. Steroids 2009, 74, 133−162. 11. Gao, S.; Wang, Q.; Chen, C. J. Am. Chem. Soc. 2009, 131, 1410−1412.

Inverse electronic demand Diels–Alder reaction

‡ ‡ EWG EWG LUMO EWG EDG Δ EDG EDG

HOMO Diene dienophile adduct

Example 12

EtO Cat. OO OO = B B N O 3 mol% Cat., BaO, rt, 5 h Cr Cl O O O OEt

CO Et OHC 2 EtO2C o O OEt 110 C, 48 h H 76% 2 steps OH 98% dr, 95% ee

Example 23

Mes O N N Cl N O R1 O O R R O 5 mol% 2 3 H R1 − R2 R3 70 90% yield Cl 95−99% ee 1.5 equiv NEt3, EtOAc, rt, 6 h

187

Example 3, Catalytic asymmetric inverse-electron-demand Diels–Alder reaction4

OEt SO2Ar N 5 equiv O2 Ph OEt Ph N S 10 mol% Ni(ClO4)2•6H2O 10 mol% DBFOX-Ph 97:3 endo/exo CH Cl , rt, 73% yield 2 2 Ph 88% ee Ph

O O DBFOX-Ph = O N N

Ph Ph

Example 45

O MeO OMe O EWG EWG 1. MeO OMe solvent, 135 oC O O OMe EWG = CONEt , CO Et, 2 2 OMe COR, SO Ph, CN, Aryl 2. Et2O•BF3, CH2Cl2, rt 2

O MeO O EWG EWG MeO NR2

O PhH, Δ O EWG = CONEt2, CO2Et, OMe COR, SO2Ph, CN, Aryl

References

1. Boger, D. L.; Patel, M. Prog. Heterocycl. Chem. 1989, 1, 30–64. (Review). 2. Gao, X.; Hall, D. G. J. Am. Chem. Soc. 2005, 127, 1628–1629. 3. He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088–15089. 4. Esquivias, J.; Gomez Arrayas, R.; Carretero, J. C. J. Am. Chem. Soc. 2007, 129, 1480– 1481. 5. Dang, A.-T.; Miller, D. O.; Dawe, L. N.; Bodwell, G. J. Org. Lett. 2008, 10, 233–236.

Hetero-Diels–Alder reaction Heterodiene addition to dienophile or heterodienophile addition to diene. Typical hetero-Diels–Alder reactions are aza-Diels–Alder reaction and oxo-Diels–Alder reaction.

188

X X Y Y

Y X X Y X X e.g.: ‡ SO2Ph EtO2C SO2Ph SO2Ph EtO2C N OEt N EtO2C N OEt

Ph OEt Ph H Ph

Example 1, Heterodienophile addition to diene1

MeO toluene MeO CO2Et CO2Et O O 110 oC, 60%

Example 2, Similar to the Boger pyridine synthesis (see page 59)2

MeO2C CO2Me N OMe MeO N CHCl3, reflux MeO N N MeO NN OMe 5 days, 65% CO2Me MeO MeO2C CO2Me CO2Me NN

Example 3, Using the Rawal diene4

NMe2 CHCl , −40 oC O O 3 Me O Me CO Me 71% MeO C 2 OTBS 2 Rawal diene

Example 4, Also similar to the Boger pyridine synthesis6

N N N Δ or MW n n = 1, 75% n = 2, 65% N SCH3 n = 3, 54% O N SCH3 n = 4, 30% n O 189

Example 57

MeMe O O OTf O N N O Cu EtO O CMe EtO O Me3C 3 OEt OEt H2O OH2 OTf 2 mol% 24:1 endo/exo o Me 3 Å MS, THF, 0 C, 87% Me 97% ee

References

1. Wender, P. A.; Keenan, R. M.; Lee, H. Y. J. Am. Chem. Soc. 1987, 109, 4390–4392. 2. Boger, D. L. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 451−512. (Review). 3. Boger, D. L.; Baldino, C. M. J. Am. Chem. Soc. 1993, 115, 11418−11425. 4. Huang, Y.; Rawal, V. H. Org. Lett. 2000, 2, 3321−3323. 5. Jørgensen, K. A. Eur. J. Org. Chem. 2004, 2093−2102. (Review). 6. LipiĔska, T. M. Tetrahedron 2006, 62, 5736−5747. 7. Evans, D. A.; Kvaerno, L.; Dunn, T. B.; Beauchemin, A.; Raymer, B.; Mulder, J. A.; Olhava, E. J.; Juhl, M.; Kagechika, K.; Favor, D. A. J. Am. Chem. Soc. 2008, 130, 16295−16309.

190

Dienone–phenol rearrangement Acid-promoted rearrangement of 4,4-disubstituted cyclohexadienones to 3,4- disubstituted phenols.

O OH H

R RR R

H H O OH OH : O 1,2-alkyl − H H shift H R R RR R R RR

Example 14

O O O O 50% aq. H2SO4 reflux, 80%

O OH

Example 25

O OH HO HO conc. H2SO4

Et2O, 95%

Example 39

OH O

conc. HCl, CH CN O 3 1.5 h, rt, 73% NH O O NBoc O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_81, © Springer-Verlag Berlin Heidelberg 2009 191

Example 410

Ac2O O OAc H2SO4 (1:1) OAc 0 oC to rt AcO 62% O

References

1. Shine, H. J. In Aromatic Rearrangements; Elsevier: New York, 1967, pp 55−68. (Re- view). 2. Schultz, A. G.; Hardinger, S. A. J. Org. Chem. 1991, 56, 1105−1111. 3. Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1992, 114, 1824−1829. 4. Hart, D. J.; Kim, A.; Krishnamurthy, R.; Merriman, G. H.; Waltos, A.-M. Tetrahedron 1992, 48, 8179−8188. 5. Frimer, A. A.; Marks, V.; Sprecher, M.; Gilinsky-Sharon, P. J. Org. Chem. 1994, 59, 1831−1834. 6. Oshima, T.; Nakajima, Y.-i.; Nagai, T. Heterocycles 1996, 43, 619−624. 7. Draper, R. W.; Puar, M. S.; Vater, E. J.; Mcphail, A. T. Steroids 1998, 63, 135−140. 8. Kodama, S.; Takita, H.; Kajimoto, T.; Nishide, K.; Node, M. Tetrahedron 2004, 60, 4901−4907. 9. Bru, C.; Guillou, C. Tetrahedron 2006, 62, 9043−9048. 10. Sauer, A. M.; Crowe, W. E.; Henderson, G.; Laine, R. A. Tetrahedron Lett. 2007, 48, 6590−6593.

192

Di-π-methane rearrangement Conversion of 1,4-dienes to vinylcyclopropanes under photolysis. Also known as the Zimmerman rearrangement.

R R1 R ν 2 1 R2 h R R

3 4 R R4 R3 R

1,4-diene vinylcyclopropane

1 1 1 R R R R R R R 2 R1 R2 R R2 hν R2 3 4 R 4 3 R 4 3 4 3 R R R R R R diradical diradical

Example 1, Aza-π-methane rearrangement2

hν, acetophenone Ph N N benzene, 86% OAc Ph OAc Ph Ph

Example 24

CN CN hν, acetone CN 90% CN

Example 38

X hv, 300 nM CH3COCH3

S 23−64% S O2 X O2

X = CH3, CH2Ph, COCMe3, CO2CH2Ph SiMe3, SnBu3, SePh, (CH ) CH 2 3 3

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_82, © Springer-Verlag Berlin Heidelberg 2009 193

Example 4, Oxa-π-methane rearrangement8

O Me Me Me H hv, acetone O Pyrex, 76% MeH

References

1. (a) Zimmerman, H. E.; Grunewald, G. L. J. Am. Chem. Soc. 1966, 88, 183–184. Known for the Traxler–Zimmerman trasition state for the asymmetric synthesis, How- ard E. Zimmerman is a professor at the University of Wisconsin at Madison. (b) Zimmerman, H. E.; Armesto, D. Chem. Rev. 1996, 96, 3065–3112. (Review). (c) Zimmerman, H. E.; Církva, V. Org. Lett. 2000, 2, 2365–2367. 2. Armesto, D.; Horspool, W. M.; Langa, F.; Ramos, A. J. Chem. Soc., Perkin Trans. I 1991, 223–228. 3. Jiménez, M. C.; Miranda, M. A.; Tormos, R. Chem. Commun. 2000, 2341–2342. 4. Ünaldi, N. S.; Balci, M. Tetrahedron Lett. 2001, 42, 8365–8367. 5. Altundas, R.; Dastan, A.; Ünaldi, N. S.; Güven, K.; Uzun, O.; Balci, M. Eur. J. Org. Chem. 2002, 526–533. 6. Zimmerman, H. E.; Chen, W. Org. Lett. 2002, 4, 1155–1158. 7. Tanifuji, N.; Huang, H.; Shinagawa, Y.; Kobayashi, K. Tetrahedron Lett. 2003, 44, 751–754. 8. Dura, R. D.; Paquette, L. A. J. Org. Chem. 2006, 71, 2456–2459. 9. Singh, V.; Chandra, G.; Mobin, S. M. Synlett 2008, 2267–2270.

194

Doebner quinoline synthesis Three-component coupling of an aniline, pyruvic acid, and an aldehyde to provide a quinoline-4-carboxylic acid.

CO2H

CO H N NH2 OHC 2

H O O H OH − CO2H 2 H2O NH H : : 2 N H N H

B: HO CO2H H O CO2H H H2O CO2H H H N N H N H H

CO2H CO2H − air oxidation H2O − N 2 H N H

Example 12

CO2H H MeO MeO O NO EtOH O 2 NO2 CO2H Δ, 95% N NH2

Example 26

CO2H H O EtOH, reflux O N NH2 CO2H 3 h, 20%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_83, © Springer-Verlag Berlin Heidelberg 2009 195

Example 3, Combinatorial Doebner reaction7

N R2 R3 O PhH R1 H NH2 N R3 N R1 reflux, 8 h H H OHC N O O O N H O

References

1. Doebner, O. G. Ann. 1887, 242, 265. Oscar Gustav Doebner (1850−1907) was born in Meininggen, Germany. After studying under Liebig, he actively took part in the Franco-Prussian War. He apprenticed with Otto and Hofmann for a few years after the war, then began his independent researches at the University at Halle. 2. Mathur, F. C.; Robinson, R. J. Chem. Soc. 1934, 1520−1523. 3. Elderfield, R. C. Heterocyclic Compounds; Elderfield, R. C., Ed.; John Wiley & Sons, Inc.: New York, 1952, Vol. 4, Quinoline, Isoquinoline and Their Benzo Derivatives, pp. 25−29. (Review). 4. Jones, G. In Chemistry of Heterocyclic Compounds, Jones, G., ed.; John Wiley & Sons, Inc.: New York, 1977, Vol. 32; Quinolines, pp. 125−131. (Review). 5. Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1989, 32, 396−401. 6. Herbert, R. B.; Kattah, A. E.; Knagg, E. Tetrahedron 1990, 46, 7119−7138. 7. Gopalsamy, A.; Pallai, P. V. Tetrahedron Lett. 1997, 38, 907−910. 8. Pflum, D. A. Doebner quinoline synthesis. In Name Reactions in Heterocyclic Chemis- try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 407−410. (Re- view).

196

Doebner–von Miller reaction Doebner–von Miller reaction is a variant of the Skraup quinoline synthesis (page 509). Therefore, the mechanism for the Skraup reaction is also operative for the Doebner–von Miller reaction. The following mechanism is favored by Denmark’s mechnistic study using 13C-labelled α,β-unsaturated ketones.9

O HCl or N ZnCl NH2 2 H

O O reversible NH conjugate addition NH 2 O irreversible condensation

fragmentation N

NH2 N NH conjugate addition N

cyclization

rearomatization N H NH2

Example 15

CO2Me NH2 O TsOH, CH2Cl2

MeO2C CO2Me reflux, 24 h N CO Me 2

Example 26

F F H F 6 N HCl, Tol. F O NHAc 100 °C, 2 h, 70% N Me

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_84, © Springer-Verlag Berlin Heidelberg 2009 197

Example 3, A novel variant10

R3 R2 3% [RhCl(cod)]2 B(OH)2 KOH, rt, 24 h R2 R3 O then 10% Pd/C NH2 R 1 air, reflux, 4 h N R1 2 equiv − 42 96%

References

1. Doebner, O.; von Miller, W. Ber. 1883, 16, 2464. 2. Corey, E. J.; Tramontano, A. J. Am. Chem. Soc. 1981, 103, 5599−5600. 3. Eisch, J. J.; Dluzniewski, T. J. Org. Chem. 1989, 54, 1269−1274. 4. Zhang, Z. P.; Tillekeratne, L. M. V.; Hudson, R. A. Tetrahedron Lett. 1998, 39, 5133−5134. 5. Carrigan, C. N.; Esslinger, C. S.; Bartlett, R. D.; Bridges, R. J. Bioorg. Med. Chem. Lett. 1999, 9, 2607−2712. 6. Sprecher, A.-v.; Gerspacher, M.; Beck, A.; Kimmel, S.; Wiestner, H.; Anderson, G. P.; Niederhauser, U.; Subramanian, N.; Bray, M. A. Bioorg. Med. Chem. Lett. 1998, 8, 965−970. 7. Fürstner, A.; Thiel, O. R.; Blanda, G. Org. Lett. 2000, 2, 3731−3734. 8. Moore, A. Skraup Doebner–von Miller Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 488−494. (Review). 9. Denmark, S. E.; Venkatraman, S. J. Org. Chem. 2006, 71, 1668−1676. Mechanistic study using 13C-labelled α,β-unsaturated ketones. 10. Horn, J.; Marsden, S. P.; Nelson, A.; House, D.; Weingarten, G. G. Org. Lett. 2008, 10, 4117−4120.

198

Dötz reaction

Cr(CO)3-coordinated hydroquinone from vinylic alkoxy pentacarbonyl chromium carbene (Fischer carbene) complex and alkynes.

OH OR 2 Δ R RL (OC)5Cr RL RS 1 R1 R2 R RS OR Cr(CO)3

RL RS OR OR − OR CO (OC)4Cr alkyne 3 (OC)5Cr (OC)4Cr R coordination 1 2 R1 R2 1 2 R R R R 1 1 R R R2 R2 OR alkyne OR O insertion CO insertion C R RS L RS RL Cr Cr CO OC CO OC CO CO OC O OH 2 R2 R R RL L electrocyclic tautomerization 1 R1 R ring closure R RS S Cr(CO) OR Cr(CO)3 OR 3

Example 15

O NO OMe 2 1. THF, reflux Se (OC)5Cr Se 2. CAN, 22% NO2 O

Example 38

H MOMO OMe MOMO OMe

ClCH2CH2Cl Cr(CO)5 O O 70 oC, 1 h, 76% O MOMO OH O MOMO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_85, © Springer-Verlag Berlin Heidelberg 2009 199

Example 38

BnO

Cr(CO)5

MOMO MeO OMOM OMe BnO OH THF, 50 oC, 61%

MeO OMe Example 39

1. 1.5 equiv t-BuLi, THF, −78 oC Cr(CO)5 2. 1.02 equiv Cr(CO) , THF O 6 O MeO −78 oC to rt MeO OEt MeO F 3. 1.02 equiv Et O•FB , rt MeO F OMe 3 4 29% OMe

OEt O Cr(CO)n O O CAN−HNO 5 equiv Ph H MeO 3 MeO 84%, 2 steps MeO Ph THF, 80 oC MeO Ph F MeO O MeO O

References

1. Dötz, K. H. Angew. Chem., Int. Ed. 1975, 14, 644−645. Karl H. Dötz (1943−) was a professor at the University of Munich in Germany. 2. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press, Greenwich, CT; 1989; Vol. 1. (Review). 3. Wulff, W. D. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon Press: Oxford, 1995; Vol. 12. (Review). 4. Torrent, M.; Solá, M.; Frenking, G. Chem. Rev. 2000, 100, 439−494. (Review). 5. Caldwell, J. J.; Colman, R.; Kerr, W. J.; Magennis, E. J. Synlett 2001, 1428−1430. 6. Solá, M.; Duran, M.; Torrent, M. The Dötz reaction: A chromium Fischer carbene- mediated benzannulation reaction. In Computational Modeling of Homogeneous Ca- talysis Maseras, F.; Lledós, eds.; Kluwer Academic: Boston; 2002, 269−287. (Re- view). 7. Pulley, S. R.; Czakó, B. Tetrahedron Lett. 2004, 45, 5511−5514. 8. White, J. D.; Smits, H. Org. Lett. 2005, 7, 235−238. 9. Boyd, E.; Jones, R. V. H.; Quayle, P.; Waring, A. J. Tetrahedron Lett. 2005, 47, 7983−7986. 200

Dowd−Beckwith ring expansion Radical-mediated ring expansion of 2-halomethyl cycloalkanones.

O O Br Bu3SnH, AIBN CO CH 2 3 PhH, reflux CO2CH3

Δ ↑ NC NN CN N2 2 CN homolytic cleavage

2,2ƍ-azobisisobutyronitrile (AIBN)

n-Bu3Sn H CN n-Bu3Sn H CN

SnBu3 O O O Br Bu3SnBr CO2CH3 CO2CH3 CO2CH3

O O

H SnBu 3 Bu3Sn CHO CH CO2CH3 2 3

Example 14

H H H O 1.2 eq. Bu3SnH cat. AIBN O H O H H CO2Et CO2Et Tol., reflux, 23 h CO2Et H 13% I 86%

Example 29

O O O CO2Me O CO2Me CO Me AIBN, Bu3SnD 2 H D I PhH, 80 oC CO Me D 2 D 8% 15% 77%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_86, © Springer-Verlag Berlin Heidelberg 2009 201

References

1. Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1987, 109, 3493−3494. Paul Dowd (1936−1996) was a professor at the University of Pittsburgh. 2. (a) Beckwith, A. L. J.; O’Shea, D. M.; Gerba, S.; Westwood, S. W. J. Chem. Soc., Chem. Commun. 1987, 666−667. Athelstan L. J. Beckwith is a professor at University of Adelaide, Adelaide, Australia. (b) Beckwith, A. L. J.; O’Shea, D. M.; Westwood, S. W. J. Am. Chem. Soc. 1988, 110, 2565−2575. (c) Dowd, P.; Choi, S.-C. Tetrahedron 1989, 45, 77−90. (d) Dowd, P.; Choi, S.-C. Tetrahedron Lett. 1989, 30, 6129−6132. (e) Dowd, P.; Choi, S.-C. Tetrahedron 1991, 47, 4847−4860. 3. Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091−2115. (Review). 4. Banwell, M. G.; Cameron, J. M. Tetrahedron Lett. 1996, 37, 525−526. 5. Studer, A.; Amrein, S. Angew. Chem., Int. Ed. 2000, 39, 3080−3082. 6. Kantorowski, E. J.; Kurth, M. J. Tetrahedron 2000, 56, 4317−4353. (Review). 7. Sugi, M.; Togo, H. Tetrahedron 2002, 58, 3171−3177. 8. Ardura, D.; Sordo, T. L. Tetrahedron Lett. 2004, 45, 8691−8694. 9. Ardura, D.; Sordo, T. L. J. Org. Chem. 2005, 70, 9417−9423.

202

Dudley reagent

CH3

O N O N CH3 OTf H3CO Dudley benzyl reagent Dudley PMB reagent

The Dudley reagents are employed for the protection of alcohols as benzyl1 or PMB2 ethers, respectively, under mild conditions. Carboxylic acids are readily protected as well.3 Activation of the appropriate Dudley reagent in the presence of an alcohol furnishes the desired arylmethyl ether. The benzyl reagent is activated upon warming to approximately 80–85 °C, whereas activation of the PMB reagent occurs at room temperature upon treatment with methyl triflate (CH3OTf) or protic acid.4 Aromatic solvents, most commonly trifluorotoluene, often provide the best results. Magnesium oxide (MgO) is typically included in the reaction mixture as 5 an acid scavenger. For benzylation of carboxylic acids, triethylamine (Et3N) is used in place of MgO.3

Preparation:1–3

CH3OTf, toluene O N O N 0 °C to rt, 1 h, 99% CH3 OTf Dudley benzyl reagent

CH3

CH3 OH KOH, 18-crown-6 O N H3CO toluene, reflux (–H2O) Cl N 90–93% H CO 3 Dudley PMB reagent

The Dudley reagents are conveniently prepared from readily available starting materials and are indefinitely stable to storage and handling under standard laboratory conditions. Alternatively, both reagents are commercially available.

Example 16

OH Dudley benzyl reagent, MgO OBn OAc PhCF , 85 °C, 24 h, 96% OAc 3

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_87, © Springer-Verlag Berlin Heidelberg 2009 203

Benzylation of a monoacetylated diol is shown in Example 1.6 The Dudley benzyl reagent was uniquely effective for protection of the free alcohol without loss and/or migration of the labile acetyl group.

Example 22 Dudley PMB reagent OH OPMB CH3OTf, MgO Si(CH3)3 Si(CH3)3 Ph PhCF , rt, 1 h, 80% Ph 3

PMB-protection of a β-hydroxysilane can be accomplished without competition from the Peterson elimination (Example 2),2 which would occur under the basic or acidic conditions required for many other alkylation reactions.

Example 34

O O

O Dudley PMB reagent, CSA O OH OPMB CH2Cl2, rt, 72 h, 85% OO OO

The Dudley PMB reagent can also be activated under mildly acidic conditions us- 4 ing catalytic camphorsulfonic acid (CSA) in lieu of CH3OTf (Example 3).

Example 4, In situ-formation of the Dudley benzyl reagent is achieved by treating 7 a mixture of an alcohol and 2-benzyloxypyridine with CH3OTf

OH O OBn CH3OTf, MgO, toluene O OCH3 O N O N 0 to 85 °C, 24 h, 84% OCH3 H O N O H O

References

1. Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006, 71, 3923–3927. 2. Nwoye, E. O.; Dudley, G. B. Chem. Commun. 2007, 1436–1437. 3. Tummatorn, J.; Albiniak, P. A.; Dudley, G. B. J. Org. Chem. 2007, 72, 8962–8964. 4. Stewart, C. A.; Peng, X.; Paquette, L. A. Synthesis 2008, 433–437. 5. Poon, K. W. C.; Albiniak, P. A.; Dudley, G. B. Org. Synth. 2007, 84, 295–305. 6. Schmidt, J. P.; Beltrân-Rodil, S.; Cox, R. J.; McAllister, G. D.; Reid, M.; Taylor, R. J. K. Org. Lett. 2007, 9, 4041–4044. 7. Lopez, S. S.; Dudley, G. B. Beilstein J. Org. Chem. 2008, 4, No. 44. 204

Erlenmeyer−Plöchl azlactone synthesis Formation of 5-oxazolones (or “azlactones”) by intramolecular condensation of acylglycines in the presence of acetic anhydride.

HN Ac2O N CO2H O R1 O R1 O

AcO O O H N HN N O O 2 AcOH O R O O 1 O O R O R1 O O 1 H mixed anhydride

Example 12

O NaOAc, Ac O O HN H 2 CO2H N Ph o − O O 110 C, 69 73% O O Ph O O

Example 28

O OH HN Pb(OAc)4, Ac2O O CO2H Ph O O THF, reflux, 15 h OH O

H O H O

BuNH2 O NH-Bu O O O HN O O N 67% Ph Ph 5.5:1 Z/E

Example 39

O O HN NaOAc, Ac O BnO OBn 2 O CO2H H Ph N O 95% F F Ph

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_88, © Springer-Verlag Berlin Heidelberg 2009 205

References

1. (a) Plöchl, J. Ber. 1884, 17, 1616−1624. (b) Erlenmeyer, E., Jr. Ann. 1893, 275, 1−3. Emil Erlenmeyer, Jr. (1864−1921) was born in Heidelberg, Germany to Emil Erlen- meyer (1825−1909), a famous chemistry professor at the University of Heidelberg. He investigated the Erlenmeyer−Plöchl azlactone synthesis while he was a Professor of Chemistry at Strasburg. The Erlenmeyer flasks “ ” are ubiquitous in organic chemistry laboratories. 2. Buck, J. S.; Ide, W.S. Org. Synth. Coll. II, 1943, 55. 3. Carter, H. E. Org. React. 1946, 3, 198−239. (Review). 4. Baltazzi, E. Quart. Rev. Chem. Soc. 1955, 9, 150−173. (Review). 5. Filler, R.; Rao, Y. S. New Development in the Chemistry of Oxazolines, In Adv. Het- erocyclic Chem; Katritzky, A. R.; Boulton, A. J., Eds; Academic Press, Inc: New York, 1977, Vol. 21, pp 175−206. (Review). 6. Mukerjee, A. K.; Kumar, P. Heterocycles 1981, 16, 1995−2034. (Review). 7. Mukerjee, A. K. Heterocycles 1987, 26, 1077−1097. (Review). 8. Combs, A. P.; Armstrong, R. W. Tetrahedron Lett. 1992, 33, 6419−6422. 9. Konkel, J. T.; Fan, J.; Jayachandran, B.; Kirk, K. L. J. Fluorine Chem. 2002, 115, 27−32. 10. Brooks, D. A. Erlenmeyer−Plöchl Azlactone Synthesis. In Name Reactions in Hetero- cyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 229−233. (Review).

206

Eschenmoser’s salt

CH2 I N H3CCH3

Eschenmoser’s salt, dimethylmethylideneammonium iodide, is a strong dimethylaminomethylating agent, used to prepare derivatives of the type RCH2N(CH3)2. Enolates, enolsilylethers, and even more acidic ketones undergo efficient dimethylaminomethylation—employed in the Mannich reaction.

Mechanism

CH2 I O LDA OLi N H3CCH3 R R R 2 THF R 2 1 1

Li O O R2 R1 CH3 R1 N CH2 R2 CH3 N H3CCH3

Example 13 Once prepared, the resulting tertiary amines can be further methylated and then subjected to base-induced elimination to afford methylenated ketones.

1. 15 equiv NaN(SiMe3)2, THF o OTBS −78 C, 45 min. H3C H + − O then 15 equiv of Me2(CH2)N I H o O 0 C, 15 min. O O CO Me H H H 2 2. 20 equiv MeI, MeOH, 0.5 h TBSO 3. 10 equiv DBU, PhH, rt, 1 h CH3 51% 3 steps

OTBS H3C H O H O O O CO Me H H H 2 TBSO CH3

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_89, © Springer-Verlag Berlin Heidelberg 2009 207

Example 24

O CH2 H O I N O S O H N N O S O H3CCH3 N O N O N Et N, DMF, rt : Et3NH N Et NH 3 N H 3 12 h, 64% CH3 CH 3

O H H N N O S O O H N O N O S O N N N H Et3NH N O N CH3 N CH3 H

Example 35

O O CH2 O I N H3CCH3 O O O DMF, 90 oC, 62% O N H N O H

References

1. Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew. Chem., Int. Ed. 1971, 10, 330–331. 2. Kleinman, E. F. Dimethylmethyleneammonium Iodide and Chloride. In Encyclopedia of Reagents for Organic Synthesis (Ed: Paquette, L. A.) 2004, John Wiley & Sons, New York. (Review). 3. Nicolaou, K. C.; Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao, X. Y.; Hwang, C. K. J. Am. Chem. Soc. 1993, 115, 3558–3575. 4. Saczewski, J.; Gdaniec, M. Tetrahedron Lett. 2007, 48, 7624–7627. 5. Hong, A.-W.; Cheng, T.-H.; Raghukumar, V.; Sha, C.-K. J. Org. Chem. 2008, 73, 7580–7585. 6. Cesario, C.; Miller, M. J. Org. Lett. 2009, 11, 449–452.

208

Eschenmoser−Tanabe fragmentation Fragmentation of α,β-epoxyketones via the intermediacy of α,β-epoxy sulfonylhydrazones.

O − 1. H2O2, OH

+ 2. H2NNHSO2Ar, H 3. −OH O

OOH OH O O O H2NNHSO2Ar

H N O N SO2Ar O O H

O O O OH ↑ SO2Ar N2 N N SHO Ar N 2 NSO2Ar

Example 14

O Tol-SO2NHNH2 CHCl3-AcOH (1:1) O rt, 5 h, 73% AcO AcO O

Example 27

Me Me 1. TsNHNH2, rt

o O Me 2. 55 C, 2 h, 50% O Me O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_90, © Springer-Verlag Berlin Heidelberg 2009 209

Example 39

O O H H 1. NsNHNH , AcOH, THF; O 2 evaporation, 60 oC, o NaBH4, AcOH, THF, 0 C OMe OMe O TESO OAc OAc 2. TESOTf, 2,6-lutidine NNs NNs CH2Cl2, rt 60%, 2 steps

References

1. Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta 1967, 50, 708−713. Albert Eschenmoser (Switzerland, 1925−) is best known for his work on, among many others, the monumental total synthesis of Vitamin B12 with R. B. Woodward in 1973. He now holds appointments at ETH Zürich and Scripps Research Institute, La Jolla. 2. Tanabe, M.; Crowe, D. F.; Dehn, R. L. Tetrahedron Lett. 1967, 3943−3946. 3. Felix, D.; Müller, R. K.; Horn, U.; Joos, R.; Schreiber, J.; Eschenmoser, A. Helv. Chim. Acta 1972, 55, 1276−1319. 4. Batzold, F. H.; Robinson, C. H. J. Org. Chem. 1976, 41, 313−317. 5. Covey, D. F.; Parikh, V. D. J. Org. Chem. 1982, 47, 5315−5318. 6. Chinn, L. J.; Lenz, G. R.; Choudary, J. B.; Nutting, E. F.; Papaioannou, S. E.; Metcalf, L. E.; Yang, P. C.; Federici, C.; Gauthier, M. Eur. J. Med. Chem. 1985, 20, 235−240. 7. Dai, W.; Katzenellenbogen, J. A. J. Org. Chem. 1993, 58, 1900−1908. 8. Mück-Lichtenfeld, C. J. Org. Chem. 2000, 65, 1366−1375. 9. Kita, Y.; Toma, T.; Kan, T.; Fukuyama, T. Org. Lett. 2008, 10, 3251−3253.

210

Eschweiler–Clarke reductive alkylation of amines Reductive methylation of primary or secondary amines using formaldehyde and formic acid. Cf. Leuckart–Wallach reaction.

RNH2 CH2O HCO2H RN

formic acid is the hydride source as a reducing agent

H O OH H H OH2 RN RN : H RNH H H 2

H O H H

↑ H H : OH2 RN O O CO : RN HO RNH

H − H RN O O CO↑ RNH RN HO

Example 17

O O CD NH N 3 DCOD, DCO2D, DMSO H3C CH3 H3C CH3 microwave (120 W) 1−3 min. d3-tamoxifen

Example 29

H CH3 N 1.2 equiv 37% CH2O in H2O N 5 equiv 85% HCO2H in H2O steam bath, 84% OH OH

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_91, © Springer-Verlag Berlin Heidelberg 2009 211

Example 310

N N CHO OH

NH N: N N varenicline (Chantix)

O N N H O N N N N

References

1 (a) Eschweiler, W. Chem. Ber. 1905, 38, 880–892. Wilhelm Eschweiler (1860−1936) was born in Euskirchen, Germany. (b) Clarke, H. T.; Gillespie, H. B.; Weisshaus, S. Z. J. Am. Chem. Soc. 1933, 55, 4571–4587. Hans T. Clarke (1887−1927) was born in Harrow, England. 2 Moore, M. L. Org. React. 1949, 5, 301–330. (Review). 3 Pine, S. H.; Sanchez, B. L. J. Org. Chem. 1971, 36, 829–832. 4 Bobowski, G. J. Org. Chem. 1985, 50, 929–931. 5 Alder, R. W.; Colclough, D.; Mowlam, R. W. Tetrahedron Lett. 1991, 32, 7755–7758. 6 Bulman Page, P. C.; Heaney, H.; Rassias, G. A.; Reignier, S.; Sampler, E. P.; Talib, S. Synlett 2000, 104–106. 7 Harding, J. R.; Jones, J. R.; Lu, S.-Y.; Wood, R. Tetrahedron Lett. 2002, 43, 9487– 9488. 8 Brewer, A. R. E. Eschweiler–Clarke reductive alkylation of amine. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 86−111. (Review). 9 Weis, R.; Faist, J.; di Vora, U.; Schweiger, K.; Brandner, B.; Kungl, A. J.; Seebacher, W. Eur. J. Med. Chem. 2008, 43, 872–879. 10 Waterman, K. C.; Arikpo, W. B.; Fergione, M. B.; Graul, T. W.; Johnson, B. A.; Mac- donald, B. C.; Roy, M. C.; Timpano, R. J. J. Pharm. Sci. 2008, 97, 1499–1507.

212

Evans aldol reaction Asymmetric aldol condensation of aldehyde and chiral acyl oxazolidinone, the Evans chiral auxiliary.

O O OH O Lewis acid R* + R* R' H R' base Me Me Evans syn chiral auxiliary O O O O O

R* = NO NO NO NO NO

Bn Ph Me Ph t-Bu i-Pr

Example 12 O O OH O O 1. Bu2BOTf, R3N ON Ph ON 2. PhCHO, − 78 oC 79%, 80:20 de

BuBu Bu2BOTf B O O O H O O Z-(O)-boron enolate PhCHO O N Bu H ON B O Bu ON H formation O H Ph

R3N:

Bu Bu B O O O OH O O aldol workup Ph ON Ph ON condensation

Example 25 O O

MeO N ON O O TiCl4, DIPEA o MeO C CH2Cl2, −78 C, 1.5 h 2 ON N OMe then rt, overnight, 52% CO2Me

OMe

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_92, © Springer-Verlag Berlin Heidelberg 2009 213

Example 39

1 eq. Bu BOT 2 f S O OH S O 1.1 eq. Et N O 3 OTES NO NO PhMe, 0.15 M OBn OBn o OTES − 50 to − 30 C Bn Bn 2 h, 72%

Example 4, Crimmins procedure10

O O TiCl4 OH O O (−)-sparteine TBDPSO N O TBDPSO N O CHO 96%, 96% de Bn Bn

References

1. (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127−2129. David Evans is a professor at Harvard University. (b) Evans, D. A.; McGee, L. R. J. Am. Chem. Soc. 1981, 103, 2876−2878. 2. Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org. Chem. 1990, 55, 173−181. 3. Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3−12. (Review). 4. Braddock, D. C.; Brown, J. M. Tetrahedron: Asymmetry 2000, 11, 3591−3607. 5. Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki, T. Tetrahedron 2000, 56, 7411−7422. 6. Williams, D. R.; Patnaik, S.; Clark, M. P. J. Org. Chem. 2001, 66, 8463−8469. 7. Guerlavais, V.; Carroll, P. J.; Joullié, M. M. Tetrahedron: Asymmetry 2002, 13, 675−680. 8. Li, G.; Xu, X.; Chen, D.; Timmons, C.; Carducci, M. D.; Headley, A. D. Org. Lett. 2003, 5, 329−331. 9. Zhang, W.; Carter, R. G.; Yokochi, A. F. T. J. Org. Chem. 2004, 69, 2569−2572. 10. Ghosh, S.; Kumar, S. U.; Shashidhar, J. J. Org. Chem. 2008, 73, 1582−1585. 11. Zhang, J. Evans aldol reaction. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 532−553. (Review).

214

Favorskii rearrangement Transformation of enolizable α-haloketones to esters, carboxylic acids, or amides via alkoxide-, hydroxide-, or amine-catalyzed rearrangements, respectively.

O H O R1 R1 R3 Nuc-H X = Cl, Br, I R Nuc X H 2 Nuc = OH, OR, NRR' R2 R4 base R3 R4

The intramolecular Favorskii Rearrangement:

O O ( ) R R n 1 2 Nuc-H Nuc n = 0−5 X H R1 ( ) base n R2 H

O O OR Cl OR

enolizable α-haloketone

O OR O O Cl H Cl Cl HOR OR

cyclopropanone intermediate

OOR O OR OOR HOR HOR OR

Example 12

O H CO2H O Br2, CH3CO2H KOH, DMSO

50 oC, 1 h, 97% o Br Br 100 C, 1 h 47%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_93, © Springer-Verlag Berlin Heidelberg 2009 215

Example 2, Homo-Favorskii rearrangement3

O O TsO O O 1.96 eq. NaOH H dioxane/H2O 90 oC, 3 h, 86% 51 : 40 : 9

Example 36

O O O Br CO Me Br CO2Me 2 Br2 NaOMe, MeOH MeO MeO Et2O 37% 2 steps O

Example 4, Photo-Favorskii Rearrangement7

O O 300 nm light hν Cl Cl electron 5% aq. CH3CN homolysis transfer propylene oxide H H 4 h, 81%

O H H Cl OH Cl 1,2-aryl H2O O migration H H O

Example 58

O O O NC NC Br KCN, α-cyclodextrin Br NC Br Br Br MeCN, H2O 10−15 oC, 12 h 80%

216

HO O HO O NC O H H H NC H NC H NC H

Ratio 9 : 1

Example 610

O O NaOMe OMe Cl THPO MeOH THPO 0 oC, 15 min. 96%

References

1. (a) Favorskii, A. E. J. Prakt. Chem. 1895, 51, 533−563. Aleksei E. Favorskii (1860−1945), born in Selo Pavlova, Russia, studied at St. Petersburg State University, where he became a professor since 1900. (b) Favorskii, A. E. J. Prakt. Chem. 1913, 88, 658. 2. Wagner, R. B.; Moore, J. A. J. Am. Chem. Soc. 1950, 72, 3655−3658. 3. Wenkert, E.; Bakuzis, P.; Baumgarten, R. J.; Leicht, C. L.; Schenk, H. P. J. Am. Chem. Soc. 1971, 93, 3208−3216. 4. Chenier, P. J. J. Chem. Ed. 1978, 55, 286−291. (Review). 5. Barreta, A.; Waegell, B. In Reactive Intermediates; Abramovitch, R. A., ed.; Plenum Press: New York, 1982, 2, pp 527−585. (Review). 6. White, J. D.; Dillon, M. P.; Butlin, R. J. J. Am. Chem. Soc. 1992, 114, 9673−9674. 7. Dhavale, D. D.; Mali, V. P.; Sudrik, S. G.; Sonawane, H. R. Tetrahedron 1997, 53, 16789−16794. 8. Kitayama, T.; Okamoto, T. J. Org. Chem. 1999, 64, 2667−2672. 9. Mamedov, V. A.; Tsuboi, S.; Mustakimova, L. V.; Hamamoto, H.; Gubaidullin, A. T.; Litvinov, I. A.; Levin, Y. A. Chem. Heterocyclic Compd. 2001, 36, 911. (Review). 10. Pogrebnoi, S.; Saraber, F. C. E.; Jansen, B. J. M.; de Groot, A. Tetrahedron 2006, 62, 1743−1748. 11. Filipski, K.J.; Pfefferkorn, J. A. Favorskii rearrangement. In Name Reactions for Ho- mologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 238−252. (Review).

217

Quasi-Favorskii rearrangement If there are no enolizable hydrogens present, the classical Favorskii rearrangement is not possible. Instead, a semi-benzylic mechanism can lead to a rearrangement referred to as quasi-Favorskii.

O R5 O R4 X = Cl, Br, I R1 R3 Nuc R3 Nuc X R4 Nuc = OH, OR, NRR' R2 R5 R2 R1 R3,4,5 = H

Example 1, Arthur C. Cope’s initial discovery1

OEt OEt O O Hg(OAc)2

EtOH, reflux CO2Et 4 h, 71% Br Br non-enolizable ketone

Example 25 NHLi O Br N H O Et2O, hexane 25 oC, 67%

Example 36 Li

Br THF, −78 to −30 oC, 90% O O

References

1. Cope, A. C.; Graham, E. S. J. Am. Chem. Soc. 1951, 73, 4702−4706. 2. Smissman, E. E.; Diebold, J. L. J. Org. Chem. 1965, 30, 4005−4007. 3. Sasaki, T.; Eguchi, S.; Toru, T. J. Am. Chem. Soc. 1969, 91, 3390−3391. 4. Baudry, D.; Begue, J. P.; Charpentier-Morize, M. Tetrahedron Lett. 1970, 2147−2150. 5. Stevens, C. L.; Pillai, P. M.; Taylor, K. G. J. Org. Chem. 1974, 39, 3158−3161. 6. Harmata, M.; Wacharasindhu, S. Org. Lett. 2005, 7, 2563−2565. 7. Harmata, M.; Wacharasindhu, S. J. Org. Chem. 2005, 70, 725−728. 8. Filipski, K.J.; Pfefferkorn, J. A. Favorskii rearrangement. In Name Reactions for Ho- mologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 438−452. (Review). 9. Harmata, M.; Wacharasindhu, S. Synthesis 2007, 2365−2369. 218

Feist–Bénary furan synthesis α-Haloketones react with β-ketoesters in the presence of base to fashion furans.

O O O O Et3N, 0 °C, 52 h Cl OEt 54−57% CO2Et

Et N: 3 Et3NH OH Cl CO2Et H CO2Et O rate-determining CO2Et H Cl step O O :NEt O 3

CO2Et CO2Et HO H O CO2Et 2 CO2Et Et3NH H O O

O O: Et N: 3

Example 12,3

O H3CO2C O O O KOH, MeOH

OEt 57% OCH3 Cl O H CO O 3

Example 24

O O O O pyridine, rt to 50 °C, 4 h Cl H OEt then rt, overnight, 86% CO Et 2

Example 3, Ionic liquid-promoted interrupted Feist–Benary reaction10

HO R1OC R OC CO Et Br O CO Et 1 2 O O [bmim]OH 2 [pmim]Br R3 OEt R R1 R2 R1 O 3 − o R R O rt 70 75 C 1 O 3 interrupted − Feist−Benary Feist Benary products products

R1 = CH3, Et, Ph, n-Pr, etc. OH Br R = CH , OCH , PEt 2 3 3 [bmim]OH = N N [pmim]Br = N N R = H, n-Bu, CO Et C4H9 C4H9 3 2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_94, © Springer-Verlag Berlin Heidelberg 2009 219

References

1. (a) Feist, F. Ber. 1902, 35, 1537−1544. (b) Bénary, E. Ber. 1911, 44, 489−492. 2. Gopalan, A.; Magnus, P. J. Am. Chem. Soc. 1980, 102, 1756−1757. 3. Gopalan, A.; Magnus, P. J. Org. Chem. 1984, 49, 2317−2321. 4. Padwa, A.; Gasdaska, J. R. Tetrahedron 1988, 44, 4147−4160. 5. Dean, F. M. Recent Advances in Furan Chemistry. Part I. In Advances in Heterocyclic Chemistry, Katritzky, A. R., Ed.; Academic Press: New York, 1982; Vol. 30, 167−238. (Review). 6. Cambie, R. C.; Moratti, S. C.; Rutledge, P. S.; Woodgate, P. D. Synth. Commun. 1990, 20, 1923−1929. 7. Friedrichsen, W. Furans and Their Benzo Derivatives: Synthesis. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V.; Bird, C. V. Eds.; Pergamon: New York, 1996; Vol. 2, 351−393. (Review). 8. König, B. Product Class 9: Furans. In Science of Synthesis: Houben−Weyl Methods of Molecular Transformations; Maas, G., Ed.; Georg Thieme Verlag: New York, 2001; Cat. 2, Vol. 9, 183−278. (Review). 9. Shea, K. M. Feist–Bénary Furan Synthesis. In Name Reactions in Heterocyclic Chem- istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 160−167. (Review). 10. Ranu, B. C.; Adak, L.; Banerjee, S. Tetrahedron Lett. 2008, 49, 4613−4617.

220

Ferrier carbocyclization This process (also known as the “Ferrier II Reaction”) has proved to be of consid- erable value for the efficient, one-step conversion of 5,6-unsaturated hexopyranose derivatives into functionalized cyclohexanones useful for the preparation of such enantiomerically pure compounds as inositols and their amino, deoxy, unsaturated and selectively O-substituted derivatives, notably phosphate esters. In addition, the products of the carbocyclization have been incorporated into many complex compounds of interest in biological and medicinal chemistry.1,2 General examples:3

HgCl HgCl Me CO, H O BzO O 2, 2 2 BzO O BzO reflux, 4.5 h, 83% BzO TsO OMe TsO OMe 1

HgCl HgCl O BzO BzO BzO O BzO BzO BzO O O TsO OH 2 HO O OMe 3 Ts O 4 Ts

OBz O BzO O O BzO BzO OBz BzO BzO BzO OBz BzO OMe OMe O O O OBz BzO BzO BzO OH BzO BzO 83%6 OBz 80%6 BzO 93%4 OH OH More complex products:

O O BzO BzO O AcO O AcO OMe AcO OMe AcO OMe O OC6H4OMe(p) O O O BzO OH BzO AcO O OAc AcO OH OAc OH O 8 OC H OMe(p) 83%7 7 86% (2:1) 6 4 75%

Complex bioactive compounds made following the application of the reaction: OH HO OH HO OH H NH O HO OH HO H O O NH HO O O Paniculide A9 OH O Pancratistatin10 Calystegine B 11 2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_95, © Springer-Verlag Berlin Heidelberg 2009 221

Modified hex-5-enopyranosides and reactions

OAc HO a,b BnO OAc BnO O BnO BnO BnO OH BnO OMe 14 85% BnO H BnO c HO O Bn OMe BnO O 79%13 BnO O BnO OMe d BnO BnO 13 BnO OMe 98% o a, Hg(OCOCF3)2, Me2CO, H2O, 0 C; b, NaBH(OAc)3, AcOH, MeCN, rt; c, i- Bu3Al, PhMe, 40 °C; d, Ti(Oi-Pr)Cl3, CH2Cl2, –78 °C, 15 min. (Note: The aglycon is retained in the Al- and Ti-induced reactions).

References

1. Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779−2831. (Review). 2. Ferrier, R. J. Top. Curr. Chem. 2001, 215, 277−291 (Review). 3. Ferrier, R. J. J. Chem. Soc., Perkin Trans. 1 1979, 1455−1458. The discovery (1977) was made in the Pharmacology Department, University of Edinburgh, while R. J. Fer- rier was on leave from Victoria University of Wellington, New Zealand where he was Professor of Organic Chemistry. He is now a consultant with Industrial Research Ltd., Lower Hutt, New Zealand. 4. Blattner, R.; Ferrier, R. J.; Haines, S. R. J. Chem. Soc., Perkin Trans. 1, 1985, 2413−2416. 5. Chida, N.; Ohtsuka, M.; Ogura, K.; Ogawa, S. Bull. Chem. Soc. Jpn. 1991, 64, 2118−2121. 6. Machado, A. S.; Olesker, A.; Lukacs, G. Carbohydr. Res. 1985, 135, 231−239. 7. Sato, K.-i.; Sakuma, S.; Nakamura, Y.; Yoshimura, J.; Hashimoto, H. Chem. Lett. 1991, 17−20. 8. Ermolenko, M. S.; Olesker, A.; Lukacs, G. Tetrahedron Lett. 1994, 35, 711−714. 9. Amano, S.; Takemura, N.; Ohtsuka, M.; Ogawa, S.; Chida, N. Tetrahedron 1999, 55, 3855−3870. 10. Park, T. K.; Danishefsky, S. J. Tetrahedron Lett. 1995, 36, 195−196. 11. Boyer, F.-D.; Lallemand, J.-Y. Tetrahedron 1994, 50, 10443−10458. 12. Das, S. K.; Mallet, J.-M.; Sinaÿ, P. Angew. Chem., Int. Ed. 1997, 36, 493−496. 13. Sollogoub, M.; Mallet, J.-M.; Sinaÿ, P. Tetrahedron Lett. 1998, 39, 3471−3472. 14. Bender, S. L.; Budhu, R. J. J. Am. Chem. Soc. 1991, 113, 9883−9884. 15. Estevez, V. A.; Prestwich, E. D. J. Am. Chem. Soc. 1991, 113, 9885−9887. 16. Yadav, J. S.; Reddy, B. V. S.; Narasimha Chary, D.; Madavi, C.; Kunwar, A. C. Tetrahedron Lett. 2009, 50, 81−84.

222

Ferrier glycal allylic rearrangement In the presence of Lewis acid catalysts O-substituted glycal derivatives can react with O-, S-, C- and, less frequently, N-, P- and halide nucleophiles to give 2,3- unsaturated glycosyl products.1,2 This allylic transformation has been termed the “Ferrier Reaction” or, to avoid complications, the “Ferrier I Reaction” or the “Fer- rier Rearrangement”. However, the reaction was first noted by Emil Fischer when he heated tri-O-acetyl-D-glucal in water.3 When carbon nucleophiles are involved, the term “Carbon Ferrier Reaction” has been used,4 although the only contribution the Ferrier group made in this area was to find that tri-O-acetyl-D-glucal dimerizes under acid catalysis to give a C-glycosidic product.5 The general reaction is illustrated by the separate conversions of tri-O-acetyl-D-glucal with O-, S- and C- nucleophiles to the corresponding 2,3-unsaturated glycosyl derivatives. Normally, Lewis acids are used as catalysts, boron trifluoride etherate being the most common. Allyloxycarbenium ions are involved as intermediates, high yields of products are obtained, and glycosidic compounds with quasi-axial bonds (as illustrated) predominate (commonly in the Į,ȕ-ratio of about 7:1). The examples illustrated4,6,7 are typical of a very large number of literature reports.1

6 i) HOCH2CCH 7 6 ii) HSPh OAc R = i) OCH2CCH 7 AcO ii) SPh O + Lewis acid AcO O AcO O iii) 4 AcO 4 OAc R iii) AcO

General examples4

OAc OAc AcO O SnBr4, C6H14, EtOAc H AcO O AcO rt, 5 min, 94%

More complex products made directly from the corresponding glycols:

O OH O OAc O AcO O NHC(O)CCl OH O O 3

Ph OMe O OH O EtO AcO O O O By spontaneous sigmatropic In PhCOCH2CO2Et, rearrangement of the glycal BF3.OEt2, In benzene, BF3•OEt2, 3-trichloroacetimidate made o rt, 15 min, with NaH, Cl CCN, 5 C, 10 min, (67%, α 9 3 α 8 (81% -anomer). (78% α-anomer).10 -anomer).

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_96, © Springer-Verlag Berlin Heidelberg 2009 223

Products formed without acid catalysts

O O HO O OMe AcO O O O O O O O O O Promoter: O DEAD, Ph3P DDQ (80%, α-anomer)11 (88%, mainly α)12 N-iodonium dicollidine perchlorate 13 C-3 leaving group of glycal: (65%, mainly α) hydroxy acetoxy pent-4-enoyloxy

Modified glycals and their reactions:

OBn OH O Me O O N N OBn + Ph + BnO O N N H OAc I OBn O Cl O O N N O Ph BnO O N N H

o BF3•OEt2, CH2Cl2, 0 C AgNO3, Na2CO3, reflux MeNO2, α)14 6 h (58%, α,β 1:1).15 (70%, mainly

References

1. Ferrier, R. J.; Zubkov, O. A. Transformation of glycals into 2,3-unsaturated glycosyl derivatives, In Org. React. 2003, 62, 569−736. (Review). It was almost 50 years after Fischer’s seminal finding that water took part in the reaction3 that Ann Ryan, working in George Overend’s Department in Birkbeck College, University of London, found, by chance, that p-nitrophenol likewise participates.16 Robin Ferrier, her immediate su- pervisor, who suggested her experiment, then found that simple alcohols at high temperatures also take part,17 and with other students, notably Nagendra Prasad and George Sankey, he explored the reaction extensively. They did not apply it to make the very important C-glycosides. 2. Ferrier, R. J. Top. Curr. Chem. 2001, 215, 153−175. (Review). 3. Fischer, E. Chem. Ber. 1914, 47, 196−210. 4. Herscovici, J.; Muleka, K.; Boumaïza, L.; Antonakis, K. J. Chem. Soc., Perkin Trans. 1 1990, 1995−2009. 5. Ferrier, R. J.; Prasad, N. J. Chem. Soc. (C) 1969, 581−586. 6. Moufid, N.; Chapleur, Y.; Mayon, P. J. Chem. Soc., Perkin Trans. 1 1992, 999−1007. 7. Whittman, M. D.; Halcomb, R. L.; Danishefsky, S. J.; Golik, J.; Vyas, D. J. Org. Chem. 1990, 55, 1979−1981. 8. Klaffke, W.; Pudlo, P.; Springer, D.; Thiem, J. Ann. 1991, 509−512. 9. Yougai, S.; Miwa, T. J. Chem. Soc., Chem. Commun. 1983, 68−69. 10. Armstrong, P. L.; Coull, I. C.; Hewson, A. T.; Slater, M. J. Tetrahedron Lett. 1995, 36, 4311−4314. 224

11. Sobti, A.; Sulikowski, G. A. Tetrahedron Lett. 1994, 35, 3661−3664. 12. Toshima, K.; Ishizuka, T.; Matsuo, G.; Nakata, M.; Kinoshita, M. J. Chem. Soc., Chem. Commun. 1993, 704−705. 13. López, J. C.; Gómez, A. M.; Valverde, S.; Fraser-Reid, B. J. Org. Chem. 1995, 60, 3851−3858. 14. Booma, C.; Balasubramanian, K. K. Tetrahedron Lett. 1993, 34, 6757−6760. 15. Tam, S. Y.-K.; Fraser-Reid, B. Can. J. Chem. 1977, 55, 3996−4001. 16. Ferrier, R. J.; Overend, W. G.; Ryan, A. E. J. Chem. Soc. (C) 1962, 3667−3670. 17. Ferrier, R. J. J. Chem. Soc. 1964, 5443−5449. 18. De, K.; Legros, J.; Crousse, Be.; Bonnet-Delpon, D. Tetrahedron 2008, 64, 10497−10500.

225

Fiesselmann thiophene synthesis Condensation reaction of thioglycolic acid derivatives with Į,ȕ-acetylenic esters, which upon treatment with base result in the formation of 3-hydroxy-2- thiophenecarboxylic acid derivatives.

CO2Me O NaOMe OH MeO C CO Me HS S 2 2 OMe

MeO2C

O MeO2C OCH3 O

O S OMe O S H3CO H S OMe OMe O

O MeO2C O MeO2C OMe S OMe O S S H S MeO C O CO Me OMe 2 MeO C 2 S 2 OMe

OMe OMe O CO2Me O H O O MeO O NaOMe S S OMe OMe S OMe S S MeO2C S CO2Me CO2Me MeO2C CO2Me MeO2C

CO2Me CO Me H MeO CO2Me 2 H S O HOMe OH S O S OMe MeO C H 2 S MeO C MeO2C CO Me 2 2

Example 15

O 12 equiv HSCH CO H S CO2R3 S 2 2 NaOR3, R3OH CO2R3 CO R R OH, HCl (g), −10 oC, 1 h rt, 24 h, 46−98% 2 3 3 CO2R3 OH

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_97, © Springer-Verlag Berlin Heidelberg 2009 226

Example 26

CH3 N CH CH3 CH3 3 N CH N 3 CH3 O OCH O NaOMe 3 HSCH2CO2H O MeOH S O HCl, MeOH S O O O CO2CH3

Example 37 O HS N S N Cl OEt CO2Et NaH, DMSO, 89% CN NH 2

Example 49 S CO Me HSCH2CO2Me 2 CN NaOMe, 68% NH2

References

1. Fiesselmann, H.; Schipprak, P. Ber. 1954, 87, 835−841; Fiesselmann, H.; Schipprak, P.; Zeitler, L. Ber. 1954, 87, 841−848; Fiesselmann, H.; Pfeiffer, G. Ber. 1954, 87, 848; Fiesselmann, H.; Thoma, F. Ber. 1956, 89, 1907−1912; Fiesselmann, H.; Schip- prak, P. Ber. 1956, 89, 1897−1902. 2. Gronowitz, S. In Thiophene and Its Derivatives, Part 1, Gronowitz, S., Ed.; Wiley & Sons: New York, 1985, 88−125. (Review). 3. Nicolaou, K. C.; Skokotas, G.; Furuya, S.; Suemune, H.; Nicolaou, D. C. Angew. Chem., Int. Ed. 1990, 29, 1064−1068. 4. Mullican, M. D.; Sorenson, R. J.; Connor, D. T.; Thueson, D. O.; Kennedy, J. A.; Con- roy, M. C. J. Med. Chem. 1991, 34, 2186−2194. 5. Donoso, R.; Jordan de Urries, P.; Lissavetzky, J. Synthesis 1992, 526−528. 6. Ram, V. J.; Goel, A.; Shukla, P. K.; Kapil, A. Bioorg. Med. Chem. Lett. 1997, 7, 3101−3106. 7. Showalter, H. D. H.; Bridges, A. J.; Zhou, H.; Sercel, A. D.; McMichael, A.; Fry, D. W. J. Med. Chem. 1999, 42, 5464−5474. 8. Shkinyova, T. K.; Dalinger, I. L.; Molotov, S. I.; Shevelev, S. A. Tetrahedron Lett. 2000, 41, 4973−4975. 9. Redman, A. M.; Johnson, J. S.; Dally, R.; Swartz, S.; Wild, H.; Paulsen, H.; Caringal, Y.; Gunn, D.; Renick, J.; Osterhout, M. Bioorg. Med. Chem. Lett. 2001, 11, 9−12. 10. Migianu, E.; Kirsch, G. Synthesis, 2002, 1096. 11. Mullins, R. J.; Williams, D. R. Fiesselmann Thiophene Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 184−192. (Review). 227

Fischer indole synthesis Cyclization of arylhydrazones to indoles.

R1 R1 1 R R2 2 H R R2 NH3 N N N H O N NH3 H H

phenylhydrazine phenylhydrazone

1 1 1 R R R H H 2 R2 R2 [3,3]-sigmatropic R tautomerization NH2 N NH2 rearrangement N N N H H H H H protonation ene-hydrazine double imine

1 1 R R1 H R1 H R 2 2 NH R R2 R 3 R2 NH2 N NH2 N NH3 N N H H H H2 H

Example 13 N

O HN Ph 1. neat, 160 oC, 24 h N N O NH 2 2. NH NH , 120 oC, 12 h N N N 2 2 H H 71% N H

Example 213

Δ, AcOH, 5 h CN NH2 CN N NH 57% H CO2Et CO2Et

Example 4 (Severe racemization)9

H H

1. PhNHNH2 CO2Me or CO2Me N O O N 2. AcOH H H Ph Ph

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_98, © Springer-Verlag Berlin Heidelberg 2009 228

CO2Me CO Me H Ph Ph 2 N N H H CO2Me H N N H H H Ph N N 22% H H 16% 6%

H H H CO Me 2 CO Me N N CO2Me 2 H H N N N N Ph H H H H 5% Ph Ph 4% 4%

References

1. (a) Fischer, E.; Jourdan, F. Ber. 1883, 16, 2241−2245. H. Emil Fischer (1852−1919) is arguably the greatest organic chemist ever. He was born in Euskirchen, near Bonn, Germany. When he was a boy, his father, Lorenz, said about him: “The boy is too stupid to go in to business; so in God’s name, let him study.” Fischer studied at Bonn and then Strassburg under Adolf von Baeyer. Fischer won the Nobel Prize in Chemis- try in 1902 (three years ahead of his master, von Baeyer) for his synthetic studies in the area of sugar and purine groups. (b) Fischer, E.; Hess, O. Ber. 1884, 17, 559. 2. Robinson, B. The Fisher Indole Synthesis, John Wiley & Sons: New York, NY, 1982. (Book). 3. Martin, M. J.; Trudell, M. L.; Arauzo, H. D.; Allen, M. S.; LaLoggia, A. J.; Deng, L.; Schultz, C. A.; Tan, Y.; Bi, Y.; Narayanan, K.; Dorn, L. J.; Koehler, K. F.; Skolnick, P.; Cook, J. M. J. Med. Chem. 1992, 35, 4105−4117. 4. Hughes, D. L. Org. Prep. Proc. Int. 1993, 25, 607−632. (Review). 5. Bosch, J.; Roca, T.; Armengol, M.; Fernández-Forner, D. Tetrahedron 2001, 57, 1041−1048. 6. Ergün, Y.; Patir, S.; Okay, G. J. Heterocycl. Chem. 2002, 39, 315−317. 7. Pete, B.; Parlagh, G. Tetrahedron Lett. 2003, 44, 2537−2539. 8. Li, J.; Cook, J. M. Fischer Indole Synthesis. In Name Reactions in Heterocyclic Chem- istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 116−127. (Review). 9. Borregán, M.; Bradshaw, B.; Valls, N.; Bonjoch, J. Tetrahedron: Asymmetry 2008, 19, 2130−2134. 10. Donald, J. R.; Taylor, R. J. K. Synlett 2009, 59−62.

229

Fischer oxazole synthesis Oxazoles from the condensation of equimolar amounts of aldehyde cyanohydrins and aromatic aldehydes in dry ether in the presence of dry hydrochloric acid.

OH ether R2 O R2CHO R1 H2O HCl R1 CN HCl N

H H H H OH O R O R2 O R2 2 R N R1 HCl 1

OH : R1 N N NH HO H2O R Cl 1 Cl Cl Cl

R R2 2 R2 O H O SN2 isomerization H N elimination O R N N 1 R1 HCl R Cl Cl 1

Example 14

OH TsOH, Tol. NH2 H3C CHO reflux O

o POCl3, 80−85 C O O CH HN 3 15 min., 40% CH3 N O

Example 28

OH Cl dry HCl gas NH CN SOCl2, ether Cl HO HO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_99, © Springer-Verlag Berlin Heidelberg 2009 230

N N

O CHO OH N dry HCl gas, 16.5% halfordinal

References

1. Fischer, E. Ber. 1896, 29, 205. 2. Ladenburg, K.; Folkers, K.; Major, R. T. J. Am. Chem. Soc. 1936, 58, 1292−1294. 3. Wiley, R. H. Chem. Rev. 1945, 37, 401−442. (Review). 4. Cornforth, J. W.; Cornforth, R. H. J. Chem. Soc. 1949, 1028-1030. 5. Cornforth, J. W. In Heterocyclic Compounds 5; Elderfield, R. C. Ed.; Wiley & Sons: New York, 1957, 5, 309−312. (Review). 6. Crow, W. D.; Hodgkin, J. H. Tetrahedron Lett. 1963, 2, 85−89. 7. Brossi, A.; Wenis, E. J. Heterocycl. Chem. 1965, 2, 310−312. 8. Onaka, T. Tetrahedron Lett. 1971, 4393−4394. 9. Brooks, D. A. Fisher Oxazole Synthesis. In Name Reactions in Heterocyclic Chemis- try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 234−236. (Re- view).

231

Fleming−Kumada oxidation Stereoselective oxidation of alkyl-silanes into the corresponding alkyl-alcohols using peracids.

1. HX SiMe2Ph 2. ArCO3H, base OH

R R1 3. hydrolysis R R1

retention of configuration

ipso H X H Ar Si : Si Si O substitution 1 O O H X R R 1 1 R R R R the β-carbocation is stabilized by the silicon group

H O O Ar O Ar : O Ar O HX O ArCO2 Si Si O Si O O O O

R R1 1 R R1 R R

O H O O O Ar O Ar − : O Ar O ArCO2 O Si O Si O Si O O O O O 1 1 1 R R R R R R

O O HO O HO Ar OH O Ar hydrolysis O O Ar O Si O 1 O O Si 1 R R OH O O R R 1 R R 1 R R

Example 14

O O O O OH O O OH C H C8H18 m-CPBA, KHF2, DMF 8 18 NBoc NBoc 0 to 25 oC, 55−70% (EtO)2PhSi HO OTBS OTBS

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_100, © Springer-Verlag Berlin Heidelberg 2009 232

Example 25

O O O TsO H O O N TsO H O N H2O2, KHCO3 TBSO Ph TBSO Ph H THF, H O H i-Pr Si O 2 OH OH 55 oC, 90% i-Pr

Example 38

H C CH 3 3 HO Si HO O H3C H3C H2O2, KF, KHCO3 CH3 CH3 H C H C 3 H CH3 3 H CH3 DMF, 93% BnO BnO

H C H C 3 3

Example 49

SiMe (OMe) OH 2 KF, KHCO MeO2C 3 MeO2C THF/MeOH

30% H O , 77% 2 2 CO Me CO2Me 2

References

1. (a) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem. Commun. 1984, 29−31. (b) Fleming, I.; Sanderson, P. E. J. Tetrahedron Lett. 1987, 28, 4229−4232. (c) Flem- ing, I.; Dunoguès, J.; Smithers, R. Org. React. 1989, 37, 57−576. (Review). 2. Hunt, J. A.; Roush, W. R. J. Org. Chem. 1997, 62, 1112−1124. 3. Knölker, H.-J.; Jones, P. G.; Wanzl, G. Synlett 1997, 613−616. 4. Barrett, A. G. M.; Head, J.; Smith, M. L.; Stock, N. S.; White, A. J. P.; Williams, D. J. J. Org. Chem. 1999, 64, 6005−6018. 5. Denmark, S.; Cottell, J. J. Org. Chem. 2001, 66, 4276−4284. 6. Lee, T. W.; Corey, E. J. Org. Lett. 2001, 3, 3337−3339. 7. Jung, M. E.; Piizzi, G. J. Org. Chem. 2003, 68, 2572−2582. 8. Paquette, L. A.; Yang, J.; Long, Y. O. J. Am. Chem. Soc. 2003, 125, 1567−1574. 9. Clive, D. L. J.; Cheng, H.; Gangopadhyay, P.; Huang, X.; Prabhudas, B. Tetrahedron 2004, 60, 4205−4221. 10. Mullins, R. J.; Jolley, S. L.; and Knapp, A. R. Tamao–Kumada–Fleming Oxidation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 237−247. (Review). 233

Tamao−Kumada oxidation Oxidation of alkyl fluorosilanes to the corresponding alcohols. A variant of the Fleming−Kumada oxidation.

F F KF, H2O2 Si 2 ROH R R KHCO3, DMF

F F F F FF F F R RSi Si Si RSi O O F R R R F R F R HO : HO H O H H F H O

F F F F OSi OSi 2 ROH R O R F R F R

Example 13

O O

NaCO3, CH3CO3H Me2FSi HO CO2Me 3 h, 64% CO2Me O O

Example 24

Et Et OH SiEt F Si H2O2, KF, KHCO3 2 OH OH O − R THF MeOH R R OSiMe 51−85% OH 3 OH

References

1. Tamao, K.; Ishida, N.; Kumada, M. J. Org. Chem. 1983, 48, 2120−2122. 2. Fleming, I.; Dunoguès, J.; Smithers, R. Org. React. 1989, 37, 57−576. (Review). 3. Kim, S.; Emeric, G.; Fuchs, P. L. J. Org. Chem. 1992, 57, 7362−7364. 4. Mullins, R. J.; Jolley, S. L.; Knapp, A. R. Tamao–Kumada–Fleming Oxidation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 237−247. (Review). 5. Beignet, J.; Jervis, P. J.; Cox, L. R. J. Org. Chem. 2008, 73, 5462−5475. 6. Cardona, F.; Parmeggiani, C.; Faggi, E.; Bonaccini, C.; Gratteri, P.; Sim, L.; Gloster, T. M.; Roberts, S.; Davies, G. J.; Rose, D. R.; Goti, A. Chem. Eur. J. 2009, 15, 1627– 1636. 234

Friedel–Crafts reaction Friedel–Crafts acylation reaction Introduction of an acyl group onto an aromatic substrate by treating the substrate with an acyl halide or anhydride in the presence of a Lewis acid.

O O R Cl R HCl AlCl3

O R O: O O complexation AlCl3 AlCl3 AlCl4 R Cl: R Cl R

acylium ion

Cl Cl Al Cl O electrophilic Cl aromatization O R AlCl substitution H HCl 3 R

Example 1, Intermolecular Friedel–Crafts acylation6

O F O F Cl N AlCl3, CH2Cl2 N CHO 88% F CHO

Example 2, Intramolecular Friedel–Crafts acylation7

OMe OMe OMe (COCl)2, DMF OMe

O OH then AlCl3, 84% O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_101, © Springer-Verlag Berlin Heidelberg 2009 235

Example 3, Intramolecular Friedel–Crafts acylation8

CO2CH3

CO2CH3 PPSE, CH3NO2 HN CO2H reflux, 10 min., 44% N H O

PPSE = Trimethylsilyl polyphosphate

Example 4, Intramolecular Friedel–Crafts acylation9

O CONMe2 POCl3, K2CO3

o N CH3CN, 60 C NH H 74%

O CO2H o MeO PPA, 80 C MeO

N 35% NH H

O O 20 mol% BF3OEt2 O O O o MeNO2, 100 C 15 min., 98% N N Ns Ns

References

1. Friedel, C.; Crafts, J. M. Compt. Rend. 1877, 84, 1392−1395. Charles Friedel (1832−1899) was born in Strasbourg, France. He earned his Ph.D. In 1869 under Wurtz at Sorbonne and became a professor and later chair (1884) of organic chemistry at Sorbonne. Friedel was one of the founders of the French Chemical Society and served as its president for four terms. James Mason Crafts (1839−1917) was born in Boston, Massachusetts. He studied under Bunsen and Wurtz in his youth and became a professor at Cornell and MIT. From 1874 to 1891, Crafts collaborated with Friedel at École de Mines in Paris, where they discovered the Friedel–Crafts reaction. He returned to MIT in 1892 and later served as its president. The discovery of the Friedel– Crafts reaction was the fruit of serendipity and keen observation. In 1877, both Friedel and Crafts were working in Charles A. Wurtz’s laboratory. In order to prepare amyl iodide, they treated amyl chloride with aluminum and iodide using benzene as the solvent. Instead of amyl iodide, they ended up with amylbenzene! Unlike others before them who may have simply discarded the reaction, they thoroughly investigated 236

the Lewis acid-catalyzed alkylations and acylations and published more than 50 papers and patents on the Friedel–Crafts reaction, which has become one of the most useful organic reactions. 2. Pearson, D. E.; Buehler, C. A. Synthesis 1972, 533−542. (Review). 3. Hermecz, I.; Mészáros, Z. Adv. Heterocyclic Chem. 1983, 33, 241−330. (Review). 4. Metivier, P. Friedel-Crafts Acylation. In Friedel-Crafts Reaction Sheldon, R. A.; Bek- kum, H., eds.; Wiley-VCH: New York. 2001, pp 161−172. (Review). 5. Basappa; Mantelingu, K.; Sadashira, M. P.; Rangappa, K. S. Indian J. Chem. B. 2004, 43B, 1954−1957. 6. Olah, G. A.; Reddy, V. P.; Prakash, G. K. S. Chem. Rev. 2006, 106, 1077−1104. (Re- view). 7. Simmons, E.M.; Sarpong, R. Org. Lett. 2006, 8, 2883−2886. 8. Bourderioux, A.; Routier, S.; Beneteau, V.; Merour, J.-Y. Tetrahedron 2007, 63, 9465−9475. 9. Fillion, E.; Dumas, A. M. J. Org. Chem. 2008, 73, 2920−2923. 10. de Noronha, R. G.; Fernandes, A. C.; Romao, C. C. Tetrahedron Lett. 2009, 50, 1407−1410.

Friedel–Crafts alkylation reaction Introduction of an alkyl group onto an aromatic substrate by treating the substrate with an alkylating agent such as alkyl halide, alkene, alkyne and alcohol in the presence of a Lewis acid.

Cl Cl Al Cl R Cl aromatization AlCl R AlCl3 H R 3 AlCl R R Cl: Cl 4 HCl

alkyl cation

Example 11 O O

SnCl4, CH2Cl2 O O O O o 0 C, 1 h, 84% O O Br

Example 24

MeMe O O O OH H O N N R3 Cu CMe3 R R2 R Me3C TfO OTf 3 OH N 10 mol% R R2 R R = aryl, alkyl N 1 3 32−96% yield, 83−98% ee R1

237

MeMe O O R O N N 3 Cu H CMe N Me3C TfO OTf 3 O N R3 Me OH 10 mol% Me R = aryl, alkyl 3 80−95% yield, 68−97% ee OH

Example 35

O Me N Bu N Me N Me O 20 mol% H•HCl Me O B(OH) Me O 2 Me O DME, rt, 36 h 1 equiv HF 51% yield, 92% ee

References

1. Patil, M. L.; Borate, H. B.; Ponde, D. E.; Bhawal, B. M.; Deshpande, V. H. Tetrahe- dron Lett. 1999, 40, 4437−4438. 2. Meima, G. R.; Lee, G. S.; Garces, J. M. Friedel-Crafts Alkylation. In Friedel−Crafts Reaction Sheldon, R. A.; Bekkum, H., eds.; Wiley-VCH: New York. 2001, pp 550−556. (Review). 3. Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550−556. (Review). 4. Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127, 4154−4155. 5. Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 15438−15439. 6. Poulsen, T. B.; Jorgensen, K. A. Chem. Rev. 2008, 108, 2903−2915. (Review). 7. Silvanus, A. C.; Heffernan, S. J.; Liptrot, D. J.; Kociok-Kohn, G.; Andrews, B. I.; Car- bery, D. R. Org. Lett. 2009, 11, 1175−1178.

238

Friedländer quinoline synthesis The Friedländer quinoline synthesis combines an α-amino aldehyde or ketone with another aldehyde or ketone with at least one methylene α adjacent to the carbonyl to furnish a substituted quinoline. The reaction can be promoted by acid, base, or heat.

CHO O OH R R R1 1 NH2 N R

O O OH R R 1 OH R1 R Aldol R O H H 1 condensation COR H NH2 HO NH 2

R R R OH 1 N 1 R R 1 : N R O H NH2 HO

Example 15

CHO NBn NaOMe, EtOH NBn

reflux, 3 h, 90% N NH2 O

Example 27

H N O N O N O AcOH, 100 °C O 88% NHBoc OBn OBn

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_102, © Springer-Verlag Berlin Heidelberg 2009 239

Example 38

CHO Me Me

N NH2 O Me N N Me N N Me

Conditions Conversion Ratio NaOH, rt > 99% 37:63 pyrrolidine, 5% H2SO4, rt 97% 86:14 TBAO , 5% H2SO4, rt > 99% 87:13 TBAO, 5% H SO , slow addition, 65 °C > 99% 94:6 2 4 H Me N TBAO = 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane Me Me Example 410

Mes NNMes

Cl Ru Cl O Ph OH 1 mol% PCy3 R2 R2 R1 NH2 KOH, 1,4-dioxane N R1 o 80 C, 1 h

References

1. Friedländer, P. Ber. 1882, 15, 2572−2575. Paul Friedländer (1857−1923), born in Königsberg, Prussia, apprenticed under Carl Graebe and Adolf von Baeyer. He was interested in music and was an accomplished pianist. 2. Elderfield, R. C. In Heterocyclic Compounds, Elderfield, R. C., ed.; Wiley & Sons,: New York, 1952, 4, Quinoline, Isoquinoline and Their Benzo Derivatives, 45–47. (Review). 3. Jones, G. In Heterocyclic Compounds, Quinolines, vol. 32, 1977; Wiley & Sons: New York, pp 181–191. (Review). 4. Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37−201. (Review). 5. Shiozawa, A.; Ichikawa, Y.-I.; Komuro, C.; Kurashige, S.; Miyazaki, H.; Yamanaka, H.; Sakamoto, T. Chem. Pharm. Bull. 1984, 32, 2522−2529. 6. Gladiali, S.; Chelucci, G.; Mudadu, M. S.; Gastaut, M.-A.; Thummel, R. P. J. Org. Chem. 2001, 66, 400−405. 7. Henegar, K. E.; Baughman, T. A. J. Heterocycl. Chem. 2003, 40, 601−605. 8. Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.; McWilliams, J. C.; Reider, P. J.; Sager, J. W.; and Volante, R. P. J. Org. Chem. 2003, 68, 467−477. 9. Pflum, D. A. Friedländer Quinoline Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 411−415. (Review). 10. Vander Mierde, H.; Van Der Voot, P.; De Vos, D.; Verpoort, F. Eur. J. Org. Chem. 2008, 1625−1631. 240

Fries rearrangement Lewis acid-catalyzed rearrangement of phenol esters and lactams to 2- or 4- ketophenols. Also known as the Fries−Finck rearrangement.

O OH OH O O R AlCl 3 and/or R

O R

AlCl3 Cl Al O: 3 O AlCl3 O O complexation C−O bond O R O R fragmentation R

aluminum phenolate, acylium ion

AlCl3 H OH O O O O H O R R R

AlCl O 3 O H OH

H O O R O R R

Example 15

Br OH O OH OMe O ZrCl4, PhCl

O Br 160 oC, 3 h, 63% Br Br

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_103, © Springer-Verlag Berlin Heidelberg 2009 241

Example 26 O OH O O 10% Bi(OTf)3, PhMe

110 oC, 15 h, 64%

OAc OAc

Example 3, Photo-Fries rearrangement7

O Ph NH2 O HN Low-pressure Hg lamp Ph

254 nM, MeCN, 36 h, 65%

Example 4, ortho-Fries rearrangement8

MeO OMe MeO OMe O 2.1 equiv LTMP O CONEt2 OCONEt 2 −78 oC to rt, 97% O

Example 5, Thia-Fries rearrangement9

O CF H S 3 O LDA, THF, −78 oC O S CF3 O O + OH then H3O , 80% Cl Cl

References

1. Fries, K.; Finck, G. Ber. 1908, 41, 4271−4284. Karl Theophil Fries (1875−1962) was born in Kiedrich near Wiesbaden on the Rhine. He earned his doctorate under Theo- dor Zincke. Although G. Finck co-discovered the rearrangement of phenolic esters, somehow his name has been forgotten by history. In all fairness, the Fries rearrangement should really be the Fries−Finck rearrangement. 2. Martin, R. Org. Prep. Proced. Int. 1992, 24, 369−435. (Review). 3. Boyer, J. L.; Krum, J. E.; Myers, M. C.; Fazal, A. N.; Wigal, C. T. J. Org. Chem. 2000, 65, 4712−4714. 4. Guisnet, M.; Perot, G. The Fries rearrangement. In Fine Chemicals through Hetero- geneous Catalysis 2001, 211−216. (Review). 5. Tisserand, S.; Baati, R.; Nicolas, M.; Mioskowski, C. J. Org. Chem. 2004, 69, 8982−8983. 6. Ollevier, T.; Desyroy, V.; Asim, M.; Brochu, M.-C. Synlett 2004, 2794−2796. 242

7. Ferrini, Serena; Ponticelli, Fabio; Taddei, Maurizio. Org. Lett. 2007, 9, 69−72. 8. Macklin, T. K.; Panteleev, J.; Snieckus, V. Angew. Chem., Int. Ed. 2008, 47, 2097−2101. 9. Dyke, A. M.; Gill, D. M.; Harvey, J. N.; Hester, A. J.; Lloyd-Jones, G.C.; Munoz, M. P.; Shepperson, I. R. Angew. Chem., Int. Ed. 2008, 47, 5067−5070.

243

Fukuyama amine synthesis Transformation of a primary amine to a secondary amine using 2,4-dinitro- benzenesulfonyl chloride and an alcohol. Also known as the Fuku- yama−Mitsunobu procedure.

SO Cl 1 2 1. R NH2, pyr. S CO2H 2 NO2 2. R OH, PPh , DEAD 3 H NO2 N SO R1 R2 2 3. HSCH2CO2H NO 2 NO2

H S CO H Cl : 2 SO NHR1 SO 2 1 2 : 2 SO NR R NO R2OH, PPh 2 R1NH NO H 2 3 2 2 NO2 DEAD

NO2 NO2 NO 2 See page 365 for mechanism of the Mitsunobu reaction.

NR1R2 S CO2H S SO S Ar 2 NO2 N HO C NO H 2 2 N SO2 R1 R2 H NO2 NO 2 Meisenheimer complex

Example 16

Ns NH HO 2 NsHN Cs2CO3 NsN Br DEAD, PPh 3 Br n-Bu NI 67–74% 4 n n 62–66% n for n = 1–3

Example 27

Et Et O O OH NsHN

NsNH2

DEAD, PPh3 N MsO N OTBDPS MsO Boc CO Me Boc 2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_104, © Springer-Verlag Berlin Heidelberg 2009 244

OH NsN Et

K2CO3 OTBDPS DMF MsO N CO2Me Boc Example 38

H N 2 SO K CO , PhSH 2 PyPh P, DTBAD HN 2 3 2 SO2 OH NO2 CH CN, 80% NO2 3 NH2 CH2Cl2, 84%

PyPh2P = diphenyl 2-pyridylphosphine; DTBAD = di-tert-butylazodicarbonate

References

1. (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373−6374. Tohru Fukuyama moved to the University of Tokyo from Rice University in 1995. (b) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5831−5834. 2. Piscopio, A. D.; Miller, J. F.; Koch, K. Tetrahedron Lett. 1998, 39, 2667−2670. 3. Bolton, G. L.; Hodges, J. C. J. Comb. Chem. 1999, 1, 130−133. 4. Lin, X.; Dorr, H.; Nuss, J. M. Tetrahedron Lett. 2000, 41, 3309−3313. 5. Olsen, C. A.; JØrgensen, M. R.; Witt, M.; Mellor, I. R.; Usherwood, P. N. R.; Jaroszewski, J. W.; Franzyk, H. Eur. J. Org. Chem. 2003, 3288-3299. 6. Kan, T.; Fujiwara, A.; Kobayashi, H.; Fukuyama, T. Tetrahedron 2002, 58, 6267−6276. 7. Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fu- kuyama, T. Pure Appl. Chem. 2003, 75, 29−38. 8. Guisado, C.; Waterhouse, J. E.; Price, W. S.; JØrgensen, M. R.; Miller, A. D. Org. Biomol. Chem. 2005, 3, 1049−1057. 9. Olsen, C. A.; Witt, M.; Hansen, S. H.; Jaroszewski, J. W.; Franzyk, H. Tetrahedron 2005, 61, 6046−6055. 10. Janey, J. M. Fukuyama amine synthesis. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 424−437. (Review).

245

Fukuyama reduction

Aldehyde synthesis through reduction of thiol esters with Et3SiH in the presence of Pd/C catalyst.

O Et3SiH, Pd/C O

R SEt THF, rt R H

Path A:

O Pd(0) O Et SiH O reductive O 3 Pd(0) R SEt SEt H oxidative R Pd R Pd elimination R H Et Si SEt addition 3

Path B: Et SiH 3 Pd(0) Et3SiPdH

OSiEt O 3 OSiEt3 O Et3SiPdH R SEt R SEt R SEt R H Pd Pd(0) Et3Si SEt H

Example 11 CO Me CO2Me 2 O O

Et3SiH, 10% Pd/C OO OO CHO COSEt acetone, rt, 92%

Example 23

EtSH, DCC, DMAP EtS HO2C CO2Me CO2Me NHBoc CH CN, rt, 1 h, > 70% O NHBoc 3

Et3SiH, 10% Pd/C H CO2Me O NHBoc acetone, rt, 30 min., >74%

Example 38

COSEt 0.5 mol% Pd/C CHO

2 equiv Et SiH MeO 3 MeO rt, 2 h, 92%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_105, © Springer-Verlag Berlin Heidelberg 2009 246

References

1. Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112, 7050–7051. 2. Kanda, Y.; Fukuyama, T. J. Am. Chem. Soc. 1993, 115, 8451–8452. 3. Fujiwara, A.; Kan, T.; Fukuyama, T. Synlett 2000, 1667–1673. 4. Tokuyama, H.; Yokoshima, S.; Lin, S.-C.; Li, L.; Fukuyama, T. Synthesis 2002, 1121– 1123. 5. Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002, 41, 4569– 4573. 6. Shimada, K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 4048–4049. 7. Kimura, M.; Seki, M. Tetrahedron Lett. 2004, 45, 3219–3223. (Possible mechanisms were proposed in this paper). 8. Miyazaki, T.; Han-ya, Y.; Tokuyama, H.; Fukuyama, T. Synlett 2004, 477–480.

247

Gabriel synthesis Synthesis of primary amines using potassium phthalimide and alkyl halides.

O CO H 1. R⎯X 2 N K H2NR 2. Nu or R'OH CO2H O

O RX O OH O OH hydrolysis SN2 N K N R N R

O O O OH H O CO2 O CO2 H H N H2NR N R R CO OOH 2 O OH

Example 12

Br O KNPhth, DMF NPhth O O O O O 90 oC, 40 min. O Br O NPhth 90%

NH2 O H2NNH2, CH3OH O O reflux, 1 h, 80% O NH 2

Example 26

DIAD, PPh R1 R1 3 R1 phthalimide NH2H2 or CH3NH2 R OH R NPhth CH3OH R2 NH2 2 THF, rt, 4 h 2 R3 R3 − R3 76−88% 76 98%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_106, © Springer-Verlag Berlin Heidelberg 2009 248

Example 38

O O CO2Et Br CO2Et NK N DMF, 90 oC, 3 h, 77% O O

O O O O O 6 M HCl, reflux O OH 13 N = C 14 h, 93% HCl•H2N O

Example 49

OH NPht NH2 phthalimide, PPh3 1. NH2NH2•H2O, THF, reflux, 8 h DEAD, THF 2. Pd/C, H2, THF, 95%, 2 steps OH 54% NPht NH 2

References

1. Gabriel, S. Ber. 1887, 20, 2224−2226. Siegmund Gabriel (1851−1924), born in Ber- lin, Germany, studied under Hofmann at Berlin and Bunsen in Heidelberg. He taught at Berlin, where he discovered the Gabriel synthesis of amines. Gabriel, a good friend of Emil Fischer, often substituted for Fischer in his lectures. 2. Sheehan, J. C.; Bolhofer, V. A. J. Am. Chem. Soc. 1950, 72, 2786−2788. 3. Han, Y.; Hu, H. Synthesis 1990, 122−124. 4. Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1991, 24, 285–289. (Review). 5. Toda, F.; Soda, S.; Goldberg, I. J. Chem. Soc., Perkin Trans. 1 1993, 2357−2361. 6. Sen, S. E.; Roach, S. L. Synthesis, 1995, 756−758. 7. Khan, M. N. J. Org. Chem. 1996, 61, 8063−8068. 8. Iida, K.; Tokiwa, S.; Ishii, T.; Kajiwara, M. J. Labelled. Compd. Radiopharm. 2002, 45, 569−570. 9. Tanyeli, C.; Özçubukçu, S. Tetrahedron Asymmetry 2003, 14, 1167−1170. 10. Ahmad, N. M. Gabriel synthesis. In Name Reactions for Functional Group Transfor- mations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 438−450. (Review). 11. Al-Mousawi, S. M.; El-Apasery, M. A.; Al-Kanderi, N. H. ARKIVOC 2008, (16), 268−278.

249

Ing–Manske procedure A variant of Gabriel amine synthesis where hydrazine is used to release the amine from the corresponding phthalimide:

O O 1. RX NH N H NR K 2 NH 2. NH2NH2 O O

:NH NH O RX O 2 2 O NHNH2 SN2 N K N R N R

O O O O O O

NHNH: 2 NH NH H NR NH 2 NH NH ONH O R O R

Example 16

O O Br H2NNH2, EtOH P(OEt)3 PO(OEt)2 PO(OEt)2 N N H2N Δ rt, 18 h, 97% O O

References

1. Ing, H. R.; Manske, R. H. F. J. Chem. Soc. 1926, 2348–2351. H. R. Ing was a professor of pharmacological chemistry at Oxford. R. H. F. Manske, Ing’s collaborator at Oxford, was of German origin but trained in Canada before studying at Oxford. Man- ske left England to return to Canada, eventually to become Director of Research in the Union Rubber Company, Guelph, Ontario, Canada. 2. Ueda, T.; Ishizaki, K. Chem. Pharm. Bull. 1967, 15, 228–237. 3. Khan, M. N. J. Org. Chem. 1995, 60, 4536–4541. 4. Hearn, M. J.; Lucas, L. E. J. Heterocycl. Chem. 1984, 21, 615–622. 5. Khan, M. N. J. Org. Chem. 1996, 61, 8063–8063. 6. Tanyeli, C.; Özçubukçu, S. Tetrahedron: Asymmetry 2003, 14, 1167–1170. 7. Ariffin, A.; Khan, M. N.; Lan, L. C.; May, F. Y.; Yun, C. S. Synth. Commun. 2004, 34, 4439–4445. 8. Ali, M. M.; Woods, M.; Caravan, P.; Opina, A. C. L.; Spiller, M.; Fettinger, J. C.; Sherry, A. D. Chem. Eur. J. 2008, 14, 7250–7258. 250

Gabriel–Colman rearrangement

Reaction of the enolate of a maleimidyl acetate to provide isoquinoline 1,4-diol.

O O OH O R NaOR Ar N R ROH Ar G NH G G = CO, SO2

O O OMe O OMe OMe O N N N R R R O O O O O O Me OMe O O OH O O O O H R R N R NH N NH O O O OH O Example 16 O O OH O Oi-Pr 4 equiv i-PrONa Oi-Pr N S i-PrOH, reflux NH O 5 min., 85% S O O O Example 29 O OH NaOMe, MeOH CO2Et N CO2Et reflux, 24 h NH O 91% O References

1. (a) Gabriel, S.; Colman, J. Ber. 1900, 33, 980−995. (b) Gabriel, S.; Colman, J. Ber. 1900, 33, 2630−2634. (c) Gabriel, S.; Colman, J. Ber. 1902, 35, 1358−1368. 2. Allen, C. F. H. Chem. Rev. 1950, 47, 275−305. (Review). 3. Gensler, W. J. Heterocyclic Compounds, Vol. 4, R. C. Elderfield, Ed., Wiley & Sons., New York, N.Y., 1952, 378. (Review). 4. Hill, J. H. M. J. Org. Chem. 1965, 30, 620−622. (Mechanism). 5. Lombardino, J. G.; Wiseman, E. H.; McLamore, W. M. J. Med. Chem. 1971, 14, 1171−1175. 6. Schapira, C. B.; Perillo, I. A.; Lamdan, S. J. Heterocycl. Chem. 1980, 17, 1281−1288. 7. Lazer, E. S.; Miao, C. K.; Cywin, C. L.; et al. J. Med. Chem. 1997, 40, 980−989. 8. Pflum, D. A. Gabriel−Colman Rearrangement. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 416−422. (Review). 9. Kapatsina, E.; Lordon, M.; Baro, A.; Laschat, S. Synthesis 2008, 2551−2560.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_107, © Springer-Verlag Berlin Heidelberg 2009 251

Gassman indole synthesis The Gassman indole synthesis involves a one-pot process in which a hypohalite, a ȕ-carbonyl sulfide derivative, and a base are added sequentially to an aniline or a substituted aniline to provide 3-thioalkoxyindoles. The sulfur can be easily re- moved by hydrogenolysis or Raney nickel.

t-BuOCl R Et3N S R NH2 NH O N Cl H

Et3N : R S O : SN2 O H NH R Cl S N H sulfonium ion

: O Et3N S [2,3]-sigmatropic H H NEt3 R O S rearrangement − R N (Sommelet Hauser) NH H

Et N: 3 S S H S R R : R OH N N N H H H

Example 11

1. t-BuOCl S

CH3 NH2 2. S N Me O H 3. Et N, 69% 3

SCH3 1. t-BuOCl LiAlH4, Et2O O o NH2 SCH N 0 C, 48% overall N 2. 3 H 3. Et3N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_108, © Springer-Verlag Berlin Heidelberg 2009 252

Example 22

MeS MeS t-BuOCl, PhNH2 O O Et3N, 93% NH2 O O O O

Ra-Ni p-TsOH, PhH, reflux

EtOH NH O 71% 2 steps N O 2 O H O O

References

1. (a) Gassman, P. G.; van Bergen, T. J.; Gilbert, D. P.; Cue, B. W., Jr. J. Am. Chem. Soc. 1974, 96, 5495−5508. Paul G. Gassman (1935−1993) was a professor at the Univer- sity of Minnesota (1974−1993). (b) Gassman, P. G.; van Bergen, T. J. J. Am. Chem. Soc. 1974, 96, 5508−5512. (c) Gassman, P. G.; Gruetzmacher, G.; van Bergen, T. J. J. Am. Chem. Soc. 1974, 96, 5512−5517. 2. Wierenga, W. J. Am. Chem. Soc. 1981, 103, 5621−5623. 3. Ishikawa, H.; Uno, T.; Miyamoto, H.; Ueda, H.; Tamaoka, H.; Tominaga, M.; Naka- gawa, K. Chem. Pharm. Bull. 1990, 38, 2459−2462. 4. Smith, A. B., III; Sunazuka, T.; Leenay, T. L.; Kingery-Wood, J. J. Am. Chem. Soc. 1990, 112, 8197−8198. 5. Smith, A. B., III; Kingery-Wood, J.; Leenay, T. L.; Nolen, E. G.; Sunazuka, T. J. Am. Chem. Soc. 1992, 114, 1438−1449. 6. Savall, B. M.; McWhorter, W. W.; Walker, E. A. J. Org. Chem. 1996, 61, 8696−8697. 7. Li, J.; Cook, J. M. Gassman Indole Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 128−131. (Review).

253

Gattermann–Koch reaction Formylation of arenes using carbon monoxide and hydrogen chloride in the presence of aluminum chloride under high pressure.

AlCl3 CHO CO HCl Cu2Cl2

Cl : :

: CO :: : O HCl Cl AlCl3 C : O : : :CO C AlCl3 CO AlCl3 AlCl3 H

O : AlCl : O O O 3 Cl Al AlCl4 3 Cl H H H Cl H acylium ion

Cl CHO H CHO CHO HCl AlCl3 AlCl AlCl4 4

Example, A more practical variant4

OH OH H2O OH o Zn(CN)2, AlCl3 0 to 100 C CHO NH2 HCl (g), 0 oC 95% HO HO Cl HO orcinol References

1. Gattermann, L.; Koch, J. A. Ber.1897, 30, 1622−1624. Ludwig Gattermann (1860−1920) was born in Freiburg, Germany. His textbook, “Die Praxis de organischen Chemie” (1894) was one of his major contributions to organic chemistry. 2. Crounse, N. N. Org. React. 1949, 5, 290−300. (Review). 3. Truce, W. E. Org. React. 1957, 9, 37−72. (Review). 4. Solladié, G.; Rubio, A.; Carreño, M. C.; García Ruano, J. L. Tetrahedron: Asymmetry 1990, 1, 187−198. 5. (a) Tanaka, M.; Fujiwara, M.; Ando, H. J. Org. Chem. 1995, 60, 2106−2111. (b) Tanaka, M.; Fujiwara, M.; Ando, H.; Souma, Y. Chem. Commun. 1996, 159−160. (c) Tanaka, M.; Fujiwara, M.; Xu, Q.; Souma, Y.; Ando, H.; Laali, K. K. J. Am. Chem. Soc. 1997, 119, 5100−5105. (d) Tanaka, M.; Fujiwara, M.; Xu, Q.; Ando, H.; Raeker, T. J. J. Org. Chem. 1998, 63, 4408−4412. 6. Kantlehner, W.; Vettel, M.; Gissel, A; Haug, E.; Ziegler, G.; Ciesielski, M.; Scherr, O.; Haas, R. J. Prakt. Chem. 2000, 342, 297−310.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_109, © Springer-Verlag Berlin Heidelberg 2009 254

Gewald aminothiophene synthesis Base-promoted aminothiophene formation from ketone, α-active methylene nitrile and elemental sulfur.

2 R O 2 R CO2R CO2R Base S8 1 R1 R CN S NH2

1 R R O O O OR2 2 Knoevenagel HO O R OR NC OR2 H BH condensation H B: CN R1 CN : B

O OR2 O OR2 1 R R CN R R BH O CN HO R1 S S NC OR2 R1 H S S S S :B SS

2 R O2C O OR2 NH R CO R2 H BH R 2 R S7 B N S S S S R1 NH : R1 H S S 2 1 S R S S S S 6 S Ylidene-sulfur adduct

Example 14

H CCH 3 N 3 CO2Et

CO2Et S8 NH2 S CN morpholine N 82% N

Example 27

Me CO2Et OO CO2Et S8, EtOH, morpholine O CN 60 oC, 5 h, 74% t-BuO C NH 2 S 2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_110, © Springer-Verlag Berlin Heidelberg 2009 255

Example 39

O HN(TMS)3, HOAc toluene, 65 oC, 90% Me NC CN Knoevenagel O2N condensation

NH2 NC CN NC 1.2 atom equiv S8 1 equiv NaHCO3 S Me − THF, H2O, 80 85% O N O N 2 2

Example 410

O O 3 equiv morpholine NH O 1 equiv S8, 55 oC, 24 h 2 NC O O S O 85% conversion O 64% yield O O

Example 511

O 3 equiv morpholine O O 2 equiv S8, MeOH N NH O − o 2 N 20 45 C, 24 h S O 72% N

O O Addition O Condensation O MPS = of sulfur N morpholine- N S N polysulfide N S Sx ylidene ylidene-sulfur adduct

Dimerization Cyclization

NH2 CO CH NC 2 3 O CN O CN Re-cyclization

NH2 S N dimer 256

References

1. (a) Gewald, K. Z. Chem. 1962, 2, 305−306. (b) Gewald, K.; Schinke, E.; Böttcher, H. Chem. Ber. 1966, 99, 94−100. (c) Gewald, K.; Neumann, G.; Böttcher, H. Z. Chem. 1966, 6, 261. (d) Gewald, K.; Schinke, E. Chem. Ber. 1966, 99, 271−275. 2. Mayer, R.; Gewald, K. Angew. Chem., Int. Ed. 1967, 6, 294−306. (Review). 3. Gewald, K. Chimia 1980, 34, 101−110. (Review). 4. Bacon, E. R.; Daum, S. J. J. Heterocycl. Chem. 1991, 28, 1953-1955. 5. Sabnis, R. W. Sulfur Reports 1994, 16, 1−17. (Review). 6. Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J. Heterocycl. Chem. 1999, 36, 333−345. (Review). 7. Gütschow, M.; Kuerschner, L.; Neumann, U.; Pietsch, M.; Löser, R.; Koglin, N.; Eger, K. J. Med. Chem. 1999, 42, 5437. 8. Tinsley, J. M. Gewald Aminothiophene Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 193−198. (Review). 9. Barnes, D. M.; Haight, A. R.; Hameury, T.; McLaughlin, M. A.; Mei, J.; Tedrow, J. S.; Dalla Riva Toma, J. Tetrahedron 2006, 62, 11311−11319. 10. Tormyshev, V. M.; Trukhin, D. V.; Rogozhnikova, O. Yu.; Mikhalina, T. V.; Troit- skaya, T. I.; Flinn, A. Synlett 2006, 2559−2564. 11. Puterová, Z.; Andicsová, A.; Végh, D. Tetrahedron 2008, 64, 11262−11269.

257

Glaser coupling Oxidative homo-coupling of terminal alkynes using copper catalyst in the presence of oxygen.

CuCl R CCH R CCC C R NH4OH, EtOH

+2 +2 L L L L

Cu Cu R R X X X Cu Cu R Cu Cu LL LL

R : or + +2 Cu L L L = Amine +2 Cu R Cu X = Cl, OAc R R

R Cu LL 2 Cu

Alternatively, the radical mechanism is also operative:

Base H CuCl Cu(I)

O2 Cu(II) Cu(I)

dimerization

Example 11

O2 2 Cu NH4OH, EtOH 90%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_111, © Springer-Verlag Berlin Heidelberg 2009 258

Example 2, Homo-coupling2

Cu, NH4Cl O , 90% HO 2 HO OH

Example 37 R R

S S

R S S CuCl S S TMEDA R S S O2, CH2Cl2, 0°C 47% R = n-Hexyl S S

S S S S R R S S R R References

1. Glaser, C. Ber. 1869, 2, 422–424. 2. Bowden, K.; Heilbron, I.; Jones, E. R. H.; Sondheimer, F. J. Chem. Soc. 1947, 1583– 1590. 3. Hoeger, S.; Meckenstock, A.-D.; Pellen, H. J. Org. Chem. 1997, 62, 4556–4557. 4. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632– 2657. (Review). 5. Youngblood, W. J.; Gryko, D. T.; Lammi, R. K.; Bocian, D. F.; Holten, D.; Lindsey, J. S. J. Org. Chem. 2002, 67, 2111–2117. 6. Moriarty, R. M.; Pavlovic, D. J. Org. Chem. 2004, 69, 5501–5504. 7. Andersson, A. S.; Kilsa, K.; Hassenkam, T.; Gisselbrecht, J.-P.; Boudon, C.; Gross, M.; Nielsen, M. B.; Diederich, F. Chem. Eur. J. 2006, 12, 8451–8459. 8. Gribble, G. W. Glaser Coupling. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 236−257. (Review). 259

Eglinton coupling Oxidative homo-coupling of terminal alkynes mediated by stoichiometric (or often excess) Cu(OAc)2. A variant of the Glaser coupling reaction.

Cu(OAc)2 R H R R pyridine/MeOH

AcO Cu OAc pyridine R H R R Cu OAc N H

R dimerization R R R

Example 12

Cu(OAc)2 pyr., 25 °C 20%

Example 2, Cross-coupling3

SPh SPh

Cu(OAc)2 pyridine/MeOH (1:1)

rt, 72% CO2Me Ph CO Me Ph 2

Example 3, Homo-coupling4 Cl NC N NC N Cu(OAc)2, pyridine N MeOH, 1.5 h, 68% CN Cl Cl 260

Example 45

TMS R

Cu(OAc)2

R K2CO3 TIPS pyr., MeOH TIPS 61–70% 1. TBAF R = H, t-Bu 2. CuCl, Cu(OAc)2 pyr. R R 51–64% TIPS

R R R

Example 511

CN 2 equiv Cu(OAc)2•H2O O Fe 1 : 1 Pyr : MeOH 70 oC, 12 h, 41%

CN O Fe Fe O CN

Example 612

Cu(OAc)2

Pyr./MeOH/Et2O 62%

261

References

1. (a) Eglinton, G.; Galbraith, A. R. Chem. Ind. 1956, 737−738. Geoffrey Eglinton (1927−) was born in Cardiff, Wales. (b) Behr, O. M.; Eglinton, G.; Galbraith, A. R.; Raphael, R. A. J. Chem. Soc. 1960, 3614−3625. (c) Eglinton, G.; McRae, W. Adv. Org. Chem. 1963, 4, 225−328. (Review). 2. McQuilkin, R. M.; Garratt, P. J.; Sondheimer, F. J. Am. Chem. Soc. 1970, 92, 6682– 6683. 3. Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E.; Uenishi, J. J. Am. Chem. Soc. 1982, 104, 5558−5560. 4. Srinivasan, R.; Devan, B.; Shanmugam, P.; Rajagopalan, K. Indian J. Chem., Sect. B 1997, 36B, 123−125. 5. Haley, M. M.; Bell, M. L.; Brand, S. C.; Kimball, D. B.; Pak, J. J.; Wan, W. B. Tetra- hedron Lett. 1997, 38, 7483–7486. 6. Nakanishi, H.; Sumi, N.; Aso, Y.; Otsubo, T. J. Org. Chem. 1998, 63, 8632-8633. 7. Kaigtti-Fabian, K. H. H.; Lindner, H.-J.; Nimmerfroh, N.; Hafner, K. Angew. Chem., Int. Ed. 2001, 40, 3402−3405. 8. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632−2657. (Review). 9. Inouchi, K.; Kabashi, S.; Takimiya, K.; Aso, Y.; Otsubo, T. Org. Lett. 2002, 4, 2533−2536. 10. Xu, G.-L.; Zou, G.; Ni, Y.-H.; DeRosa, M. C.; Crutchley, R. J.; Ren, T. J. Am. Chem. Soc. 2003, 125, 10057−10065. 11. Shanmugam, P.; Vaithiyananthan, V.; Viswambharan, B.; Madhavan, S. Tetrahedron Lett. 2007, 48, 9190−9194. 12. Miljanic, O. S.; Dichtel, W. R.; Khan, S. I.; Mortezaei, S.; Heath, J. R.; Stoddart, J. F. J. Am. Chem. Soc. 2007, 129, 8236−8246. 262

Gomberg–Bachmann reaction Base-promoted radical coupling between an aryl diazonium salt and an arene to form a diaryl compound.

O N2 OH

N N Ph Ph Ph

: N N NN ↑ N N N2 N N OH O O OH NN Ph Ph N N O Ph N N H O O OH

Example 14

O N KOAc, 18-C-6 O 2 BF4 O rt, 55% O O O

Example 25

NH2 N N ONO N N MeO N N PhH, TFAA, reflux MeO N N 2 d, 33%

References

1. Gomberg, M.; Bachmann, W. E. J. Am. Chem. Soc. 1924, 46, 2339−2343. Moses Gomberg (1866−1947) was born in Elizabetgrad, Russia. He discovered the triphenyl- methyl stable radical at the University of Michigan in Ann Arbor, Michigan. In this article, Gomberg declared that he had reserved the field of radical chemistry for himself! Werner Bachmann (1901−1951), Gomberg’s Ph.D. student, was born in Detroit, Michigan. After his postdoctoral trainings in Europe Bachmann returned to the Uni- versity of Michigan as the Moses Gomberg Professor of Chemistry. 2. Beadle, J. R.; Korzeniowski, S. H.; Rosenberg, D. E.; Garcia-Slanga, B. J.; Gokel, G. W. J. Org. Chem. 1984, 49, 1594−1603. 3. McKenzie, T. C.; Rolfes, S. M. J. Heterocycl. Chem. 1987, 24, 859−861. 4. Lai, Y.-H.; Jiang, J. J. Org. Chem. 1997, 62, 4412−4417.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_112, © Springer-Verlag Berlin Heidelberg 2009 263

Gould–Jacobs reaction The Gould–Jacobs reaction is a sequence of the following reactions: a. Substitution of an aniline with either alkoxy methylenemalonic ester or acyl malonic ester providing the anilinomethylenemalonic ester; b. Cyclization of to the 4-hydroxy-3-carboalkoxyquinoline (4-hydroxyquinolines exist predominantly in 4-oxoform); c. Saponification to form acid; d. Decarboxylation to give the 4-hydroxyquinoline. Extension could lead to unsubstituted parent heterocycles with fused pyridine ring of Skraup type.

RO C 2 CO2R RO2C CO2R heat Δ − R''OH NH N R' 2 R' OR'' H

OH OH O − Δ CO2R HO CO2H

N R' N R' N R' H

R = alkyl; R' = alkyl, aryl, or H; R'' = alkyl or H

O O O EtO2C EtO EtO2C OEt substitution OEt − EtOH CO2Et

NH2 OEt N OEt : N H2 H

O O OH H CO2Et CO Et CO2Et cyclization 2 tautomerization N N N H

Example 13

O EtO2C CO2Et O O Ph2O, reflux O CO2Et O CO2Et 75%, 10:1 N N H H N H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_113, © Springer-Verlag Berlin Heidelberg 2009 264

Example 28

EtO H H H N H N 2 PhOPh EtO2C CO2Et N N EtO2C o EtOH, reflux CO2Et 250 C R R

O Cl N POCl3 N EtO2C R EtO2C R 70 oC N N H

Example 3, Microwave-assisted Gould–Jacobs reaction9

NH CO2Et R 2 R HN EtO2C CO2Et Ph−O−Ph CO Et N N 2 N − o N H OEt 130 140 C N N R 1 R1 Ph−O−Ph 250 oC

CO2Et R N Microwave, neat N O 10−12 min., 64−75% N N R1

Example 410

Ar Ar EtO2C CO2Et EtO2C CO2Et EtOH N N reflux N H N NH2 H OEt N H Ph Ph POCl3 reflux

Ar O Ar Cl CO2Et CO2Et Ph-O-Ph POCl3 N N heat N N reflux N N H Ph Ph

References

1. Gould, R. G.; Jacobs, W. A. J. Am. Chem. Soc. 1939, 61, 2890−2895. R. Gordon Gould was born in Chicago in 1909. He earned his Ph.D. at Harvard University in 1933. After serving as an instructor at Harvard and Iowa, Gould worked at Rockefel- 265

ler Institute for Medical Research where he discovered the Gould–Jacobs reaction with his colleague Walter A. Jacobs. 2. Reitsema, R. H. Chem. Rev. 1948, 53, 43−68. (Review). 3. Cruickshank, P. A., Lee, F. T., Lupichuk, A. J. Med. Chem. 1970, 13, 1110−1114. 4. Elguero J., Marzin C., Katritzky A. R., Linda P., The Tautomerism of Heterocycles, Academic Press, New York, 1976, pp 87−102. (Review). 5. Wang, C. G., Langer, T., Kiamath, P. G., Gu, Z. Q., Skolnick, P., Fryer, R. I. J. Med. Chem. 1995, 38, 950−957. 6. Milata, V.; Claramunt, R. M.; Elguero, J.; Zálupský, P. Targets in Heterocyclic Sys- tems 2000, 4, 167–203. (Review). 7. Curran, T. T. Gould–Jacobs Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 423−436. (Review). 8. Ferlin, M. G.; Chiarelotto, G.; Dall’Acqua, S.; Maciocco, E.; Mascia, M. P.; Pisu, M. G.; Biggio, G. Bioorg. Med. Chem. 2005, 13, 3531−3541. 9. Desai, N. D. J. Heterocycl. Chem. 2006, 43, 1343−1348. 10. Kendre, D. B.; Toche, R. B.; Jachak, M. N. J. Heterocycl. Chem. 2008, 45, 1281−1286. 266

Grignard reaction Addition of organomagnesium compounds (Grignard reagents), generated from organohalides and magnesium metal, to electrophiles.

O Mg(0) 1 2 R1 R2 R R RX RMgX R OH

Formation of the Grignard reagent:

Mg Mg Mg Mg

RX R X

Mg Mg single electron RMgX transfer R MgX

Grignard reaction, ionic mechanism:

δ ‡ R2 δ R2 1 2 O O R R R1 R1 RMgX RMgX R OMgX δ δ

Radical mechanism,

R2 R O 1 2 H R1 R2 R1 R R R2 O R OMgX R OH RMgX R1 MgX

Example 14

EtMgBr NH reflux, tol./ether, 76% NOH H

This reaction is known as the Hoch–Campbell aziridine synthesis, which entails treatment of ketoximes with excess Grignard reagents and subsequent hydrolysis of the organometallic complex to produce aziridines.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_114, © Springer-Verlag Berlin Heidelberg 2009 267

Example 25 O O O O O O O Br Mg O Ph 65% O Ph OMe O MeO MeO N N OMe MeO MeO MeO OMe OMe

Example 510

OH O THF O MgBr O CHO O 0 oC to rt, 91% Garner's aldehyde

Example 611

OH HO OH O 3 equiv BrMg O O THF, 55 oC, 1 h, 85% HO HO 52% 28% 5%

References

1. Grignard, V. C. R. Acad. Sci. 1900, 130, 1322−1324. Victor Grignard (France, 1871−1935) won the Nobel Prize in Chemistry in 1912 for his discovery of the Grig- nard reagent. 2. Ashby, E. C.; Laemmle, J. T.; Neumann, H. M. Acc. Chem. Res. 1974, 7, 272−280. (Review). 3. Ashby, E. C.; Laemmle, J. T. Chem. Rev. 1975, 75, 521−546. (Review). 4. Sasaki, T.; Eguchi, S.; Hattori, S. Heterocycles 1978, 11, 235−242. 5. Meyers, A. I.; Flisak, J. R.; Aitken, R. A. J. Am. Chem. Soc. 1987, 109, 5446−5452. 6. Grignard Reagents Richey, H. G., Jr., Ed.; Wiley: New York, 2000. (Book). 7. Holm, T.; Crossland, I. In Grignard Reagents Richey, H. G., Jr., Ed.; Wiley: New York, 2000, Chapter 1, pp 1−26. (Review). 8. Shinokubo, H.; Oshima, K. Eur. J. Org. Chem. 2004, 2081−2091. (Review). 9. Graden, H.; Kann, N. Cur. Org. Chem. 2005, 9, 733−763. (Review). 10. Babu, B. N.; Chauhan, K. R. Tetrahedron Lett. 2008, 50, 66−67. 11. Mlinaric-Majerski, K.; Kragol, G.; Ramljak, T. S. Synlett 2008, 405−409. 12. Chen, D.; Yang, C.; Xie, Y.; Ding, J. Heterocycles 2009, 77, 273−277. 268

Grob fragmentation The C−C bond cleavage primarily via a concerted process involving a five atom system. General scheme:

: L D L D

− + D = O , NR2; L = OH2 , OTs, I, Br, Cl

Example 12

OMOM OMOM OMOM NaH MsO 15-crown-5 MsO

0 oC to rt, 95% OH O O

Example 2, Aza-Grob fragmentation3

15 eq. NaBH4, THF OH N O SH N 70 oC, 31 h, 53% S H

Example 37

OTs NaH, DMSO, 40 oC, 1 h;

o O OH then tosylate, 40 C, 1 h 52% MeO MeO

Example 48

OMs H H HO 1.1 equiv KHMDS H H OH THF, 0 oC, 15 min. 93% H H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_115, © Springer-Verlag Berlin Heidelberg 2009 269

References

1. (a) Grob, C. A.; Baumann, W. Helv. Chim. Acta 1955, 38, 594−603. (b) Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. 1967, 6, 1−15. Cyril A. Grob (1917−2003) was born in London (UK) to Swiss parents, studied chemistry at ETH Zürich and completed his PhD in 1943 under the guidance of Leopold Ruzicka (A Nobel laureate) on artificial steroidal antigens. He then moved to Basel to work with Taddeus Reichstein (another Nobel laureate) first at the pharmaceutical institute and from 1947 at the organic chemistry institute of the university, where he moved up the academic career ladder to become the director of the institute and holder of the chair there as Reich- stein’s successor in 1960. An investigation of the reductive elimination of bromine from 1,4-dibromides in the presence of zinc led in 1955 to the recognition of heterolytic fragmentation as a general reaction principle. The heterolytic fragmentation has now entered textbooks under his name. Experimental evidence for vinyl cations as dis- crete reactive intermediates was also first provided by Grob. Cyril Grob never acted impulsively, but always calmly and deliberately. He never sought attention in public, but fulfilled his social duties efficiently, reliably, and without a fuss. He died in his home in Basel (Switzerland) on December 15, 2003 at the age of 86. (Schiess, P. Angew. Chem., Int. Ed. 2004, 43, 4392.) 2. Yoshimitsu, T.; Yanagiya, M.; Nagaoka, H. Tetrahedron Lett. 1999, 40, 5215−5218. 3. Hu, W.-P.; Wang, J.-J.; Tsai, P.-C. J. Org. Chem. 2000, 65, 4208−4029. 4. Molander, G. A.; Le Huerou, Y.; Brown, G. A. J. Org. Chem. 2001, 66, 4511−4516. 5. Paquette, L. A.; Yang, J.; Long, Y. O. J. Am. Chem. Soc. 2002, 124, 6542−6543. 6. Barluenga, J.; Alvarez-Perez, M.; Wuerth, K.; Rodriguez, F.; Fananas, F. J. Org. Lett. 2003, 5, 905−908. 7. Khripach, V. A.; Zhabinskii, V. N.; Fando, G. P.; et al. Steroids 2004, 69, 495−499. 8. Maimone, T. J.; Voica, A.-F.; Baran, P. S. Angew. Chem., Int. Ed. 2008, 47, 3054−3056. 9. Yuan, D.-Y.; Tu, Y.-Q.; Fan, C.-A. J. Org. Chem. 2008, 73, 7797−7799. 10. Barbe, G.; St-Onge, M.; Charette, A. B. Org. Lett. 2008, 10, 5497−5499.

270

Guareschi–Thorpe condensation 2-Pyridone formation from the condensation of cyanoacetic ester with diketone in the presence of ammonia.

R R CN CN O NH3 1 R O R O O R N O H

: H3NH H3N O : CN H CN H3N CN 1 H2N R OH R 1 CN 1 R O O R O O H2N O R O H H N O 2

: R H3N R R OH R CN H CN CN CN OH H2O :NH H 3 R O R O : R N O R N O O NH2 O H O NH2 H NH H 3 H

Example6

NC CN CN NH3 75% O CO2Et OON H Guareschi imide References

1. (a) Guareschi, I. Mem. R. Accad. Sci. Torino 1896, II, 7, 11, 25. (b) Baron, H.; Renfry, F. G. P.; Thorpe, J. F. J. Chem. Soc. 1904, 85, 1726−1961. Jocelyn F. Thorpe spent two years in Germany where he worked in the laboratory of a dyestuff manufacturer before taking a post as a lecturer at Manchester. Thorpe later became FRS (Fellow of the Royal Society) and professor of organic chemistry at Imperial College. 2. Vogel, A. I. J. Chem. Soc. 1934, 1758−1765. 3. McElvain, S. M.; Lyle, R. E. Jr. J. Am. Chem. Soc. 1950, 72, 384−389. 4. Brunskill, J. S. A. J. Chem. Soc. (C) 1968, 960−966. 5. Brunskill, J. S. A. J. Chem. Soc., Perkin Trans. 1 1972, 2946−2950. 6. Holder, R. W.; Daub, J. P.; Baker, W. E.; Gilbert, R. H. III; Graf, N. A. J. Org. Chem. 1982, 47, 1445−1451. 7. Krstic, V.; Misic-Vukovic, M.; Radojkovic-Velickovic, M. J. Chem. Res. (S) 1991, 82. 8. Galatsis, P. Guareschi−Thorpe Pyridine Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 307−308. (Review).

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_116, © Springer-Verlag Berlin Heidelberg 2009 271

Hajos–Wiechert reaction Asymmetric Robinson annulation catalyzed by (S)-(−)-proline.

O HO C 2 O cat. H N H

O CH3CN O O

H O O HO2C Michael H N H addition O enamine formation O O O

O O O catalytic H O: : 2 asymmetric hydrolysis N O N N O H OH of iminium salt enamine aldol H CO CO2 2 N CO2 H CO2

O O O O

: E1cB HO O OH O N OH OH H O CO B: 2

Example 11a

O O 3 mol% (S)-proline

CH CN, 100%, 93.4% ee O 3 O O

Example 23 O O O 1 equiv L−phenylalanine

D-CSA, DMF, rt, 24 h, O O then increase temperature 10 oC every 24 h for 5 days. 79%, 91% ee

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_117, © Springer-Verlag Berlin Heidelberg 2009 272

Example 38

O O L-phenylalanine, PPTS

o DMSO, 50 C, 24 h O O O sonication, 94%, 73% ee OBn OBn

Example 49

O O O 1 equiv L-phenylalanine 0.5 equiv 1 N HClO4

o O DMSO, 90 C O 86%, 48% ee

References

1. (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615−1621. Hajos and Parrish were chemists at Hoffmann−La Roche. (b) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. 1971, 10, 496−497. 2. Brown, K. L.; Dann, L.; Duntz, J. D.; Eschenmoser, A.; Hobi, R.; Kratky, C. Helv. Chim. Acta 1978, 61, 3108−3135. 3. Hagiwara, H.; Uda, H. J. Org.Chem. 1998, 53, 2308–2311. 4. Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357−389. 5. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395−2396. 6. List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573−576. 7. Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16−17. 8. Shigehisa, H.; Mizutani, T.; Tosaki, S.-y.; Ohshima, T.; Shibasaki, M. Tetrahedron 2005, 61, 5057−5065. 9. Nagamine, T.; Inomata, K.; Endo, Y.; Paquette, L. A. J. Org. Chem. 2007, 72, 123– 131. 10. Kennedy, J. W. J.; Vietrich, S.; Weinmann, H.; Brittain, D. E. A. J. Org. Chem. 2009, 73, 5151−5154. 11. Christen, D. P. Hajos–Wiechert Reaction. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 554−582. (Re- view). 12. Zhu, H.; Clemente, F. R.; Houk, K. N.; Meyer, M. P. J. Am. Chem. Soc. 2009, 131, 1632−1633.

273

Haller–Bauer reaction Base-induced cleavage of non-enolizable ketones leading to carboxylic amide derivative and a neutral fragment in which the carbonyl group is replaced by a hydrogen.

O O NaNH H R5 R R5 2 R NH2 4 1 4 1 3 R R R PhH, reflux R 2 R R2 R3 R

non-enolizable ketone O 5 O NH O R R 2 R5 H R5 R R5 R 1 4 4 4 R 2 3 R NH3 R R R R R1 R4 R1 R3 R3 R2 R3 R2 NH 2 Example 14

CO2H t-BuOK, t-BuOH

43% O Example 29 O OMe O O 1. KOH, dioxane

2. CH2N2 OMe 77% 2 steps OMe O OMe OMe Example 3, Racemization10

O NHC6H11 H H LiNHC6H11 O PhH, 80 oC H 46% H

References

1. Haller, A.; Bauer, E. Compt. Rend. 1908, 147, 824−829. 2. Gilday, J. P.; Gallucci, J. C.; Paquette, L. A. J. Org. Chem. 1989, 54, 1399−1408. 3. Paquette, L. A.; Gilday, J. P.; Maynard, G. D. J. Org. Chem. 1989, 54, 5044−5053. 4. Paquette, L. A.; Gilday, J. P. Org. Prep. Proc. Int. 1990, 22, 167−201. 5. Mehta, G.; Praveen, M. J. Org. Chem. 1995, 60, 279−280. 6. Mehta, G.; Venkateswaran, R. V. Tetrahedron 2000, 56, 1399−1422. (Review). 7. Arjona, O.; Medel, R.; Plumet, J. Tetrahedron Lett. 2001, 42, 1287−1288. 8. Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983−1986. 9. Patra, A.; Ghorai, S. K.; De, S. R.; Mal, D. Synthesis 2006, 2556−2562. 10. Braun, I.; Rudroff, F.; Mihovilovic, M. D.; Bach, T. Synthesis 2007, 24, 3896−3906.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_118, © Springer-Verlag Berlin Heidelberg 2009 274

Hantzsch dihydropyridine synthesis 1,4-Dihydropyridine from the condensation of aldehyde, β-ketoester and ammonia. Hantzsch 1,4-dihydropyridines are popular reducing reagents in organocatalysis.

R CO Et O 2 NH3 EtO2C CO2Et

R H 1 O R R1 N R1 H

O : H3N H CO2Et enolate R H aldol CO2Et formation condensation O R1 H H N: 1 3 O R : OH NH3 OH H CO Et R 2 R CO2Et R CO2Et 1 1 1 O R O R O R CO2Et CO2Et : enamine − H O NH3 2 O R1 formation HO R1 H N: 2 : NH3 H NH R R 2 H H CO Et EtO2C CO2Et H N: 2 EtO2C Michael 3 CO2Et 1 H N R1 1 : addition R1 R 2 R O 1 O N H2N R H H N: R 3 R R EtO2C CO2Et H tautomerization EtO2C CO2Et EtO2C CO2Et R1 O R1 NH HO 1 1 1 H NH 2 1 N R R N R 2 R H H

Example 12

O CO2Et NH3 NO2 H EtO2C CO2Et O NO2 N H nifedipine

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_119, © Springer-Verlag Berlin Heidelberg 2009 275

Example 29

O SiO HO3S O 2 R H O O O R1O2C CO2R2 CO2R2 NH4OAc R' H - (SiO2 SO3H), solvent-free N o − H 60 C, 83 95%

Example 3, Hantzsch 1,4-dihydropyridine as a hydrogen donor10

EtO2C CO2Et

N H

N R N R H O O 84−99% ee P O OH

References

1. Hantzsch, A. Ann. 1882, 215, 1−83. 2. Bossert, F.; Vater, W. Naturwissinschaften 1971, 58, 578−585. 3. Balogh, M.; Hermecz, I.; Naray-Szabo, G.; Simon, K.; Meszaros, Z. J. Chem. Soc., Perkin Trans. 1 1986, 753−757. 4. Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43, 5171−5187. 5. Menconi, I.; Angeles, E.; Martinez, L.; Posada, M. E.; Toscano, R. A.; Martinez, R. J. Heterocycl. Chem. 1995, 32, 831−833. 6. Raboin, J.-C.; Kirsch, G.; Beley, M. J. Heterocycl. Chem. 2000, 37, 1077−1080. 7. Sambongi, Y.; Nitta, H.; Ichihashi, K.; Futai, M.; Ueda, I. J. Org. Chem. 2002, 67, 3499−3501. 8. Galatsis, P. Hantzsch Dihydro-Pyridine Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 304−307. (Review). 9. Gupta, R.; Gupta, R.; Paul, S.; Loupy, A. Synthesis 2007, 2835−2838. 10. Metallinos, C.; Barrett, F. B.; Xu, S. Synlett 2008, 720−724.

276

Hantzsch pyrrole synthesis Reaction of α-chloromethyl ketones with β-ketoesters and ammonia to assemble pyrroles.

CO2Et O CO2Et NH3

Cl O N H

CO Et CO Et 2 enamine 2 H CO Et CO2Et : − : 2 NH3 H2O H3N formation HO O : H N H2N H2N 2

H3NH OH − O H2O CO2Et Cl CO2Et Cl H H N 2 : HN :NH

CO2Et CO2Et Cl CO2Et

: : H H3N N N HN H H Example 14 DME, 87−140 oC F3C O F C 2.5 h, 60% 3 N CO2Me Br H2N CO2Me H Example 27

CO Et CO2Et NH , EtOH 2 O 3 Cl 48 h, 48% O N H

References

1. Hantzsch, A. Ber. 1890, 23, 1474−1483. 2. Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43, 5171−5186. 3. Kirschke, K.; Costisella, B.; Ramm, M.; Schulz, B. J. Prakt. Chem. 1990, 332, 143−147. 4. Kameswaran, V.; Jiang, B. Synthesis 1997, 530−532. 5. Trautwein, A. W.; Süȕmuth, R. D.; Jung, G. Bioorg. Med. Chem. Lett. 1998, 8, 2381−2384. 6. Ferreira, V. F.; De Souza, M. C. B. V.; Cunha, A. C.; Pereira, L. O. R.; Ferreira, M. L. G. Org. Prep. Proced. Int. 2001, 33, 411−454. (Review). 7. Matiychuk, V. S.; Martyak, R. L.; Obushak, N. D.; Ostapiuk, Yu. V.; Pidlypnyi, N. I. Chem. Heterocycl. Compounds 2004, 40, 1218−1219.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_120, © Springer-Verlag Berlin Heidelberg 2009 277

Heck reaction The palladium-catalyzed alkenylation or arylation of olefins.

H R2 Pd(0) (catalytic) R1 R2 R1 X R3 R4 base R3 R4

R1 = aryl, alkenyl, alkyl (with no β-hydrogen) + X = Cl, Br, I, OTf, OTs, N2

The catalytic cycle: Pd(0) or Pd(II) precatalysts

base•HX R1 X LnPd(0) base E A

X X

LnPd(II) LnPd(II) H R1 R1 R2 D B 2 R3 R4 H R

R3 R4 1 H Pd(II)LnX R Pd(II)LnX 2 C R1 R R3 R2 R3 R4 H R4

A: Oxidative addition D: syn-β-elimination B: Migratory insertion (syn) E: Reductive elimination C: C−C bond rotation

Example 1, Asymmetric intermolecular Heck reaction6

Pd[(R)-BINAP]2 EtO2C CO2Et 3 mol% * N N OTf proton sponge CO2Me PhH, 60 oC CO2Me 95%, > 99% ee

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_121, © Springer-Verlag Berlin Heidelberg 2009 278

Example 2, Intramolecular Heck7

OTBS N N I 0.3 eq. Pd(OAc)2 N Bu4NCl, DMF, K2CO3 H H N o H 70 C, 3 h, 74% O OTBS O

Example 38 O O Cl O O MeO 1.5% Pd2(dba)3, 6% P(t-Bu)3 MeO 1.1. eq. Cs2CO3, dioxane 120 oC, 24 h, 82%

Example 4, Intramolecular Heck9

N Cl 10 mol% Pd(OAc)2 N N N Bu NCl, K CO N N H 4 2 3 H DMF, 100 oC, 67%

Example 5, Intramolecular Heck13

Me Me O Bn NTs TsN N O H H H H N N N Me Me MeN MeN Bn Me N Me TfO Me

OTf Pd(OAc)2 (R)-Tol-BINAP NMe Bn NMe N N N MeCN, 80 oC H H H H (62%, 90% ee) O N NTs Bn O TsN Me Me

Example 6, Reductive Heck reaction17

Me Me H Me Me H 5 mol% Pd(P(o-tol)3(OAc)2 Me O Br O NaOCHO, TBAB, Et3N NH DMF, 80 oC, 65% N H

279

References

1. Heck, R. F.; Nolley, J. P., Jr. J. Am. Chem. Soc. 1968, 90, 5518−5526. Richard Heck discovered the Heck reaction when he was an assistant professor at the University of Delaware. Despite having discovered a novel methodology that would see ubiquitous utility in organic chemistry and having published a popular book,4 Heck had difficul- ties in securing funding for his research, he left chemistry and moved to Asia. Now he is retired in Florida. 2. Heck, R. F. Acc. Chem. Res. 1979, 12, 146−151. (Review). 3. Heck, R. F. Org. React. 1982, 27, 345−390. (Review). 4. Heck, R. F. Palladium Reagents in Organic Synthesis, Academic Press, London, 1985. (Book). 5. Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecule 1994, University Science Books: Mill Valley, CA, pp 103−113. (Book). 6. Ozawa, F.; Kobatake, Y.; Hayashi, T. Tetrahedron Lett. 1993, 34, 2505−2508. 7. Rawal V. H.; Iwasa, H. J. Org. Chem. 1994, 59, 2685−2686. 8. Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10−11. 9. Li, J. J. J. Org. Chem. 1999, 64, 8425−8427. 10. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009−3066. (Review). 11. Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314−321. (Review). 12. Link, J. T. Org. React. 2002, 60, 157−534. (Review). 13. Lebsack, A. D.; Link, J. T.; Overman, L. E.; Stearns, B. A. J. Am. Chem. Soc. 2002, 124, 9008−9009. 14. Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945−2963. (Review). 15. Beller, M.; Zapf, A.; Riermeier, T. H. Transition Metals for Organic Synthesis (2nd edn.) 2004, 1, 271−305. (Review). 16. Oestreich, M. Eur. J. Org. Chem. 2005, 783−792. (Review). 17. Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404−406. 18. Fuchter, M. J. Heck Reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 2−32. (Review). 19. The Mizoroki-Heck Reaction; Oestreich, M., Ed.; Wiley & Sons: Hoboken, NJ, 2009.

280

Heteroaryl Heck reaction Intermolecular or intramolecular Heck reaction that occurs onto a heteroaryl recipient.

N Pd(Ph3P)4, Ph3P, CuI S I o N S Cs2CO3, DMF, 140 C

N S

Pd(0) S N I Pd(II)I H Pd(II) oxidative addition insertion B: I

Cs2CO3 S Pd(0) CsI CsCHO N 3

Example 12

N N Br Pd(OAc)2, NaHCO3 N N n-Bu NCl, DMA N 4 N O 150 oC, 24 h, 83% Bu O Bu Example 23

N N N O N Pd(Ph3P)4, KOAc NCl DMA, reflux, 65% N

References

1. Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaka, R.; Miyafuji, A.; Nakata, T.; Tani, N. Aoyagi, Y. Heterocycles 1990, 31, 1951−1958. 2. Kuroda, T.; Suzuki, F. Tetrahedron Lett. 1991, 32, 6915−6918. 3. Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Tokunaga, K.; Gohma, K.; Koma- tsu, J.; Sekine, K.; Miyafuji, A.; Kunoh, J. Honma, R. Akita, Y.; Ohta, A. Heterocy- cles 1992, 33, 257−272. 4. Proudfoot, J. R.; Patel, U. R.; Kapadia, S. R.; Hargrave, K. D. J. Med. Chem. 1995, 38, 1406−1410. 5. Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467−473. 6. Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic Chemistry; 2nd ed.; 2007, El- sevier: Oxford, UK. (Review). 281

Hegedus indole synthesis Stoichiometric Pd(II)-mediated oxidative cyclization of alkenyl anilines to indoles. Cf. Wacker oxidation.

PdCl2(CH3CN)2, THF CH3 then, Et3N, 84% MeO C N MeO2C NH2 2 H

PdCl2(CH3CN)2 Et3N Cl palladation Pd MeO2C NH2 MeO2C NH2 Cl precipitate Cl Cl Et N Pd Et N 3 3 Cl H Pd – HCl Cl : – "PdH" MeO C N MeO C N 2 H MeO2C NH2 2 H 2 H "PdH" β-elimination PdLn CH3 MeO C N N CH3 2 H MeO2C H Example 11a

10 mol% (CH3CN)2PdCl2 100 mol% benzoquinone CH3 NH 10 eq. Et N, THF, reflux, 84% N 2 3 H Example 21d Br Br 10 mol % (CH3CN)2PdCl2 100 mol% benzoquinone

10 eq. LiCl, THF, reflux, 77% NHTs N Ts References

1. (a) Hegedus, L. S.; Allen, G. F.; Waterman, E. L. J. Am. Chem. Soc. 1976, 98, 2674−2676. Lou Hegedus is a professor at Colorado State University. (b) Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100, 5800−5807. (c) Hegedus, L. S.; Winton, P. M.; Varaprath, S. J. Org. Chem. 1981, 46, 2215−2221. (d) Harrington, P. J.; Hegedus, L. S. J. Org. Chem. 1984, 49, 2657−2662. (e) Hegedus, L. S. Angew. Chem., Int. Ed. 1988, 27, 1113−1126. (Review). 2. Brenner, M.; Mayer, G.; Terpin, A.; Steglich, W. Chem. Eur. J. 1997, 3, 70−74. 3. Osanai, Y. Y.; Kondo, K.; Murakami, Y. Chem. Pharm. Bull. 1999, 47, 1587−1590. 4. Kondo, T.; Okada, T.; Mitsudo, T. J. Am. Chem. Soc. 2002, 124, 186−187. A ruthenium variant. 5. Johnston, J. N. Hegedus Indole Synthesis. In Name Reactions in Heterocyclic Chemis- try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 135−139. (Re- view).

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_122, © Springer-Verlag Berlin Heidelberg 2009 282

Hell–Volhard–Zelinsky reaction

α-Halogenation of carboxylic acids using X2/PBr3.

O O O PBr3 H O R 2 R R Br OH OH Br2 Br Br

α-bromoacid

O Br O Br R PBr O Br Br R P Br R P OPBr O O Br O Br H Br R H O Br Br

H O H B: enolization H O R O hydrolysis Br O R R OH Br R Br Br Br Br : OH Br OH2 Br

Example 15

Cl CO H CO2H Cl2, cat. PCl3 2

o 97 C, 6 h, 77%

Example 26

Br CO2H PBr3 Br H Br2, 57% CO H CO2H 2

References

1. (a) Hell, C. Ber. 1881, 14, 891−893. Carl M. von Hell (1849−1926) was born in Stutt- gart, Germany. He studied under Fehling and Erlenmeyer. After serving in the war of 1870, he became very ill. Hell became a professor at Stuttgart in 1883 where he discovered the Hell–Volhard–Zelinsky reaction. (b) Volhard, J. Ann. 1887, 242, 141−163. Jacob Volhard (1849−1909) was born in Darmstadt, Germany. He apprenticed under Liebig, Will, Bunsen, Hofmann, Kolbe, and von Baeyer. He improved Hell’s original procedure in preparing α-bromo-acid during his research in thiophenes. (c) Zelinsky, N. D. Ber. 1887, 20, 2026. Nikolai D. Zelinsky (1861−1953) was born in

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_123, © Springer-Verlag Berlin Heidelberg 2009 283

Tyaspol, Russia. He studied at Göttingen under Victor Meyer, receiving his Ph.D. In 1889. Zelinsky returned to Russia and became a professor at the University of Mos- cow. On his ninetieth birthday in 1951, he was awarded the Order of Lenin. 2. Watson, H. B. Chem. Rev. 1930, 7, 173−201. (Review). 3. Sonntag, N. O. V. Chem. Rev. 1953, 52, 237−246. (Review). 4. Harwood, H. J. Chem. Rev. 1962, 62, 99−154. (Review). 5. Jason, E. F.; Fields, E. K. US Patent 3,148,209 (1964). 6. Chow, A. W.; Jakas, D. R.; Hoover, J. R. E. Tetrahedron Lett. 1966, 5427−5431. 7. Liu, H.-J.; Luo, W. Synth. Commun. 1991, 21, 2097−2102. 8. Zhang, L. H.; Duan, J.; Xu, Y.; Dolbier, W. R., Jr. Tetrahedron Lett. 1998, 39, 9621−9622. 9. Sharma, A.; Chattopadhyay, S. J. Org. Chem. 1999, 64, 8059−8062. 10. Stack, D. E.; Hill, A. L.; Diffendaffer, C. B.; Burns, N. M. Org. Lett. 2002, 4, 4487−4490.

284

Henry nitroaldol reaction The nitroaldol condensation reaction involving aldehydes and nitronates, derived from deprotonation of nitroalkanes by bases.

R1 R3 O R H Base 3 HO NO2 R NO R2 R4 R1 R2 4 2 2-nitroalcohols

H R1 R1 O R1 O R1 B HB NO2 NO2 N N R HB B 2 R2 R2 O R2 OH nitroalkanes nitronates nitronic acids O or aci-nitroalkanes

R3 H

NO2 R3 NO2 R 3 HB R1 R1 OH B R2 R2 O 2-nitroalcohols

Example 14

CHO HO NO2 Amberlyst A-21 (basic) rt, 62% NO2

Example 2, Retro-Henry reaction5

OH CuSO4, SiO2 O NO2 NO2 PhH, reflux 67%

Example 3, Aza-Henry reaction8

O O o P Ph P Ph 5 mol% TMG, 100 C HN N Ph Ph Ph NO2 0.1 mBar, 26 h Ph Ph Ph NO 95%, anti:syn = 98:2 2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_124, © Springer-Verlag Berlin Heidelberg 2009 285

Example 4, Intramolecular Henry reaction10

H HO O DBU, MeCN N O N O2N NO2 62% O

References

1. Henry, L. Compt. Rend. 1895, 120, 1265–1268. 2. Barrett, A. G. M.; Robyr, C.; Spilling, C. D. J. Org. Chem. 1989, 54, 1233–1234. 3. Rosini, G. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Per- gamon, 1991, 2, 321−340. (Review). 4. Chen, Y.-J.; Lin, W.-Y. Tetrahedron Lett. 1992, 33, 1749–1750. 5. Saikia, A. K.; Hazarika, M. J.; Barua, N. C.; Bezbarua, M. S.; Sharma, R. P.; Ghosh, A. C. Synthesis 1996, 981–985. 6. Luzzio, F. A. Tetrahedron 2001, 57, 915–945. (Review). 7. Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151–153. (Review on aza-Henry reaction). 8. Bernardi, L.; Bonini, B. F.; Capito, E.; Dessole, G.; Comes-Franchini, M.; Fochi, M.; Ricci, A. J. Org. Chem. 2004, 69, 8168–8171. 9. Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem., Int. Ed. 2005, 44, 3881–3884. 10. Kamimura, A.; Nagata, Y.; Kadowaki, A.; Uchidaa, K.; Uno, H. Tetrahedron 2007, 63, 11856–11861. 11. Wang, A. X. Henry Reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 404−419. (Review). 286

Hinsberg synthesis of thiophene derivatives Condensation of diethyl thiodiglycolate and α-diketones under basic conditions, which provides 3,4-disubstituted thiophene-2,5-dicarbonyls upon hydrolysis of the crude ester product with aqueous acid.

O O O O 1. S EtO OEt HO S O

NaOEt, EtOH Ph OH O + 2. H3O Ph

O Ph O O OO Ph Ph Ph EtO O Ph O CO2Et S CO Et H 2 O S S Ph CO2Et EtO CO2Et O Ph Ph Ph Ph + Ph H , H2O O2C Ph CO Et reflux CO H SCOEt HO2C S 2 HO2C S 2 2 Example 12

CH3 O H C O O O O 3 CH 3 S SOCl2, pyr. S O Ar Ar Ar Ar O NaOMe H3C CH3 95% 90% HO OH H3C CH3 S

O 81% O O O O NaOMe S SOCl , pyr. S O Ar Ar 2 Ar Ar Ph Ph Ph 89% Ph HO OH Ph Ph CH3 O

Example 24

O O

(CHO)3, NaOMe S S MeOH, 42%

O O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_125, © Springer-Verlag Berlin Heidelberg 2009 287

Example 35

1. O O Ph S Ph Ph O O KOH S 2. SOCl2, pyr. O 9% yield, 2 steps Ph O

Example 46

H3C CH3 H3C CH3 NaOH, MeOH NC S CN NH2 94% NC O O S O

Example 5, Polymer-support Hinsberg thiophene synthesis9

O OO KOt-Bu S R O 1 R2 R2 R1 = CO2i-Pr CONEt2 + PPh3

O O S S 10% TFA HO R O 1 R1 CH2Cl2 R 2 R R2 2 R2

References

1. Hinsberg, O. Ber. 1910, 43, 901−906. 2. Miyahara, Y.; Inazu, T.; Yoshino, T. Bull. Chem. Soc. Jpn. 1980, 53, 1187−1188. 3. Gronowitz, S. In Thiophene and Its Derivatives, Part 1, Gronowitz, S., ed.; Wiley- Interscience: New York, 1985, pp 34−41. (Review). 4. Miyahara, Y.; Inazu, T.; Yoshino, T. J. Org. Chem. 1984, 49, 1177−1182. 5. Christl, M.; Krimm, S.; Kraft, A. Angew. Chem., Int. Ed. 1990, 29, 675−677. 6. Beye, N.; Cava, M. P. J. Org. Chem. 1994, 59, 2223−2226. 7. Vogel, E.; Pohl, M.; Herrmann, A.; Wiss, T.; König, C.; Lex, J.; Gross, M.; Gissel- brecht, J. P. Angew. Chem., Int. Ed. 1996, 35, 1520−1525. 8. Mullins, R. J.; Williams, D. R. Hinsberg Synthesis of Thiophene Derivatives. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Ho- boken, NJ, 2005, pp 199−206. (Review). 9. Traversone, A.; Brill, W. K.-D. Tetrahedron Lett. 2007, 48, 3535−3538. 288

Hiyama cross-coupling reaction Palladium-catalyzed cross-coupling reaction of organosilicons with organic halides, triflates, etc. In the presence of an activating agent such as fluoride or hydroxide (transmetallation is reluctant to occur without the effect of an activating agent). For the catalytic cycle, see the Kumada coupling on page 325.

Pd catalyst 1 2 R1 SiY R2 X R R activator

R1 = alkenyl, aryl, alkynyl, alkyl R2 = aryl, alkyl, alkenyl Y = (OR)3, Me3, Me2OH, Me(3-n)F(n+3) X = Cl, Br, I, OTf activator = TBAF, base

Ar1 Ar2 Pd(0) Ar1 X reductive oxidative elimination addition

1 2 Ar Pd(II) Ar Ar1 Pd(II) X

trans"metal"lation

R3SiF X R R Ar2 Si Bu4N R F Example 11a

MeO C 2 S S

Si(Et)F2 η3 S ( -C3H5PdCl)2 o MeO C DMF, KF, 100 C 2 S 82%

Example 22

Br N C5H11 Si(OMe)3 C5H11 Bu4NF, Pd(OAc)2, Ph3P N DMF, reflux, 72%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_126, © Springer-Verlag Berlin Heidelberg 2009 289

Example 37

I Me HO Si O [allylPdCl]2 (7.5 mol%) Me O O TBAF, THF, 25 °C, 60 h CH3 Me 61% PMBO OPMB

Example 49

CO2Me CO2Me MOMO MOMO

Me Me H3C [allylPdCl]2 Me O O TBAF (12 mol%) O O I Me3Si Me Me H THF, 60 °C, 20 h 20% Me Me H OO O O Ph Ph

References

1. (a) Hatanaka, Y.; Fukushima, S.; Hiyama, T. Heterocycles 1990, 30, 303−306. (b) Hiyama, T.; Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471−1478. (c) Matsuhashi, H.; Kuroboshi, M.; Hatanaka, Y.; Hiyama, T. Tetrahedron Lett. 1994, 35, 6507−6510. 2. Shibata, K.; Miyazawa, K.; Goto, Y. Chem. Commun. 1997, 1309−1310. 3. Hiyama, T. In Metal-Catalyzed Cross-Coupling Reactions; 1998, Diederich, F.; Stang, P. J., Eds.; Wiley–VCH: Weinheim, Germany, pp 421–53. (Review). 4. Denmark, S. E.; Wang, Z. J. Organomet. Chem. 2001, 624, 372−375. 5. Hiyama, T. J. Organomet. Chem. 2002, 653, 58−61. 6. Pierrat, P.; Gros, P.; Fort, Y. Org. Lett. 2005, 7, 697−700. 7. Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc. 2004, 126, 12432−12440. 8. Domin, D.; Benito-Garagorri, D.; Mereiter, K.; Froehlich, J.; Kirchner, K. Or- ganometallics 2005, 24, 3957−3965. 9. Anzo, T.; Suzuki, A.; Sawamura, K.; Motozaki, T.; Hatta, M.; Takao, K.-i.; Tadano, K.-i. Tetrahedron Lett. 2007, 48, 8442−8448. 10. Yet L. Hiyama Cross-Coupling Reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 33−416. (Re- view).

290

Hofmann rearrangement Upon treatment of primary amides with hypohalites, primary amines with one less carbon are obtained via the intermediacy of isocyanate. Also know as the Hof- mann degradation reaction.

O Br H O 2 2 ↑ RNC O RNH2 CO2 R NH2 NaOH

O O Br R NH R N O O Br Br H H Br R NH R N OH OH H R NCO N O ↑ R H RNH2 CO2 O OH OH isocyanate intermediate

Example 1, NBS variant2 O H NBS, DBU, MeOH N O NH2 reflux, 25 min., 70% O O N O2N 2

Example 2, Iodosobenzene diacetate5 OCOCF O 3 O Ph O I : I OCOCF3 NH2 N O CF3 H CH CN/H O, 4.5 h, 100% OH 3 2 OH

H O H C N N O

: O OH

Example 3, Bromine and alkoxide6

O H N NH O Br2, NaOMe O → H H H H MeOH, rt reflux 75% HO AcO H H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_127, © Springer-Verlag Berlin Heidelberg 2009 291

Example 4, Sodium hypochlorite7

OH OH NaOCl HO O HO O HO HO CONH2 aq. NaOH NH2 50 °C, 81%

Example 5, The original conditions, bromine and hydroxide9

Ph Ph Ph Ph N N Br2, aq. KOH N N N N CONH2 NH2 N N 0 °C to reflux N N N N Me Me 80%

Example 6, Lead tetraacetate10

O O Pb(OAc)4 CONH2 NHBoc t-BuOH, Et3N NO2 reflux, 75% NO 2

References

1. Hofmann, A. W. Ber. 1881, 14, 2725–2736. 2. Jew, S.-s.; Kang, M.-h. Arch. Pharmacol Res. 1994, 17, 490–491. 3. Huang, X.; Seid, M.; Keillor, J. W. J. Org. Chem. 1997, 62, 7495–7496. 4. Togo, H.; Nabana, T.; Yamaguchi, K. J. Org. Chem. 2000, 65, 8391–8394. 5. Yu, C.; Jiang, Y.; Liu, B.; Hu, L. Tetrahedron Lett. 2001, 42, 1449–1452. 6. Jiang, X.; Wang, J.; Hu, J.; Ge, Z.; Hu, Y.; Hu, H.; Covey, D. F. Steroids 2001, 66, 655–662. 7. Stick, R. V.; Stubbs, K. A. J. Carbohydr. Chem. 2005, 24, 529–547. 8. Moriarty, R. M. J. Org. Chem. 2005, 70, 2893−2903. (Review). 9. El-Mariah, F.; Hosney, M.; Deeb, A. Phosphorus, Sulfur Silicon Relat. Elem. 2006, 181, 2505–2517. 10. Jia, Y.-M.; Liang, X.-M.; Chang, L.; Wang, D.-Q. Synthesis 2007, 744–748. 11. Gribble, G. W. Hofmann rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 164−199. (Re- view).

292

Hofmann–Löffler–Freytag reaction Formation of pyrrolidines or piperidines by thermal or photochemical decomposition of protonated N-haloamines.

Cl 1. H+, Δ R1 N − N R1 R2 2. OH R2

Δ Cl H H Cl H H Cl N 1 N N homolytic 1 R R R1 R2 R R2 2 cleavage

chloroammonium salt nitrogen radical cation

NH2 H R N 1,5-hydrogen 1 2 2 R R1 R N H R1 H atom transfer Cl R2 H N R1 R2

OH S 2 N R1 1 : N OH R 1 NH2 NH H N R Cl Cl 1 2 2 2 2 R R R R R

Example 12

NH N O 1. NaOCl, 95% O H H 2. TFA, hv, 87% 3. NaOH, MeOH, 76% H H H H HO HO

Example 24

O Ph 84% H2SO4 Ph N o N Br 65 C, 30 min. N N N 25%

Example 35

NCS, ether, Et3N then hv, (Hg0 lamp) NH N N N o 0 C, 3.5 h in N2 100%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_128, © Springer-Verlag Berlin Heidelberg 2009 293

Example 47

PhI(OAc)2 or Pb(OAc)4

I2, hv, 99% HN P(O)(OEt)2 N P(O)(OEt)2 AcO AcO H H

Example 512

O CF O CF3 3 1.0 equiv CBr4, hv 0.05 M PhCF Me O N 3 Me O N Br H Br 100 W flood lamp Me Me Me Me rt, 7 min. Me Me O 1.25 equiv Ag2CO3 CH2Cl2, rt, 1 h Me OO

then AcOH, 15 min. Me Me > 69% overall Me

References

1. (a) Hofmann, A. W. Ber. 1883, 16, 558−560. (b) Löffler, K.; Freytag, C. Ber. 1909, 42, 3727. 2. Wolff, M. E.; Kerwin, J. F.; Owings, F. F.; Lewis, B. B.; Blank, B.; Magnani, A.; Karash, C.; Georgian, V. J. Am. Chem. Soc. 1960, 82, 4117−4118. 3. Wolff, M. E. Chem. Rev. 1963, 63, 55−64. (Review). 4. Dupeyre, R.-M.; Rassat, A. Tetrahedron Lett. 1973, 2699−2701. 5. Kimura, M.; Ban, Y. Synthesis 1976, 201−202. 6. Stella, L. Angew. Chem., Int. Ed. 1983, 22, 337−422. (Review). 7. Betancor, C.; Concepcion, J. I.; Hernandez, R.; Salazar, J. A.; Suarez, E. J. Org. Chem. 1983, 48, 4430−4432. 8. Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095−7129. (Review). 9. Togo, H.; Katohgi, M. Synlett 2001, 565−581. (Review). 10. Pellissier, H.; Santelli, M. Org. Prep. Proced. Int. 2001, 33, 455−476. (Review). 11. Li, J. J. Hofmann–Löffler–Freytag Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 89−97. (Review). 12. Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 17247−17249.

294

Horner–Wadsworth–Emmons reaction Olefin formation from aldehydes and phosphonates. Workup is more advantageous than the corresponding Wittig reaction because the phosphate by-product can be washed away with water. Typically gives the trans- rather than the cis- olefins.

O O NaH, then CO2Et O EtO EtO P P EtO OEt RCHO R EtO ONa

O O O O O O EtO EtO P EtO P P EtO OEt EtO OEt EtO OEt H H OR OR H The stereochemical outcome: erythro (kinetic) or threo (thermodynamic)

O O OEt OEt PO OEt PO OEt R CO2Et H H H H CO Et CO Et R 2 R 2 erythro, kinetic adduct

O O OEt OEt CO2Et PO OEt PO OEt CO Et H 2 H CO2Et R R H R H threo, thermodynamic adduct Example 13

O O O O EtO P CO2Et CHO EtO OEt

NaH, THF, 95% OMe OMe Example 24 O O CHO EtO P CO2Et EtO OEt

BnO KOH, THF, 95% BnO

Example 37 OMe OMOM EtO OMOM OMe H N H O O EtO P O N O O OTBDPS OTBDPS O NaH, THF 92%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_129, © Springer-Verlag Berlin Heidelberg 2009 295

Example 4, Intramolecular Horner–Wadsworth–Emmons9 TBSO

O O OTBS N O K CO O 2 3 O 18-crown-6 3 O N O 2 OMe 3 Toluene O −20 oC O Br 67% Z/E = 5:1 N O 2 O OTIPS OTIPS O P OEt MeO O Br MeO O O N OEt

O MeO MeO MeO

References

1. (a) Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G. Chem. Ber. 1959, 92, 2499– 2505. (b) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733– 1738. (c) Wadsworth, D. H.; Schupp, O. E.; Seus, E. J.; Ford, J. A., Jr. J. Org. Chem. 1965, 30, 680–685. 2. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863−927. (Review). 3. Shair, M. D.; Yoon, T. Y.; Mosny, K. K.; Chou, T. C.; Danishefsky, S. J. J. Am. Chem. Soc. 1996, 118, 9509–9525. 4. Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.; Hughes, R. J.; Natarajan, S.; Jain, N. F.; Ramanjulu, J. M.; Bräse, S.; Solomon, M. E. Chem. Eur. J. 1999, 5, 2602– 2621. 5. Comins, D. L.; Ollinger, C. G. Tetrahedron Lett. 2001, 42, 4115–4118. 6. Lattanzi, A.; Orelli, L. R.; Barone, P.; Massa, A.; Iannece, P.; Scettri, A. Tetrahedron Lett. 2003, 44, 1333–1337. 7. Ahmed, A.; Hoegenauer. E. K.; Enev, V. S.; Hanbauer, M.; Kaehlig, H.; Öhler, E.; Mulzer, J. J. Org. Chem. 2003, 68, 3026–3042. 8. Blasdel, L. K.; Myers, A. G. Org. Lett. 2005, 7, 4281–4283. 9. Li, D.-R.; Zhang, D.-H.; Sun, C.-Y.; Zhang, J.-W.; Yang, L.; Chen, J.; Liu, B.; Su, C.; Zhou, W.-S.; Lin, G.-Q. Chem. Eur. J. 2006, 12, 1185–1204. 10. Rong, F. Horner–Wadsworth–Emmons reaction in. In Name Reactions for Homologa- tions-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 420−466. (Review). 296

Houben−Hoesch reaction Acid-catalyzed acylation of phenols as well as phenolic ethers using nitriles.

OH OH OH RCN H2O

HCl, AlCl3 OH OH OH R NH•HCl R O

H : OH O complexation electrophilic AlCl3 : R N OH substitution OH H R N AlCl 3 R NH

OH OH OH

hydrolysis : OH H2O OH NH H R 2 OH R NH•HCl O H R O

Example 1, Intramolecular Houben−Hoesch reaction3

O OMe O OMe

1. ZnCl2, HCl(g), Et2O CN 2. H2O, reflux, 89% OMe O OMe Example 26

OPiv

F OH MeO F PivO CN CO2Me OMe SbCl5, 2-chloropropane N OMe MeO OH CH2Cl2, rt, 2 h, 95% H O OH CO2Me Example 38

NC Cl NH2 NH •HCl 2 BCl3•CH2Cl2, ZnCl2 14C 14C = 14C-labelled 14 u u Cu Cl then aq. HCl O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_130, © Springer-Verlag Berlin Heidelberg 2009 297

Example 49 Cl

OMe Cl NC HCl (g), THF, overnight MeO N OMe H then 2% aq. HCl reflux, 3 h, 43% O

MeO N H

References

1. (a) Hoesch, K. Ber. 1915, 48, 1122−1133. Kurt Hoesch (1882−1932) was born in Krezau, Germany. He studied at Berlin under Emil Fischer. During WWI, Hoesch was Professor of Chemistry at the University of Istanbul, Turkey. After the war he gave up his scientific activities to devote himself to the management of a family business. (b) Houben, J. Ber. 1926, 59, 2878−2891. 2. Yato, M.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 691−692. 3. Rao, A. V. R.; Gaitonde, A. S.; Prakash, K. R. C.; Rao, S. P. Tetrahedron Lett. 1994, 35, 6347−6350. 4. Sato, Y.; Yato, M.; Ohwada, T.; Saito, S.; Shudo, K. J. Am. Chem. Soc. 1995, 117, 3037−3043. 5. Kawecki, R.; Mazurek, A. P.; Kozerski, L.; Maurin, J. K. Synthesis 1999, 751−753. 6. Udwary, D. W.; Casillas, L. K.; Townsend, C. A. J. Am. Chem. Soc. 2002, 124, 5294−5303. 7. Sanchez-Viesca, F.; Gomez, M. R.; Berros, M. Org. Prep. Proc. Int. 2004, 36, 135−140. 8. Wager, C. A. B.; Miller, S. A. J. Labelled Compd. Radiopharm. 2006, 49, 615−622. 9. Black, D. St. C.; Kumar, N.; Wahyuningsih, T. D. ARKIVOC 2008, (6), 42−51.

298

Hunsdiecker−Borodin reaction Conversion of silver carboxylate to halide by treatment with halogen.

O X2 ↑ Ag RX CO2 AgX R O

XX O homolytic O AgX X Ag RO cleavage R O O X O R O O ↑ X CO2 R RX R O R O

Example 15

Δ HgO, Br2, Cl CO2H Cl Br CCl − 4, dark, 35 46%

Example 26 Br CO2H + − NBS, n-Bu4N CF3CO2

ClCH2CH2Cl, 96% MeO MeO

Example 38 Cl

CO2H N Br 2 BF4

N "Select fluor" F HO KBr, CH CN, 82% HO 3

Example 4, One-pot microwave-Hunsdiecker−Borodin followed by Suzuki10

Br CO2H NBS, LiOAc BnO − BnO CH3CN H2O 9:1 OMe MW 1 min. OMe

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_131, © Springer-Verlag Berlin Heidelberg 2009 299

PhB(OH)2, K2CO3 Pd(PPh3)4 / CH3CN H2O 2:1 microwave, 5 min. BnO 64% 2 steps OMe

References

1. (a) Borodin, A. Ann. 1861, 119, 121−123. Aleksandr Porfireviþ Borodin (1833−1887) was born in St Petersburg, the illegitimate son of a prince. He prepared methyl bromide from silver acetate in 1861, but another eighty years elapsed before Heinz and Cläre Hunsdiecker converted Borodin’s synthesis into a general method, the Huns- diecker or Hunsdiecker−Borodin reaction. Borodin was also an accomplished com- poser and is now best known for his musical masterpiece, opera Prince Egor. He kept a piano outside his laboratory. (b) Hunsdiecker, H.; Hunsdiecker, C. Ber. 1942, 75, 291−297. Cläre Hunsdiecker was born in 1903 and educated in Cologne. She developed the bromination of silver carboxylate alongside her husband, Heinz. 2. Sheldon, R. A.; Kochi, J. K. Org. React. 1972, 19, 326−421. (Review). 3. Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron Lett. 1983, 24, 4979−4982. 4. Crich, D. In Comprehensive Organic Synthesis; Trost, B. M.; Steven, V. L., Eds.; Per- gamon, 1991, Vol. 7, pp 723−734. (Review). 5. Lampman, G. M.; Aumiller, J. C. Org. Synth. 1988, Coll. Vol. 6, 179. 6. Naskar, D.; Chowdhury, S.; Roy, S. Tetrahedron Lett. 1998, 39, 699−702. 7. Das, J. P.; Roy, S. J. Org. Chem. 2002, 67, 7861−7864. 8. Ye, C.; Shreeve, J. M. J. Org. Chem. 2004, 69, 8561−8563. 9. Li, J. J. Hunsdiecker reaction. In Name Reactions for Functional Group Transforma- tions; Li, J. J., Corey, E. J., Eds., John Wiley & Sons: Hoboken, NJ, 2007, pp 623−629. (Review). 10. Bazin, M.-A.; El Kihel, L.; Lancelot, J.-C.; Rault, S. Tetrahedron Lett. 2007, 48, 4347−4351.

300

Jacobsen–Katsuki epoxidation Mn(III)salen-catalyzed asymmetric epoxidation of (Z)-olefins.

R R

N N Mn R1 O O R1 Cl 3 O 5 R3 R5 R R R2 R2 6 R4 R6 R4 **R terminal oxidant, solvent

1. Concerted oxygen transfer (cis-epoxide):

R R1 R R1 R R1 O R R1 O Mn(V) O O Mn(V) Mn(V)

2. Oxygen transfer via radical intermediate (trans-epoxide):

R R R R1 1 R R O 1 R R1 Mn(V) O O O Mn(V) Mn(V)

3. Oxygen transfer via manganaoxetane intermediate (cis-epoxide):

O R1 [2 + 2] R1 R R1 R R1 O O Mn(V) Mn(V) cycloaddition Mn(V) O R R

Example 12

cat, 4-phenylpyridine-N-oxide CO Et CO Et 2 2 o NaOCl, CH2Cl2, 4 C, 12 h 56%, 95−97% ee O

H H N N Mn cat. = t-Bu O O t-Bu Cl t-Bu t-Bu

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_132, © Springer-Verlag Berlin Heidelberg 2009 301

Example 25

OMe OMe O cat., NaOCl O

58% yield, 89% ee N N O Ph Ph

Example 26 Ph N OH OH H cat. NaOCl N N N 88% O NHt-Bu 88% ee O Crixivan

References

1. (a) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1990, 112, 2801–2903. (b) Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.; Katsuki, T. Tetrahe- dron Lett. 1990, 31, 7345–7348. (c) Irie, R.; Noda, K.; Ito, Y.; Katsuki, T. Tetrahe- dron Lett. 1991, 32, 1055–1058. (d) Deng, L.; Jacobsen, E. N. J. Org. Chem. 1992, 57, 4320–4323. (e) Palucki, M.; McCormick, G. J.; Jacobsen, E. N. Tetrahedron Lett. 1995, 36, 5457–5460. 2. Zhang, W.; Jacobsen, E. N. J. Org. Chem. 1991, 56, 2296–2298. 3. Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: Weinheim, New York, 1993, Ch. 4.2. (Review). 4. Jacobsen, E. N. In Comprehensive Organometallic Chemistry II, Eds. G. W. Wilkin- son, G. W.; Stone, F. G. A.; Abel, E. W.; Hegedus, L. S., Pergamon, New York, 1995, vol 12, Chapter 11.1. (Review). 5. Lynch, J. E.; Choi, W.-B.; Churchill, H. R. O.; Volante, R. P.; Reamer, R. A.; Ball, R. G. J. Org. Chem. 1997, 62, 9223–9228. 6. Senananyake, C. H. Aldrichimica Acta 1998, 31, 3–15. (Review). 7. Jacobsen, E. N.; Wu, M. H. In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Eds.; Springer: New York; 1999, Chapter 18.2. (Review). 8. Katsuki, T. In Catalytic Asymmetric Synthesis; 2nd edn.; Ojima, I., Ed.; Wiley-VCH: New York, 2000, 287. (Review). 9. Katsuki, T. Synlett 2003, 281–297. (Review). 10. Palucki, M. Jacobsen–Katsuki epoxidation. In Name Reactions in Heterocyclic Chem- istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 29−43. (Re- view). 11. Engelhardt, U.; Linker, T. Chem. Commun. 2005, 1152–1154. 12. Fernandez de la Pradilla, R.; Castellanos, A.; Osante, I.; Colomer, I.; Sanchez, M. I. J. Org. Chem. 2009, 74, 170–181. 302

Japp–Klingemann hydrazone synthesis Hydrazones from β-ketoesters and diazonium salts with the acid or base.

KOH H O ArN2 Cl CO2R N O Ar N CO2R OH

Diazonium salt β-keto-ester hydrazone

Ar N OH NNAr HO N H deprotonation coupling CO2R CO2R CO2R O O O

Ar N H O H N N Ar N CO R CO R N 2 2 OH Ar N CO2R OOH

Example 14

CO2Et CO2Et

N NaNO2 N Me S Me S Cl O O conc. HCl, H2O O O NH o N 2 0 C N

O CO2Et NMe2 Me NMe2 N Me S CO2Et O O N NaOAc (pH 3−4) N o H 0 to 50 C CO2Et 72%

Example 26

H 0.5 N KOH, THF, rt, 1 h N NH N NH then HO2C O OBn O + N2 Cl 62% yield OBn

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_133, © Springer-Verlag Berlin Heidelberg 2009 303

Example 310

NR1R2

O O KOAc, H2O OEt −4 oC to rt − N 60 85% N NR1R2

CO2H

+ o H , 100 C NR1R2 HN N − 70 85% CO Et OEt 2 HO C N 2 H O

References

1. (a) Japp, F. R.; Klingemann, F. Ber. 1887, 20, 2942−2944. (b) Japp, F. R.; Klinge- mann, F. Ber. 1887, 21, 2934−2936. (c) Japp, F. R.; Klingemann, F. Ber. 1887, 20, 3398−3401. (d) Japp, F. R.; Klingemann, F. Ann. 1888, 247, 190−225. (e) Japp, F. R.; Klingemann, F. J. Chem. Soc. 1888, 53, 519−544. 2. Phillips, R. R. Org. React. 1959; 10, 143−178. (Review). 3. Loubinoux, B.; Sinnes, J.-L.; O’Sullivan, A. C.; Winkler, T. J. Org. Chem. 1995, 60, 953−959. 4. Pete, B.; Bitter, I.; Harsanyi, K.; Toke, L. Heterocycles 2000, 53, 665−673. 5. Atlan, V.; Kaim, L. E.; Supiot, C. Chem. Commun. 2000, 1385−1386. 6. Dubash, N. P.; Mangu, N. K.; Satyam, A. Synth. Commun. 2004, 34, 1791−1799. 7. He, W.; Zhang, B.-L.; Li, Z.-J.; Zhang, S.-Y. Synth. Commun. 2005, 35, 1359−1368. 8. Li, J. Japp–Klingemann hydrazone synthesis. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 630−634. (Review). 9. Chen, Y.; Shibata, M.; Rajeswaran, M.; Srikrishnan, T.; Dugar, S.; Pandey, R. K. Tet- rahedron Lett. 2007, 48, 2353−2356. 10. Pete, B. Tetrahedron Lett. 2008, 49, 2835−2838. 304

Jones oxidation The Collins/Sarett oxidation (chromium trioxide-pyridine complex), and Corey´s PCC (pyridinium chlorochromate) and PDC (pyridinium dichromate) oxidations follow a similar pathway as the Jones oxidation (chromium trioxide and sulfuric acid in acetone). All these oxidants have a chromium (VI), normally black or yellow, which is reduced to Cr(IV), often green.

CrO Cl Cr2O7 CrO 3 CrO3/H2SO4 3 N N 2 N 2 H H

Jones Collins/Sarett PCC PDC

Jones oxidation By the Jones oxidation, the primary alcohols are oxidized to the corresponding aldehyde or carboxylic acids, whereas the secondary alcohols are oxidized to the corresponding ketones. O OH CrO3

H SO , acetone R1 R2 R1 R2 2 4

CrO3 + H2O ĺ H2CrO4

O O OH2 Cr Cr O Cr(VI) OO O OH Cr(III) H Cr O: OH black H H R1 R2 O green R1 R : R R 2 B 1 2

The intramolecular mechanism is also operative:

O OH Cr O OH O O Cr R R OOH R H 1 2 1 R 2

Example 16 OH O H O 1. Jones reagent H O O O O acetone, 20 min. O O O O O O O 2. HCO2H, rt, 1 h 96% 2 steps CO2t-Bu (−)-CP-263114 CO2H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_134, © Springer-Verlag Berlin Heidelberg 2009 305

Example 27

O O CO Me CO2Me 2 HO CrO3, H2SO4 O acetone/H O H 2 H rt, 74%

H H Example 319

CrO3, H2SO4

acetone, 0 oC 1−2 h, 86% O HO O

References

1. Bowden, K.; Heilbron, I. M., Jones, E. R. H.; Weedon, B. C. L. J. Chem. Soc. 1946, 39−45. Ewart R. H. (Tim) Jones worked with Ian M. Heilbron at Imperial College. Jones later succeeded Robert Robinson to become the prestigious Chair of Organic Chemistry at Manchester. The recipe for the Jones reagent: 25 g CrO3, 25 mL conc. H2SO4, and 70 mL H2O. 2. Ratcliffe, R. W. Org. Synth. 1973, 53, 1852. 3. Vanmaele, L.; De Clerq, P.; Vandewalle, M. Tetrahedron Lett. 1982, 23, 995−998. 4. Luzzio, F. A. Org. React. 1998, 53, 1−222. (Review). 5. Zhao, M.; Li, J.; Song, Z.; Desmond, R. J.; Tschaen, D. M.; Grabowski, E. J. J.; Rei- der, P. J. Tetrahedron Lett. 1998, 39, 5323−5326. (Catalytic CrO3 oxidation). 6. Waizumi, N.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 2000, 122, 7825−7826. 7. Hagiwara, H.; Kobayashi, K.; Miya, S.; Hoshi, T.; Suzuki, T.; Ando, M. Org. Lett. 2001, 3, 251−254. 8. Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2003, 44, 1275−1278. 9. Hunter, A. C.; Priest, S.-M. Steroids 2006, 71, 30−33. 10. Dong, J.; Chen, W.; Wang, S.; Zhang, J. J. Chromatogr., B 2007, 858, 239−246.

Collins–Sarett oxidation Different from the Jones oxidation, the Collins–Sarett oxidation converts primary alcohols to the corresponding aldehydes.

Example 15 O O CHO OH 8 eq CrO •2Pyr 3 O Ph O O Ph O CH Cl , 15 min., 86% 2 2 O O 306

Example 27

OMe OMe

Me Me 7 equiv CrO3•Py2

CH2Cl2, 30 min., 75% CHO

OH MeO2C Me MeO2C Me

Example 39

R1 R2 R1 R2 R3 R3 CrO3, Pyr. N R 50−60 oC, 48 h 4 N R4 − PhO2S O PhO S 50 65% 2

References

1. Poos, G. I.; Arth, G. E.; Beyler, R. E.; Sarett, L. H. J. Am. Chem. Soc. 1953, 75, 422– 429. 2. Collins, J. C; Hess, W. W.; Frank, F. J. Tetrahedron Lett. 1968, 3363–3366. J. C. Collins was a chemist at Sterling-Winthrop in Resselaer, New York. 3. Collins, J. C; Hess, W. W. Org. Synth. 1972, Coll. Vol. V, 310. 4. Hill, R. K.; Fracheboud, M. G.; Sawada, S.; Carlson, R. M.; Yan, S.-J. Tetrahedron Lett. 1978, 945–948. 5. Krow, G. R.; Shaw, D. A.; Szczepanski, S.; Ramjit, H. Synth. Commun. 1984, 14, 429–433. 6. Li, M.; Johnson, M. E. Synth. Commun. 1995, 25, 533–537. 7. Harris, P. W. R.; Woodgate, P. D. Tetrahedron 2000, 56, 4001–4015. 8. Nguyen-Trung, N. Q.; Botta, O.; Terenzi, S.; Strazewski, P. J. Org. Chem. 2003, 68, 2038–2041. 9. Arumugam, N.; Srinivasan, P. C. Synth. Commun. 2003, 33, 2313–2320.

PCC oxidation

Example 1, One-pot PCC–Wittig reactions2

O t-Bu PCC, Celite, CH2Cl2, rt, 3 h t-Bu Si Si OH O then Ph3P=CHCO2CH3 80% 95 : 5 E : Z

307

Example 23

O OH 1.5 eq PCC, CH2Cl2 EtO C EtO2C 2 N N rt, 3 h, 75%

Example 34 O

OAc O PCC, pyr. OAc O Ph CH2Cl2, reflux Ph OAc OAc 8 h, 64% OAc OAc

Example 45 HO O

O O

PCC, CH2Cl2 75%, 93:7 er

Cl Cl

References

1. Corey, E. J.; Suggs, W. Tetrahedron Lett. 1975, 16, 2647–2650. 2. Bressette, A. R.; Glover, L. C., IV Synlett 2004, 738–740. 3. Breining, S. R.; Bhatti, B. S.; Hawkins, G. D.; Miao, L.; Mazurov, A.; Phillips, T. Y.; Miller, C. H. WO2005037832 (2005). 4. Srikanth, G. S. C.; Krishna, U. M.; Trivedi, G. K.; Cannon, J. F. Tetrahedron 2006, 62, 11165–11171. 5. Kim, S.-G. Tetrahedron Lett. 2008, 49, 6148–6151.

PDC oxidation

Example 12

PDC, CH2Cl2 S S O 24 h, 68% O CHO S S OH

308

Example 2, Cleavage of primary carbon–boron bond3

PDC, DMF B(OH) 2 CO H rt, 24 h 2 75%

Example 34

OTBDMS PDC, DMF OH rt, 24 h, 56% OH OTBDMS O O

References

1 Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 399–402. 2 Terpstra, J. W.; Van Leusen, A. M. J. Org. Chem. 1986, 51, 230–208. 3 Brown, H. C.; Kulkarni, S. V.; Khanna, V. V.; Patil, V. D.; Racherla, U. S. J. Org. Chem. 1992, 57, 6173–6177. 4 Chênevert, R. Courchene, G.; Caron, D. Tetrahedron: Asymmmetry 2003, 2567–2571. 5 Jordão, A. K Synlett 2006, 3364–3365. (Review).

309

Julia–Kocienski olefination Modified one-pot Julia olefination to give predominantly (E)-olefins from heteroarylsulfones and aldehydes. A sulfone reduction step is not required.

N N N N R1 1. KHMDS R2 OH SO N SO2 R N 2 N 1 N 2. R2CHO Ph Ph

N(TMS) O 2 R 2 K R2 H O R2 H N N N O N N R1 N R1 N N SO N R1 N 2 N S R N SO2 SO N 1 N N 2 O2 N Ph Ph Ph Ph N N N N O R2 N N R OH R 2 N SO2 Ph O 1 N R1 S Ph O Alternatives to tetrazole:

N F3C N N N N N N N N N S t- Ph Bu F3C PT BT PYR TBT BTFP

The use of larger counterion (such as K+) and polar solvents (such as DME) favors an open transition state (PT = phenyltetrazolyl): O SO PT R1 H 2 R2 R1 H R2 SO PT OK 2 Example 1, (BT = benzothiazole)2 NaHMDS, DMF OTIPS SO2BT OHC OTIPS −78 oC to rt, 90% E:Z (78:22)

Example 23

OTBS OPiv

O O N OMe

O S S − o O KHMDS, THF, 78 C, 85% O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_135, © Springer-Verlag Berlin Heidelberg 2009 310

OPiv OTBS

O OMe

Example 37

O KHMDS, toluene S CHO N O 25 oC, 64% OTIPS OTIPS TIPSO

88 : 12

Example 48

MeO OMe 1) P4−t-Bu, THF, −78 oC F3C OMe O CHO 2) OMe S 74%, yield O MeO MeO E/Z = 98/2 F3C

References

1. (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32, 1175−1178. (b) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 336−357. (c) Baudin, J. B.; Hareau, G.; Julia, S. A.; Loene, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856−878. (d) Blakemore, P. R.; Cole, W. J.; Kocien- ski, P. J.; Morely, A. Synlett 1998, 26−28. 2. Charette, A. B.; Lebel, H. J. Am. Chem. Soc. 1996, 118, 10327−10328. 3. Blakemore, P. R.; Kocienski, P. J.; Morley, A.; Muir, K. J. Chem. Soc., Perkin Trans. 1 1999, 955−968. 4. Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc. 1999, 121, 4924−4925. 5. Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365−366. 6. Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772−10773. 7. Charette, A. B.; Berthelette, C.; St-Martin, D. Tetrahedron Lett. 2001, 42, 5149–5153. 8. Alonso, D. A.; Najera, C.; Varea, M. Tetrahedron Lett. 2004, 45, 573–577. 9. Alonso, D. A.; Fuensanta, M.; Najera, C.; Varea, M. J. Org. Chem. 2005, 70, 6404. 10. Rong, F. Julia–Lythgoe olefination. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 447−473. (Review). 311

Julia–Lythgoe olefination (E)-Olefins from sulfones and aldehydes.

1. n-BuLi SO Ar 1 2 Ar 2. R CHO Na(Hg) 1 R1 R R S R R O O 3. Ac O CH3OH 2 OAc

SO2Ar R1 n-Bu R SO2Ar O α-deprotonation 1 coupling acetylation H R R O Ar R S HO O O O O

SO2Ar 1 SO Ar R 2 Na(Hg) 1 R 1 R R SO Ar R O O R 2 single electron OAc OAc transfer (SET) O O

4 possible diastereomers

Na(Hg) R1 R R1 OAc R single electron OAc transfer (SET)

Example 12

1. n-BuLi, THF, −78 oC 3. Ac2O SO Ph 2 2. 4. Na(Hg) 43% E:Z (99:1) OHC Example 23 OTBS O

OTBS SO2Ph O Li N TEOC H N TEOC H 1. THF, −78 oC 2. Ac2O 3. 5% Na(Hg), 77% CHO

Example 37

Ph n-BuLi, THF, 0 oC to rt Ph Ph S CH3 61−75% m-CPBA, CH2Cl2 SO2 S CH 3 0 oC, 80−98% OHC CH3 HO OH

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_136, © Springer-Verlag Berlin Heidelberg 2009 312

Ph Na/Hg CH3 SO Ac2O, DMPA, CH2Cl2 2 THF, MeOH H3C 0 oC to rt, 60−95% −20 oC, 53% OAc

Example 48 O 1. LDA, THF, −78 oC Ph S Ph Ph CHO 2. BzCl, −78 oC to rt 3. Me2N(CH2)3OH Ph SmI2, THF HMPA, −78 oC Ph Ph Ph S Ph O OBz 67%, E/Z = > 95:1

References

1. (a) Julia, M.; Paris, J. M. Tetrahedron. Lett. 1973, 4833–4836. (b) Lythgoe, B. J. Chem. Soc., Perkin Trans. 1 1978, 834–837. 2. Kocienski, P. J.; Lythgoe, B.; Waterhause, I. J. Chem. Soc., Perkin Trans. 1 1980, 1045–1050. 3. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003– 2005. 4. Keck, G. E.; Savin, K. A.; Weglarz, M. A. J. Org. Chem. 1995, 60, 3194–3204. 5. Breit, B. Angew. Chem., Int. Ed. 1998, 37, 453–456. 6. Marino, J. P.; McClure, M. S.; Holub, D. P.; Comasseto, J. V.; Tucci, F. C. J. Am. Chem. Soc. 2002, 124, 1664–1668. 7. Bernard, A. M.; Frongia, A.; Piras, P. P.; Secci, F. Synlett 2004, 6, 1064–1068. 8. Pospíšil, J.; Pospíšil, T, Markó, I. E. Org. Lett. 2005, 7, 2373–2376. 9. Gollner, A.; Mulzer, J. Org. Lett. 2008, 10, 4701−4704. 10. Rong, F. Julia–Lythgoe olefination. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 447−473. (Review).

313

Kahne glycosidation Diastereoselective glycosidation of a sulfoxide at the anomeric center as the glycosyl acceptor. The sulfoxide activation is achieved using Tf2O.

OPiv PivO Ph O O O O O HO PivO S N PivO Ph 3 SPh

CH3

OPiv PivO t-Bu N t-Bu Ph O O O O o PivO O Tf2O, CH2Cl2, −78 to −30 C PivO N3 SPh

F O O F F SOS F OPiv OPiv F F PivO PivO O O SN1 TfO O: OTf O O PivO S PivO S PivO Ph PivO Ph OPiv OPiv PivO PivO S Ph O O Ph OTf O O Ph O O O O PivO HO PivO O PivO N3 PivO N SPh 3 SPh oxonium ion

Example 11d

O OMOM OMOM S(O)Ph Tf O, DTBMP, CH Cl O OMOM O 2 2 2 BzO OMe O OMOM OBn OMe OH OBn o O BzO OBn −70 to −50 C, 38% OBn OBn OBn

Example 24

O O SPh O OTIPS O

Ph O OTBS MeO OTBS OH OPMB

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_137, © Springer-Verlag Berlin Heidelberg 2009 314

Ph O MeO Tf2O, DTBMP, CH2Cl2 O O O −78 to 0 oC, 67% PMBO O OTIPS OTBS OTBS

Example 3, Reverse Kahne-type glycosylation6

O Et S Nu O O O O O Tf2O, CH2Cl2 O O O −78 oC, NuH

MeO OMe MeO OMe OCbz OCbz NuH = ROH, ArOH, ArNH2, CH2=CHCH2TMS

References

1. (a) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc. 1989, 111, 6881−6882. (b) Yan, L.; Taylor, C. M.; Goodnow, R., Jr.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 6953−6954. (c) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239−9248. (d) Gildersleeve, J.; Pascal, R. A.; Kahne, D. J. Am. Chem. Soc. 1998, 120, 5961−5969. Daniel Kahne now teaches at Harvard University. 2. Boeckman, R. K., Jr.; Liu, Y. J. Org. Chem. 1996, 61, 7984−7985. 3. Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435−436. 4. Crich, D.; Li, H. J. Org. Chem. 2000, 65, 801−805. 5. Nicolaou, K. C.; Rodríguez, R. M.; Mitchell, H. J.; Suzuki, H.; Fylaktakidou, K. C.; Baudoin, O.; van Delft, F. L. Chem. Eur. J. 2000, 6, 3095−3115. 6. Berkowitz, D. B.; Choi, S.; Bhuniya, D.; Shoemaker, R. K. Org. Lett. 2000, 2, 1149−1152. 7. Crich, D.; Li, H.; Yao, Q.; Wink, D. J.; Sommer, R. D.; Rheingold, A. L. J. Am. Chem. Soc. 2001, 123, 5826−5828. 8. Crich, D.; Lim, L. B. L. Org. React. 2004, 64, 115−251. (Review).

315

Knoevenagel condensation Condensation between carbonyl compounds and activated methylene compounds catalyzed by amines.

N CO R1 OH H 2 RCHO CH (CO R1) R CO2H 2 2 2 1 R CO2R

1 deprotonation H CH(CO2R )2 1 : NH CH(CO2R )2 NH 2

1 H (CO2R )2CH NH H iminium ion 2

: OH H NH R : formation N R O R N

NH O OH : O R HO O R O 1 1 R H hydrolysis R 1 R O R O CO R1 R H 2 O O O R1 N CO R1 O O O 2 HO OH

OH H decarboxylation H R O ↑ R • O CO2H CO2 H R workup H O O OH Example 13 O S H O N N N O O H

S piperidine, AcOH O N N N toluene, reflux O O H Dean−Stark trap 95% Example 2, EDDA = Ethylenediamine diacetate5

O O NCbz N OO H Boc NCbz Meldrum's acid N O O H Boc EDDA, PhH, 60 oC OO CHO 12 h, 84%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_138, © Springer-Verlag Berlin Heidelberg 2009 316

Example 3, Using ionic liquid ethylammonium nitrate (EAN) as solvent8

CHO CN ethylammonium nitrate CN

CO Et rt, 10 h, 87% CO2Et 2

Example 49

SO Me 2 O N N N MeO2S

SO2Me

N piperidine

2-propanol, reflux 89% H O N N MeO2S

References

1. Knoevenagel, E. Ber. 1898, 31, 2596−2619. Emil Knoevenagel (1865−1921) was born in Hannover, Germany. He studied at Göttingen under Victor Meyer and Gat- termann, receiving a Ph.D. In 1889. He became a full professor at Heidelberg in 1900. When WWI broke out in 1914, Knoevenagel was one of the first to enlist and rose to the rank of staff officer. After the war, he returned to his academic work until his sudden death during an appendectomy. 2. Jones, G. Org. React. 1967, 15, 204−599. (Review). 3. Cantello, B. C. C.; Cawthornre, M. A.; Cottam, G. P.; Duff, P. T.; Haigh, D.; Hindley, R. M.; Lister, C. A.; Smith, S. A. Thurlby, P. L. J. Med. Chem. 1994, 37, 3977−3985. 4. Paquette, L. A.; Kern, B. E.; Mendez-Andino, J. Tetrahedron Lett. 1999, 40, 4129−4132. 5. Tietze, L. F.; Zhou, Y. Angew. Chem., Int. Ed. 1999, 38, 2045−2047. 6. Pearson, A. J.; Mesaros, E. F. Org. Lett. 2002, 4, 2001−2004. 7. Kourouli, T.; Kefalas, P.; Ragoussis, N.; Ragoussis, V. J. Org. Chem. 2002, 67, 4615−4618. 8. Hu, Y.; Chen, J.; Le, Z.-G.; Zheng, Q.-G. Synth. Commun. 2005, 35, 739−744. 9. Conlon, D. A.; Drahus-Paone, A.; Ho, G.-J.; Pipik, B.; Helmy, R.; McNamara, J. M.; Shi, Y.-J.; Williams, J. M.; MacDonald, D. Org. Process Res. Dev. 2006, 10, 36−45. 10. Rong, F. Julia–Lythgoe olefination. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 474−501. (Review). 317

Knorr pyrazole synthesis Reaction of hydrazine or substituted hydrazine with 1,3-dicarbonyl compounds to provide the pyrazole or pyrazolone ring system. Cf. Paal–Knorr pyrrole synthesis (page 411).

R R3 N R N R N R2 NH O O N R2

NH3 R1 R2 R1 R3 R1 R3

R = H, Alkyl, Aryl, Het-aryl, Acyl, etc.

R R R3 R N N NH O O N OH N O

NH2 R1 OR2 R1 R3 R1 R3

R R OH R R O NH2NH2 NH N N O NH NH NH R OH R R OH R

Alternatively,

R R R R O NH2NH2 N N N NH 2 NH NH O O R R R OH R

Example 12

Me OMe O MeNHNH2 HCl, H2O N N MeO Me 68% Me Example 28

O O O EtO CCF , NaH, THF 2 3 CF Me 3 −5 to 0 oC, 30 min., Me Me rt, 5 h, 95%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_139, © Springer-Verlag Berlin Heidelberg 2009 318

O H • CF 2N SH N NH2 HCl 3 N N O

EtOH, reflux, 46% O S H NO Celebrex 2

References

1 (a) Knorr, L. Ber 1883, 16, 2597. Ludwig Knorr (1859−1921) was born near Munich, Germany. After studying under Volhard, Emil Fischer, and Bunsen, he was appointed professor of chemistry at Jena. Knorr made tremendous contributions in the synthesis of heterocycles in addition to discovering the important pyrazolone drug, pyrine. (b) Knorr, L. Ber 1884, 17, 546, 2032. (c) Knorr, L. Ber. 1885, 18, 311. (d) Knorr, L. Ann. 1887, 238, 137. 2 Burness, D. M. J. Org. Chem. 1956, 21, 97−101. 3 Jacobs, T. L. in Heterocyclic Compounds, Elderfield, R. C., Ed.; Wiley: New York, 1957, 5, 45. (Review). 4 Houben−Weyl, 1967, 10/2, 539, 587, 589, 590. (Review). 5 Elguero, J., In Comprehensive Heterocyclic Chemistry II, Katrizky, A. R.; Rees, C. W.: Scriven, E. F. V., Eds; Elsevier: Oxford, 1996, 3, 1. (Review). 6 Stanovnik, E.; Svete, J. In Science of Synthesis, 2002, 12, 15; Neier, R., Ed.; Thieme. (Review). 7 Sakya, S. M. Knorr Pyrazole Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds, Wiley & Sons: Hoboken, NJ, 2005, pp 292−300. (Review). 8 Ahlstroem, M. M.; Ridderstroem, M.; Zamora, I.; Luthman, K. J. Med. Chem. 2007, 50, 4444−4452.

319

Koch–Haaf carbonylation Strong acid-catalyzed tertiary carboxylic acid formation from alcohols or olefins and CO.

R OH R CO2H CO, H2O

H H R : R O CH2 R O protonation H H

O R :CO: R alkyl

migration

The tertiary carbocation is thermodynamically favored

O O O R R R OH2 H OH : OH2

acylium ion Example 13

OH CO2H HCO2H, H2SO4

rt, 66%

Example 25

HCO2H, H2SO4 OH CO2H CCl , 5 oC, 95% 4 References

1. Koch, H.; Haaf, W. Ann. 1958, 618, 251–266. 2. Hiraoka, K.; Kebarle, P. J. Am. Chem. Soc. 1977, 99, 366–370. 3. Langhals, H.; Mergelsberg, I.; Rüchardt, C. Tetrahedron Lett. 1981, 22, 2365–2366. 4. Takeuchi, K.; Akiyama, F.; Miyazaki, T.; Kitagawa, I.; Okamoto, K. Tetrahedron 1987, 43, 701–709. 5. Takahashi, Y.; Yoneda, N. Synth. Commun. 1989, 19, 1945–1954. 6. Stepanov, A. G.; Luzgin, M. V.; Romannikov, V. N.; Zamaraev, K. I. J. Am. Chem. Soc. 1995, 117, 3615–3616. 7. Olah, G. A.; Prakash, G. K. S.; Mathew, T.; Marinez, E. R. Angew. Chem., Int. Ed. 2000, 39, 2547–2548. 8. Li, T.; Tsumori, N.; Souma, Y.; Xu, Q. Chem. Commun. 2003, 2070–2071. 9. Davis, M. C.; Liu, S. Synth. Commun. 2006, 36, 3509–3514.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_140, © Springer-Verlag Berlin Heidelberg 2009 320

Koenig–Knorr glycosidation Formation of the β-glycoside from α-halocarbohydrate under the influence of silver salt.

AcO O AcO H ROH O AcO OR AgBr CO ↑ H O O AcO 2 2 AcO H Br Ag CO AcO H O Ac 2 3 H H H Ac

AcO O: AcO H O AcO AcO H O AcO Br AcO H O : H Ac O Ag H

oxonium ion

H AcO : O AcO O β O R -anomer is OR AcO AcO AcO H O O O favored AcO H H H Ac H β-anomer

Example 17

NO2 MeO2C O Br HO N PivO OPiv N CF3 OPiv

NO2 MeO2C O O Ag2O, 10 eq. HMTTA N

N CF3 CH3CN, rt, 6 h, 41% PivO OPiv OPiv

Example 28

AcO OMe O H AcO O AcO H Br Ac OH H

OMe

Cd2CO3, Tol. AcO O O reflux, 6 h, 84% AcO AcO H O Ac H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_141, © Springer-Verlag Berlin Heidelberg 2009 321

Example 39

PivO H O H H PivO O H H PivO H Br Piv HO H cholesterol

H H

AgOTf, TMU, CH2Cl2 PivO H H O O 4 Å MS, −20 oC to rt PivO O 16 h, 58% PivO H Piv H

References

1. Koenig, W.; Knorr, E. Ber. 1901, 34, 957−981. 2. Igarashi, K. Adv. Carbohydr. Chem. Biochem. 1977, 34, 243−83. (Review). 3. Schmidt, R. R. Angew. Chem. 1986, 98, 213−236. 4. Smith, A. B., III; Rivero, R. A.; Hale, K. J.; Vaccaro, H. A. J. Am. Chem. Soc. 1991, 113, 2092−2112. 5. Fürstner, A.; Radkowski, K.; Grabowski, J.; Wirtz, C.; Mynott, R. J. Org. Chem. 2000, 65, 8758−8762. 6. Yashunsky, D. V.; Tsvetkov, Y. E.; Ferguson, M. A. J.; Nikolaev, A. V. J. Chem. Soc., Perkin Trans. 1 2002, 242−256. 7. Stazi, F.; Palmisano, G.; Turconi, M.; Clini, S.; Santagostino, M. J. Org. Chem. 2004, 69, 1097−1103. 8. Wimmer, Z.; Pechova, L.; Saman, D. Molecules 2004, 9, 902−912. 9. Presser, A.; Kunert, O.; Pötschger, I. Monat. Chem. 2006, 137, 365−374. 10. Steinmann, A.; Thimm, J.; Thiem, J. Eur. J. Org. Chem. 2007, 5506−5513. 11. Schoettner, E.; Simon, K.; Friedel, M.; Jones, P. G.; Lindel, T. Tetrahedron Lett. 2008, 49, 5580−5582.

322

Kostanecki reaction Also known as Kostanecki−Robinson reaction. Transformation 1→2 represents an Allan−Robinson reaction (see page 8), whereas 1→3 is a Kostanecki (acylation) reaction:

O O OH R R O O O O R

R O 1 O 2 3

R R H O

: O O O O O O acyl H O O O R enolization O R transfer R O O H O O O O O O 6-exo-trig − O O H2O R R ring closure R H R OH :B OH O Example 12 O O OH O H O OEt OEt HCO2Na, rt, 15 h, 76% O O O O Example 23

O O NaOAc, Ac2O, reflux

HO O O 62 % O O O

O O

References

1. von Kostanecki, S.; Rozycki, A. Ber. 1901, 34, 102−109. 2. Pardanani, N. H.; Trivedi, K. N. J. Indian Chem. Soc. 1972, 49, 599−604. 3. Flavin, M. T.; Rizzo, J. D.; Khilevich, A.; et al. J. Med. Chem. 1996, 39, 1303−1313. 4. Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Litvinov, I. A.; Levin, Y. A. Chemistry of Heterocyclic Compounds 2003, 39, 96−100. 5. Limberakis, C. Kostanecki−Robinson Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 521−535. (Review).

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_142, © Springer-Verlag Berlin Heidelberg 2009 323

Kröhnke pyridine synthesis Pyridines from α-pyridinium methyl ketone salts and α,β-unsaturated ketones.

O R1 R1 R2 O Br N NH OAc, HOAc R 4 R N R2

H Br H Br R O O Michael N N enolization N O R R addition 1 O R H Br H O 1 2 H R R R2 AcO

Br R R R N O O O 1 1 1 R R R O HO

H2N: O H : NH3 R2 R2 2 R The ketone is more reactive than the enone R R1 R1 O 1 R R 2 HN NR OH OAc 2 H H H NR R R2 AcO

Example 11b Ph Ph NH4OAc N AcOH 90% PhN Ph Ph O O Ph

Example 24 N N N N N NH4OAc AcOH N N 81% O N N N O N N O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_143, © Springer-Verlag Berlin Heidelberg 2009 324

Example 36

N NH4OAc, AcOH X = H, 65% X = F, 83% N O O o X = Br, 82% 115 C, overnight X X = OMe, 40% X

References

1. (a) Zecher, W.; Kröhnke, F. Ber. 1961, 94, 690−697. (b) Kröhnke, F.; Zecher, W. Angew. Chem. 1962, 74, 811−817. (c) Kröhnke, F. Synthesis 1976, 1−24. (Review). 2. Potts, K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G. J. Am. Chem. Soc. 1981, 103, 3584−3585, 3585−3586. 3. Newkome, G. R.; Hager, D. C.; Kiefer, G. E. J. Org. Chem. 1986, 51, 850−853. 4. Kelly, T. R.; Lee, Y.-J.; Mears, R. J. J. Org. Chem. 1997, 62, 2774−2781. 5. Bark, T.; Von Zelewsky, A. Chimia 2000, 54, 589−592. 6. Malkov, A. V.; Bella, M.; Stara, I. G.; Kocovsky, P. Tetrahedron Lett. 2001, 42, 3045−3048. 7. Cave, G. W. V.; Raston, C. L. J. Chem. Soc., Perkin Trans. 1 2001, 3258−3264. 8. Malkov, A. V.; Bell, M.; Vassieu, M.; Bugatti, V.; Kocovsky, P. J. Mol. Cat. A: Chem. 2003, 196, 179−186. 9. Galatsis, P. Kröhnke Pyridine Synthesis. In Name Reactions in Heterocyclic Chemis- try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 311−313. (Re- view). 10. Yan, C.-G.; Wang, Q.-F.; Cai, X.-M.; Sun, J. Central Eur. J. Chem. 2008, 6, 188−198.

325

Kumada cross-coupling reaction

The Kumada cross-coupling reaction (also occasionally known as the Kharasch cross-coupling reaction) was originally reported as the nickel-catalyzed cross- coupling of Grignard reagents with aryl- or alkenyl halides. It has subsequently been developed to encompass the coupling of organolithium or organomagnesium compounds with aryl-, alkenyl or alkyl halides, catalyzed by nickel or palladium. The Kumada cross-coupling reaction, as well as the Negishi, Stille, Hiyama, and Suzuki cross-coupling reactions, belong to the same category of Pd-catalyzed cross-coupling reactions of organic halides, triflates and other electrophiles with organometallic reagents. These reactions follow a general mechanistic catalytic cycle as shown below. There are slight variations for the Hiyama and Suzuki reactions, for which an additional activation step is required for the transmetallation to occur.

Pd(0) 1 1 RX R MgX RR MgX2

1 oxidative R L R MgX RX L Pd(0) Pd 2 transmetallation addition L X isomerization L L reductive 1 MgX2 Pd R R L2Pd(0) 1 elimination R R

The catalytic cycle: 1 R reductive transmetallation 1 1 L Pd(II) R1M L Pd(II) R R LnPd(0) n n 1 R elimination

L2Pd(0) R R1

oxidative addition

R L Pd L X R1M reductive elimination transmetallation and isomerization

L L Pd 1 R R MX

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_144, © Springer-Verlag Berlin Heidelberg 2009 326

Example 12

Pd(dppf)Cl2, Et2O O Br S MgBr –30 oC to rt, 5 h, 98% O S

Example 23

Me H Me MgBr Ni/Ligand Me MeO − Me Ph2P Fe Br (2 5 mol%) 69% Me Ligand 95% ee

Example 35

Br N MgBr N N Br PdCl •(dppb) N 2 Br THF, rt, 87%

MgBr S N N PdCl2•(dppb) THF, reflux, 98% S

Example 48

S S OTBS 3 equiv OTBS N MgBr N

23 mol% PdCl2(dppf) Et2O, rt, 12 h, 75% I

Example 59

O EtO Me P EtO O MeO 2.5 equiv MeMgCl MeO

10 mol% Ni(acac)2 C5H11 C H o 5 11 THF, 0 C, 10 min. TESO MeO TESO MeO 90%

327

References

1. Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka, A.; Kodma, S.-i.; Naka- jima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc. Jpn. 1976, 49, 1958−1969. 2. Carpita, A.; Rossi, R.; Veracini, C. A. Tetrahedron 1985, 41, 1919−1929. 3. Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 8153−8156. 4. Kalinin, V. N. Synthesis 1992, 413−432. (Review). 5. Meth-Cohn, O.; Jiang, H. J. Chem. Soc., Perkin Trans. 1 1998, 3737−3746. 6. Stanforth, S. P. Tetrahedron 1998, 54, 263−303. (Review). 7. Huang, J.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 9889−9890. 8. Rivkin, A.; Njardarson, J. T.; Biswas, K.; Chou, T.-C.; Danishefsky, S. J. J. Org. Chem. 2002, 67, 7737−7740. 9. William, A. D.; Kobayashi, Y. J. Org. Chem. 2002, 67, 8771−8782. 10. Fuchter, M. J. Kumada cross-coupling reaction. In Name Reactions for Homologa- tions-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 47−69. (Review).

328

Lawesson’s reagent 2,4-Bis(4-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-disulfide transforms the carbonyl groups of aldehydes, ketones, amides, lactams, esters and lactones into the corresponding thiocarbonyl compounds. Cf. Knorr thiophene synthesis.

S O SP SP O O S S 1 2 1 2 R R Lawesson's reagent R R R1,R2 = H, R, OR, NHR

S O SP SP O S O S N Lawesson's reagent N H H

S S 2 O P S O SP S O P S O SP O : O NH NH S

S H O S N O P O P N S S O H

Example 14 H H O O Lawesson's reagent O (Me2N)2C=S S O O H H O xylene, 160 oC, 47% S OMe OMe

Example 25

O S Lawesson's MeO C N H MeO2C N H 2 reagent, quant.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_145, © Springer-Verlag Berlin Heidelberg 2009 329

Example 3, Thiophene from dione8

O O R R Lawesson's reagent

N N toluene, reflux 88−99% SO2Ph SO2Ph

R R R = H S R = Me R = OMe N N R = Cl SO Ph SO Ph R = Br 2 2

Example 410

Me O Me O O O O O MeO MeO Lawesson's reagent Me Me S O toluene, reflux, 100% N N

References

1. Scheibye, S.; Shabana, R.; Lawesson, S. O.; Rømming, C. Tetrahedron 1982, 38, 993– 1001. 2. Navech, J.; Majoral, J. P.; Kraemer, R. Tetrahedron Lett. 1983, 24, 5885–5886. 3. Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061–5087. (Review). 4. Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E.; Nugiel, D. A.; Abe, Y.; Bal Reddy, K.; DeFrees, S. A.; Reddy, D. R.; Awartani, R. A.; Conley, S. R.; Rutjes, F. P. J. T.; Theodorakis, E. A. J. Am. Chem. Soc. 1995, 117, 10227–10238. 5. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003– 2005. 6. Luheshi, A.-B. N.; Smalley, R. K.; Kennewell, P. D.; Westwood, R. Tetrahedron Lett. 1990, 31, 123–127. 7. Ishii, A.; Yamashita, R.; Saito, M.; Nakayama, J. J. Org. Chem. 2003, 68, 1555–1558. 8. Diana, P.; Carbone, A.; Barraja, P.; Montalbano, A.; Martorana, A.; Dattolo, G.; Gia, O.; Dalla Via, L.; Cirrincione, G. Bioorg. Med. Chem. Lett. 2007, 17, 2342–2346. 9. Ozturk, T.; Ertas, E.; Mert, O. Chem. Rev. 2007, 107, 5210–5278. (Review). 10. Taniguchi, T.; Ishibashi, H. Tetrahedron 2008, 64, 8773–8779. 11. de Moreira, D. R. M. Synlett 2008, 463–464. (Review).

330

Leuckart–Wallach reaction Amine synthesis from reductive amination of a ketone and an amine in the presence of excess formic acid, which serves as the reducing reagent by delivering a hydride. When the ketone is replaced by formaldehyde, it becomes the Eschweiler–Clarke reductive alkylation of amines on page 210.

1 3 1 3 R R HCO H R R HN 2 ↑ O N CO2 H2O 4 R2 R R2 R4

1 H R HO H R1 R3

4 HO − H O

R : 2 N O 1 3 : R N R 1 3 N 2 R N R H R H 2 4 R2 R4 3 R R 2 4 R R R gem-aminoalcohol; iminium ion intermediate

R1 R3 1 3 R1 R3 HCO H 2 N R4 − CO R R H 2 R 2 2 4 N HH R N R R2 R4 O H H O reduction

Example 14 H HCO H N 2 O N CHO 60 oC, 57% O

Example 26

O HCO2H, H2O N 190 oC, autoclave N OHC 16 h, 75%

Example 37 N O N HCO2H, reflux HN N H N N 7 h, 45% S S H 2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_146, © Springer-Verlag Berlin Heidelberg 2009 331

Example 48

H2NCHO HCO H O NHCOCH 2 3 150oC OHCHN NHCOCH3

An unexpected intramolecular transamidation via a Wagner–Meerwein shift after the Leuckart–Wallach reaction

H2NCHO, HCO2H

o O 150 C CH3COHN NHCHO NHCOCH3

References

1. Leuckart, R. Ber. 1885, 18, 2341−2344. Carl L. R. A. Leuckart (1854−1889) was born in Giessen, Germany. After studying under Bunsen, Kolbe, and von Baeyer, he became an assistant professor at Göttingen. Unfortunately, chemistry lost a brilliant con- tributor by his sudden death at age 35 as a result of a fall in his parent’s house. 2. Wallach, O. Ann. 1892, 272, 99. Otto Wallach (1847−1931), born in Königsberg, Prussia, studied under Wöhler and Hofmann. He was the director of the Chemical In- stitute at Göttingen from 1889 to 1915. His book “Terpene und Kampfer” served as the foundation for future work in terpene chemistry. Wallach was awarded the Nobel Prize in Chemistry in 1910 for his work on alicyclic compounds. 3. Moore, M. L. Org. React. 1949, 5, 301−330. (Review). 4. DeBenneville, P. L.; Macartney, J. H. J. Am. Chem. Soc. 1950, 72, 3073−3075. 5. Lukasiewicz, A. Tetrahedron 1963, 19, 1789−1799. (Mechanism). 6. Bach, R. D. J. Org. Chem. 1968, 33, 1647−1649. 7. Musumarra, G.; Sergi, C. Heterocycles 1994, 37, 1033−1039. 8. Martínez, A. G.; Vilar, E. T.; Fraile, A. G.; Ruiz, P. M.; San Antonio, R. M.; Alcazar, M. P. M. Tetrahedron: Asymmetry 1999, 10, 1499−1505. 9. Kitamura, M.; Lee, D.; Hayashi, S.; Tanaka, S.; Yoshimura, M. J. Org. Chem. 2002, 67, 8685−8687. 10. Brewer, A. R. E. Leuckart–Wallach reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 451−455. (Review). 11. Muzalevskiy, V. M.; Nenajdenko, V. G.; Shastin, A. V.; Balenkova, E. S.; Haufe, G. J. Fluorine Chem. 2008, 129, 1052−1055.

332

Lossen rearrangement The Lossen rearrangement involves the generation of an isocyanate via thermal or base-mediated rearrangement of an activated hydroxamate which can be generated from the corresponding hydroxamic acid. Activation of the hydroxamic acid can be achieved through O-acylation, O-arylation, chlorination, or O-sulfonylation. Such hydroxamic acids can also be activated using polyphosphoric acid, carbodiimide, Mitsunobu conditions, or silyation. The product of the Lossen rearrangement, an isocyanate can be subsequently converted to an urea or an amine resulting in the net loss of one carbon atom relative to the starting hydroxamic acid.

O 2 H2O O R OH 1 1 ↑ R1 N R N C O R NH2 CO2 H O

O 2 HO H 1 O R O R N 2 1 O R2 R CO2 R N C O H O R1 N : O OH2 OH isocyanate intermediate

H N O decarboxylation R1 H 1 CO ↑ R NH2 2 O : B

Example 16

O O N O N O MsO O o NH BnOH, CH3CN, 85 C, 78%

Example 27

O H O N CO2Et C EtO C O N EtOH, H O NH2 Cl 2 2

Et3N, H2O 50% Br Br Br

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_147, © Springer-Verlag Berlin Heidelberg 2009 333

Example 38

H3C NH2 NHCONHAr N O S O PhH, rt, 6 h, 54% CONHAr O O ArNH2:

ArNH2

O O N C O N OSO2Ph Lossen N OSO2Ph H H N N N Ar Ar O H Ar O 2 O

Example 49

N N N DBU, THF, H O H 2 N N N N N AcO reflux, 1 h C H2N O O O O O OMe OMe OMe MeO MeO MeO

References

1. Lossen, W. Ann. 1872, 161, 347. Wilhelm C. Lossen (1838−1906) was born in Kreuznach, Germany. After his Ph.D. studies at Göttingen in 1862, he embarked on his independent academic career, and his interests centered on hydroxyamines. 2. Bauer, L.; Exner, O. Angew. Chem., Int. Ed. 1974, 13, 376. 3. Lipczynska-Kochany, E. Wiad. Chem. 1982, 36, 735−756. 4. Casteel, D. A.; Gephart, R. S.; Morgan, T. Heterocycles 1993, 36, 485−495. 5. Zalipsky, S. Chem. Commun. 1998, 69−70. 6. Stafford, J. A.; Gonzales, S. S.; Barrett, D. G.; Suh, E. M.; Feldman, P. L. J. Org Chem. 1998, 63, 10040–10044. 7. Anilkumar, R.; Chandrasekhar, S.; Sridhar, M. Tetrahedron Lett. 2000, 41, 5291−5293. 8. Abbady, M. S.; Kandeel, M. M.; Youssef, M. S. K. Phosphorous, Sulfur and Silicon 2000, 163, 55–64. 9. Ohmoto, K.; Yamamoto, T.; Horiuchi, T.; Kojima, T.; Hachiya, K.; Hashimoto, S.; Kawamura, M.; Nakai, H.; Toda, M. Synlett 2001, 299−301. 10. Choi, C.; Pfefferkorn, J. A. Lossen rearrangement. In Name Reactions for Homologa- tions-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 200−209. (Review).

334

McFadyen–Stevens reduction Treatment of acylbenzenesulfonylhydrazines with base delivers the corresponding aldehydes.

O H Base O N R N SO2Ar H R H

O H O O N homolytic O R N SO2Ar N ↑ R N H N2 H cleavage R H R H : B Example 18 O O N 2 NH HN O SO2 K2CO3, MeOH O N 2 H reflux, 1 h, 75%

Example 210

O Na2CO3, glass powder O N O ethylene glycol N O

N NHNHTs microwave (450 W) N H 90% H H References

1. McFadyen, J. S.; Stevens, T. S. J. Chem. Soc. 1936, 584−587. Thomas S. Stevens (1900−2000) was born in Renfrew, Scotland. After earning his Ph.D. under W. H. Perkin at Oxford University, he became a reader at the University of Sheffield. J. S. McFadyen (1908−?) was born in Toronto, Canada. After studying under Stevens at the University of Glasgow, he worked for ICI for 15 years before returning to Canada where he worked for the Canadian Industries, Ltd., Montreal. 2. Newman, M. S.; Caflisch, E. G., Jr. J. Am. Chem. Soc. 1958, 80, 862−864. 3. Sprecher, M.; Feldkimel, M.; Wilchek, M. J. Org. Chem. 1961, 26, 3664−3666. 4. Babad, H.; Herbert, W.; Stiles, A. W. Tetrahedron Lett. 1966, 7, 2927−2931. 5. Graboyes, H.; Anderson, E. L.; Levinson, S. H.; Resnick, T. M. J. Heterocycl. Chem. 1975, 12, 1225−1231. 6. Eichler, E.; Rooney, C. S.; Williams, H. W. R. J. Heterocycl. Chem. 1976, 13, 841−844. 7. Nair, M.; Shechter, H. J. Chem. Soc., Chem. Commun. 1978, 793−796. 8. Dudman, C. C.; Grice, P.; Reese, C. B. Tetrahedron Lett. 1980, 21, 4645−4648. 9. Manna, R. K.; Jaisankar, P.; Giri, V. S. Synth. Commun. 1998, 28, 9−16. 10. Jaisankar, P.; Pal, B.; Giri, V. S. Synth. Commun. 2002, 32, 2569−2573.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_148, © Springer-Verlag Berlin Heidelberg 2009 335

McMurry coupling Olefination of carbonyls with low-valent titanium such as Ti(0) derived from TiCl3/LiAlH4. A single-electron process.

1 1 1 R 1. TiCl3, LiAlH4 R R O TiO 2 2 2 R 2. H2O R R

Ti(III)Cl LiAlH Ti(0) 3 4 Ti Ti R1 single electron O O homocoupling O :Ti(0) R1 R1 R2 transfer 2 2 R R radical anion intermediate

Ti Ti Ti Ti 1 1 O O OO R R Ti Ti R1 R1 R1 R1 2 2 OO 2 2 2 2 R R R R R R oxide-coated titanium surface

Example 1, Cross-McMurry coupling7

OH MeO2S OH MeO2S

Zn, TiCl4, reflux O 4.5 h, 75%, > 99% Z O

Example 2, Homo-McMurry coupling8

o Zn, TiCl4, THF,110 C S CHO S S microwave (10 W), 10 min. 87%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_149, © Springer-Verlag Berlin Heidelberg 2009 336

Example 3, Cross-McMurry coupling9

OMe

OMe N Zn, TiCl O O 4 N N THF, 78% N N ON O O O

Example 4, Cross-McMurry coupling10

MeO Zn−TiCl , THF O CHO OHC O 4 O −5 to 0 oC then BnO OH MeO O reflux, 2.5 h, 77% BnO OH

References

1. (a) McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc. 1974, 96, 4708−4712. (b) McMurry, J. E. Chem. Rev. 1989, 89, 1513−1524. (Review). 2. Hirao, T. Synlett 1999, 175−181. 3. Sabelle, S.; Hydrio, J.; Leclerc, E.; Mioskowski, C.; Renard, P.-Y. Tetrahedron Lett. 2002, 43, 3645−3648. 4. Williams, D. R.; Heidebrecht, R. W., Jr. J. Am. Chem. Soc. 2003, 125, 1843−1850. 5. Honda, T.; Namiki, H.; Nagase, H.; Mizutani, H. Tetrahedron Lett. 2003, 44, 3035−3038. 6. Ephritikhine, M.; Villiers, C. In Modern Carbonyl Olefination Takeda, T., Ed.; Wiley- VCH: Weinheim, Germany, 2004, 223−285. (Review). 7. Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Synlett 2004, 1513−1516. 8. Stuhr-Hansen, N. Tetrahedron Lett. 2005, 46, 5491−5494. 9. Zeng, D. X.; Chen, Y. Synlett 2006, 490−492. 10. Duan, X.-F.; Zeng, J.; Zhang, Z.-B.; Zi, G.-F. J. Org. Chem. 2007, 72, 10283−10286. 11. Debroy, P.; Lindeman, S. V.; Rathore, R. J. Org. Chem. 2009, 74, 2080−2087.

337

Mannich reaction Three-component aminomethylation from amine, aldehyde and a compound with an acidic methylene moiety.

O O R O H R R1 N R2 NH R2 R H H R R1

H O OH OH2

H : R H H R R N H N H N H : R N R R R R + When R = Me, the Me2N=CH2 salt is known as Eschenmoser’s salt (page 206)

H O 1 O O R H R2 R R1 N R2 R2 enolization R N R R1 R

The Mannich reaction can also operate under basic conditions:

O O R1 O R1 enolate R2 R2 R N R2 H formation R N R R1 : R B Mannich Base

Example 1, Asymmetric Mannich reaction2

O NH2 O OHC 35 mol% L-proline O HN

DMSO, rt, 50%, 94% ee NO2 O NO 2

Example 2, Asymmetric Mannich-type reaction9

o-Ts o-Ts O NH O N In(Oi-Pr)3, ligand N N OH 5 Å MS, THF, rt, 80% O OH O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_150, © Springer-Verlag Berlin Heidelberg 2009 338

Example 3, Asymmetric Mannich reaction10

H O HO O O N O HN R3 R NH R 3 N H 10 mol % 1 R1 R4 ArO2S R4 − R2 O Na2CO3, NaCl, 15 ºC R O − 2 72 98%, 99:1 er

Example 411 PMP O NH O PMP N L-proline, DMSO EtO2C EtO C H rt, 81% syn 2

PhPh PhPh O NH O L-proline, DMSO N O O rt, 81% O O

References

1. Mannich, C.; Krösche, W. Arch. Pharm. 1912, 250, 647–667. Carl U. F. Mannich (1877−1947) was born in Breslau, Germany. After receiving a Ph.D. at Basel in 1903, he served on the faculties of Göttingen, Frankfurt and Berlin. Mannich synthesized many esters of p-aminobenzoic acid as local anesthetics. 2. List, B. J. Am. Chem. Soc. 2000, 122, 9336–9337. 3. Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron 2000, 56, 10023–10030. 4. Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221–3242. (Review). 5. Martin, S. F. Acc. Chem. Res. 2002, 35, 895−904. (Review). 6. Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851−862. (Review). 7. Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580−591. (Re- view). 8. Córdova, A. Acc. Chem. Res. 2004, 37, 102−112. (Review). 9. Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 4365–4368. 10. Lou, S.; Dai, P.; Schaus, S. E. J. Org. Chem. 2007, 72, 9998–10008. 11. Hahn, B. T.; Fröhlich, R.; Harms, K.; Glorius, F. Angew. Chem., Int. Ed. 2008, 47, 9985−9988. 12. Galatsis, P. Mannich reaction. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 653−670. (Review). 339

Martin’s sulfurane dehydrating reagent Dehydrates secondary and tertiary alcohols to give olefins, but forms ethers with primary alcohols. Cf. Burgess dehydrating reagent.

OH Ph2S[OC(CF3)2Ph]2 Ph2S O HOC(CF3)2Ph

− HOt-Bu O C(CF3)2Ph Ph2S OC(CF3)2Ph Ph2S HOC(CF3)2Ph O : OC(CF3)2Ph

The alcohol is acidic HOC(CF) Ph 3 2 H

: − O C(CF3)2Ph OC(CF3)2Ph protonation Ph S Ph S 2 2 OC(CF3)2Ph O O

Ph2S β-elimination O OC(CF3)2Ph Ph2S O HOC(CF3)2Ph H E1cB

Example 15 OMe OBn OH Martin's sulfurane O O O OPMB Et N, CHCl , 50 oC O O 3 3 BzO OMe O 85% OBn OMe OBn O O O OPMB O BzO OMe O O OBn

Example 26

OBn BnO OH OBn Martin's OBn sulfurane

OBn PhH, reflux O OBn O 88% O O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_151, © Springer-Verlag Berlin Heidelberg 2009 340

Example 37

HO CO2Me CO2Me

1.5 eq. Martin's sulfurane TBSO O TBSO O OMe CH2Cl2, rt, 24 h, 84% OMe O O MeO MeO

Example 49

i-PrO OMOM i-PrO OMOM

O O H3CO H3CO OCH3 HN OCH3 HN Martin's O N O sulfurane N Cl Cl O OTIPS O OTIPS PhH, rt OH 83% O O

O O TESO TESO

References

1. (a) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 2339–2341; (b0 Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 2341–2342; (c) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327–4329. (d) Martin, J. C.; Arhart, R. J.; Franz, J. A.; Perozzi, E. F.; Kaplan, L. J. Org. Synth. 1977, 57, 22–26. 2. Gallagher, T. F.; Adams, J. L. J. Org. Chem. 1992, 57, 3347–3353. 3. Tse, B.; Kishi, Y. J. Org. Chem. 1994, 59, 7807–7814. 4. Winkler, J. D.; Stelmach, J. E.; Axten, J. Tetrahedron Lett. 1996, 37, 4317–4320. 5. Nicolaou, K. C.; Rodríguez, R. M.; Fylaktakidou, K. C.; Suzuki, H.; Mitchell, H. J. Angew. Chem., Int. Ed. 1999, 38, 3340–3345. 6. Kok, S. H. L.; Lee, C. C.; Shing, T. K. M. J. Org. Chem. 2001, 66, 7184–7190. 7. Box, J. M.; Harwood, L. M.; Humphreys, J. L.; Morris, G. A.; Redon, P. M.; White- head, R. C. Synlett 2002, 358–360. 8. Myers, A. G.; Glatthar, R.; Hammond, M.; Harrington, P. M.; Kuo, E. Y.; Liang, J.; Schaus, S. E.; Wu, Y.; Xiang, J.-N. J. Am. Chem. Soc. 2002, 124, 5380–5401. 9. Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem., Int. Ed. 2002, 41, 1062–1067. 10. Shea, K. M. Martin’s sulfurane dehydrating reagent. In Name Reactions for Func- tional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hobo- ken, NJ, 2007, pp 248−264. (Review). 11. Sparling, B. A.; Moslin, R. M.; Jamison, T. F. Org. Lett. 2008, 10, 1291−1294.

341

Masamune–Roush conditions for the Horner–Emmons reaction Applicable to base-sensitive aldehydes and phosphonates for the Horner– Wadsworth–Emmons reaction. α-Keto or α-alkoxycarbonyl phosphonate required.

O O CHO (EtO) P AcO 2 OEt

N DBU CO Et AcO 2 LiCl, CH3CN, 70%

DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene

O O (EtO) P 2 OEt O O LiCl H deprotonation (EtO) P 2 OEt chelation : N

Li O O O (EtO)2P OEt EtO2C P OEt OEt H AcO O AcO O

O EtO2C CO Et P(OEt)2 AcO 2 O AcO

Example 15

O O O O TFA P RCHO N (OEt) N R H2N R 2 LiBr, Et N 75−95% H 3 H

Example 26 O O 7

H O LiCl, Hunig base OMe O O MOMO OMe MOMO 7 O OO MeCN, rt, 14 h, 58% O (EtO)2(O)P MeO MeO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_152, © Springer-Verlag Berlin Heidelberg 2009 342

Example 37

Ph Ph Ph Ph N O (EtO)2(O)P N O BocN CHO O O BocN O O O O LiBr, DBU, CH3CN, rt, 67%

Example 48

N O O N N H CO2Et P CO Et Ph (EtO) 2 Ph 2 THF, 92%

Example 510

O O Ph MeO CHO (MeO)2P N CO2Me H DBU, LiCl, THF, rt 90% OMe

O Ph O Ph N CO2Me H MeO 98 : 2 N CO2Me H

References

1. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183–2186. 2. Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624–2636. 3. Tius, M. A.; Fauq, A. H. J. Am. Chem. Soc. 1986, 108, 1035–1039, and 6389–6391. 4. Marshall, J. A.; DuBay, W. J. J. Org. Chem. 1994, 59, 1703–1708. 5. Johnson, C. R.; Zhang, B. Tetrahedron Lett. 1995, 36, 9253–9256. 6. Rychnovsky, S. D.; Khire, U. R.; Yang, G. J. Am. Chem. Soc. 1997, 119, 2058–2059. 7. Dixon, D. J.; Foster, A. C.; Ley, S. V. Org. Lett. 2000, 2, 123–125. 8. Simoni, D.; Rossi, M.; Rondannin, R.; Mazzali, A.; Baruchello, R.; Malagutti, C.; Roberti, M.; Invidiata, F. P. Org. Lett. 2000, 2, 3765–3768. 9. Crackett, P.; Demont, E.; Eatherton, A.; Frampton, C. S.; Gilbert, J.; Kahn, I.; Red- shaw, S.; Watson, W. Synlett 2004, 679–683. 10. Ordonez, M.; Hernandez-Fernandez, E.; Montiel-Perez, M.; Bautista, R.; Bustos, P.; Rojas-Cabrera, H.; Fernandez-Zertuche, M.; Garcia-Barradas, O. Tetrahedron: Asymmetry 2007, 18, 2427–2436. 11. Zanato, C.; Pignataro, L.; Hao, Z.; Gennari, C. Synthesis 2008, 2158–2162.

343

Meerwein’s salt Meerwein’s salts, also known as the Meerwein reagent, refer to trimethyloxonium + − + − tetrafluoroborate (Me3O BF4 ) and triethyloxonium tetrafluoroborate (Et3O BF4 ). Named after the inventor Hans Meerwein,1 these trialkyloxonium salts are powerful alkylating agents.

F F F B F F B F F F O O

Preparation:2

+ − 3 Me3O BF4 + 4 Et2O 4 BF3•OEt2 + 6 Me2O O + B O Me + 3 Cl O Cl 3

+ − 3 Et3O BF4 4 BF3•OEt2 + 2 Et2O + B O Et O O + 3 Cl Cl 3

Example 1, The Meerwein reagent is an excellent O-alkylating agent:5

Et O O O H3O Et Et3O•BF4, NaHPO4 O N N 81% H CH CN, rt, 6 h Cl 3 Cl Cl Transforming an amide into its corresponding ethyl or methyl esters

Example 2, Metal-methylation4

OH o OMe 1. PhLi, Et2O, 0 C t-Bu, t-BuOMe t-Bu Co(OC) Co(CO)6 5 Ph 45 oC, 79% 2. Me3O•BF4 Dötz reaction OMe

Example 3, N-Alkylation, the product is an ionic liquid8

Me3O•BF4 BF CH NN 4 NN 3 Et O, 94% H3C 2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_153, © Springer-Verlag Berlin Heidelberg 2009 344

Example 4, N-Methylation9

SPh SPh 1. Me3O•BF4, slow addition Me CH Cl , rt N N N SO2NMe2 2 2 N 2. BuMeNH, CH CN, Δ, quant. 3 I I

References

1. (a) Meerwein, H.; Hinz, G.; Hofmann, P.; Kroning, E.; Pfeil, E. J. Prakt. Chem. 1937, 147, 257–285. (b) Meerwein, H.; Bettenberg, E.; Pfeil, E.; Willfang, G. J. Prakt. Chem. 1939, 154, 83–156. 2. (a) Meerwein, H. Org. Synth.; Coll. Vol. V, 1973, 1080. Triethyloxonium tetrafluoroborate. (b) Curphey, T. J. Org. Synth.; Coll. Vol. VI, 1988, 1019. Trimethy- loxonium tetrafluoroborate. 3. Chen, F. M. F.; Benoiton, N. L. Can. J. Chem. 1977, 55, 1433–1534. 4. Dötz, K. H.; Möhlemeier, J.; Schubert, U.; Orama, O. J. Organomet. Chem. 1983, 247, 187–201. 5. Downie, I. M.; Heaney, H.; Kemp, G.; King, D.; Wosley, M. Tetrahedron 1992, 48, 4005–4016. 6. Kiessling, A. J.; McClure, C. K. Synth. Commun. 1997, 27, 923–937. 7. Pichlmair, S. Synlett 2004, 195−196. (Review). 8. Egashira, M.; Yamamoto, Y.; Fukutake, T.; Yoshimoto, N.; Morita, M. J. Fluorine Chem. 2006, 127, 1261–1264. 9. Delest, B.; Nshimyumukiza, P.; Fasbender, O.; Tinant, B.; Marchand-Brynaert, J.; Darro, F.; Robiette, R. J. Org. Chem. 2008, 73, 6816–6823. 10. Perst, H.; Seapy, D. G. Triethyloxonium Tetrafluoroborate In Encyclopedia of Reagents for Organic Synthesis John Wiley & Sons, New York, 2008, (Review).

345

Meerwein–Ponndorf–Verley reduction

Reduction of ketones to the corresponding alcohols using Al(Oi-Pr)3 in isopropanol. Reverse of the Oppernauer oxidation.

O Al(Oi-Pr)3 OH O R1 R2 HOi-Pr R1 R2

‡ Al(Oi-Pr)3 ‡ i-PrO Oi-Pr R1 Oi-Pr

: Al coordination O O O R2 O Al Oi-Pr HO R1 H R1 R2 R2

cyclic transition state Al(Oi-Pr) hydride O O 2 H OH

transfer 1 2 R1 R2 R R

Example 12 O OH H H H Al(Oi-Pr)3 O O H HOi-Pr, 90% H MeO2C H O H

Example 24 (R)-BINOL (0.1 eq) O OH AlMe3 (0.1 eq) 43−99% yield R * R 30−80% ee i-PrOH (4 eq) toluene

Example 37

MeMe Me Me MeMe MeO OH MeO O MeO OH 4 equiv Me Al, i-PrOH 3 O O O 0 oC to rt, 24 h OTBDPS OTBDPS OTBDPS 15% 84%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_154, © Springer-Verlag Berlin Heidelberg 2009 346

Example 49

MeO O O OMe 3 equiv AlMe3 9 equiv HOCH(Ph)2

CH2Cl2 O O MeO O O OMe MeO O O OMe

OH OH OH 12% OH 73%

References

1. Meerwein, H.; Schmidt, R. Ann. 1925, 444, 221−238. Hans L. Meerwein, born in Hamburg Germany in 1879, received his Ph.D. at Bonn in 1903. In his long and pro- ductive academic career, Meerwein made many notable contributions in organic chemistry. 2. Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W. Tetrahedron 1958, 2, 1−57. 3. de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J. Synthesis 1994, 1007−1017. (Review). 4. Campbell, E. J.; Zhou, H.; Nguyen, S. T. Angew. Chem., Int. Ed. 2002, 41, 1020−1022. 5. Sominsky, L.; Rozental, E.; Gottlieb, H.; Gedanken, A.; Hoz, S. J. Org. Chem. 2004, 69, 1492−1496. 6. Cha, J. S. Org. Proc. Res. Dev. 2006, 10, 1032−1053. 7. Manaviazar, S.; Frigerio, M.; Bhatia, G. S.; Hummersone, M. G.; Aliev, A. E.; Hale, K. J. Org. Lett. 2006, 8, 4477−4480. 8. Clay, J. M. Meerwein–Ponndorf–Verley reduction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 123−128. (Review). 9. Dilger, A. K.; Gopalsamuthiram, V.; Burke, S. D. J. Am. Chem. Soc. 2007, 129, 16273−16277.

347

Meisenheimer complex Also known as the Meisenheimer−Jackson salt, the stable intermediate for certain SNAr reactions.

R RNH: 2 R HN F R NH F NH NO NO2 F 2 NO SNAr, slow, fast 2 NO2 F rate-determining step NO NO2 2 NO2 NO2 Meisenheimer complex Sanger’s reagent, ipso attack ipso substitution

Example 17

O O N NO CO Et 2 t-BuOK, DMF/THF 2 CO2Et − o Ph CN 70 C, argon H NC Ph nitronate Example 29

O2N NO2 CH2Cl2 2 NCN argon, rt, 3 h

NO 2

H O O N N N N i-Pr i-Pr H N N O2N O2N NO2 NO2

15.8% 15.5% NO N 2 O O

The reaction using Sanger’s reagent is faster than using the corresponding chloro-, bromo-, and iododinitrobenzene—the fluoro-Meisenheimer complex is the most stabilized because F is the most electron-withdrawing. The reaction rate does not depend upon the capacity of the leaving group.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_155, © Springer-Verlag Berlin Heidelberg 2009 348

Example 310 R' R R' F R NH F NH NO NO2 2 R NO2 HN R' F NO NO2 2 NO2

H H

R' R R' N FN R NO NO2 2

F NO NO2 2

References

1. Meisenheimer, J. Ann. 1902, 323, 205–214. 2. Strauss, M. J. Acc. Chem. Res. 1974, 7, 181–188. (Review). 3. Bernasconi, C. F. Acc. Chem. Res. 1978, 11, 147–152. (Review). 4. Terrier, F. Chem. Rev. 1982, 82, 77–152. (Review). 5. Manderville, R. A.; Buncel, E. J. Org. Chem. 1997, 62, 7614–7620. 6. Hoshino, K.; Ozawa, N.; Kokado, H.; Seki, H.; Tokunaga, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 4572–4573. 7. Adam, W.; Makosza, M.; Zhao, C.-G.; Surowiec, M. J. Org. Chem. 2000, 65, 1099– 1101. 8. Gallardo, I.; Guirado, G.; Marquet, J. J. Org. Chem. 2002, 67, 2548–2555. 9. Al-Kaysi, R. O.; Guirado, G.; Valente, E. J. Eur. J. Org. Chem. 2004, 3408–3411. 10. Um, I.-H.; Min, S.-W.; Dust, J. M. J. Org. Chem. 2007, 72, 8797–8803. 11. Han, T. Y.-J.; Pagoria, P. F.; Gash, A. E.; Maiti, A.; Orme, C. A.; Mitchell, A. R.; Fried, L. E. New J. Chem. 2009, 33, 50–56.

349

[1,2]-Meisenheimer rearrangement [1,2]-Sigmatropic rearrangement of tertiary amine N-oxides to substituted hydroxylamines.

R R 1 R1 R Δ R 1 N N N R R2 O R2 O R2 O

Example 17 O 35% H2O2, CHCl3/MeOH, rt, 15 h O N then PtO2, rt, 4.5 h

O THF, reflux, 1 h O N O O O N 64%, 2 steps O

References

1. Meisenheimer, J. Ber. 1919, 52, 1667–1677. 2. Castagnoli, N., Jr.; Craig, J. C.; Melikian, A. P.; Roy, S. K. Tetrahedron 1970, 26, 4319–4327. 3. Johnstone, R. A. W. Mech. Mol. Migr. 1969, 2, 249–266. (Review). 4. Kurihara, T.; Sakamoto, Y.; Tsukamoto, K.; Ohishi, H.; Harusawa, S.; Yoneda, R. J. Chem. Soc., Perkin Trans. 1, 1993, 81–87. 5. Yoneda, R.; Sakamoto, Y.; Oketo, Y.; Minami, K.; Harusawa, S.; Kurihara, T. Tetra- hedron Lett. 1994, 35, 3749–3752. 6. Kurihara, T.; Sakamoto, Y.; Takai, M.; Ohishi, H.; Harusawa, S.; Yoneda, R. Chem. Pharm. Bull. 1995, 43, 1089–1095. 7. Yoneda, R.; Sakamoto, Y.; Oketo, Y.; Harusawa, S.; Kurihara, T. Tetrahedron 1996, 52, 14563–14576. 8. Yoneda, R.; Araki, L.; Harusawa, S.; Kurihara, T. Chem. Pharm. Bull. 1998, 46, 853– 856.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_156, © Springer-Verlag Berlin Heidelberg 2009 350

[2,3]-Meisenheimer rearrangement [2,3]-Sigmatropic rearrangement of allylic tertiary amine-N-oxides to give O-allyl hydroxylamines:

3 3 2 2 2' Δ O 1 O 1' N 1 N R 2' R R R 1'

Example 17

O Ph N PhSO2 * N Et2O, rt, 48 h N 48%, 61% de O

Example 28

Bn Bn HO O O m-CPBA Al2O3 (alumina) N O N O OH OH CH2Cl2, 100% MeOH

Bn Bn O O CDCl3, rt O N O O N O OH OH 67%, 65% de *

References

1. Meisenheimer, J. Ber. 1919, 52, 1667–1677. 2. Yamamoto, Y.; Oda, J.; Inouye, Y. J. Org. Chem. 1976, 41, 303–306. 3. Johnstone, R. A. W. Mech. Mol. Migr. 1969, 2, 249–266. (Review). 4. Kurihara, T.; Sakamoto, Y.; Matsumoto, H.; Kawabata, N.; Harusawa, S.; Yoneda, R. Chem. Pharm. Bull. 1994, 42, 475–480. 5. Blanchet, J.; Bonin, M.; Micouin, L.; Husson, H.-P. Tetrahedron Lett. 2000, 41, 8279– 8283. 6. Enders, D.; Kempen, H. Synlett 1994, 969–971. 7. Buston, J. E. H.; Coldham, I.; Mulholland, K. R. Synlett 1997, 322–324. 8. Guarna, A.; Occhiato, E. G.; Pizzetti, M.; Scarpi, D.; Sisi, S.; van Sterkenburg, M. Tet- rahedron: Asymmetry 2000, 11, 4227–4238. 9. Mucsi, Z.; Szabó, A.; Hermecz, I.; Kucsman, Á.; Csizmadia, I. G. J. Am. Chem. Soc. 2005, 127, 7615–7621. 10. Bourgeois, J.; Dion, I.; Cebrowski, P. H.; Loiseau, F.; Bedard, A.-C.; Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131, 874–875.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_157, © Springer-Verlag Berlin Heidelberg 2009 351

Meyers oxazoline method Chiral oxazolines employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon–carbon bonds.

Ph O Ph 1. LDA O

N OMe 2. R-X R N OMe

N(i-Pr) 2 Ph Ph Ph H C H O 3 O H3C O N H Ph N N O H C H H 3 Li Li R O XR O O N OMe Me Me Me

Example 12 Ph 1. LDA TMSO O Ph O 2. TMSO Br O H3O N H O 3. LDA N 66% yield OMe 4. Me2SO4 70% ee OMe

Example 25

OMe Ph Ph OO OMe

NO 1. Li O N 2. OO I 99% yield

Example 39

3 equiv n-BuLi NO NO − NO 3 equiv ( )-sparteine Li MeOH n-Bu n-Bu − o Et2O, 78 C, 4 h 79%

er (S:R) = 86:14

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_158, © Springer-Verlag Berlin Heidelberg 2009 352

References

1. (a) Meyers, A. I.; Knaus, G.; Kamata, K. J. Am. Chem. Soc. 1974, 96, 268–270. While Albert I. Meyers was an assistant professor at Wayne State University, neighboring pharmaceutical firm Parke–Davis (Drs. George Moersch and Harry Crooks) donated several kilograms of (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol (Meyers referred to it as the Parke–Davis diol), from which his chemistry with chiral oxazolines began. He taught at Colorado State University since 1972. Meyers passed away in 2007. (b) Meyers, A. I.; Knaus, G. J. Am. Chem. Soc. 1974, 96, 6508–6510. (c) Meyers, A. I.; Knaus, G. Tetrahedron Lett. 1974, 15, 1333–1336. (d) Meyers, A. I.; Whitten, C. E. J. Am. Chem. Soc. 1975, 97, 6266–6267. (e) Meyers, A. I.; Mihelich, E. D. J. Org. Chem. 1975, 40, 1186–1187. (f) Meyers, A. I.; Mihelich, E. D. Angew. Chem., Int. Ed. 1976, 15, 270–271. (Review). (g) Meyers, A. I. Acc. Chem. Res. 1978, 11, 375– 381. (Review). 2. Meyers, A. I.; Yamamoto, Y.; Mihelich, E. D.; Bell, R. A. J. Org. Chem. 1980, 45, 2792–2796. 3. Meyers, A. I., Lutomski, K. A. In Asymmetric Synthesis, Morrison, J. D. Ed.; Vol III, Part B, Chapter 3, Academic Press, 1983. (Review). 4. Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837–860. (Review). 5. Robichaud, A. J.; Meyers, A. I. J. Org. Chem. 1991, 56, 2607–2609. 6. Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297–2360. (Review). 7. Meyers, A. I. J. Heterocycl. Chem. 1998, 35, 991–1002. (Review). 8. Wolfe, J. P. Meyers Oxazoline Method. In Name Reactions in Heterocycl. Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 237–248. (Review). 9. Hogan, A.-M. L.; Tricotet, T.; Meek, A.; Khokhar, S. S.; O’Shea, D. F. J. Org. Chem. 2008, 73, 6041–6044.

353

Meyer–Schuster rearrangement The isomerization of secondary and tertiary α-acetylenic alcohols to α,β- unsaturated carbonyl compounds via 1,3-shift. When the acetylenic group is terminal, the products are aldehydes, whereas the internal acetylenes give ketones. Cf. Rupe rearrangement.

OH R R O H , H2O R R R1 R1

OH OH2 R H R R R R R R R R 1 1 1 R R H tautomerization R O R • R1 R • R1 R R :OH2 1 OH

Example 16

O OH N H Br H 98% H2SO4 Br N 50% O O

Example 27 O P O O O O O P P O PhS O TMSO O P OTMS 54% OH OTMS PhS PhS o ClCH2CH2Cl, 83 C, 30 min. 6%

Example 38

O O O

OO OO OO 10% H2SO4 THF, rt, 1.5 h HO HO 70% OEt CO Et 21% CO Et 2 2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_159, © Springer-Verlag Berlin Heidelberg 2009 354

Example 49

PMBN PMBN CO2Et CO2Et OMe OMe BF ·Et O 3 2 OMe OH TFA, 89% EtO2C OMe EtO2C O

References

1. Meyer, K. H.; Schuster, K. Ber. 1922, 55, 819–823. 2. Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429–438. (Review). 3. Edens, M.; Boerner, D.; Chase, C. R.; Nass, D.; Schiavelli, M. D. J. Org. Chem. 1977, 42, 3403–3408. 4. Andres, J.; Cardenas, R.; Silla, E.; Tapia, O. J. Am. Chem. Soc. 1988, 110, 666–674. 5. Tapia, O.; Lluch, J. M.; Cardenas, R.; Andres, J. J. Am. Chem. Soc. 1989, 111, 829– 835. 6. Brown, G. R.; Hollinshead, D. M.; Stokes, E. S.; Clarke, D. S.; Eakin, M. A.; Foubis- ter, A. J.; Glossop, S. C.; Griffiths, D.; Johnson, M. C.; McTaggart, F.; Mirrlees, D. J.; Smith, G. J.; Wood, R. J. Med. Chem. 1999, 42, 1306–1311. 7. Yoshimatsu, M.; Naito, M.; Kawahigashi, M.; Shimizu, H.; Kataoka, T. J. Org. Chem. 1995, 60, 4798–4802. 8. Crich, D.; Natarajan, S.; Crich, J. Z. Tetrahedron 1997, 53, 7139–7158. 9. Williams, C. M.; Heim, R.; Bernhardt, P. V. Tetrahedron 2005, 61, 3771–3779. 10. Mullins, R. J.; Collins, N. R. Meyer–Schuster Rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 305−318. (Review).

355

Michael addition Also known as conjugate addition, Michael addition is the 1,4-addition of a nucleophile to an α,β-unsaturated system.

R1 O R1 O Nuc: Nuc R2 Y R Y 2 H R3 R3

R1 O Nuc R1 O R1 O Nuc Nuc: conjugate workup R2 Y R2 Y R2 Y H H addition R3 R3 R3 enolate

Example 1, Asymmetric Michael addition2

O O O O Ph N Si(Me) Ph PhMgBr, CuBr•DMS 2 N Si(Me)2Ph ether, THF, −55 oC O 92%, 92% de O CPh3 CPh 3

Example 2, Thia-Michael addition3

O O

H2S, NaOMe HS O O N MeOH, 75% N

Example 3, Phospha-Michael addition7

O (EtO)2P(O)H O R OEt R = H, 71% NH MeO R cat. MeO P R = Me, 51% O OEt Me N NMe 2 2

Example 4, Asymmetric aza-Michael addition9

Ph NH2 MeO2C MeO2C MeO C N N 2 Cl NaI, Na2CO3, Bu4NBr 2 : 1 Ph CH CN, 82% Ph 3

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_160, © Springer-Verlag Berlin Heidelberg 2009 356

Example 5, Intramolecular Michael addition10

O H O Me O O LiHMDS, DMF Boc Me H N o H −60 C, 20 min. CO2Me CO Me 95% N H 2 Boc

References

1. Michael, A. J. Prakt. Chem. 1887, 35, 349. Arthur Michael (1853−1942) was born in Buffalo, New York. He studied under Robert Bunsen, August Hofmann, Adolphe Wurtz, and Dimitri Mendeleev, but never bothered to take a degree. Back to the United States, Michael became a Professor of Chemistry at Tufts University, where he married one of his most brilliant students, Helen Abbott, one of the few female organic chemists in this period. Since he failed miserably as an administrator, Michael and his wife set up their own private laboratory at Newton Center, Massachusetts, where the Michael addition was discovered. 2. Hunt, D. A. Org. Prep. Proced. Int. 1989, 21, 705−749. 3. D’Angelo, J.; Desmaële, D.; Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459−505. 4. Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135−631. (Review). 5. Hoz, S. Acc. Chem. Res. 1993, 26, 69−73. (Review). 6. Ihara, M.; Fukumoto, K. Angew. Chem., Int. Ed. 1993, 32, 1010−1022. (Review). 7. Simoni, D.; Invidiata, F. P.; Manferdini, M.; Lampronti, I.; Rondanin, R.; Roberti, M.; Pollini, G. P. Tetrahedron Lett. 1998, 39, 7615−7618. 8. Enders, D.; Saint-Dizier, A.; Lannou, M.-I.; Lenzen, A. Eur. J. Org. Chem. 2006, 29−49. (Review on the phospha-Michael addition). 9. Chen, L.-J.; Hou, D.-R. Tetrahedron: Asymmetry 2008, 19, 715−720. 10. Sakaguchi, H.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2008, 10, 1711−1714. 11. Thaler, T.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 645−648. 357

Michaelis−Arbuzov phosphonate synthesis Phosphonate synthesis from the reaction of alkyl halides with phosphites. General scheme:

Δ O 1 1 R P OR1 R X (R O)3P R2 X 2 OR1

1 R = alkyl, etc.; R2 = alkyl, acyl, etc.; X = Cl, Br, I

For instance: O O Δ Br CH3 S 2 (CH3O)3P Br O N O (CH O) P: 3 3 Br CH3 O O O O SN2 CH O ↑ CH O 3 P CH3Br 3 P CH O O 3 CH O CH O 3 3

Example 12

Br (EtO)3P, Tol. P(OEt)2 O 145 oC, 4 h, 70% Br

Example 26

O 140 oC O O BnO BnO OBn P Cl (BnO)3P P P BnO OBn BnO 8 h, 92%

Example 37

O (EtO) P, NiCl F O Br 3 2 F O P OEt OEt 100 oC, 72 h, 10% F F F F

Example 49

O Me (MeO)3P O O Me Br (MeO)2P N Ph 105−110 oC N Ph Bn 92−98% Bn

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_161, © Springer-Verlag Berlin Heidelberg 2009 358

Example 510

BnO BnO − O TMSO P(OEt)2 O S SCN BnO BnO P(OEt)2 O 50 oC, 1 h, 82% BnO O BnO O Bn Bn

References

1. (a) Michaelis, A.; Kaehne, R. Ber. 1898, 31, 1048−1055. (b) Arbuzov, A. E. J. Russ. Phys. Chem. Soc. 1906, 38, 687. 2. Surmatis, J. D.; Thommen, R. J. Org. Chem. 1969, 34, 559−560. 3. Gillespie, P.; Ramirez, F.; Ugi, I.; Marquarding, D. Angew. Chem., Int. Ed. 1973, 12, 91−119. (Review). 4. WaschbĦsch, R.; Carran, J.; Marinetti, A.; Savignac, P. Synthesis 1997, 727−743. 5. Bhattacharya, A. K.; Stolz, F.; Schmidt, R. R. Tetrahedron Lett. 2001, 42, 5393−5395. 6. Erker, T.; Handler, N. Synthesis 2004, 668−670. 7. Souzy, R.; Ameduri, B.; Boutevin, B.; Virieux, D. J. Fluorine Chem. 2004, 125, 1317−1324. 8. Kadyrov, A. A.; Silaev, D. V.; Makarov, K. N.; Gervits, L. L.; Röschenthaler, G.-V. J. Fluorine Chem. 2004, 125, 1407−1410. 9. Ordonez, M.; Hernandez-Fernandez, E.; Montiel-Perez, M.; Bautista, R.; Bustos, P.; Rojas-Cabrera, H.; Fernandez-Zertuche, M.; Garcia-Barradas, O. Tetrahedron: Asymmetry 2007, 18, 2427−2436. 10. Piekutowska, M.; Pakulski, Z. Carbohydrate Res. 2008, 343, 785−792.

359

Midland reduction Asymmetric reduction of ketones using Alpine-borane®. Alpine-borane® = B-isopinocampheyl-9-borabicyclo[3.3.1]nonane.

O OH Alpine-borane R1 R1 neat R R

H B THF B reflux

(1R)-(+)-α-pinene 9-BBN (R)-Alpine-borane 9-BBN = 9-borabicyclo[3.3.1]nonane

B O O H R1 B R1 R R

B OH hydride O H2O2, NaOH R1 1 workup transfer R R R

Example 16 O OH (R)-Alpine-borane, THF BnO BnO −10 oC to rt, 95%, 88% ee H H

Example 27 O OH (R)-Alpine-borane OPMB OPMB TBSO 22 oC, 6 kbar, 82% TBSO 80% de

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_162, © Springer-Verlag Berlin Heidelberg 2009 360

Example 38

O OH

(R)-Alpine-borane (neat)

rt, 74%, 93% ee TBSO TBSO

References

1. Midland, M. M.; Greer, S.; Tramontano, A.; Zderic, S. A. J. Am. Chem. Soc. 1979, 101, 2352−2355. M. Mark Midland was a professor at the University of California, Riverside. 2. Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano, A. J. Am. Chem. Soc. 1980, 102, 867−869. 3. Brown, H. C.; Pai, G. G. J. Org. Chem. 1982, 47, 1606−1608. 4. Brown, H. C.; Pai, G. G.; Jadhav, P. K. J. Am. Chem. Soc. 1984, 106, 1531−1533. 5. Singh, V. K. Synthesis 1992, 605−617. (Review). 6. Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3, 2721−2724. 7. Mulzer, J.; Berger, M. J. Org. Chem. 2004, 69, 891−898. 8. Kiewel, K.; Luo, Z.; Sulikowski, G. A. Org. Lett. 2005, 7, 5163−5165. 9. Clay, J. M. Midland reduction. In Name Reactions for Functional Group Transforma- tions; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2007, pp 40−45. (Re- view).

361

Minisci reaction Radical-based carbon–carbon bond formation with electron-deficient heteroaromatics. The reaction entails an intermolecular addition of a nucleophilic radical to protonated heteroaromatic nucleus.

2 AgNO3 (NH4)2S2O8 RCO2H N R N H2SO4

N 2 AgNO3, (NH4)2S2O8, H2SO4 H RCO2H CO2 R N R H SO silver-catalyzed 2 4 H oxidative decarboxylation

Example 14

+ • S2O8 CH OH •CH OH H SO 3 2 4 SO4

CN CN (NH ) S O BF 4 2 2 8 4 MeOH, H2O N OH reflux, 1 h, 40% N OCH3

Example 25

1.6 equiv m-CPBA (CH3)3O•BF4 acetone, rt, 1.5 h N CH Cl , rt N 2 2 75% O 90 min.

Meerwein’s reagent

(NH4)2S2O8 MeOH, H2O BF N 4 OH reflux, 1 h N OCH 40%, 2 steps 3

1.6 equiv m-CPBA

N acetone, rt, 1.5 h N 78% O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_163, © Springer-Verlag Berlin Heidelberg 2009 362

OH (CH3)3O•BF4 (NH4)2S2O8 BF4 MeOH, H2O CH2Cl2, rt N 90 min., 85% reflux, 1 h, 41% OCH 3 N

Example 3, Intramolecular Minisci reaction6

EtO C CO2Et 2 N N OH O O AgNO3, (NH4)2S2O8 O CH2Cl2, H2O, AcOH, TFA rt, 1 h, 46% N NH H Example 47 H Me Me Me BzN CO2H H N BzN N N (NH4)2S2O8, AgNO3 BzN N H N N TFA, H2O, 75 °C 90 : 10 53% Cl Cl Cl

Example 510 N CO H N 2 N 10 equiv FeSO4•7H2O H2O2, H2O, H2SO4 N CH Cl , 0 oC, 15 min. HO2C CO2H 2 2 N N 1 equiv 10 equiv 24% N N References

1. Minisci, F, Bernardi. R, Bertini, F, Galli, R, Perchinummo, M. Tetrahedron 1971, 27, 3575–3579. 2. Minisci, F. Synthesis 1973, 1–24. (Review). 3. Minisci, F. Acc. Chem. Res. 1983, 16, 27–32. (Review). 4. Katz, R. B.; Mistry, J.; Mitchell, M. B. Synth. Commun. 1989, 19, 317–325. 5. Biyouki, M. A. A.; Smith, R. A. J.; Bedford, J. J.; Leader, J. P. Synth. Commun. 1998, 28, 3817–3825. 6. Doll, M. K. H. J. Org. Chem. 1999, 64, 1372–1374. 7. Cowden, C. J. Org. Lett. 2003, 5, 4497–4499. 8. Kast, O.; Bracher, F. Synth. Commun. 2003, 33, 3843–3850. 9. Benaglia, M.; Puglisi, A.; Holczknecht, O.; Quici, S.; Pozzi, G. Tetrahedron 2005, 61, 12058–12064. 10. Palde, P. B.; McNaughton, B. R.; Ross, N. T.; Gareiss, P. C.; Mace, C. R.; Spitale, R. C.; Miller, B. L. Synthesis 2007, 2287–2290. 11. Brebion, F.; Nàjera, F.; Delouvrié, B.; Lacôte, E.; Fensterbank, L.; Malacria, M. J. Heterocycl. Chem. 2008, 45, 527–532. 363

Mislow–Evans rearrangement [2,3]-Sigmatropic rearrangement of allylic sulfoxide to allylic alcohol.

Δ O Ar O P(OCH ) HO S 3 3 R S Ar R R

2 2 1 Ar O 1 R 2 [2,3]-sigmatropic S 3 3 O 1 S rearrangement R 2 Ar 1 :P(OCH ) 3 3 HO SN2 O H Ar P(OCH3)3 S R R

Example 12

O O NaIO4 dioxane/H2O

TBSO 50% TBSO OMe PhS CHO Example 27

OMe OMe MeO O O OTBS MeO O (EtO)3P, EtOH O OTBS reflux, 16 h, 98% O OH S Ph

Example 3, Seleno-Mislow-Evans8

TBDPSO TBDPSO

OTBS OTBS OH PMBO PMBO HO 1. PhSeCN, Bu3P, THF H H H H O o O 2. H2O2, pyr., THF, −30 C 62%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_164, © Springer-Verlag Berlin Heidelberg 2009 364

References

1. (a) Tang, R.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 2100–2104. (b) Evans, D. A.; Andrews, G. C.; Sims, C. L. J. Am. Chem. Soc. 1971, 93, 4956–4957. (c) Evans, D. A.; Andrews, G. C. J. Am. Chem. Soc. 1972, 94, 3672–3674. (d) Evans, D. A.; An- drews, G. C. Acc. Chem. Res. 1974, 7, 147–155. (Review). 2. Sato, T.; Shima, H.; Otera, J. J. Org. Chem. 1995, 60, 3936–3937. 3. Jones-Hertzog, D. K.; Jorgensen, W. L. J. Am. Chem. Soc. 1995, 117, 9077–9078. 4. Jones-Hertzog, D. K.; Jorgensen, W. L. J. Org. Chem. 1995, 60, 6682–6683. 5. Mapp, A. K.; Heathcock, C. H. J. Org. Chem. 1999, 64, 23–27. 6. Zhou, Z. S.; Flohr, A.; Hilvert, D. J. Org. Chem. 1999, 64, 8334–8341. 7. Shinada, T.; Fuji, T.; Ohtani, Y.; Yoshida, Y.; Ohfune, Y. Synlett 2002, 1341–1343. 8. Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44, 3485– 3499. 9. Albert, B. J.; Sivaramakrishnan, A.; Naka, T.; Koide, K. J. Am. Chem. Soc. 2006, 128, 2792–2793. 10. Pelc, M. J.; Zakarian, A. Tetrahedron Lett. 2006, 47, 7519–7523. 11. Brebion, F.; Najera, F.; Delouvrie, B.; Lacote, E.; Fensterbank, L.; Malacria, M. Syn- thesis 2007, 2273–2278.

365

Mitsunobu reaction

SN2 inversion of an alcohol by a nucleophile using disubstituted azodicarboxylates (originally, diethyl diazodicarboxylate, or DEAD) and trisubstituted phosphines (originally, triphenylphosphine).

CO2Et OH NN Nuc H 1 2 EtO2C CO2Et R R HNuc O PPh3 N N 1 2 o 0 R R EtO C H 1 or 2 alcohol PPh3 2

CO2Et H HNuc NN Ph P EtO C CO2Et adduct 3 2 NN CO2Et EtO2C NN formation : :PPh3 Ph3P EtO2C OH R R 1 2 Diethyl azodicarboxylate (DEAD)

alcohol OPPh SN2 Nuc EtO2C H 3 NN OPPh3 activation R1 R2 reaction R1 R2 H CO2Et Nuc

Example 12

CH OAc CH2OAc 2 PhCO2H O O DIAD, PPh3, THF OAc OH OAc O2CPh − o OAc 50 C to rt, 2 h, 80% OAc 2:1 β:α OAc OAc

Example 23

DEAD, PPh3, Tol. OH O 4-O2NPhCOO O O N CO H O 2 2 O −30 to 0 oC, 1 h, 90%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_165, © Springer-Verlag Berlin Heidelberg 2009 366

Example 3, Ether formation6

BnO OBn BnO2C O OH OH O OBn BnO OBn O OBn CO2Bn

N PBu , ADDP, THF, O 3 N 0 oC to rt, overnight O 100% OMe OMe ADDP = 1,1'-(azodicarbonyl)dipiperidine Example 47

TMS OH PPh3, DIAD, PhCH3 O HN TMS reflux, 60% N Ph Ph

Example 58

CH CH3 H 3 H n-BuLi Ph PO HO 2 N N CH CH3 then Ph2PCl H 3 H C H H3C 3

CH O H 3 O O O O OH N CH3 80% O2N H C H O2N 3

Example 6, Intramolecular Mitsunobu reaction9

OH NHNs NsHN

DEAD, PPh3 R R CO2Et CO2Et PhH, 92 % MeO N R=CH(OMe) MeO N Boc 2 Boc OMe OMe

367

References

1. (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380−2382. (b) Mit- sunobu, O. Synthesis 1981, 1−28. (Review). 2. Smith, A. B., III; Hale, K. J.; Rivero, R. A. Tetrahedron Lett. 1986, 27, 5813−5816. 3. KocieĔski, P. J.; Yeates, C.; Street, D. A.; Campbell, S. F. J. Chem. Soc., Perkin Trans. 1, 1987, 2183−2187. 4. Hughes, D. L. Org. React. 1992, 42, 335−656. (Review). 5. Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127−164. (Review). 6. Vaccaro, W. D.; Sher, R.; Davis, H. R., Jr. Bioorg. Med. Chem. Lett. 1998, 8, 35–40. 7. Cevallos, A.; Rios, R.; Moyano, A.; Pericàs, M. A.; Riera, A. Tetrahedron: Asymmetry 2000, 11, 4407–4416. 8. Mukaiyama, T.; Shintou, T.; Fukumoto, K. J. Am. Chem. Soc. 2003, 125, 10538– 10539. 9. Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron 2003, 59, 8571– 8587. 10. Christen, D. P. Mitsunobu reaction. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 671−748. (Review).

368

Miyaura borylation Palladium-catalyzed reaction of aryl halides with diboron reagents to produce arylboronates. Also known as Hosomi−Miyaura borylation.

O O Pd(0) O Ar X B B Ar B O O base O

X = I, Br, Cl, OTf.

oxidative Ar L Ar X L2Pd(0) Pd addition X L base O O transmetallation base O O B B L B B Ar O O Pd O O I L L L Pd O B O reductive O I B Ar L Pd(0) O Ar B 2 O elimination O

Example 17 O O O B OAc O B Ph O O O Ph B CuCl, LiCl, KOAc, DMF, 92% O

Example 28

O O B B O O N B O N OTf 3% (Ph3P)2PdCl2, 6% Ph3P Cbz O Cbz o 1.5 eq. K2CO3, dioxane, 90 C 85%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_166, © Springer-Verlag Berlin Heidelberg 2009 369

Example 39

O O B B CbzHN CO2Bn CbzHN CO2Bn O O O I B O Pd(dppf)Cl2, KOAc BnO DMSO, 80 oC, 24 h BnO 85% CbzHN CO2Bn

CbzHN CO2Bn I BnO OBn BnO

Pd(dppf)Cl2, K2CO3 DMSO, 80 oC, 24 h 85% BnO2C NHCbz

Example 4, One-pot synthesis of biindolyl10

1. 1 mol% Pd (dba) , 4 mol% XPhos 2 3 MeO 3 equiv HB(pin), 3 equiv Et3N MeO dioxane, 100 oC MeO N H MeO N H 2. 1 mol% Pd2(dba)3, 3 equiv K3PO4•H2O MeO o Br dioxane/H2O (10 : 1), 100 C Br MeO N H MeO

MeO N H

References

1. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508−7510. 2. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457−2483. (Review). 3. Suzuki, A. J. Organomet. Chem. 1995, 576, 147−168. (Review). 4. Carbonnelle, A.-C.; Zhu, J. Org. Lett. 2000, 2, 3477−3480. 5. Giroux, A. Tetrahedron Lett. 2003, 44, 233−235. 6. Kabalka, G. W.; Yao, M.-L. Tetrahedron Lett. 2003, 44, 7885−7887. 7. Ramachandran, P. V.; Pratihar, D.; Biswas, D.; Srivastava, A.; Reddy, M. V. R. Org. Lett. 2004, 6, 481−484. 8. Occhiato, E. G.; Lo Galbo, F.; Guarna, A. J. Org. Chem. 2005, 70, 7324−7330. 9. Skaff, O.; Jolliffe, K. A.; Hutton, C. A. J. Org. Chem. 2005, 70, 7353−7363. 10. Duong, H. A.; Chua, S.; Huleatt, P. B.; Chai, C. L. L. J. Org. Chem. 2008, 73, 9177−9180. 11. Jo, T. S.; Kim, S. H.; Shin, J.; Bae, C. J. Am. Chem. Soc. 2009, 131, 1656−1657. 370

Moffatt oxidation Oxidation of alcohols using DCC and DMSO, aka “Pfitzner−Moffatt oxidation”.

OH DCC O

R1 R2 DMSO, HX R1 R2

DCC, 1,3-dicyclohexylcarbodiimide

H H H NCN NCN HN C N O S H O : S O 1 2 R R H O S X S O O H O H 1 2 (CH3)2S N N H R R 1 2 1 2 H H R R R R 1,3-dicyclohexylurea

Example 12 + OH DCC, DMSO, C5H5NH CF3CO2 O

PhH, rt, 70% OH O Example 28 A OH A CHO O O DCC, DMSO, Cl2CHCO2H

OO rt, 90 min., 90% OO

A = adenosine References

1. Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1963, 85, 3027−3028. 2. Schobert, R. Synthesis 1987, 741−742. 3. Liu, H. J.; Nyangulu, J. M. Tetrahedron Lett. 1988, 29, 3167–3170. 4. Tidwell, T. T. Org. React. 1990, 39, 297−572. (Review). 5. Gordon, J. F.; Hanson, J. R.; Jarvis, A. G.; Ratcliffe, A. H. J. Chem. Soc., Perkin Trans. 1, 1992, 3019−3022. 6. Krysan, D. J.; Haight, A. R.; Lallaman, J. E. Org. Prep. Proced. Int. 1993, 25, 437−443. 7. Adak, A. K. Synlett 2004, 1651−1652. 8. Wang, M.; Zhang, J.; Andrei, D.; Kuczera, K.; Borchardt, R. T.; Wnuk, S. F. J. Med. Chem. 2005, 48, 3649−3653. 9. van der Linden, J. J. M.; Hilberink, P. W.; Kronenburg, C. M. P.; Kemperman, G. J. Org. Proc. Res. Dev. 2008, 12, 911–920.

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Morgan–Walls reaction Phenanthridine cyclization by dehydrative ring closure of acyl-o-aminobiphenyls with phosphorus oxychloride in boiling nitrobenzene.

R R NH POCl O 3 N 1 R R1

O Cl P Cl POCl2 Cl O O : NH NH R R R1 R1

OPOCl2 R R N

NH: HOPOCl H 2 1 R1 R

Example 16

O2N NO2 O2N NO2

HN nitrobenzene, POCl3 N O SnCl4, 98%

CN CN

Pictet–Hubert reaction The Morgan-Walls reaction is a variant of the Pictet-Hubert reaction where the phenanthridine cyclization was accomplished by dehydrative ring closure of acyl- o-aminobiphenyls on heating with zinc chloride at 250−300 °C.

R R NH N O ZnCl2 1 1 R 250−300 oC R

Example 24

o ZnCl2, 250−300 C

N N H 80% O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_168, © Springer-Verlag Berlin Heidelberg 2009 372

References

1. (a) Pictet, A.; Hubert, A. Ber. 1896, 29, 1182−1189. (b) Morgan, C. T.; Walls, L. P. J. Chem. Soc. 1931, 2447−2456. (c) Morgan, C. T.; Walls, L. P. J. Chem. Soc. 1932, 2225−2231. 2. Gilman, H.; Eisch, J. J. Am. Chem. Soc. 1957, 79, 4423−4426. 3. Hollingsworth, B. L.; Petrow, V. J. Chem. Soc. 1961, 3664−3667. 4. Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279−1300. 5. Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1988, 31, 774−779. 6. Peytou, V.; Condom, R.; Patino, N.; Guedj, R.; Aubertin, A.-M.; Gelus, N.; Bailly, C.; Terreux, R.; Cabrol-Bass, D. J. Med. Chem. 1999, 42, 4042−4043. 7. Holsworth, D. D. Pictet–Hubert Reaction. In Name Reactions in Heterocyclic Chemis- try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 465−468. (Re- view).

373

Mori−Ban indole synthesis Intramolecular Heck reaction of o-halo-aniline with pendant olefin to prepare indole.

CO2Me CO2Me Br Pd(OAc)2, Ph3P

o N N NaHCO3, DMF, 130 C Ac Ac

Reduction of Pd(OAc)2 to Pd(0) using Ph3P:

AcO Pd OAc AcO Ph3P Pd OAc :PPh 3

O O O Pd(0) OPPh3 AcO OPPh O 3

Mori−Ban indole synthesis:

Br MeO2C CO2Me CO Me PdL 2 Br Pd(0) n PdBrLn insertion H oxidative N addition N N Ac Ac Ac β-hydride CO2Me H PdBrL addition elimination n N of PdH Ac CO Me CO2Me β-hydride 2 CO2Me PdBrLn elimination HN N N Ac Ac Ac

Regeneration of Pd(0):

HPdBrL NaHCO Pd(0) NaBr CO ↑ n 3 H2O 2

Example 11a

I Pd(OAc)2 Me

Et N, MeCN N 3 N H sealed tube H 110 °C, 87%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_169, © Springer-Verlag Berlin Heidelberg 2009 374

Example 24

N Cl 10 mol% Pd(OAc)2 N

N N Bu NBr, K CO , 4 2 3 N N DMF, 100 oC 67%

Example 37

SO2NHMe Br Cbz N SO2NHMe COCF Pd(OAc)2, Bu4NCl N 3 Br Cbz Et3N, DMF N N heat, DME, 76% H Br

References

1. Mori−Ban indole synthesis, (a) Mori, M.; Chiba, K.; Ban, Y. Tetrahedron Lett. 1977, 18, 1037−1040; (b) Ban, Y.; Wakamatsu, T.; Mori, M. Heterocycles 1977, 6, 1711−1715. 2. Reduction of Pd(OAc)2 to Pd(0), (a) Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M. A.; Meyer, G. Organometallics 1995, 14, 5605−5614; (b) Amatore, C.; Carre, E.; M’Barki, M. A. Organometallics 1995, 14, 1818−1826; (c) Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics 1992, 11, 3009−3013; (d) Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc. 1991, 113, 8375−8384. 3. Macor, J. E.; Ogilvie, R. J.; Wythes, M. J. Tetrahedron Lett. 1996, 37, 4289−4293. 4. Li, J. J. J. Org. Chem. 1999, 64, 8425−8427. 5. Gelpke, A. E. S.; Veerman, J. J. N.; Goedheijt, M. S.; Kamer, P. C. J.; van Leuwen, P. W. N. M.; Hiemstra, H. Tetrahedron 1999, 55, 6657−6670. 6. Sparks, S. M.; Shea, K. J. Tetrahedron Lett. 2000, 41, 6721−6724. 7. Bosch, J.; Roca, T.; Armengol, M.; Fernandez-Forner, D. Tetrahedron 2001, 57, 1041−1048. 8. Ma, J.; Yin, W.; Zhou, H.; Liao, X.; Cook, J. M. J. Org. Chem. 2009, 74, 264−273. 375

Mukaiyama aldol reaction Lewis acid-catalyzed aldol condensation of aldehyde and silyl enol ether.

OH O R2 Lewis R CHO R1 R R2 OSiMe acid 3 R1

O LA OH O Me3SiO O X R R2 R H R2 XSiMe3 2 R R 1 1 1 R R SiMe3 R O

Example 1, Intramolecular Mukaiyama aldol reaction3

CH(OMe) 2 CH(OMe)2 − o O 1. LDA, THF, 78 C, 10 min. OTMS EtO2C EtO C − o 2 EtO C 2. 1.8 equiv TMSCl, 78 C, 4 h 2 EtO2C 92%

O O H OMe OMe H TiCl4, CH2Cl2

−78 oC to rt, 15 h EtO C EtO2C 2 CO2Et CO2Et 40% 12%

Example 2, Mukaiyama aldol reaction7

O O

O OH BF3•OEt2, DTBMP O N N OHC − − o Boc CH2Cl2, 78 to 50 C, 73% Boc OTBDMS N O N Bn Bn

Example 3, Vinylogous Mukaiyama aldol reaction8

CHO OH OO OO 1. PhCO2H, rt O 2. TFA, 60% OSiMe3 CN NC

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_170, © Springer-Verlag Berlin Heidelberg 2009 376

Example 4, Asymmetric Mukaiyama aldol reaction10

cat. N O OTMS Ts B Bu3Sn H CHO OMe

Bu3Sn O Bu3Sn HO OMe 38% 50% OTMS

Example 5, Mukaiyama aldol reaction12

O OTIPS OTBS O OTBS Me O Me Me Br Me Br 10 mol% Bi(OTf) CHO 3 − o OH CH2Cl2, 40 C 76% out of 56% conversion

References

1. (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011−1014. (b) Mu- kaiyama, T.; Narasaka, K.; Banno, K. J. Am. Chem. Soc. 1974, 96, 7503−7509. 2. Ishihara, K.; Kondo, S.; Yamamoto, H. J. Org. Chem. 2000, 65, 9125−9128. 3. Armstrong, A.; Critchley, T. J.; Gourdel-Martin, M.-E.; Kelsey, R. D.; Mortlock, A. A. J. Chem. Soc., Perkin Trans. 1 2002, 1344−1350. 4. Clézio, I. L.; Escudier, J.-M.; Vigroux, A. Org. Lett. 2003, 5, 161−164. 5. Ishihara, K.; Yamamoto, H. Boron and Silicon Lewis Acids for Mukaiyama Aldol Re- actions. In Modern Aldol Reactions Mahrwald, R., Ed.; 2004, 25−68. (Review). 6. Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 5590−5614. (Review). 7. Adhikari, S.; Caille, S.; Hanbauer, M.; Ngo, V. X.; Overman, L. E. Org. Lett. 2005, 7, 2795−2797. 8. Acocella, M. R.; Massa, A.; Palombi, L.; Villano, R.; Scettri, A. Tetrahedron Lett. 2005, 46, 6141−6144. 9. Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. J. Am. Chem. Soc. 2007, 129, 6386−6387. 10. Webb, M. R.; Addie, M. S.; Crawforth, C. M.; Dale, J. W.; Franci, X.; Pizzonero, M.; Donald, C.; Taylor, R. J. K. Tetrahedron 2008, 64, 4778−4791. 11. Frings, M.; Atodiresei, I.; Runsink, J.; Raabe, G.; Bolm, C. Chem. Eur. J. 2009, 15, 1566−1569. 12. Gao, S.; Wang, Q.; Chen, C. J. Am. Chem. Soc. 2009, 131, 1410−1412.

377

Mukaiyama Michael addition Lewis acid-catalyzed Michael addition of silyl enol ether to an α,β-unsaturated system.

O R2 Lewis R1 O R2 O R1 OSiMe acid R 3 R

Example 12 OSiMe O 3 1. 0.1 mol% TBABB, THF, 3 h O O OMe 2. 1 N HCl, THF, 0 oC, 0.5 h O 87% TBABB = tetra-n-butylammonium bibenzoate

Example 25 O O OSiMe3 1. neat DBU, rt, 24 h OMe O 2. 1 N HCl, THF, 68% O

Example 38

OMe OMe OMe 10 mol% Sc(OTf) OMe OMe 3 CH Cl , −78 oC to rt TBSO 2 2 O O O 10% HF/CH3CN quench MeO O OMe H O 85%, 20 : 1 (syn/anti) OMe

Example 49

O OTBS 0.5 mol% Zn(OTf)2 CO Me R1 2 − o CH2Cl2, 0 25 C N R2 R3 2 78−81%

OTBS O 4 N HCl R O R1 O 1 R CO Me R2 CO2Me THF 2 2 R R3 3 N N2 2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_171, © Springer-Verlag Berlin Heidelberg 2009 378

References

1. (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011−1014. (b) Mukaiyama, T.; Narasaka, K.; Banno, K. J. Am. Chem. Soc. 1974, 96, 7503−7509. (c) Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 5590−5614. (Review). 2. Gnaneshwar, R.; Wadgaonkar, P. P.; Sivaram, S. Tetrahedron Lett. 2003, 44, 6047−6049. 3. Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku, A.; Harada, T. J. Org. Chem. 2003, 68, 10046−10057. 4. Jaber, N.; Assie, M.; Fiaud, J.-C.; Collin, J. Tetrahedron 2004, 60, 3075−3083. 5. Shen, Z.-L.; Ji, S.-J.; Loh, T.-P. Tetrahedron Lett. 2005, 46, 507−508. 6. Wang, W.; Li, H.; Wang, J. Org. Lett. 2005, 7, 1637−1639. 7. Ishihara, K.; Fushimi, M. Org. Lett. 2006, 8, 1921−1924. 8. Jewett, J. C.; Rawal, V. H. Angew. Chem., Int. Ed. 2007, 46, 6502−6504. 9. Liu, Y.; Zhang, Y.; Jee, N.; Doyle, M. P. Org. Lett. 2008, 10, 1605−1608. 10. Takahashi, A.; Yanai, H.; Taguchi, T. Chem. Commun. 2008, 2385−2387.

379

Mukaiyama reagent Mukaiyama reagent such as 2-chloro-1-methyl-pyridinium iodide for esterification or amide formation.

General scheme:

NX Y O R3 R CO H R OH R2 NO 1 2 2 R1 O base R3 X = F, Cl, Br

Example 11c

NBr BF HO 4 O CO2H O O Bu3N, CH2Cl2 O

O O O Br N SNAr − Br O O N BF : O 4 O BF O − H O N : 4 H Br HO Bn

NBu 3

OBn : HO N O O O N O O N BF4 Bn BF O H 4

Amide formation using the Mukaiyama reagent follows a similar mechanistic pathway.1d

Example 2, Polymer-supported Mukaiyama reagent5

TfO OH N O N Cl O Cl

Tf2O, CH2Cl2, 16 h, rt 1.25 mmol/g

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_172, © Springer-Verlag Berlin Heidelberg 2009 380

O NHBoc NHBoc O

NH2 NH CO2H O polymer-supported N N Mukaiyama reagent H O H O Et3N, CH2Cl2, rt 16 h, 88%

Example 39

O NHFmoc S N t-BuS HO S O N S

CO TMSE 2 NHBoc

O S N NH Mukaiyama reagent S t-BuS N S O DIPEA, CH2Cl2, 91% NHBoc CO TMSE 2

Example 4, Fluorous Mukaiyama reagent10

1. Fluorous Mukaiyama reagent 1 equiv DMAP, 3 equiv Et3N dry DMF, rt, 1h 1 2 1 2 RCO2H R NH2 or R OH RCONHR or RCO2R 2. H O, rt, 5 min., 87−100% 2

N Cl Fluorous Mukaiyama reagent TfO C F 10 21

References

1. (a) Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K. Chem. Lett. 1975, 1045–1048. (b) Hojo, K.; Kobayashi, S.; Soai, K.; Ikeda, S.; Mukaiyama, T. Chem. Lett. 1977, 635–636. (c) Mukaiyama, T. Angew. Chem., Int. Ed. 1979, 18, 707–708. (d) For amide formation, see: Huang, H.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1984, 1465– 1466. 2. Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J. Am. Chem. Soc. 1994, 116, 8402–8403. 3. Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem. 1997, 62, 1540–1542. 4. Folmer, J. J.; Acero, C.; Thai, D. L.; Rapoport, H. J. Org. Chem. 1998, 63, 8170–8182. 5. Crosignani, S.; Gonzalez, J.; Swinnen, D. Org. Lett. 2004, 6, 4579–4582. 381

6. Mashraqui, S. H.; Vashi, D.; Mistry, H. D. Synth. Commun. 2004, 34, 3129–3134. 7. Donati, D.; Morelli, C.; Taddei, M. Tetrahedron Lett. 2005, 46, 2817–2819. 8. Vandromme, L.; Monchaud, D.; Teulade-Fichou, M.-P. Synlett 2006, 3423–3426. 9. Ren, Q.; Dai, L.; Zhang, H.; Tan, W.; Xu, Z.; Ye, T. Synlett 2008, 2379–2383. 10. Matsugi, M.; Suganuma, M.; Yoshida, S.; Hasebe, S.; Kunda, Y.; Hagihara, K.; Oka, S. Tetrahedron Lett. 2008, 49, 6573–6574.

382

Myers−Saito cyclization Cf. Bergman cyclization and Schmittel cyclization.

Δ or

• hv hydrogen atom donor

H H reversible

•

allenyl enyne diradical Example 13

Ph PhH, reflux 96 h, 40% Ph Ph Ph H Example 2, Aza-Myers−Saito reaction8

MeOH CDCl CHO N OMe N 3 N o Ph 0 C, 14 h Ph 10 oC, 12 h Ph

References

1. (a) Myers, A. G.; Proteau, P. J.; Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212– 7214. (b) Myers, A. G.; Dragovich, P. S.; Kuo, E. Y. J. Am. Chem. Soc. 1992, 114, 9369–9386. 2. Schmittel, M.; Strittmatter, M.; Kiau, S. Tetrahedron Lett. 1995, 36, 4975–4978. 3. Schmittel, M.; Steffen, J.-P.; Auer, D.; Maywald, M. Tetrahedron Lett. 1997, 38, 6177–6180. 4. Bruckner, R; Suffert, J. Synlett 1999, 657−679. (Review). 5. Stahl, F.; Moran, D.; Schleyer, P. von R.; Prall, M.; Schreiner, P. R. J. Org. Chem. 2002, 67, 1453–1461. 6. Musch, P. W; Remenyi, C.; Helten, H.; Engels, B. J. Am. Chem. Soc. 2002, 124, 1823–1828. 7. Bui, B. H.; Schreiner, P. R. Org. Lett. 2003, 5, 4871–4874. 8. Feng, L.; Kumar, D.; Birney, D. M.; Kerwin, S. M. Org. Lett. 2004, 6, 2059–2062. 9. Schmittel, M.; Mahajan, A. A.; Bucher, G. J. Am. Chem. Soc. 2005, 127, 5324–5325. 10. Karpov, G.; Kuzmin, A.; Popik, V. V. J. Am. Chem. Soc. 2008, 130, 11771–11777.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_173, © Springer-Verlag Berlin Heidelberg 2009 383

Nazarov cyclization Acid-catalyzed electrocyclic formation of cyclopentenone from di-vinyl ketone.

O O H

H H HO O O protonation

OH O tautomerization

Example 12

O H O ZrCl4, (CH2Cl)2

o N N SiMe3 60 C, 36 h, 76% H CO Me CO2Me 2

Example 26

O −2 OAc HClO4 (10 M) Ph Ph Ac2O (1 M)

EtOAc, 9 h, 75% H O O

Example 39

Ph Me Me Ph MeO2C 5 mol% Cu(ClO4)2 MeO2C O OTIPS OTIPS DCE, 45 oC, 8 h, 80% O

OTIPS OTIPS

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_174, © Springer-Verlag Berlin Heidelberg 2009 384

Example 410

OAc

N MeO Ts O O OAc 10 mol% Sc(OTf)3 o LiClO4, 80 C MeO

ClCH CH Cl (0.3 M) 2 2 O N 65% Ts O Example 511

O O Cl Cl Me O Me O 1. hν (350 nm), CH CN, rt O Me 3 Me Me O o 2. i-Pr2NH, MeOH, 50 C OTBS 60%, 2 steps Br O Cl Cl O Me O Me Me 9 O OTBS O H Me O H Me Br

References

1. Nazarov, I. N.; Torgov, I. B.; Terekhova, L. N. Bull. Acad. Sci. (USSR) 1942, 200. I. N. Nazarov (1900−1957), a Soviet Union Scientist, discovered this reaction in 1942. It was said that almost as many young synthetic chemists have been lost in the pursuit of an asymmetric Nazarov cyclization as of the Bayliss−Hillman reaction. 2. Denmark, S. E.; Habermas, K. L.; Hite, G. A. Helv. Chim. Acta 1988, 71, 168−194; 195−208. 3. Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React. 1994, 45, 1−158. (Review). 4. Kim, S.-H.; Cha, J. K. Synthesis 2000, 2113−2116. 5. Giese, S.; West, F. G. Tetrahedron 2000, 56, 10221−10228. 6. Mateos, A. F.; de la Nava, E. M. M.; González, R. R. Tetrahedron 2001, 57, 1049−1057. 7. Harmata, M.; Lee, D. R. J. Am. Chem. Soc. 2002, 124, 14328−14329. 8. Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 1171−1174. 9. Marcus, A. P.; Lee, A. S.; Davis, R. L.; Tantillo, D. J.; Sarpong, R. Angew. Chem., Int. Ed. 2008, 47, 6379−6383. 10. Bitar, A. Y.; Frontier, A. J. Org. Lett. 2009, 11, 49−52. 11. Gao, S.; Wang, Q.; Chen, C. J. Am. Chem. Soc. 2009, 131, 1410−1412. 385

Neber rearrangement α-Aminoketone from tosyl ketoxime and base. The net conversion of a ketone into an α-aminoketone via the oxime.

OTs NH2 N 1. KOEt 2 1 R TsOH R1 R 2 2. H O R 2 O

ketoxime α-aminoketone

OTs N OTs deprotonation N cyclization H R 2 EtO 2 R R1 1 R NH H :OH H 2 2 hydrolysis N O R2 TsO N H R1 1 1 R R2 O R R2 azirine intermediate

Example 13 OTs O N EtO OEt 1. NH OH•HCl 1. KOEt Me 2 Me 2. TsCl, Pyr. 2. HCl NH2 N N 82% N 93%

Example 2, A variant using iminochloride5

Ph Ph Ph NH HOCl 1. KOt-Bu 2 OEt OEt OH 100% 2. HCl NH•HCl NCl O 71%

Example 38 Ts TsON N 1. KOH, H O, EtOH, 0 oC, 3 h N Br 2 MeO o N OMe 2. 6 N HCl, 60 C, 10 h 3. K2CO3, THF, H2O, 10 min. O N 96% SEM

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_175, © Springer-Verlag Berlin Heidelberg 2009 386

Ts O N N H2N Br MeO N OMe O HN

Example 49

R R R1 1. H2NOH R R heat 1 R O 2. MsCl, Et N; 1 3 N 41–89% N DBU, Bu3P H 70–91%

References

1. Neber, P. W.; v. Friedolsheim, A. Ann. 1926, 449, 109–134. 2. O’Brien, C. Chem. Rev. 1964, 64, 81–89. (Review). 3. LaMattina, J. L.; Suleske, R. T. Synthesis 1980, 329–330. 4. Verstappen, M. M. H.; Ariaans, G. J. A.; Zwanenburg, B. J. Am. Chem. Soc. 1996, 118, 8491–8492. 5. Oldfield, M. F.; Botting, N. P. J. Labelled Cpd. Radiopharm. 1998, 16, 29–36. 6. Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I. Tetrahedron Lett. 2002, 41, 5363-– 5366. 7. Ooi, T.; Takahashi, M.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2002, 124, 7640– 7641. 8. Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5970–5978. 9. Taber, D. F.; Tian, W. J. Am. Chem. Soc. 2006, 128, 1058–1059. 10. Richter, J. M. Neber rearrangement. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 464−473. (Review).

387

Nef reaction Conversion of a primary or secondary nitroalkane into the corresponding carbonyl compound.

NO2 1. NaOH O 1/2 N2O 1/2 H2O 1 2 1 2 R R 2. H2SO4 R R

HO OH O O N − N O O H HO O H2O H2O N H N H R1 R2 R1 R2 H R1 R2 : R1 R2 OH2 OH nitronate nitronic acid HO

O HO O N H N O HNO 1/2 N2O 1/2 H2O 1 2 1 2 1 2 R1 R2 R R R R R R O OH H

Example 14

O O 1. NaOH, EtOH, 0 oC, 30 min.

NO2 o O 2. 3 M HCl, 0 to 20 C, 12 h, 68%

Example 27

NO O HO 2 HO 1. 2 M NaOH, MeOH

2. ice-cooled KMnO4 45% H H

Example 39

S t-Bu OTBS O t-Bu S O

2.2 equiv PMe3, THF, rt, 30 min. NO2

OTBS O OTBS O H2O, rt, 5 min. O O 94%, 2 steps O NH

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_176, © Springer-Verlag Berlin Heidelberg 2009 388

Example 410

R * HOAc, HCl R * CO2H CO2H reflux, 2 h CO2H NO2

References

1. Nef, J. U. Ann. 1894, 280, 263−342. John Ulrich Nef (1862−1915) was born in Swit- zerland and emigrated to the US at the age of four with his parents. He went to Mu- nich, Germany to study with Adolf von Baeyer, earning a Ph.D. In 1886. Back to the States, he served as a professor at Purdue University, Clark University, and the Uni- versity of Chicago. The Nef reaction was discovered at Clark University in Worcester, Massachusetts. Nef was temperamental and impulsive, suffering from a couple of mental breakdowns. He was also highly individualistic, and had never published with a coworker save for three early articles. 2. Pinnick, H. W. Org. React. 1990, 38, 655−792. (Review). 3. Adam, W.; Makosza, M.; Saha-Moeller, C. R.; Zhao, C.-G. Synlett 1998, 1335–1336. 4. Thominiaux, C.; Rousse, S.; Desmaele, D.; d’Angelo, J.; Riche, C. Tetrahedron: Asymmetry 1999, 10, 2015–2021. 5. Capecchi, T.; de Koning, C. B.; Michael, J. P. J. Chem. Soc., Perkin Trans. 1 2000, 2681–2688. 6. Ballini, R.; Bosica, G.; Fiorini, D.; Petrini, M. Tetrahedron Lett. 2002, 43, 5233–5235. 7. Chung, W. K.; Chiu, P. Synlett 2005, 55–58. 8. Wolfe, J. P. Nef reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds; John Wiley & Sons: Hoboken, NJ, 2007, pp 645−652. (Re- view). 9. Burés, J.; Vilarrasa, J. Tetrahedron Lett. 2008, 49, 441–444. 10. Felluga, F.; Pitacco, G.; Valentin, E.; Venneri, C. D. Tetrahedron: Asymmetry 2008, 19, 945–955.

389

Negishi cross-coupling reaction The Negishi cross-coupling reaction is the nickel- or palladium-catalyzed coupling of organozinc compounds with various halides or triflates (aryl, alkenyl, alkynyl, and acyl).

NiLn or PdLn R1 X + R2Zn Y R1 R2 solvent R1 = aryl, alkenyl, alkynyl, acyl R2 = aryl, heteroaryl, alkenyl, allyl, Bn, homoallyl, homopropargyl X = Cl, Br, I, OTf Y = Cl, Br, I Ln = PPh3, dba, dppe

Pd(0) or Pd(II) complexes (precatalysts)

R1 R2 Pd(0)Ln R1 X

reductive oxidative elimination addition

1 R1 R 2 R Pd(II) Ln LnPd(II) 1 3 X

transmetallation/ trans/cis isomerization ZnX2 R2ZnX 1 X R X Zn Pd(II) R2 L 2 n

Example 13

I CH2CO2Et

N N

BrZnCH2CO2Et, Pd(Ph3P)4 HO HO

O HMPA/(CH2OCH3)2 (1:1) O O Ph 3.5 h, 40% O Ph O O Ph Ph O O

Example 24

O O activated I ZnI BnO BnO Zn/Cu couple NHTr NHTr

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_177, © Springer-Verlag Berlin Heidelberg 2009 390

Boc N NHBoc Boc O N NHBoc I N CO2t-Bu BnO N CO2t-Bu PdCl (Ph P) , DMA 2 3 2 NHTr 40 oC, 79%

Example 38

1. Zn, DMA, TMSCl, BrCH2CH2Br, 65 °C Boc N I Boc N Ar

2. ArX (X = Br, OTf), PdCl2(dppf) (3 mol%) CuI (6 mol%), DMA, 80 °C 41–97%

Example 49

1. t-BuLi, ZnCl2, Et2O, –78 °C 2. Me Me Me Me Me Me Me Me PivO I OTBS I OTBS PivO

Pd(PPh3)4, THF, 0 °C 85%

References

1. (a) Negishi, E.-I.; Baba, S. J. Chem. Soc., Chem. Commun. 1976, 596−597. (b) Negi- shi, E.-I.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821−1823. (c) Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340−348. (Review). 2. Erdik, E. Tetrahedron 1992, 48, 9577−9648. (Review). 3. De Vos, E.; Esmans, E. L.; Alderweireldt, F. C.; Balzarini, J.; De Clercq, E. J. Hetero- cycl. Chem. 1993, 30, 1245−1252. 4. Evans, D. A.; Bach, T. Angew. Chem., Int. Ed. 1993, 32, 1326−1327. 5. Negishi, E.-I.; Liu, F. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley–VCH: Weinheim, Germany, 1998, pp 1–47. (Review). 6. Arvanitis, A. G.; Arnold, C. R.; Fitzgerald, L. W.; Frietze, W. E.; Olson, R. E.; Gilli- gan, P. J.; Robertson, D. W. Bioorg. Med. Chem. Lett. 2003, 13, 289−291. 7. Ma, S.; Ren, H.; Wei, Q. J. Am. Chem. Soc. 2003, 125, 4817−4830. 8. Corley, E. G.; Conrad, K.; Murry, J. A.; Savarin, C.; Holko, J.; Boice, G. J. Org. Chem. 2004, 69, 5120−5123. 9. Inoue, M.; Yokota, W.; Katoh, T. Synthesis 2007, 622−637. 10. Yet, L. Negishi cross-coupling reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 70−99. (Review). 391

Nenitzescu indole synthesis 5-Hydroxylindole from condensation of p-benzoquinone and β-aminocrotonate.

3 CO R3 H CO2R 2 O Δ HO HN 1 1 N R O 2 R R R2

3 CO2R O 3 H H CO2R conjugate HO

1 : N R O HN addition R1 O R2 R2 H

3 3 H CO2R CO2R HO HO

1 R N R1 N OH 2 R R2 H

Example 15

O O NH Bn 2 O HN HO O N 1. acetone, rt, 48 h N H 2. 20% TFA, CH2Cl2 86% Bn

Example 26

CO CH H CO2CH3 2 3 HO O HN CH3NO2, rt N O 95%

Example 37

O O O R4 R4-NH2 NH R1 R2 rt R1 R2 HOAc, rt

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_178, © Springer-Verlag Berlin Heidelberg 2009 392

Me N R1 Me R HO 1 HCHO, HNMe2 HO R2 R o 2 N ethanol, 50 C N R4 R 4

Example 410 O HO OEt OEt O N NH O ZnCl2, CH2Cl2

NH O reflux, 80% N O OEt HO OEt O

References

1. Nenitzescu, C. D. Bull. Soc. Chim. Romania 1929, 11, 37−43. 2. Allen, G. R., Jr. Org. React. 1973, 20, 337−454. (Review). 3. Kinugawa, M.; Arai, H.; Nishikawa, H.; Sakaguchi, A.; Ogasa, T.; Tomioka, S.; Kasai, M. J. Chem. Soc., Perkin Trans. 1 1995, 2677−2681. 4. Mukhanova, T. I.; Panisheva, E. K.; Lyubchanskaya, V. M.; Alekseeva, L. M.; Sheinker, Y. N.; Granik, V. G. Tetrahedron 1997, 53, 177−184. 5. Ketcha, D. M.; Wilson, L. J.; Portlock, D. E. Tetrahedron Lett. 2000, 41, 6253−6257. 6. Brase, S.; Gil, C.; Knepper, K. Bioorg. Med. Chem. 2002, 10, 2415−2418. 7. Böhme, T. M.; Augelli-Szafran, C. E.; Hallak, H.; Pugsley, T.; Serpa, K.; Schwarz, R. D. J. Med. Chem. 2002, 45, 3094−3102. 8. Schenck, L. W.; Sippel, A.; Kuna, K.; Frank, W.; Albert, A.; Kucklaender, U. Tetra- hedron 2005, 61, 9129−9139. 9. Li, J.; Cook, J. M. Nenitzescu indole synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 145−153. (Review). 10. Velezheva, V. S.; Sokolov, A. I.; Kornienko, A. G.; Lyssenko, K. A.; Nelyubina, Y. V.; Godovikov, I. A.; Peregudov, A. S.; Mironov, A. F. Tetrahedron Lett. 2008, 49, 7106−7109. 393

Newman−Kwart rearrangement Transformation of phenol to the corresponding thiophenol, a variant of the Smile reaction (page 513).

S S O OH SH Cl NMe 2 O NMe2 Δ S NMe2 hydrolysis

O NMe2

O S O S NMe2 Me N 2 S

The Newman−Kwart rearrangement is a member of a series of related rearrangements, such as the Schönberg rearrangement and the Chapman rearrangement (page 105), in which aryl groups migrate intramolecularly between nonadjacent atoms. The Schönberg rearrangement is the most similar and involves the 1,3- migration of an aryl group from oxygen to sulfur in a diarylthioncarbonate. The Chapman rearrangement involves an analogous migration but to nitrogen.

Schönberg rearrangement Chapman rearrangement

S O NAr O Ar O OAr Δ S OAr O Ar Δ N Ar

Example 15

o NaH, DMF, 78% Ph2O, 208 C O S S 50 h, 55% S NMe2 O NMe OH 2 N Cl

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_179, © Springer-Verlag Berlin Heidelberg 2009 394

Example 26

S S O 275 oC Cl NMe OH 2 O NMe2 0.8 mmHg S NMe2 OH OH NaH, DMF OH 85 oC, 1 h, 45% 55%

Example 37

O o O 1. Br2, CH2Cl2, 5 to 20 C, 90 min. dimethylaniline

o Br 2. S CH2Cl2, 20 C, 16 h, 37.4% 218 oC, 7 h, 65.7% OH Me2N O Cl NMe2 S

O O 1. KOH, MeOH, reflux, 2 h Br Br 2. MeI, K2CO3, 90% Me2N S S O

References

1. (a) Kwart, H.; Evans, E. R. J. Org. Chem. 1966, 31, 410–413. (b) Newman, M. S.; Karnes, H. A. J. Org. Chem. 1966, 31, 3980–3984. (c) Newman, M. S.; Hetzel, F. W. J. Org. Chem. 1969, 34, 3604–3606. 2. Cossu, S.; De Lucchi, O.; Fabbri, D.; Valle, G.; Painter, G. F.; Smith, R. A. J. Tetra- hedron 1997, 53, 6073–6084. 3. Lin, S.; Moon, B.; Porter, K. T.; Rossman, C. A.; Zennie, T.; Wemple, J. Org. Prep. Proc. Int. 2000, 32, 547–555. 4. Ponaras, A. A.; Zain, Ö. In Encyclopedia of Reagents for Organic Synthesis, Paquette, L. A., Ed.; Wiley & Sons: New York, 1995, 2174–2176. (Review). 5. Kane, V. V.; Gerdes, A.; Grahn, W.; Ernst, L.; Dix, I.; Jones, P. G.; Hopf, H. Tetrahe- dron Lett. 2001, 42, 373–376. 6. Albrow, V.; Biswas, K.; Crane, A.; Chaplin, N.; Easun, T.; Gladiali, S.; Lygo, B.; Woodward, S. Tetrahedron: Asymmetry 2003, 14, 2813–2819. 7. Bowden, S. A.; Burke, J. N.; Gray, F.; McKown, S.; Moseley, J. D.; Moss, W. O.; Murray, P. M.; Welham, M. J.; Young, M. J. Org. Proc. Res. Dev. 2004, 8, 33–44. 8. Nicholson, G.; Silversides, J. D.; Archibald, S. J. Tetrahedron Lett. 2006, 47, 6541– 6544. 9. Gilday, J. P.; Lenden, P.; Moseley, J. D.; Cox, B. G. J. Org. Chem. 2008, 73, 3130– 3134. 10. Lloyd-Jones, G. C.; Moseley, J. D.; Renny, J. S. Synthesis 2008, 661–689. 11. Tilstam, U.; Defrance, T.; Giard, T.; Johnson, M. D. Org. Proc. Res. Dev. 2009, 13, 321–323. 395

Nicholas reaction Hexacarbonyldicobalt-stabilized propargyl cation is captured by a nucleophile. Subsequent oxidative demetallation then gives the propargylated product.

2 OR 1. Co2(CO)8 1. NuH Nu R1 R3 R1 R3 R4 2. H+ or Lewis acid 2. [O] R4

CO CO (CO) Co Co(CO) (CO)4Co Co(CO)3 − CO − CO 3 3 + H (CO)3Co Co(CO)3 1 2 2 R OR OR 1 2 4 3 1 3 R OR R R R R 4 3 4 R R R (CO) Co Co(CO) 3 3 (CO)3Co Co(CO)3 (CO)3Co Co(CO)3 SN1 NuH 1 H R O 1 R1 Nu R2 R R4 R3 4 3 4 3 R R R R propargyl cation intermediate (stabilized by the hexacarbonyldicobalt complex).

(CO)3Co Co(CO)2 Nu [O] 1 3 O CO↑ 1 R R R Nu 4 demetallation 4 3 R R R

Example 1, A chromium variant of the Nicholas reaction3 OH o 1. HBF4·Et2O, CH2Cl2, −60 C − o 2. 5 eq. X, CH2Cl2, 60 C, 86% Cl X = HN N Cr(CO)3 O CO2n-Bu Cl Cl

NN 2HCl O NN CO2n-Bu O CO2H Cr(CO) Zyrtec 3

Example 2, A Nicholas-Pauson–Khand sequence4 (CO) 3 O Co H H Co(CO)3 H H O 1. Co2(CO)8 NMO O OEt 70% H 2. Et2AlCl, 82% H O H H Me3Si

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_180, © Springer-Verlag Berlin Heidelberg 2009 396

Example 3, Intramolecular Nicholas reaction using chromium7

Cr(CO)3 BF •OEt , CH Cl OAc 3 2 2 2 o 0 C, 3.5 h, 49% Cr(CO)3

Example 49 Me H H OTIPS O H 1. Co (CO) 100% R O O 2 8, HO O 2. BF3•OEt2, 75% OH OH H H H OH Me Me Me H H OTIPS O (OC)3Co H O O (OC) Co 3 O O H H H R H OH Me Me OH

References

1. Nicholas, K. M.; Pettit, R. J. Organomet. Chem. 1972, 44, C21–C24. 2. Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207–214. (Review). 3. Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837–4840. 4. Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353–4363. 5. Teobald, B. J. Tetrahedron 2002, 58, 4133−4170. (Review). 6. Takase, M.; Morikawa, T.; Abe, H.; Inouye, M. Org. Lett. 2003, 5, 625–628. 7. Ding, Y.; Green, J. R. Synlett 2005, 271–274. 8. Pinacho Crisóstomo, F. R.; Carrillo, R.; Martin, T.; Martin, V. S. Tetrahedron Lett. 2005, 46, 2829–2832. 9. Hamajima, A.; Isobe, M. Org. Lett. 2006, 8, 1205–1208. 10. Shea, K. M. Nicholas reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 284−298. (Review).

397

Nicolaou IBX dehydrogenation α,β-Unsaturation of aldehydes and ketones mediated by stoichiometric amounts of o-iodoxybenzoic acid (IBX), alternative to the Saegusa oxidation (page 482).

O HO I O

O R2 2 O O R 1 3 R R IBX = o-iodoxybenzoic acid R1 R3

A SET mechanism has also been proposed. Additionally, silyl enol ethers are also viable substrates.

O 2 I O R2 tautomerization HO R HO O 1 3 R1 R3 R R O

O R2 O OH I O O R2 1 3 HO R R R1 R3 H

Example 11a

IBX fluorobenzene DMSO H H 65 °C, 24 h H H H H 80% O O H H

Example 23

O O H H IBX TBSO O TBSO DMSO, Tol. O H 80 °C, 3 h, 52% H MeO2C CO Me MeO C 2 2 CO2Me

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_181, © Springer-Verlag Berlin Heidelberg 2009 398

Example 37

H H H H IBX O O N N MeO N Tol., DMSO MeO N Me Me H H 70 °C H H O O

Example 4, o-Methyl-IBX (Me-IBX)9

Me OH O I O MeO O S O R R S 1 2 R1 R2 CH3CN, reflux − 40 90%

Example 5, Stabilized IBX (SIBX)10

OH O O OH OH

SIBX, THF MeO OMe MeO OMe MeO OMe rt, 98% O O O 1 : 1

References

1. (a) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596– 7597. (b) Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem., Int. Ed. 2002, 41, 993–996. (c) Nicolaou, K. C.; Gray, D. L.; Montagnon, T.; Harrison, S. T. Angew. Chem., Int. Ed. 2002, 41, 996–1000. 2. Nagata, H.; Miyazawa, N.; Ogasawara, K. Org. Lett. 2001, 3, 1737–1740. 3. Ohmori, N. J. Chem. Soc., Perkin Trans. 1 2002, 755–767. 4. Hayashi, Y.; Yamaguchi, J.; Shoji, M. Tetrahedron 2002, 58, 9839–9846. 5. Shimokawa, J.; Shirai, K.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Angew. Chem., Int. Ed. 2004, 43, 1559–1562. 6. Smith, N. D.; Hayashida. J.; Rawal, V. H. Org. Lett. 2005, 7, 4309–4312. 7. Liu, X.; Deschamp, J. R.; Cook, J. M. Org. Lett. 2002, 4, 3339–3342. 8. Herzon, S. B.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 5342–5344. 9. Moorthy, J. N.; Singhal, N.; Senapati, K. Tetrahedron Lett. 2008, 49, 80–84. 10. Pouységu, L.; Marguerit, M.; Gagnepain, J.; Lyvinec, G.; Eatherton, A. J.; Quideau, S. Org. Lett. 2008, 10, 5211–5214. 399

Noyori asymmetric hydrogenation Asymmetric reduction of carbonyls and alkenes via hydrogenation, catalyzed by a ruthenium(II) BINAP complex.

O OH

R R R R1 1 H2, (R)- or (S)-BINAP *

R2 R3 Metal [Ru(II) or Rh(I)] R2 * R3

R3 R4 R4 * R5

PPh2 (R)-BINAP-Ru = RuCl2L2 PPh2

H2 [RuCl2(binap)(solv)2] [RuHCl(binap)(solv) ] − 2 HCl

The catalytic cycle: OR1 O + (binap)ClHRu H solv O R

O O

R OR1

OR1 O [RuHCl(binap)(solv)2] (binap)ClRu O H H R

H+, solv solv

[RuCl(binap)(solv) ]+ OH O H2 2 1 R OR

Example 11b

Ru[(S)-BINAP](CF3CO2)2 OH ee OH 30 atm H2, rt, 96%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_182, © Springer-Verlag Berlin Heidelberg 2009 400

Example 21c

Ru[(R)-BINAP]Cl O 2 OH

100 atm H2, rt, 92% ee Br Br Example 39 O O 5 bar H2 O O O 3.2 mol% Ru(II)-(+)-(R)-BINAP O OH O

OMe o 8 OMe 8 MeOH, 70 C, 24 h, 90% H H H H

Example 410 100 atm H 2 OH O O O Ru[(S)-BINAP]Cl2

C5H11 OMe C5H11 OMe EtOH, rt, 75% 98% ee

References

1. (a) Noyori, R.; Ohta, M.; Hsiao, Y.; Kitamura, M.; Ohta, T.; Takaya, H. J. Am. Chem. Soc. 1986, 108, 7117−7119. Ryoji Noyori (Japan, 1938−) and William S. Knowles (USA, 1917−) shared half of the Nobel Prize in Chemistry in 2001 for their work on chirally catalyzed hydrogenation reactions. K. Barry Sharpless (USA, 1941−) shared the other half for his work on chirally catalyzed oxidation reactions. (b) Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Inoue, S.; Kasahara, I.; Noyori, R.; J. Am. Chem. Soc. 1987, 109, 1596−1598. (c) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J. Am. Chem. Soc. 1988, 110, 629−631. (d) Noyori, R.; Ohkuma, T.; Kitamura, H.; Ta- kaya, H.; Sayo, H.; Kumobayashi, S.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856−5858. (e) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40−73. (Review). (f) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008−2022. (Review, No- bel Prize Address). 2. Noyori, R. In Asymmetric Catalysis in Organic Synthesis; Ojima, I., ed.; Wiley: New York, 1994, Chapter 2. (Review). 3. Chung, J. Y. L.; Zhao, D.; Hughes, D. L.; McNamara, J. M.; Grabowski, E. J. J.; Rei- der, P. J. Tetrahedron Lett. 1995, 36, 7379−7382. 4. Bayston, D. J.; Travers, C. B.; Polywka, M. E. C. Tetrahedron: Asymmetry 1998, 9, 2015−2018. 5. Berkessel, A.; Schubert, T. J. S.; Mueller, T. N. J. Am. Chem. Soc. 2002, 124, 8693−8698. 6. Fujii, K.; Maki, K.; Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 733−736. 7. Ishibashi, Y.; Bessho, Y.; Yoshimura, M.; Tsukamoto, M.; Kitamura, M. Angew. Chem., Int. Ed. 2005, 44, 7287−7290. 8. Lall, M. S. Noyori asymmetric hydrogenation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 46−66. (Review). 9. Bouillon, M. E.; Meyer, H. H. Tetrahedron 2007, 63, 2712−2723. 10. Case-Green, S. C.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Tetra- hedron: Asymmetry 2008, 19, 2620−2631. 401

Nozaki–Hiyama–Kishi reaction Cr−Ni bimetallic catalyst-promoted redox addition of vinyl halides to aldehydes.

O OH Cr(II)Cl2 2 3 R1 X 1 R R aprotic solvent R Cr(III)ClX R1 R3 R2 organochromium(III) reagent allylic or homoallylic 1 R = alkenyl, aryl, allyl, vinyl, propargyl, alkynyl, allenyl alcohols R2 = R3 = aryl, alkyl, alkenyl, H X = Cl, Br, I, OTf Solvent = DMF, DMSO, THF

The catalytic cycle:2

OCr(III)X2 2Cr(II)Cl2 R1 R3 Ni(II)Cl2 R2 2Cr(III)Cl3 O

R2 R3 Ni(0)

R1 Cr(III)Cl 2 R1 X

oxidative transmetallation R1 Ni(II) X addition Cr(III)Cl 3

Example 13 OTHP AcO I OTBDPS CHO OTHP 10 eq CrCl2, cat. NiCl2 AcO OTBDPS DMSO, 25 oC, 12 h, 80% OH

Example 25

O OH O 4 eq CrCl OTf OHC 2 O 0.008 eq NiCl2 O

O DMF, rt, 15 h O 35%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_183, © Springer-Verlag Berlin Heidelberg 2009 402

Example 3, Intramolecular Nozaki–Hiyama–Kishi reaction8

I OH

5 equiv CrCl , NiCl 2 2 OTBDMS

CHO THF, 84% OTBDMS

Example 4, Intramolecular Nozaki–Hiyama–Kishi reaction9

1. HCl, THF, 0.003 M dark O HO 2. CrCl2, NiCl2, DMSO O 0.0025 M, 50 oC 37%, 2 steps

References

1. (a) Okude, C. T.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc. 1977, 99, 3179−3181. Hitosi Nozaki and T. Hiyama are professors at the Japanese Academy. (b) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281−5284. Kazuhiko Takai was Prof. Nozaki’s student during the discovery of the reaction and is a professor at Okayama University. (c) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644−5646. Yoshito Kishi at Harvard independently discovered the catalytic effect of nickel during his total synthesis of polytoxin. (d) Takai, K.; Tagahira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048−6050. (e) Kress, M. H.; Ruel, R.; Miller, L. W. H.; Kishi, Y. Tetrahedron Lett. 1993, 34, 5999−6002. 2. Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349−12357. (The catalytic cycle). 3. Chakraborty, T. K.; Suresh, V. R. Chem. Lett. 1997, 565−566. 4. Fürstner, A. Chem. Rev. 1999, 99, 991−1046. (Review). 5. Blaauw, R. H.; Benningshof, J. C. J.; van Ginkel, A. E.; van Maarseveen, J. H.; Hiem- stra, H. J. Chem. Soc., Perkin Trans. 1 2001, 2250−2256. 6. Berkessel, A.; Menche, D.; Sklorz, C. A.; Schroder, M.; Paterson, I. Angew. Chem., Int. Ed. 2003, 42, 1032−1035. 7. Takai, K. Org. React. 2004, 64, 253−612. (Review). 8. Karpov, G. V.; Popik, V. V. J. Am. Chem. Soc. 2007, 129, 3792−3793. 9. Valente, C.; Organ, M. G. Chem. Eur. J. 2008, 14, 8239−8245. 10. Yet, L. Nozaki–Hiyama–Kishi reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 299−318. (Review). 403

Nysted reagent The Nysted reagent, cyclo-dibromodi-ȝ-methylene(ȝ-tetrahydrofuran)trizinc, is used for the olefination of ketones and aldehydes.

O Br Br Zn Zn

Example 1, The Wittig reagent opened the lactone:6 OMOM OMOM TBDPSO TBDPSO excess CH O Zn(CH2ZnBr)2•THF 2 O O TiCl4, THF reflux, 64% O O O O Example 28

OTBS 1.5 equiv OTBS OTBS Zn(CH2ZnBr)2•THF

O CH2 OH 1.5 equiv TiCl4 THF, reflux 42% CH 14% OH OH 2 Example 39 O 2 equiv CH2 Zn(CH2ZnBr)2•THF BnO BnO 2 equiv TiCl4 o H OH THF, 0 C to rt H OH TBDPSO 1 h, 74% TBDPSO

References

1. Nysted, L. N. US Patent 3,865,848 (1975). 2. Tochtermann, W.; Bruhn, S.; Meints, M.; Wolff, C.; Peters, E.-M.; Peters, K.; von Schnering, H. G. Tetrahedron 1995, 51, 1623í1630. 3. Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett 1998, 313í315. 4. Tanaka, M.; Imai, M.; Fujio, M.; Sakamoto, E.; Takahashi, M.; Eto-Kato, Y.; Wu, X. M.; Funakoshi, K.; Sakai, K.; Suemune, H. J. Org. Chem. 2000, 65, 5806í5816. 5. Tarraga, A.; Molina, P.; Lopez, J. L.; Velasco, M. D. Tetrahedron Lett. 2001, 42, 8989í8992. 6. Aïssa, C.; Riveiros, R.; Ragot, J.; Fürstner, A. J. Am. Chem. Soc. 2003, 125, 15512í15520. 7. Clark, J. S.; Marlin, F.; Nay, B.; Wilson, C. Org. Lett. 2003, 5, 89í92. 8. Paquette, L. A. Hartung, R. E., Hofferberth, J. E., Vilotijevic, I., Yang, J. J. Org. Chem. 2004, 69, 2454í2460. 9. Hanessian, S.; Mainetti, E.; Lecomte, F. Org. Lett. 2006, 8, 4047í4049.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_184, © Springer-Verlag Berlin Heidelberg 2009 404

Oppenauer oxidation Alkoxide-catalyzed oxidation of secondary alcohols. Reverse of the Meerwein– Ponndorf–Verley reduction.

OH Al(Oi-Pr)3 O OH O R1 R2 R1 R2

Oi-Pr O Al(Oi-Pr)2 Al(Oi-Pr) OH O 2 : OH R1 R2 coordination R R 1 2

Oi-Pr i-PrO Oi-Pr R hydride O OH 1 Al Al O Oi-Pr O O HO transfer R1 R2 R2 H R2 R1

cyclic transition state

Example 1, Mg-Oppenauer oxidation3 O OH 1. EtMgBr, i-Pr2O

2. PhCHO, 60%

Example 26 OH O (i-PrO)2AlO2CCF3 p-O2N-Ph-CHO

PhH, rt, 24 h, 70% OH OH

Example 3, Mg-Oppenauer oxidation8 RMgCl•LiCl

−20 oC R'CHO

R PhCHO R OMgCl O PhCH2OMgCl o R' 0 C to rt R'

H H R R Mg Mg Ph O Cl Ph O Cl HO HO R' R'

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_185, © Springer-Verlag Berlin Heidelberg 2009 405

Example 410

O Al H OH EtOAlEt O H OH 2 R O O 1 H C CF R R 3 3 R R1 H2C CF3 CH2Cl2, rt, 1 h 1 2 equiv R H H3C CF3

References

1. Oppenauer, R. V. Rec. Trav. Chim. 1937, 56, 137−144. Rupert V. Oppenauer (1910−), born in Burgstall, Italy, studied at ETH in Zurich under Ruzicka and Reich- stei, both Nobel laureates. After a string of academic appointments around Europe and a stint at Hoffman−La Roche, Oppenauer worked for the Ministry of Public Health in Buenos Aires, Argentina. 2. Djerassi, C. Org. React. 1951, 6, 207−235. (Review). 3. Byrne, B.; Karras, M. Tetrahedron Lett. 1987, 28, 769−772. 4. Ooi, T.; Otsuka, H.; Miura, T.; Ichikawa, H.; Maruoka, K. Org. Lett. 2002, 4, 2669−2672. 5. Suzuki, T.; Morita, K.; Tsuchida, M.; Hiroi, K. J. Org. Chem. 2003, 68, 1601−1602. 6. Auge, J.; Lubin-Germain, N.; Seghrouchni, L. Tetrahedron Lett. 2003, 44, 819−822. 7. Hon, Y.-S.; Chang, C.-P.; Wong, Y.-C. Byrne, B.; Karras, M. Tetrahedron Lett. 2004, 45, 3313−3315. 8. Kloetzing, R. J.; Krasovskiy, A.; Knochel, P. Chem. Eur. J. 2006, 13, 215−227. 9. Fuchter, M. J. Oppenauer oxidation. In Name Reactions for Functional Group Trans- formations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 265−373. (Review). 10. Mello, R.; Martinez-Ferrer, J.; Asensio, G.; Gonzalez-Nunez, M. E. J. Org. Chem. 2008, 72, 9376−9378. 11. Borzatta, V.; Capparella, E.; Chiappino, R.; Impala, D.; Poluzzi, E.; Vaccari, A. Cat. Today 2009, 140, 112−116.

406

Overman rearrangement Stereoselective transformation of allylic alcohol to allylic trichloroacetamide via trichloroacetimidate intermediate.

CCl CCl3 3 OH cat. NaH Δ HN O HN O R R1 or Hg(II) or Pd(II) Cl3CCN 1 R R1 R R

trichloroacetimidate

CCl3 N CCl3 H H O H O N O H2↑ O 1 1 R R1 R R R R 1 R R

CCl3 H CCl3 CCl3 Δ , [3,3]-sigmatropic R1 HN O HN O rearrangement O R R1 R R1 HN R

Example 15 O H O O H O O O O O Cl3CCN, DBU O O − o CH2Cl2, 78 C HN O HO Cl C 3 O H O K2CO3, p-xylene O O HN reflux, 90%, 2 steps Cl3C O O

Example 26

TBDMSO TBDMSO

Cl C O O 3 O K2CO3, p-xylene NH O O reflux, 77% Cl3C NH O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_186, © Springer-Verlag Berlin Heidelberg 2009 407

Example 37

OBn OBn O O O O OH CF3CN, n-BuLi; toluene, 120 °C

30% HN CF3 O O O O O

Example 49

O O OH O O NHC(O)CCl3 DBU, CCl3CN N (CH2)3OTBDPS N (CH2)3OTBDPS toluene, reflux Me F Me F 51% Bn Bn

References

1. (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597−599. (b) Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901−2910. (c) Overman, L. E. Acc. Chem. Res. 1980, 13, 218– 224. (Review). 2. Demay, S.; Kotschy, A.; Knochel, P. Synthesis 2001, 863−866. 3. Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.; Iida, M.; Chida, N. Org. Lett. 2002, 4, 151−154. 4. Reilly, M.; Anthony, D. R.; Gallagher, C. Tetrahedron Lett. 2003, 44, 2927−2930. 5. Tsujimoto, T.; Nishikawa, T.; Urabe, D.; Isobe, M. Synlett 2005, 433−436. 6. Montero, A.; Mann, E.; Herradon, B. Tetrahedron Lett. 2005, 46, 401−405. 7. Hakansson, A. E.; Palmelund, A.; Holm, H.; Madsen, R. Chem. Eur. J. 2006, 12, 3243−3253. 8. Bøjstrup, M.; Fanejord, M.; Lundt, I. Org. Biomol. Chem. 2007, 5, 3164−3171. 9. Lamy, C.; Hifmann, J.; Parrot-Lopez, H.; Goekjian, P. Tetrahedron Lett. 2007, 48, 6177−6180. 10. Wu, Y.-J. Overman rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 210−225. (Review).

408

Paal thiophene synthesis Thiophene synthesis from addition of a sulfur atom to 1,4-diketones and subsequent dehydration.

OO P2S5, tetralin H3C S H3CCH3 CH3 reflux

The reaction now is frequently carried out using the Lawesson’s reagent. For the mechanism of carbonyl to thiocarbonyl transformation, see Lawesson’s reagent on page 328. S O CH P S H C 3 CH3 2 5 3 tautomerization H3C X = O or S X O

SH H3C XH − H C S H2X 3 S CH 3 CH3 H3C CH3 X H

Example 12 O Lawesson's reagent S N Ph N Ph 110 ºC, 10 min, 82% O Example 23

O Lawesson's reagent chlorobenzene, reflux, 36 h Ph Ph O Ph 69% S Ph S Ph O Ph Ph O Ph

References

1. (a) Paal, C. Ber. 1885, 18, 2251−2254. (b) Paal, C. Ber. 1885, 18, 367−371. 2. Thomsen, I.; Pedersen, U.; Rasmussen, P. B.; Yde, B.; Andersen, T. P.; Lawesson, S.- O. Chem. Lett. 1983, 809−810. 3. Parakka, J. P.; Sadannandan, E. V.; Cava, M. P. J. Org. Chem. 1994, 59, 4308−4310. 4. Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.; Tai, K.; Hida, T.; Yamauchi, T.; Nagai, M. J. Med. Chem. 2000, 43, 409−423. 5. Sonpatki, V. M.; Herbert, M. R.; Sandvoss, L. M.; Seed, A. J. J. Org. Chem. 2001, 66, 7283−7286. 6. Kiryanov, A. A.; Sampson, P.; Seed, A. J. J. Org. Chem. 2001, 66, 7925−7929. 7. Mullins, R. J.; Williams, D. R. Paal Thiophene Synthesis. In Name Reactions in Het- erocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 207−217. (Review). 8. Kaniskan, N.; Elmali, D.; Civcir, P. U. ARKIVOC 2008, xii, 17−29.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_187, © Springer-Verlag Berlin Heidelberg 2009 409

Paal–Knorr furan synthesis Acid-catalyzed cyclization of 1,4-diketones to form furans.

2 O R R1 R2 cat. H R3 R or P O 3 R1 O 2 5 R O R

H 1 2 R R R1 2 R1 R2 O R2 H R 3 H3O R R : 3 R R 3 R R3 HO O R R O 1 O

R O: H

Example 13

Cl F Cl O O TsOH O F toluene, reflux

N N

Example 26

MeO OMe OMe O n-Bu O p-TsOH O MeO toluene n-Bu 98%

OMe MeO

Example 39

O phosphoric acid O CH N CH3 N 3 H 130−140 oC, 4−6 h H O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_188, © Springer-Verlag Berlin Heidelberg 2009 410

Example 410

SMe Br SMe O O Br2, CHCl3 SnCl2, H R CH C R R 88−92% R R − R O O SMe 72 89% − − 30% HBr HOAc, CHCl3, 58 64%

References

1. (a) Paal, C. Ber. 1884, 17, 2756−2767. (b) Knorr, L. Ber. 1885, 17, 2863−2870. (c) Paal, C. Ber. 1885, 18, 367−371. 2. Friedrichsen, W. Furans and Their Benzo Derivatives: Synthesis. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Per- gamon: New York, 1996; Vol. 2, 351−393. (Review). 3. de Laszlo, S. E.; Visco, D.; Agarwal, L.; et al. Bioorg. Med. Chem. Lett. 1998, 8, 2689−2694. 4. Gupta, R. R.; Kumar, M.; Gupta, V. Heterocyclic Chemistry, Springer: New York, 1999; Vol. 2, 83−84. (Review). 5. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell Science: Cambridge, 2000; 308−309. (Review). 6. Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2001, 44, 3838−3848. 7. König, B. Product Class 9: Furans. In Science of Synthesis: Houben−Weyl Methods of Molecular Transformations; Maas, G., Ed.; Georg Thieme Verlag: New York, 2001; Cat. 2, Vol. 9, 183−278. (Review). 8. Shea, K. M. Paal–Knorr Furan Synthesis. In Name Reactions in Heterocyclic Chemis- try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 168−181. (Re- view). 9. Kaniskan, N.; Elmali, D.; Civcir, P. U. ARKIVOC 2008, xii, 17−29. 10. Yin, G.; Wang, Z.; Chen, A.; Gao, M.; Wu, A.; Pan, Y. J. Org. Chem. 2008, 73, 3377−3383.

411

Paal–Knorr pyrrole synthesis Reaction between 1,4-diketones and primary amines (or ammonia) to give pyrroles. A variation of the Knorr pyrazole synthesis (page 317).

O 2 R NH2 R1 R R1 R N O R2

H N R2 2 : O O R1 slow HO OH R1 R : R HN OH R N R1 2 2 O R R

H H H H H

1 HO HO : R N R N R1 1 R N 1 R R N R R 2 R2 2 2 R R R

Example 14

EtO OEt

OEt F F O H2N OEt N

1 eq. pivalic acid O THF, reflux, 43% CONHPh CONHPh

Ca2+ HO CO2 HO

F N

H N O

Lipitor 2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_189, © Springer-Verlag Berlin Heidelberg 2009 412

Example 25

N Cl O NH4OAc HOAc O F 110 °C N 90% F H Cl N

Example 39

NH4OAc, CSA

MeOH, 50 oC NH O O O O 93% MeO MeO

Example 410

o RNH2, AcOH, MeOH, 40 C; or o R O RNH2, AcOH, NaOAc, toluene, 60 C; or N N N H NH OAc, 28% NH OH, EtOH, 40 oC H 4 4 H O 30−96%

References

1. (a) Paal, C. Ber. 1885, 18, 367−371. (b) Paal, C. Ber. 1885, 18, 2251−2254. (c) Knorr, L. Ber. 1885, 18, 299−311. 2. Corwin, A. H. Heterocyclic Compounds Vol. 1, Wiley, NY, 1950; Chapter 6. (Re- view). 3. Jones, R. A.; Bean, G. P. The Chemistry of Pyrroles, Academic Press, London, 1977, pp 51−57, 74−79. (Review). 4. (a) Brower, P. L.; Butler, D. E.; Deering, C. F.; Le, T. V.; Millar, A.; Nanninga, T. N.; Roth, B. D. Tetrahedron Lett. 1992, 33, 2279-2282. (b) Baumann, K. L.; Butler, D. E.; Deering, C. F.; Mennen, K. E.; Millar, A.; Nanninga, T. N.; Palmer, C. W.; Roth, B. D. Tetrahedron Lett. 1992, 33, 2279, 2283−2284. 5. de Laszlo, S. E.; Visco, D.; Agarwal, L.; et al. Bioorg. Med. Chem. Lett. 1998, 8, 2689−2694. 6. Braun, R. U.; Zeitler, K.; Müller, T. J. J. Org. Lett. 2001, 3, 3297−3300. 7. Quiclet-Sire, B.; Quintero, L.; Sanchez-Jimenez, G.; Zard, Z. Synlett 2003, 75−78. 8. Gribble, G. W. Knorr and Paal−Knorr Pyrrole Syntheses. In Name Reactions in Het- erocyclic Chemistry; Li, J. J., Corey, E. J., Eds, Wiley & Sons: Hoboken, NJ, 2005, 77−88. (Review). 9. Salamone, S. G.; Dudley, G. B. Org. Lett. 2005, 7, 4443−4445. 10. Fu, L.; Gribble, G. W. Tetrahedron Lett. 2008, 49, 7352−7354. 413

Parham cyclization The Parham cyclization is the generation by halogen–lithium exchange of aryllith- iums and heteroaryllithiums, and their subsequent intramolecular cyclization onto an electrophilic site.

Li X RLi E E

E.g.

CH3O I 2.2 eq. t-BuLi CH3O I halogen-metal N CH3O N exchange THF, −78 oC→rt I NEt2 CH3O O NEt2 O O Et N O Et2N O 2 CH3O cyclization CH3O CH3O Li N N CH O N CH O 3 CH O 3 3

The fate of the second equivalent of t-BuLi:

I H I

Example 12

O Br O O NMe2 MeO t-BuLi MeO O O O THF, –95 °C 92%

MeO OMe MeO OMe

Example 24 OPMB OPMB O O O O O n-BuLi O Et O, –78 °C H O Br O 2 OH O 64% O O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_190, © Springer-Verlag Berlin Heidelberg 2009 414

Example 35 O I MeO 2 eq. n-BuLi N N O o MeO O THF, −78 C MeO 2.5 h, 83% OMe

Example 49

O O Br − o O t-BuLi, THF, 100 C O N PMB N OMe Ar, 30 min., 55% PMB

References

1. (a) Parham, W. E.; Jones, L. D.; Sayed, Y. J. Org. Chem. 1975, 40, 2394−2399. Wil- liam E. Parham was a professor at Duke University. (b) Parham, W. E.; Jones, L. D.; Sayed, Y. J. Org. Chem. 1976, 41, 1184−1186. (c) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300−305. (Review). 2. Paleo, M. R.; Lamas, C.; Castedo, L.; Domínguez, D. J. Org. Chem. 1992, 57, 2029– 2033. 3. Gray, M.; Tinkl, M.; Snieckus, V. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Exeter, 1995; Vol. 11; p 66. (Review). 4. Gauthier, D. R., Jr.; Bender, S. L. Tetrahedron Lett. 1996, 37, 13–16. 5. Collado, M. I.; Manteca, I.; Sotomayor, N.; Villa, M.-J.; Lete, E. J. Org. Chem. 1997, 62, 2080−2092. 6. Mealy, M. M.; Bailey, W. F. J. Organomet. Chem. 2002, 646, 59−67. (Review). 7. Sotomayor, N.; Lete, E. Current Org. Chem. 2003, 7, 275−300. (Review). 8. González-Temprano, I.; Osante, I.; Lete, E.; Sotomayor, N. J. Org. Chem. 2004, 69, 3875−3885. 9. Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Org. Biomol. Chem. 2005, 3, 2305−2309. 10. Gribble, G. W. Parham cyclization. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 749−764. (Review).

415

Passerini reaction Three-component condensation (3CC) of carboxylic acids, C-isocyanides, and carbonyl compounds to afford α-acyloxycarboxamides. Cf. Ugi reaction.

2 3 O O H R R 4 N R1 N C R CO2H R1 O R R2 R3 4 O

isocyanide

H O O H 2 4 R OO 2 O R O 3 4 R 4 R R R CO2H R3 R2 R3 C O N N 1 1 R R H 2 O O R R2 R3 O acyl 3 H R4 R N O 1 O R4 transfer R N O 1 R H

Example 13 Ts OMe H OMe CN TFA, PhH MeO N Ts MeO OMe rt, 2 h, 93% O OMe MeO MeO OMe OMe OMe

Example 25

HOAc, THF CHO HN rt, 93% O CN AcO Et

Example 36

Me CbzNH

Me Me

FmocNH CHO CN CO Bn 2 BocNH CO2H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_191, © Springer-Verlag Berlin Heidelberg 2009 416

Me O Me → CH2Cl2, 0 °C rt FmocNH N CO2Bn H 3–5 days, 80% O O

CbzNH NHBoc

Example 47

OBn(Cl ) H2N N 2 NO2 O NH O CN N OH N CO2Me H Alloc Ph BocHN CHO H2N N NO2 OBn(Cl2) NH

Ph O CH2Cl2, 0 °C → rt H N BocHN N 2 days, 59% H O O O CO2Me

NAlloc

References

1. Passerini, M. Gazz. Chim. Ital. 1921, 51, 126−129. (b) Passerini, M. Gazz. Chim. Ital. 1921, 51, 181−188. Mario Passerini (b, 1891) was born in Scandicci, Italy. He obtained his Ph.D. In chemistry and pharmacy at the University of Florence, where he was a professor for most of his career. 2. Ferosie, I. Aldrichimica Acta 1971, 4, 21. (Review). 3. Barrett, A. G. M.; Barton, D. H. R.; Falck, J. R.; Papaioannou, D.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1 1979, 652−661. 4. Ugi, I.; Lohberger, S.; Karl, R. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 2, p.1083. (Review). 5. Bock, H.; Ugi, I. J. Prakt. Chem. 1997, 339, 385−389. 6. Banfi, L.; Guanti, G.; Riva, R. Chem. Commun. 2000, 985–986. 7. Owens, T. D.; Semple, J. E. Org. Lett. 2001, 3, 3301–3304. 8. Xia, Q.; Ganem, B. Org. Lett. 2002, 4, 1631−1634. 9. Banfi, L.; Riva, R. Org. React. 2005, 65, 1−140. (Review). 10. Klein, J. C.; Williams, D. R. Passerini reaction. In Name Reactions for Homologa- tions-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 765−785. (Review). 417

Paternó–Büchi reaction Photoinduced electrocyclization of a carbonyl with an alkene to form polysubstituted oxetane ring systems

O O hv 1 R R R R1

oxetane

O hv O R R1 1 R R n, π* triplet

O O O R R R 1 1 1 R R R triplet diradical singlet diradical

Example 12

O O H O O O O Ph Ph ν *ROOC Me O h , C6H6, 99% O Me Ph H

Example 24

i-Pr hν, C6H6 O i-Pr O Ph Ph Ph SMe 73% Ph SMe (E/Z = 6/1)

Example 36

hv, MeCN O

82% H H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_192, © Springer-Verlag Berlin Heidelberg 2009 418

Example 48

Ph OH Ph hv HO O O 100% O solvent O References

1. (a) Paternó, E.; Chieffi, G. Gazz. Chim. Ital. 1909, 39, 341−361. Emaubuele Paternó (1847−1935) was born in Palermo, Sicily, Italy. (b) Büchi, G.; Inman, C. G.; Lipin- sky, E. S. J. Am. Chem. Soc. 1954, 76, 4327−4331. George H. Büchi (1921−1998) was born in Baden, Switzerland. He was a professor at MIT when he elucidated the structure of oxetanes, the products from the light-catalyzed addition of carbonyl compounds to olefins, which had been observed by E. Paternó in 1909. Büchi died of heart failure while hiking with his wife in his native Switzerland. 2. Koch, H.; Runsink, J.; Scharf, H.-D. Tetrahedron Lett. 1983, 24, 3217−3220. 3. Carless, H. A. J. In Synthetic Organic Photochemistry; Horspool, W. M., Ed.; Plenum Press: New York, 1984, 425. (Review). 4. Morris, T. H.; Smith, E. H.; Walsh, R. J. Chem. Soc., Chem. Commun. 1987, 964−965. 5. Porco, J. A., Jr.; Schreiber, S. L. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 5, 151−192. (Review). 6. de la Torre, M. C.; Garcia, I.; Sierra, M. A. J. Org. Chem. 2003, 68, 6611−6618. 7. Griesbeck, A. G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res. 1994, 27, 70−75. (Re- view). 8. D’Auria, M.; Emanuele, L.; Racioppi, R. Tetrahedron Lett. 2004, 45, 3877−3880. 9. Liu, C. M. Paternó–Büchi Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 44−49. (Review). 10. Cho, D. W.; Lee, H.-Y.; Oh, S. W.; Choi, J. H.; Park, H. J.; Mariano, P. S.; Yoon, U. C. J. Org. Chem. 2008, 73, 4539−4547.

419

Pauson−Khand reaction Formal [2 + 2 +1] cycloaddition of an alkene, alkyne, and carbon monoxide mediated by octacarbonyl dicobalt to form cyclopentenones.

H O Co2(CO)8 Co(CO)3 Co(CO)3 toluene, 60−80 oC O 4−6 d, 60%

H CO H O Co(CO)3 (CO) Co Co(CO) − − CO 4 3 CO Co(CO)3 Co(CO)3 OC Co(CO)3 H hexacarbonyldicobalt complex

H H Co(CO)3 + (CO)3Co O − CO CO + CO Co(CO)2 O insertion insertion toward CH (CO)3Co H H exo complex sterically-favored isomer

(CO) Co H 3 (CO) Co H 3 O (CO)3Co O O reductive reductive elimination

elimination − (CO)3Co Co2(CO)6 O O O

Example 13

O Co2(CO)8 O O O o benzene, 65 C O 16 h, 23%

Example 2, A catalytic version6

5 mol% Co2(CO)8 20 mol% P(OPh)3 Ts N Ts N O 3 atm CO, DME 120 oC, 48 h, 94%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_193, © Springer-Verlag Berlin Heidelberg 2009 420

Example 3, Intramolecular Pauson−Khand reaction9

O Co (CO) , DMSO N Cbz 2 8 Cbz N o H N THF, 65 C, 94% N H H

Example 4, Intramolecular Pauson−Khand reaction10

Co2(CO)8 H 5 equiv Me3NO•2H2O O N N S o S O THF/H2O (3:1), 0 C to rt O NO2 O O NH 7 h, 71% 2

References

1. (a) Pauson, P. L.; Khand, I. U.; Knox, G. R.; Watts, W. E. J. Chem. Soc., Chem. Com- mun. 1971, 36. Ihsan U. Khand and Peter L. Pauson were at the University of Strath- clyde, Glasgow in Scotland. (b) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973, 975−977. (c) Bladon, P.; Khand, I. U.; Pauson, P. L. J. Chem. Res. (S), 1977, 9. (d) Pauson, P. L. Tetrahedron 1985, 41, 5855−5860. (Review). 2. Schore, N. E. Chem. Rev. 1988, 88, 1081−1119. (Review). 3. Billington, D. C.; Kerr, W. J.; Pauson, P. L.; Farnocchi, C. F. J. Organomet. Chem. 1988, 356, 213−219. 4. Schore, N. E. In Comprehensive Organic Synthesis; Paquette, L. A.; Fleming, I.; Trost, B. M., Eds.; Pergamon: Oxford, 1991, Vol. 5, p.1037. (Review). 5. Schore, N. E. Org. React. 1991, 40, 1−90. (Review). 6. Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, J. J. Am. Chem. Soc. 1994, 116, 3159−3160. 7. Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263−3283. (Review). 8. Tsujimoto, T.; Nishikawa, T.; Urabe, D.; Isobe, M. Synlett 2005, 433−436. 9. Miller, K. A.; Martin, S. F. Org. Lett. 2007, 9, 1113−1116. 10. Kaneda, K.; Honda, T. Tetrahedron 2008, 64, 11589−11593. 11. Gao, P.; Xu, P.-F.; Zhai, H. J. Org. Chem. 2009, 74, 2592−2593. 421

Payne rearrangement The isomerization of 2,3-epoxy alcohol under the influence of a base to 1,2- epoxy-3-ol is referred to as the Payne rearrangement. Also known as epoxide migration.

OH R aq. NaOH O R OH O

O OH R R S 2 H O OH O N H O R workup R O O O

Example 12

O O NaOMe, MeOH OH TrO TrO HO OTr reflux, 1 h, 84% OTr HO HO

Example 23

OBz OH OTs K2CO3, MeOH rt, 2 h, 98% O CO2Me CO2Me BzO

Example 3, Aza-Payne rearrangement8

HO H H O NaOH, t-BuOH/H2O H TsHN N rt, 4 h, 98% H Ts

Example 4, Aza-Payne rearrangement9

OCH3 OCH3 0.28 M NaOH, H t-BuOH/H O/THF (4:5:1), Me O H H 2 rt, 30%, or Me N NH OH OCH NaH, Boc Boc 3 THF/HMPA (10:1), OCH rt, 80% 3

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_194, © Springer-Verlag Berlin Heidelberg 2009 422

References

1. Payne, G. B. J. Org. Chem. 1962, 27, 3819−3822. George B. Payne was a chemist at Shell Development Co. in Emeryville, CA. 2. Buchanan, J. G.; Edgar, A. R. Carbohydr. Res. 1970, 10, 295−302. 3. Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.; Mioskowski, C.; Samuelsson, B.; Hammerstrom, S. J. Am. Chem. Soc. 1980, 102, 1436−1439, and 3663−3665. 4. Ibuka, T. Chem. Soc. Rev. 1998, 27, 145−154. (Review). 5. Hanson, R. M. Org. React. 2002, 60, 1−156. (Review). 6. Yamazaki, T.; Ichige, T.; Kitazume, T. Org. Lett. 2004, 6, 4073−4076. 7. Bilke, J. L.; Dzuganova, M.; Froehlich, R.; Wuerthwein, E.-U. Org. Lett. 2005, 7, 3267−3270. 8. Feng, X.; Qiu, G.; Liang, S.; Su, J.; Teng, H.; Wu, L.; Hu, X. Russ. J. Org. Chem. 2006, 42, 514−500. 9. Feng, X.; Qiu, G.; Liang, S.; Teng, H.; Wu, L.; Hu, X. Tetrahedron: Asymmetry 2006, 17, 1394−1401. 10. Kumar, R. R.; Perumal, S. Payne rearrangement. In Name Reactions for Homologa- tions-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 474−488. (Review).

423

Pechmann coumarin synthesis Lewis acid-mediated condensation of phenol with β-ketoester to produce coumarin.

O O OH O O AlCl3 R OEt R

EtO O O AlCl3 : H EtO AlCl3 O O O O O O O: O H O R H R R R OH O O O O H O O Michael H

addition H ROH2 ROH R Example 16 O O

OEt [bimim]Cl•2AlCl HO OH 3 HO O O 130 oC, 35 min., 90%

Example 28 O O O OH O OH OEt

o BiCl3, 75 C, 2 h, 66% OH O O References

1. von Pechmann, H.; Duisberg, C. Ber. 1883, 16, 2119. Hans von Pechmann (1850−1902) was born in Nürnberg, Germany. After his doctorate, he worked with Frankland and von Baeyer. Pechmann taught at Munich and Tübingen. He committed suicide by taking cyanide. 2. Corrie, J. E. T. J. Chem. Soc., Perkin Trans. 1 1990, 2151–2997. 3. Hua, D. H.; Saha, S.; Roche, D.; Maeng, J. C.; Iguchi, S.; Baldwin, C. J. Org. Chem. 1992, 57, 399–403. 4. Li, T.-S.; Zhang, Z.-H.; Yang, F.; Fu, C.-G. J. Chem. Res., (S) 1998, 38–39. 5. Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. Tetrahedron Lett. 2001, 42, 9285–9287. 6. Khandekar, A. C.; Khandilkar, B. M. Synlett. 2002, 152–154. 7. Smitha, G.; Sanjeeva Reddy, C. Synth. Commun. 2004, 34, 3997–4003. 8. De, S. K.; Gibbs, R. A. Synthesis 2005, 1231–1233. 9. Manhas, M. S.; Ganguly, S. N.; Mukherjee, S.; Jain, A. K.; Bose, A. K. Tetrahedron Lett. 2006, 47, 2423–2425. 10. Rodriguez-Dominguez, J. C.; Kirsch, G. Synthesis 2006, 1895–1897.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_195, © Springer-Verlag Berlin Heidelberg 2009 424

Perkin reaction Cinnamic acid synthesis from aryl aldehyde and acetic anhydride.

OAc O O O AcONa OH Ar CHO Ac O 2 Ar O H2O Ar OH

cinnamic acid

O O O enolate aldol O O O O O OAc H Ar H formation condensation O Ar O O

O O O O O O O intramolecular O O Ar O acyl transfer Ar O H O O O O O O AcOH acyl E2 Ar O Ar O transfer elimination H OH OH

O HO O O HOAc O Ar O Ar O Ar OH

Example 17 MeO H MeO o Ac2O, Et3N, 90 C CO2H CHO MeO MeO CO2H 5 h, 66% MeO MeO

Example 29

Δ ClF2C Ac2O, ClF2C O AcONa, 46% Ph CO H Ph 2

References

1. Perkin, W. H. J. Chem. Soc. 1868, 21, 53. William Henry Perkin (1838−1907), born in London, England, studied under A. W. von Hofmann at the Royal College of Chem- istry. In an attempt to synthesize quinine in his home laboratory in 1856, Perkin synthesized mauve, the purple dye. He then started a factory to manufacture mauve and later other dyes including alizarin. Perkin was the first person to show that organic chemistry was not just mere intellectual curiosity but could be profitable, which cata- pulted the discipline into a higher level. In addition, Perkin was also an exceptionally talented pianist. 2. Gaset, A.; Gorrichon, J. P. Synth. Commun. 1982, 12, 71−79. 3. Kinastowski, S.; Nowacki, A. Tetrahedron Lett. 1982, 23, 3723−3724. 4. Koepp, E.; Vögtle, F. Synthesis 1987, 177−179. 5. Brady, W. T.; Gu, Y.-Q. J. Heterocycl. Chem. 1988, 25, 969−971. 6. Pálinkó, I.; Kukovecz, A.; Török, B.; Körtvélyesi, T. Monatsh. Chem. 2001, 131, 1097−1104. 7. Gaukroger, K.; Hadfield, J. A.; Hepworth, L. A.; Lawrence, N. J.; McGown, A. T. J. Org. Chem. 2001, 66, 8135−8138. 8. Solladié, G.; Pasturel-Jacopé, Y.; Maignan, J. Tetrahedron 2003, 59, 3315−3321. 9. Sevenard, D. V. Tetrahedron Lett. 2003, 44, 7119−7126. 10. Chandrasekhar, S.; Karri, P. Tetrahedron Lett. 2006, 47, 2249−2251. 11. Lacova, M.; Stankovicova, H.; Bohac, A.; Kotzianova, B. Tetrahedron 2008, 64, 9646−9653.

426

Petasis reaction Allylic amine from the three-component reaction of a vinyl boronic acid, a carbonyl and an amine. Also known as boronic acid-Mannich or Petasis boronic acid-Mannich reaction. Cf. Mannich reaction.

O R2 R3 R B(OH) R2 R3 N 1 2 N H H OH OH R1

R2 R3 R R N O 2 N 3 R R 2 N 3 H OH O R OH : R1 B 1 R2 NH OH HO OH R3 R B(OH) 1 2

Example 12 Ph N OH C5H11 EtOH, rt O B Ph N C5H11 Ph OH OH H 84%, 99% de Ph OH

Example 24 Me HO N Bn (HO)2B HO CHO MeNHBn, EtOH, rt HO 24 h, 72%, 99% de HO OMe OMe

Example 39

Ph CO2H H N R N 3 R OHC−CO H, PhB(OH) 3 R2 2 2 N R2 N 50−94% BnS N R1 BnS N R1

Example 4, Asymmetric Petasis reaction10

R2 R3 H O N R1 N 15 mol% (S)-VAPOL B(OEt)2 R3 R2 H CO2Et R1 CO2Et 3 A MS, −15 oC, Tol. 70−92% yield R1 = aryl, alkyl R2 = Bn, allyl R = alkyl 89:11 to 98:2 er 3

References

1. (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583–586. (b) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445–446. (c) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463–16470. (d) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798–11799. 2. Koolmeister, T.; Södergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5969–5970. 3. Orru, R. V. A.; deGreef, M. Synthesis 2003, 1471–1499. (Review). 4. Sugiyama, S.; Arai, S.; Ishii, K. Tetrahedron: Asymmetry 2004, 15, 3149–3153. 5. Chang, Y. M.; Lee, S. H.; Nam, M. H.; Cho, M. Y.; Park, Y. S.; Yoon, C. M. Tetrahe- dron Lett. 2005, 46, 3053–3056. 6. Follmann, M.; Graul, F.; Schaefer, T.; Kopec, S.; Hamley, P. Synlett 2005, 1009– 1011. 7. Danieli, E.; Trabocchi, A.; Menchi, G.; Guarna, A. Eur. J. Org. Chem. 2007, 1659– 1668. 8. Konev, A. S.; Stas, S.; Novikov, M. S.; Khlebnikov, A. F.; Abbaspour Tehrani, K. Tet- rahedron 2007, 64, 117–123. 9. Font, D.; Heras, M.; Villalgordo, J. M. Tetrahedron 2007, 64, 5226–5235. 10. Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922–6923. 11. Abbaspour Tehrani, K.; Stas, S.; Lucas, B.; De Kimpe, N. Tetrahedron 2009, 65, 1957–1966.

428

Petasis reagent

The Petasis reagent (Cp2TiMe2, dimethyltitanocene) undergoes similar olefination reactions with ketones and aldehydes as does the Tebbe’s reagent. The originally proposed mechanism5 was very different from that of Tebbe olefination. How- ever, later experimental data seem to suggest that both Petasis and Tebbe olefination share the same mechanism, i.e., the carbene mechanism involving a four- membered titanium oxide ring intermediate.9 Petasis reagent is easier to make than the Tebbe reagent.

H H C H Cp Cl CH3 − MeLi or heat CH4 Cp Ti Ti Ti H Ti CH2 Cp Cl MeMgCl CH C Cp 3 H H

H R1 H2 O Ti C R1 − R1 H Cp2Ti=O R2 Ti R1 R2 O O R2 R2

Example 12 O O Cp TiMe O N Ph 2 2 O N Ph

CH3 CH MeO2C THF, 65 °C MeO2C 3 CHO 8 h, 52%

Example 23

Ti Cp Cp O O PhMe, 50 °C, 67% O

Example 35

CF3 CF3

O O CF 0.75 eq CF 3 O Ph 3 O O 2.4 eq MeLi O O

N 6 mol% Cp2TiCl2 N PhMe, 80 °C, 6.5 h 91% 250 kg F F (474 mol) 227 kg

Example 48

R3 R1 OMe 1.8 equiv Cp2TiMe2 R3 R1 OMe

o R N R2 N O Tol., THF, microwave, 65 C 2 − − 3 10 min., ~ 50 60%

References

1. Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392−6394. 2. Colson, P. J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 5918−5924. 3. Petasis, N. A.; Bzowej, E. I. Tetrahedron Lett. 1993, 34, 943–946. 4. Payack, J. F.; Hughes, D. L.; Cai, D.; Cottrell, I. F.; Verhoeven, T. R. Org. Synth. 2002, 79, 19. 5. Payack, J. F.; Huffman, M. A.; Cai, D. W.; Hughes, D. L.; Collins, P. C.; Johnson, B. K.; Cottrell, I. F.; Tuma, L. D. Org. Pro. Res. Dev. 2004, 8, 256−259. 6. Cook, M. J.; Fleming, E. I. Tetrahedron Lett. 2005, 46, 297−300. 7. Morency, L.; Barriault, L. J. Org. Chem. 2005, 70, 8841−8853. 8. Adriaenssens, L. V.; Hartley, R. C. J. Org. Chem. 2007, 72, 10287−10290. 9. Naskar, D.; Neogi, S.; Roy, A.; Mandal, A. B. Tetrahedron Lett. 2008, 49, 6762−6764. 10. Zhang, J. Tebbe reagent. In Name Reactions for Homologations-Part I, Li, J. J. Ed., Wiley & Sons: Hoboken, NJ, 2009, pp 319−333. (Review).

430

Peterson olefination Alkenes from α-silyl carbanions and carbonyl compounds. Also known as the sila-Wittig reaction.

1 O H HO SiR3 acid or R H 2 M SiR3 R H R1 R2 R3 R1 R3 base R2 R3

Basic conditions:

O O SiR 1 1 2 O SiR 3 syn- R H R R 3 1 R1 H R H H 2 3 elimination 2 3 R2 R3 R R R R SiR3 3 M R β-silylalkoxide intermediate

Acidic conditions:

H O R3 HO SiR3 rotation HO R3 2 R1 R3 1 H R1 H E2 anti- R H R1 H 2 3 2 R R 2 R SiR3 2 R SiR3 elimination R H :OH 2 β-hydroxysilane

Example 16

OH SiMe2Ph KHMDS, HO H2SO4, THF HO OH 18-C-6, THF

HO OBn o HO OBn 23 C, 24 h −78 oC, 1 h HO OBn OBn OBn 95% 99%, > 20:1 dr OBn

Example 27 − o F F 1. n-BuLi, Et2O, 78 C Ph PhO S TBS PhO2S 2 2. benzophenone, 63% Ph

Example 38 1. KHMDS, THF, −78 oC CN (t-BuO)Ph2Si CN 2. N 88% yield N CHO 92:8 Z:E

Example 410

O OMOM O OMOM o 1. LiCH2TMS, THF 0 C, 15 min. 2. KHMDS, 0 oC to rt, 1.5 h

OMe OMe 3. HCl, MeOH/Et2O, 5 min. 74%

References

1. Peterson, D. J. J. Org. Chem. 1968, 33, 780−784. 2. Ager, D. J. Org. React. 1990, 38, 1−223. (Review). 3. Barrett, A. G. M.; Hill, J. M.; Wallace, E. M.; Flygare, J. A. Synlett 1991, 764−770. (Review). 4. van Staden, L. F.; Gravestock, D.; Ager, D. J. Chem. Soc. Rev. 2002, 31, 195−200. (Review). 5. Ager, D. J. Science of Synthesis 2002, 4, 789−809. (Review). 6. Heo, J.-N.; Holson, E. B.; Roush, W. R. Org. Lett. 2003, 5, 1697−1700. 7. Asakura, N.; Usuki, Y.; Iio, H. J. Fluorine Chem. 2003, 124, 81−84. 8. Kojima, S.; Fukuzaki, T.; Yamakawa, A.; Murai, Y. Org. Lett. 2004, 6, 3917−3920. 9. Kano, N.; Kawashima, T. The Peterson and Related Reactions in Modern Carbonyl Olefination; Takeda, T., Ed.; Wiley-VCH: Weinheim, Germany, 2004, 18−103. (Re- view). 10. Huang, J.; Wu, C.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 13366. 11. Ahmad, N. M. Peterson olefination. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds., Wiley & Sons: Hoboken, NJ, 2009, pp 521−538. (Review).

432

Pictet–Gams isoquinoline synthesis The isoquinoline framework is derived from the corresponding acyl derivatives of β-hydroxy-β-phenylethylamines. Upon exposure to a dehydrating agent such as phosphorus pentoxide, or phosphorus oxychloride, under reflux and in an inert solvent such as decalin, isoquinoline frameworks are formed.

OH 4 H 3 N 1 R P2O5, decalin 4 1 N 3 reflux O R

P2O5 actually exists as P4O10, an adamantane-like structure.

OH OH O O OH POP : O O :NH HN O HN O O P H ROPO R 2 R O O O H OPO O: POP 2 O O H N N N R R R

Example 14

N HO POCl , P O , decalin O NH 3 4 10

180 oC, 6 h, 14% N OH OH H H N N N

O O

Example 27

P O N N O 2 5 H o-dichlorobenzene Cl Cl 80%

Reference

1. (a) Pictet, A.; Kay, F. W. Ber. 1909, 42, 1973−1979. (b) Pictet, A.; Gams, A. Ber. 1909, 42, 2943−2952. Amé Pictet (1857−1937), born in Geneva, Switzerland, carried out a tremendous amount of work on alkaloids. 2. Ardabilchi, N.; Fitton, A. O.; Frost, J. R.; Oppong-Boachie, F. Tetrahedron Lett. 1977, 18, 4107−4110. 3. Ardabilchi, N.; Fitton, A. O.; Frost, J. R.; Oppong-Boachie, F. K.; Hadi, A. H. A.; Sharif, A. M. J. Chem. Soc., Perkin Trans. 1 1979, 539−543. 4. Dyker, G.; Gabler, M.; Nouroozian, M.; Schulz, P. Tetrahedron Lett. 1994, 35, 9697−9700. 5. Poszávácz, L.; Simig, G. J. Heterocycl. Chem. 2000, 37, 343−348. 6. Poszávácz, L.; Simig, G. Tetrahedron 2001, 57, 8573−8580. 7. Manning, H. C.; Goebel, T.; Marx, J. N.; Bornhop, D. J. Org. Lett. 2002, 4, 1075−1081. 8. Holsworth, D. D. Pictet–Gams Isoquinoline Synthesis. In Name Reactions in Hetero- cyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 457−465. (Review).

434

Pictet–Spengler tetrahydroisoquinoline synthesis Tetrahydroisoquinolines from condensation of β-arylethylamines and carbonyl compounds followed by cyclization.

R1O R1O O HCl NH NH R2 H 1 R1O 2 R O R2

H 1 R1O R O O + H H NH 1 N OH 1 : 2 R O H R O 2 R 2 R R1O R1O − H2O N: OH N R1O H 2 R1O H 2 2 R R 1 R O R1O R1O

NH NH NH R1O 1 1 H R O R O 2 H 2 2 R R R

Example 14 O HO NH O MeO HO O AcO S O silica gel AcO S O NH Me MeO 2 dry EtOH Me N 80% O N O O O

Example 27 Me N

MeO NHMe (CH2O)n MeO i-PrO i-PrO aq. HCl, EtOH

75% i-PrO i-PrO

Example 3, Asymmetric acyl Pictet–Spengler9

OHC N OTBDPS N NH2 H N CH2Cl2/Et2O (3 : 1) H o Na2SO4, 23 C, 2 h OTBDPS

t-Bu S

i-Bu2N NAc N N N H H O N Ph H

OTBDPS

AcCl, 2,6-lutidine, Et2O 81% 2 steps −78 oC to −60 oC, 23 h 94% ee

Example 4, Oxa-Pictet–Spengler10

O O CHO OH O

BF3•OEt2, CH2Cl2 o 0 C to rt, 88%, 88% de O O O O O O

References

1. Pictet, A.; Spengler, T. Ber. 1911, 44, 2030−2036. 2. Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797−1842. (Review). 3. Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 9202−9203. 4. Zhou, B.; Guo, J.; Danishefsky, S. J. Org. Lett. 2002, 4, 43−46. 5. Yu, J.; Wearing, X. Z.; Cook, J. M. Tetrahedron Lett. 2003, 44, 543−547. 6. Tsuji, R.; Nakagawa, M.; Nishida, A. Tetrahedron: Asymmetry 2003, 14, 177−180. 7. Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Tetrahedron: Asymmetry 2003, 14, 1309−1320. 8. Tinsley, J. M. Pictet–Spengler Isoquinoline Synthesis. In Name Reactions in Hetero- cyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 469−479. (Review). 9. Mergott, D. J.; Zuend, S. J.; Jacobsen, E. N. Org. Lett. 2008, 10, 745−748. 10. Eid, C. N.; Shim, J.; Bikker, J.; Lin, M. J. Org. Chem. 2009, 74, 423−426. 436

Pinacol rearrangement Acid-catalyzed rearrangement of vicinal diols (pinacols) to carbonyl compounds.

O HO OH H 2 R R2 R R 3 R1 R3 R R1

HO OH H HO OH2 − 2 H2O R R R R2 1 3 1 3 R R R R

H HO O O alkyl 2 R R2 R2 R 3 R H R 3 1 R migration 3 1 R R 1 R R R

Example 14

OMe OMe MeO MeO OH OTBDMS CHO BF3•OEt2 MeO OTBDMS H MeO THF, 68% OTBDMS OH OMe OTBDMS OMe

Example 25

Ph O OH 1. MsCl, Et3N, CH2Cl2 Ph 0 oC, 10 min.

OH − o 2. Et3Al, CH2Cl2, 78 C N 10 min., 90% N SO Ph SO Ph 2 2

Example 37

Ph OH O O Ph Ph Ph Ph OH cat. TsOH Ph

CDCl3 3 : 1

Example 49

OBn N O OBn N O R = vinyl, 92% BF •OEt R = allyl, 95% 3 2 R = furyl, 90% 98% ee R = prenyl, 94% CH Cl , 0 oC 2 2 R HO OH O R

References

1. Fittig, R. Ann. 1860, 114, 54−63. 2. Magnus, P.; Diorazio, L.; Donohoe, T. J.; Giles, M.; Pye, P.; Tarrant, J.; Thom, S. Tet- rahedron 1996, 52, 14147−14176. 3. Razavi, H.; Polt, R. J. Org. Chem. 2000, 65, 5693−5706. 4. Pettit, G. R.; Lippert III, J. W.; Herald, D. L. J. Org. Chem. 2000, 65, 7438–7444. 5. Shinohara, T.; Suzuki, K. Tetrahedron Lett. 2002, 43, 6937−6940. 6. Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143−7157. (Review). 7. Mladenova, G.; Singh, G.; Acton, A.; Chen, L.; Rinco, O.; Johnston, L. J.; Lee-Ruff, E. J. Org. Chem. 2004, 69, 2017−2023. 8. Birsa, M. L.; Jones, P. G.; Hopf, H. Eur. J. Org. Chem. 2005, 3263−3270. 9. Suzuki, K.; Takikawa, H.; Hachisu, Y.; Bode, J. W. Angew. Chem., Int. Ed. 2007, 46, 3252–3254. 10. Goes, B. Pinacol rearrangement. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds., Wiley & Sons: Hoboken, NJ, 2009, pp 319−333. (Review).

438

Pinner reaction Transformation of a nitrile into an imino ether, which can be converted to either an ester or an amidine.

O H+, H O 2 R OR1 HCl (g) NH2 Cl RCN R1 OH NH R OR1 2 NH3, EtOH R NH2•HCl

R NH protonation nucleophilic H NH2 Cl R N: 1 : R O addition R OR1 H

common intermediate

NH2 Cl hydrolysis H O R OR1 2N OH H R OR1 1 H O: R OR 2

H NH2 Cl nucleophilic 1 NH HCl•H2N OR 2 1 R OR addition R NH2 R NH2•HCl : H3N H

Example 12

Ph NH Ph NH2 O Ph EtSH, HCl, CH2Cl2 pyr., H2S Ph N NO NO H N 0 oC, 10 min., 95% 4 h, 0 oC, 42% Ph Ph

Example 22

O O O pyr., H S EtSH, HCl, CH2Cl2 2 SEt SEt Ph N Ph N Ph N N o H 0 oC, 1 h, 85% H 2 h, 0 C, 40% H NH S

Example 36

O O 2 MeOH, HCl O2 2 S S NaHCO3, Et2O S OPh OPh OPh o Et2O, 0 C −5 oC, 87−92% HCl•HN OMe HN OMe N 90%

O2 O O NH2 S 2 2 OPh S S OPh OPh Ph Me HN NH2 EtOH, rt H2N OMe MeO NH2 36 h, 78% Me Ph

Example 410

Cl N HCl N H2N S S EtOH NC 95% OEt

N N NaHCO 3 NH4Cl H N HN S 2 S 65% Cl NH OEt 2

References

1. (a) Pinner, A.; Klein, F. Ber. 1877, 10, 1889–1897. (b) Pinner, A.; Klein, F. Ber. 1878, 11, 1825. 2. Poupaert, J.; Bruylants, A.; Crooy, P. Synthesis 1972, 622–624. 3. Lee, Y. B.; Goo, Y. M.; Lee, Y. Y.; Lee, J. K. Tetrahedron Lett. 1990, 31, 1169–1170. 4. Cheng, C. C. Org. Prep. Proced. Int. 1990, 22, 643–645. 5. Siskos, A. P.; Hill, A. M. Tetrahedron Lett. 2003, 44, 789–794. 6. Fischer, M.; Troschuetz, R. Synthesis 2003, 1603–1609. 7. Fringuelli, F.; Piermatti, O.; Pizzo, F. Synthesis 2003, 2331–2334. 8. Cushion, M. T.; Walzer, P. D.; Collins, M. S.; Rebholz, S.; Vanden Eynde, J. J.; May- ence, A.; Huang, T. L. Antimicrob. Agents Chemoth. 2004, 48, 4209–4216. 9. Li, J.; Zhang, L.; Shi, D.; Li, Q.; Wang, D.; Wang, C.; Zhang, Q.; Zhang, L.; Fan, Y. Synlett 2008, 233–236. 10. Racané, L.; Tralic-Kulenovic, V.; Mihalic, Z.; Pavlovic, G.; Karminski-Zamola, G. Tetrahedron 2008, 64, 11594–11602.

440

Polonovski reaction Treatment of a tertiary N-oxide with an activating agent such as acetic anhydride, resulting in rearrangement where an N,N-disubstituted acetamide and an aldehyde are generated.

1 R1 R O (CH3CO)2O R2 N N R 2 O pyr., CH Cl R H R 2 2 O

R1 O R1 O O R2 N O R2 N acylation O R HOAc R R1 H R2 N O CH3CO2 R CH CO 3 2 iminium ion

OO R1 O 1 O 2 R O R1 R N Ac O R 2 N 2 : R 2 R N O O R H R O OO OAc

The intramolecular pathway is also operative:

1 R 1 2 R R1 R2 N R O : R N R N R O O O O R2 H O

Example 11

(CH3CO)2O N N O 100 oC O

Example 22

O O N N (CH3CO)2O

< 30 oC, 98%

Example 3, Iron salt-mediated Polonovski reaction9

Me O Me Me O O O H2O2 then FeSO4 O Cl O N HO H 2 M HCl 87%, 2 steps Me N OH NH HO H HO H Me codeine

References

1. Polonovski, M.; Polonovski, M. Bull. Soc. Chim. Fr. 1927, 41, 1190–1208. 2. Michelot, R. Bull. Soc. Chim. Fr. 1969, 4377–4385. 3. Lounasmaa, M.; Karvinen, E.; Koskinen, A.; Jokela, R. Tetrahedron 1987, 43, 2135– 2146. 4. Tamminen, T.; Jokela, R.; Tirkkonen, B.; Lounasmaa, M. Tetrahedron 1989, 45, 2683–2692. 5. Grierson, D. Org. React. 1990, 39, 85–295. (Review). 6. Morita, H.; Kobayashi, J. J. Org. Chem. 2002, 67, 5378–5381. 7. McCamley, K.; Ripper, J. A.; Singer, R. D.; Scammells, P. J. J. Org. Chem. 2003, 68, 9847–9850. 8. Nakahara, S.; Kubo, A. Heterocycles 2004, 63, 1849–1854. 9. Thavaneswaran, S.; Scammells, P. J. Bioorg. Med. Chem. Lett. 2006, 16, 2868–2871. 10. Volz, H.; Gartner, H. Eur. J. Org. Chem. 2007, 2791–2801.

442

Polonovski–Potier reaction A modification of the Polonovski reaction where trifluoroacetic anhydride is used in place of acetic anhydride. Because the reaction conditions for the Polonovski– Potier reaction are mild, it has largely replaced the Polonovski reaction.

N (CF CO) O N O 3 2

pyr., CH2Cl2 O CF3

tertiary N-oxide

N O O N O F C O CF acylation CF3 3 3 H H O N O

CF CO CF3CO2 3 2 iminium ion N: N N

CF CO 3 2 H F3C O CF3 O CF3 O CF3 O O

enamine

Example 12

O N o N N (CF3CO)2O, CH2Cl2, 0 C N H H H then, HCl, heat, 30% HO HO

Example 25

O O HN H O HHN O (CF3CO)2O, pyr. N OH N OH CH Cl , 0 oC, 65% O 2 2 H H F3C O

Example 38

O N Me 1.3 equiv m-CPBA N Me

N H O o N H O CH2Cl2, 0 C, 94% Boc H Boc H CN HO O 1. TFAA, CH Cl , rt, 3 h 2 2 N Me N

2. KCN, H O, pH 4 N H OH 2 N H O H o Boc 0 C, 30 min., Boc H then rt, 3 h 25% 22%

Example 410

OH O OH

1. m-CPBA, DMF, 0 oC, 0.5 h, 80% H H N N CH CH3 3 H o H 2. Ac2O, Et3N, DMF, 0 C, 1 h

HN HN

References

1. Ahond, A.; Cavé, A.; Kan-Fan, C.; Husson, H.-P.; de Rostolan, J.; Potier, P. J. Am. Chem. Soc. 1968, 90, 5622–5623. 2. Husson, H.-P.; Chevolot, L.; Langlois, Y.; Thal, C.; Potier, P. J. Chem. Soc., Chem. Commun. 1972, 930–931. 3. Grierson, D. Org. React. 1990, 39, 85–295. (Review). 4. Sundberg, R. J.; Gadamasetti, K. G.; Hunt, P. J. Tetrahedron 1992, 48, 277–296. 5. Kende, A. S.; Liu, K.; Brands, J. K. M. J. Am. Chem. Soc. 1995, 117, 10597–10598. 6. Renko, D.; Mary, A.; Guillou, C.; Potier, P.; Thal, C. Tetrahedron Lett. 1998, 39, 4251–4254. 7. Suau, R.; Nájera, F.; Rico, R. Tetrahedron 2000, 56, 9713–9720. 8. Thomas, O. P.; Zaparucha, A.; Husson, H.-P. Tetrahedron Lett. 2001, 42, 3291–3293. 9. Lim, K.-H.; Low, Y.-Y.; Kam, T.-S. Tetrahedron Lett. 2006, 47, 5037–5039. 10. Gazak, R.; Kren, V.; Sedmera, P.; Passarella, D.; Novotna, M.; Danieli, B. Tetrahedron 2007, 63, 10466–10478. 11. Nishikawa, Y.; Kitajima, M.; Kogure, N.; Takayama, H. Tetrahedron 2009, 65, 1608– 1617.

444

Pomeranz–Fritsch reaction Isoquinoline synthesis via acid-mediated cyclization of the appropriate aminoacetal intermediate.

OEt OEt H OEt H2N N CHO OEt N

OEt OEt H N 2 : OEt condensation OEt imine :N H H formation O OH2

H H OEt OEt :OEt HOEt OEt OEt : N N N

H OEt OEt H H N N N

Example 13

EtO OEt MeO MeO BF3•AcOH, (CF3CO)2O N N 60−82 % MeO MeO

Example 24

OMe MeO OMe H TiCl4, CH2Cl2 N −78 oC, 69 % N O O Me Me

Example 39

OMe MeO MeO OMe 6 N HCl, EtOH, dioxane N N MeO Ns MeO Ns reflux, 30 min., 68%

Example 4, Bobbitt modification10

EtO OEt MeO MeO H OEt N Br MeO N H OEt MeO H NaH, DMF

MeO

1. 5 M HCl, 12 h, rt N MeO H 2. NaBH4, TFA, CH2Cl2 38% overall

References

1. (a) Pomeranz, C. Monatsh. 1893, 14, 116−119. Cesar Pomeranz (1860−1926) received his Ph.D. degree at Vienna, where he was employed as an associate professor of chemistry. (b) Fritsch, P. Ber. 1893, 26, 419−422. Paul Fritsch (1859−1913) was born in Oels, Silesia. He studied at Munich where he received his doctorate in 1884. Fritsch eventually became a professor at Marburg after several junior positions. 2. Gensler, W. J. Org. React. 1951, 6, 191−206. (Review). 3. Bevis, M. J.; Forbes, E. J.; Naik, N. N.; Uff, B. C. Tetrahedron 1971, 27, 1253−1259. 4. Ishii, H.; Ishida, T. Chem. Pharm. Bull. 1984, 32, 3248−3251. 5. Bobbitt, J. M.; Bourque, A. J. Heterocycles 1987, 25, 601−616. (Review). 6. GluszyĔska, A.; Rozwadowska, M. D. Tetrahedron: Asymmetry 2000, 11, 2359−2368. 7. Capilla, A. S.; Romero, M.; Pujol, M. D.; Caignard, D. H.; Renard, P. Tetrahedron 2001, 57, 8297−8303. 8. Hudson, A. Pomeranz–Fritsch Reaction. In Name Reactions in Heterocyclic Chemis- try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 480−486. (Re- view). 9. Bracca, A. B. J.; Kaufman, T. S. Eur. J. Org. Chem. 2007, 5284−5293. 10. Grajewska, A.; Rozwadowska, M. D. Tetrahedron: Asymmetry 2007, 18, 2910−2914.

446

Schlittler–Müller modification Simple permutation where the amine and the aldehyde switch places for the two reactants in comparison to the Pomeranz–Fritsch reaction.

OEt

OEt OEt H NH2 N OHC OEt N R R R

Example 13

OMe OMe R OMe OMe HN R X Ts N Ts

H R N Ts

Example 24

OEt O 1. EtO H N N H2N NH2 2. oleum, 30%

References

1. Schlittler, E.; Müller, J. Helv. Chim. Acta 1948, 31, 914−924, 1119−1132. 2. Guthrie, D. A.; Frank, A. W.; Purves, C. B. Can. J. Chem. 1955, 33, 729−742. 3. Boger, D. L.; Brotherton, C. E.; Kelley, M. D. Tetrahedron 1981, 37, 3977−3980. 4. Gill, E. W.; Bracher, A. W. J. Heterocycl. Chem. 1983, 20, 1107−1109. 5. Hudson, A. Pomeranz–Fritsch Reaction. In Name Reactions in Heterocyclic Chemis- try; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 480−486. (Re- view).

447

Prévost trans-dihydroxylation Cf. Woodward cis-dihydroxylation.

OH I2 O2CPh hydrolysis

AgO2CPh OH O2CPh

I II I SN2 SN2 O O

O2CHPh Ph cyclic iodonium ion intermediate neighboring group assistance

O2CPh O2CPh OH SN2 hydrolysis OO O2CPh OH Ph Example 15

O AgOCOPh, I2 Ph O PhH, rt, 2 h, reflux, 10 h, 46% O O F F Ph Example 29 O C-C H -p-OMe 2 6 4 AgOCOPh, I2

CCl , 74% O 4 OH OAc 1. KOH, H O AcO OAc I O2C-C6H4-p-OMe 2 2. Ac O, pyr. 2 O O

References

1. Prévost, C. Compt. Rend. 1933, 196, 1129–1131. 2. Campbell, M. M.; Sainsbury, M.; Yavarzadeh, R. Tetrahedron 1984, 40, 5063–5070. 3. Ciganek, E.; Calabrese, J. C. J. Org. Chem. 1995, 60, 4439–4443. 4. Brimble, M. A.; Nairn, M. R. J. Org. Chem. 1996, 61, 4801–4805. 5. Zajc, B. J. Org. Chem. 1999, 64, 1902–1907. 6. Hamm, S.; Hennig, L.; Findeisen, M.; Muller, D. Tetrahedron 2000, 56, 1345–1348. 7. Ray, J. K.; Gupta, S.; Kar, G. K.; Roy, B. C.; Lin, J.-M. J. Org. Chem. 2000, 65, 8134–8138. 8. Sabat, M.; Johnson, C. R. Tetrahedron Lett. 2001, 42, 1209–1212. 9. Hodgson, R.; Nelson, A. Org. Biomol. Chem. 2004, 2, 373–386.

Prins reaction The Prins reaction is the acid-catalyzed addition of aldehydes to alkenes and gives different products depending on the reaction conditions.

O H OH OO or or R R OH H H H2O R OH R

OH O H H2O OH H H R OH H H R OH R the common intermediate

R OH H H R OH : B

H O OO O H H H H R OH H R R O

Example 15

OAc SnBr4, CH2Cl2 O O −78 oC, 84% TsO OBn TsO OBn

Example 27

(CH2O)n, Bi(OTf)3

AcO CH3CN, rt, 10 h, 77% AcO

Example 39

OBn OTBS

TMSEO2C O O HO O

O O

OBn OH In(OTf)3, TMSCl, CH2Cl2 TMSEO2C −78 to −40 ºC, 4 h, 42% O O O O O

Example 410

AcOH, BF •OEt O 3 2 O O o OH 0 C, CH2Cl2 X OHC X = OAc, 33% X = F, 48% O PhO SO OCH3 2 PhO S OCH3 2

References

1. Prins, H. J. Chem. Weekblad 1919, 16, 1072−1023. Born in Zaandam, The Nether- lands, Hendrik J. Prins (1889−1958) was not even an organic chemist per se. After obtaining a doctorate in chemical engineering, Prins worked for an essential oil company and then a company dealing with the rendering of condemned meats and car- casses. But he had a small laboratory near his house where he carried out his experi- ments in his spare time, which obviously was not a big distraction—for he rose to be the president-director of the firm he worked for. 2. Adam, D. R.; Bhatnagar, S. P. Synthesis 1977, 661−672. (Review). 3. Hanaki, N.; Link, J. T.; MacMillan, D. W. C.; Overman, L. E.; Trankle, W. G.; Wurster, J. A. Org. Lett. 2000, 2, 223−226. 4. Davis, C. E.; Coates, R. M. Angew. Chem., Int. Ed. 2002, 41, 491−493. 5. Marumoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett. 2002, 4, 3919−3922. 6. Braddock, D. C.; Badine, D. M.; Gottschalk, T.; Matsuno, A.; Rodriguez-Lens, M. Synlett 2003, 345−348. 7. Sreedhar, B.; Swapna, V.; Sridhar, Ch.; Saileela, D.; Sunitha, A. Synth. Commun. 2005, 35, 1177−1182. 8. Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44, 3485−3488. 9. Chan, K.-P.; Ling, Y. H.; Loh, T.-P. Chem. Commun. 2007, 939−941. 10. Bahnck, K. B.; Rychnovsky, S. D. J. Am. Chem. Soc. 2008, 130, 13177−13181. 450

Pschorr cyclization The intramolecular version of the Gomberg−Bachmann reaction.

CO2H CO2H NaNO2, HCl Cu NH2

CO2H

H N − NO O O − H O NH 2 N H 2 : 2 HO O N H O O N N 2 O O O

CO2H CO2H CO2H H H H N : NH N N N N O O OH2 H

CO H CO2H 2 − H O Cu(0) ↑ 2 Cu(I) N2

N2 H

CO H CO2H 2 6-exo-trig Cu(I) Cu(0) radical cyclization H H

Example 17

O O O O O O O O O − − 1. NaNO2, HCl H2O HOAc 0 to 5 oC, 2 h NH 2 2. CuSO , HOAc, reflux S 4 S 6 : 1 S 2 h, 86%

Example 28

O O

N NH N 2 NaNO , HCl N 2 N 5 to 20 oC, 64%

Example 310

O O hv (350 nM)

MeCN, N Br 2

O O

62% 34%

References

1. Pschorr, R. Ber. 1896, 29, 496−501. Robert Pschorr (1868−1930), born in Munich, Germany, studied under von Baeyer, Bamberger, Knorr, and Fischer. He became an assistant professor in 1899 at Berlin where he discovered the phenanthrene synthesis. During WWI, Pschorr served as a major in the German Army. 2. Kupchan, S. M.; Kameswaran, V.; Findlay, J. W. A. J. Org. Chem. 1973, 38, 405−406. 3. Wassmundt, F. W.; Kiesman, W. F. J. Org. Chem. 1995, 60, 196−201. 4. Qian, X.; Cui, J.; Zhang, R. Chem. Commun. 2001, 2656−2657. 5. Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359−1469. (Review). 6. Karady, S.; Cummins, J. M.; Dannenberg, J. J.; del Rio, E.; Dormer, P. G.; Marcune, B. F.; Reamer, R. A.; Sordo, T. L. Org. Lett. 2003, 5, 1175−1178. 7. Xu, Y.; Qian, X.; Yao, W.; Mao, P.; Cui, J. Bioorg. Med. Chem. 2003, 11, 5427−5433. 8. Tapolcsányi, P.; Maes, B. U. W.; Monsieurs, K.; Lemière, G. L. F.; Riedl, Z.; Hajós, G.; Van der Driessche, B.; Dommisse, R. A.; Mátyus, P. Tetrahedron 2003, 59, 5919−5926. 9. Mátyus, P.; Maes, B. U. W.; Riedl, Z.; Hajós, G.; Lemière, G. L. F.; TapolcĞanyi, P.; Monsieurs, K.; Éliás, O.; Dommisse, R. A.; Krajsovszky, G. Synlett 2004, 1123−1139. (Review). 10. Moorthy, J. N.; Samanta, S. J. Org. Chem. 2007, 72, 9786−9789.

452

Pummerer rearrangement The transformation of sulfoxides into α-acyloxythioethers using acetic anhydride.

O S R2 Ac2O R1 S R2 R1 OAc

O O O O O OO O S R2 acyl AcO R1 O O H transfer S R2 S R2 R1 R1 AcO S R2 HOAc R1 S R2 S R2 R1 R1 OAc AcO

Example 12

1. Me C(OMe) , H+ OH 2 2 2. m-CPBA, CH Cl , −20 oC O OAc BnO 2 2 SPh BnO SPh 3. Ac O, NaOAc, reflux, 6 h OH 2 O 81%

Example 27

MeO MeO N N CO2Et TMSOTf, DIPEA MeO MeO CO2Et N − o PhS S N CH2Cl2, 20 C N Ph O O N Bn 88%, dr = 2:1 Bn O

Example 38

MeO MeO O O H SEt CSA, PhMe N MeO N MeO O

CO2Me reflux, 88% MeO2C SEt Br Br

Example 49

Bn O O Bn O Ac O, pyr., DMAP N S 2 N S Bn Bn CH2Cl2, rt, 91% OAc Ph Ph

References

1. Pummerer, R. Ber. 1910, 43, 1401−1412. Rudolf Pummerer, born in Austria in 1882, studied under von Baeyer, Willstätter, and Wieland. He worked for BASF for a few years and in 1921 he was appointed head of the organic division of the Munich Labo- ratory, fulfilling his long-desired ambition. 2. Katsuki, T.; Lee, A. W. M.; Ma, P.; Martin, V. S.; Masamune, S.; Sharpless, K. B.; Tuddenham, D.; Walker, F. J. J. Org. Chem. 1982, 47, 1373−1378. 3. De Lucchi, O.; Miotti, U.; Modena, G. Org. React. 1991, 40, 157−406. (Review). 4. Padwa, A.; Gunn, D. E., Jr.; Osterhout, M. H. Synthesis 1997, 1353−1378. (Review). 5. Padwa, A.; Waterson, A. G. Curr. Org. Chem. 2000, 4, 175−203. (Review). 6. Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851−862. (Review). 7. Gámez Montaño, R.; Zhu, J. Chem. Commun. 2002, 2448−2449. 8. Padwa, A.; Danca, M. D.; Hardcastle, K.; McClure, M. J. Org. Chem. 2003, 68, 929. 9. Suzuki, T.; Honda, Y.; Izawa, K.; Williams, R. M. J. Org. Chem. 2005, 70, 7317. 10. Ahmad, N. M. Pummerer rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 334−352. (Re- view).

454

Ramberg–Bäcklund reaction Olefin synthesis via α-halosulfone extrusion.

X 1 Base R O SO↑ R S R1 R OO

:B R X H backside X S R1 1 displacement R S R OO OO R R1 1 SO R 2 O SO↑ S extrusion R OO episulfone intermediate

Example 14

H H KOt-Bu, THF

S Br −15 oC to rt, 71% H O 2

Example 25

Br KOt-Bu, THF/HOt-Bu

0 oC to rt, 0.5 h, 65% SO2CH2Br H Example 36

O O OH O O O 1. 2.2 eq. KOt-Bu, 10 eq. HMPA O DME, 70 oC, 5 min., 82% H H O2S O 2. 6 N HCl/THF (1:10, v/v), rt, 4 h, 85% O

Cl O O

Example 4, in situ chlorination7 TMSO

O2SO

TMSO

HO 1. t-BuOK, t-BuOH CCl , rt, 65% 4 O

2. TsOH, H2O, EtOH rt, 95% HO

References

1. Ramberg, L.; Bäcklund, B. Arkiv. Kemi, Mineral Geol. 1940, 13A, 1−50. 2. Paquette, L. A. Acc. Chem. Res. 1968, 1, 209−216. (Review). 3. Paquette, L. A. Org. React. 1977, 25, 1−71. (Review). 4. Becker, K. B.; Labhart, M. P. Helv. Chim. Acta 1983, 66, 1090−1100. 5. Block, E.; Aslam, M.; Eswarakrishnan, V.; Gebreyes, K.; Hutchinson, J.; Iyer, R.; Laf- fitte, J. A.; Wall, A. J. Am. Chem. Soc. 1986, 108, 4568−4580. 6. Boeckman, R. K., Jr.; Yoon, S. K.; Heckendorn, D. K. J. Am. Chem. Soc. 1991, 113, 9682−9784. 7. Trost, B. M.; Shi, Z. J. Am. Chem. Soc. 1994, 116, 7459−7460. 8. Taylor, R. J. K. Chem. Commun. 1999, 217−227. (Review). 9. Taylor, R. J. K.; Casy, G. Org. React. 2003, 62, 357−475. (Review). 10. Li, J. J. Ramberg–Bäcklund olefin synthesis. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 386−404. (Review). 11. Pal, T. K.; Pathak, T. Carbohydrate Res. 2008, 343, 2826−2829. 12. Baird, L. J.; Timmer, M. S. M.; Teesdale-Spittle, P. H.; Harvey, J. E. J. Org. Chem. 2009, 74, 2271−2277.

456

Reformatsky reaction Nucleophilic addition of organozinc reagents generated from α-haloesters to carbonyls.

O OR2 HO OR2 Br Zn 1 R R R O R1 O

O OR2 Zn(0) nucleophilic Br ZnBr R R1 O oxidative addition or OR2 addition electron transfer O

H O, hydrolysis HO OR2 BrZnO OR2 2 R 1 R 1 during workup R O R O

Example 14

OTBDMS OTBDMS

Ph BrCH2CO2Me Ph MeO2C S N Zn, THF, reflux, 71% N Boc Boc

Example 26

O O Zn, THF O 60 oC MeO Br

O HCl HO O O

O THF, rt, 10 h 92% MeO MeO

Example 3, Boron-mediated Reformatsky reaction8

O O O H OH H BEt3, tol. H I o OP OP Me −78 C, quant. O O H O Me H O P = TBS single diastereomer

9 Example 4, SmI2-mediated Reformatsky reaction

OTBDPS OTBDPS OSiEt3 n-Bu CHO Me Me O O O O 1. SmI , THF, −78 oC H H 2 OSiEt3 OSiEt3 OSiEt3 2. Martin sulfurane, CH2Cl2 n-Bu Br O O 72%, 2 steps Me Me

References

1. Reformatsky, S. Ber. 1887, 20, 1210−1211. Sergei Reformatsky (1860−1934) was born in Russia. He studied at the University of Kazan in Russia, the cradle of Russian chemistry professors, where he found competent guidance of a distinguished chemist, Alexander M. ZaƱtsev. Reformatsky then studied at Göttingen, Heidelberg, and Leip- zig in Germany. After returning to Russia, Reformatsky became the Chair of Organic Chemistry at the University of Kiev. 2. Rathke, M. W. Org. React. 1975, 22, 423−460. (Review). 3. Fürstner, A. Synthesis 1989, 571−590. (Review). 4. Lee, H. K.; Kim, J.; Pak, C. S. Tetrahedron Lett. 1999, 40, 2173−2174. 5. Fürstner, A. In Organozinc Reagents Knochel, P., Jones, P., Eds.; Oxford University Press: New York, 1999, pp 287−305. (Review). 6. Zhang, M.; Zhu, L.; Ma, X. Tetrahedron: Asymmetry 2003, 14, 3447−3453. 7. Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60, 9325−9374. (Review). 8. Lambert, T. H.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 426−427. 9. Moslin, R. M.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 15106−15107. 10. Cozzi, P. G. Angew. Chem., Int. Ed. 2007, 46, 2568−2571. (Review). 11. Ke, Y.-Y.; Li, Y.-J.; Jia, J.-H.; Sheng, W.-J.; Han, L.; Gao, J.-R. Tetrahedron Lett. 2009, 50, 1389−1391.

458

Regitz diazo synthesis Synthesis of 2-diazo-1,3-diketones or 2-diazo-3-oxoesters using sulfonyl azides.

N2 1 R OR TsN3, Et3N 1 R OR Ts NH2 MeCN O O O O

: O NEt3 N N N S N N SO2Tol H enolate O HN 1 R OR 1 1 formation R OR R OR O O O O O O

H N N N SO2Tol proton N O N: 1 1 R OR H2N S transfer R OR O O O O O tosyl amide is the by-product

When only one carbonyl is present, ethylformate can be used as an activating auxiliary:6−9

O O O NaH, HCO Et MsN 2 3 N OH 2 Et2O Et2O

O N : N N N S Me N SO2Me NEt3 O O O O N H H O O O

O O O O N N N HN S Me N N2 N SO2Me O O H H O

Alternatively, the triazole intermediate may be assembled via a 1,3-dipolar cycloaddition of the enol and mesyl azide:

O O N N O N N N S Me 1,3-dipolar N SO2Me O cycloaddition H OH OH

O O

HN S Me N2 O O H

Example 15

O H N Ot-Bu O O O SO N 2 3

O N2 Et3N, CH3CN Ot-Bu 0 oC, 5 h, 45% O O

Example 210

O O O O O O O O OTIPS OTIPS CH SO N N N N N 3 2 3 H H N2 CH3CN, 84% N N

References

1. (a) Regitz, M. Angew. Chem., Int. Ed. 1967, 6, 733–741. (b) Regitz, M.; Anschütz, W.; Bartz, W.; Liedhegener, A. Tetrahedron Lett. 1968, 9, 3171–3174. (c) Regitz, M. Synthesis 1972, 351–373. (Review). 2. Pudleiner, H.; Laatsch, H. Ann. 1990, 423–426. 3. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011–4030. 4. Charette, A. B.; Wurz, R. P.; Ollevier, T. J. Org. Chem. 2000, 65, 9252–9254. 5. Hodgson, D. M.; Labande, A. H.; Pierard, F. Y. T. M.; Expésito Castro, M. A. J. Org. Chem. 2003, 68, 6153–6159. 6. Sarpong, R.; Su, J. T.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 13624–13628. 7. Mejía-Oneto, J. M.; Padwa, A. Org. Lett. 2004, 6, 3241–3244. 8. Muroni, D.; Saba, A.; Culeddu, N. Tetrahedron: Asymmetry 2004, 15, 2609–2614. 9. Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron 2004, 60, 3967–3977. 10. Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7, 47–50. 460

Reimer–Tiemann reaction Synthesis of o-formylphenol from phenols and chloroform in alkaline medium.

OH OH CHO 3 KCl 2 H O CHCl3 3 KOH 2

a. Carbene generation:

− fast CCl − Cl , slow Cl3CH 2 : H2O CCl2 Cl α-elimination OH b. Addition of dichlorocarbene and hydrolysis:

O O Cl OH O H KOH CHCl CCl H2O 2 CCl2

H OH O Cl OH O Cl O O OH CHO H H H

Example 1, Photo-Reimer–Tiemann reaction without base7 CHCl OH O 2 hv (Hg lamp)

CHCl3, 5 h, 48% CN CN Example 28 OH OH CHO CHCl3, 6 eq. NaOH

2 eq. H2O, reflux CO2H 4 h, 64% CO2H NHBoc NHBoc

References

1. Reimer, K.; Tiemann, F. Ber. 1876, 9, 824–828. 2. Wynberg, H.; Meijer, E. W. Org. React. 1982, 28, 1–36. (Review). 3. Bird, C. W.; Brown, A. L.; Chan, C. C. Tetrahedron 1985, 41, 4685–4690. 4. Neumann, R.; Sasson, Y. Synthesis 1986, 569–570. 5. Cochran, J. C.; Melville, M. G. Synth. Commun. 1990, 20, 609–616. 6. Langlois, B. R. Tetrahedron Lett. 1991, 32, 3691–3694. 7. Jiménez, M. C.; Miranda, M. A.; Tormos, R. Tetrahedron 1995, 51, 5825–5828. 8. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553–1555.

Reissert reaction Treatment of quinoline or isoquinoline with acid chloride and KCN gives quinaldic acid, aldehyde, and KCN.

H H2SO4 O O N N CN NH3 R H N CO H R Cl KCN O R 2 Reissert Compound

CN H H H N N: N Cl N H CN O R R O N R O O R H

Reissert compound H H O H : H N NH N: NH N NH H O O O R R R H H

O H OH O H O N N N R H NH2 NH O O 2 NH2 R R H H

H O O N H N NH3 NH2 HO N CO2H NH2 H O: 2

Example 13 O MeO Cl NaCN, H2O, CH2Cl2 4.5 h, 95% MeO N OMe

O N CN MeO MeO 30% H2SO4 H O reflux, 1 h, 95% MeO MeO OMe OMe

Example 2, Reissert compound from isoquinoline7

chiral Al catalyst N N O TMSCN, CH2=CHOCOCl CN Br O CH Cl , −40 oC, 72 h, 53% 2 2 Br 73% ee

Example 3, Reissert compound fron isoquinoline10

Cl O N O N O

CN O CN O N 1 : 1 TMS-CN, CH2Cl2 48 h, rt, 96% Reissert compounds

References

1. (a) Reissert, A. Ber. 1905, 38, 1603–1614. (b) Reissert, A. Ber. 1905, 38, 3415–3435. Carl Arnold Reissert was born in 1860 in Powayen, Germany. He received his Ph.D. In 1884 at Berlin, where he became an assistant professor. He collaborated with Tie- mann. Reissert later joined the faculty at Marburg in 1902. 2. Popp, F. D. Adv. Heterocycl. Chem. 1979, 24, 187–214. (Review). 3. Schwartz, A. J. Org. Chem. 1982, 47, 2213–2215. 4. Lorsbach, B. A.; Bagdanoff, J. T.; Miller, R. B.; Kurth, M. J. J. Org. Chem. 1998, 63, 2244–2250. 5. Perrin, S.; Monnier, K.; Laude, B.; Kubicki, M.; Blacque, O. Eur. J. Org. Chem. 1999, 297–303. 6. Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 6801–6808. 7. Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun. 2002, 1989–1999. 8. Sieck, O.; Schaller, S.; Grimme, S.; Liebscher, J. Synlett 2003, 337–340. 9. Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491–1508. (Review). 10. Gibson, H. W.; Berg, M. A. G.; Clifton Dickson, J.; Lecavalier, P. R.; Wang, H.; Mer- ola, J. S. J. Org. Chem. 2007, 72, 5759–5770. 11. Fuchs, C.; Bender, C.; Ziemer, B.; Liebscher, J. J. Heterocycl. Chem. 2008, 45, 1651– 1658. 463

Reissert indole synthesis The Reissert indole synthesis involves base-catalyzed condensation of an o- nitrotoluene derivative with an ethyl oxalate, which is followed by reductive cyclization to an indole-2-carboxylic acid derivative.

CO Et B CO2Et 2 H R R R CO2Et O NO2 NO H N CO2H 2 H

OH CH CH EtO O 3 B 2 H OEt

CO2Et NO NO O OEt NO 2 2 2

O O hydrolysis H CO Et CO H NO 2 2 2 NO2

H H O CO2H CO H CO2H OH 2 CO H N N N NH 2 H H 2 H

Example 12

O CO Et 2 MeO MeO KOEt MeO H2, Pd/C CO2Et N N N CO2Et CO2Et 93% N EtOH, 85% NO2 H NO2

Example 23

CO2Et CO2Et KOEt, EtOH H2 (30 psi), PtO2 OK CO2Et NO2 Et2O NO2 HOAc, 41−44% N CO2Et H

Example 3, Furan ring as the masked carbonyl10

Ms Ms O NH O N HCl, EtOH O O O reflux, 84% O Ph Ph

References

1. Reissert, A. Ber. 1897, 30, 1030−1053. 2. Frydman, B.; Despuy, M. E.; Rapoport, H. J. Am. Chem. Soc. 1965, 87, 3530−3531. 3. Noland, W. E.; Baude, F. J. Org. Synth. 1973; Coll. Vol. 567−571. 4. Leadbetter, G.; Fost, D. L.; Ekwuribe, N. N.; Remers, W. A. J. Org. Chem. 1974, 39, 3580−3583. 5. Cannon, J. G.; Lee, T.; Ilhan, M.; Koons, J.; Long, J. P. J. Med. Chem. 1984, 27, 386−389. 6. Suzuki, H.; Gyoutoku, H.; Yokoo, H.; Shinba, M.; Sato, Y.; Yamada, H.; Murakami, Y. Synlett 2000, 1196−1198. 7. Butin, A. V.; Stroganova, T. A.; Lodina, I. V.; Krapivin, G. D. Tetrahedron Lett. 2001, 42, 2031−2036. 8. Katayama, S.; Ae, N.; Nagata, R. J. Org. Chem. 2001, 66, 3474−3483. 9. Li, J.; Cook, J. M. Reissert Indole Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 154−158. (Review). 10. Butin, A. V.; Smirnov, S. K.; Stroganova, T. A.; Bender, W.; Krapivin, G. D. Tetrahe- dron 2006, 63, 474−491.

465

Ring-closing metathesis (RCM)

Cy P 3 N Cy P Ph F3C 3 Ph Cl Ru F3C Mo Cl Ru Cl O Ph O Cl Mes Mes F C PCy3 NN 3 F C 3 Grubbs’ catalysts Schrock’s catalyst Mes = mesityl All three catalysts are illustrated as “LnM=CHR” in the mechanism below.

Generation of the real catalyst from the precatalysts:

R LnM CHR LnM

the active catalyst

LnM CHR [2 + 2] LnM CHR cycloreversion MLn CHR cycloaddition

[2 + 2] cycloreversion MLn LnM cycloaddition

Catalytic cycle:

LnM

LnM L M [2 + 2] n cycloreversion MLn cycloaddition

[2 + 2] MLn cycloreversion L M cycloaddition n

Example 13

10 mol% (PCy3)2Cl2Ru=CHPh

0.3 eq. Ti(Oi-Pr)4 O O C11H23 O O C11H23 CH Cl , 40 oC, 93% 2 2

Example 25

Cy P 3 Ph Cl Ru E Cl E EE Mes NNMes

45 oC, 60 min., 100%

E = CO2Et

Example 37

MesN NMes Cl cat. = Ru O Cl O O O O O O 1. cat. PhH (0.07 mM) 80 oC, then air

2. 10% Pd/C, H , EtOAc, rt OBn 2 OBn 80−85%

Example 49 Cy P 3 Ph Cl Ru Cl OBz Mes Mes O NN O H 5.4 mol% H O O CH2Cl2, rt, 73% OBz H

Cy P 3 Ph Cl Ru Cl Mes N N Mes 5 mol% O H CH Cl , rt, 93%, > 10:1 E:Z O 2 2 OBz

467

Example 510

TBSO 15 mol% Grubbs II O O TBSO O O O toluene, 110 oC, 78% single O O O isomer TES O OTES

Example 612

1. 1 mol%

N N Mo Ph O Cl Cl N N TBSO

PhH, rt, 1 h N N H H 2. H2, Pd/C, 81%, 96% ee

References

1. Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875–3886. Richard Schrock is a professor at MIT. He shared the 2005 Nobel Prize in Chemistry with Robert Grubbs of Caltech and Yves Chauvin of Institut Français du Pétrole in France for their contributions to metathesis. 2. Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446–452. (Review). 3. Scholl, M.; Tunka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247–2250. 4. Fellows, I. M.; Kaelin, D. E., Jr.; Martin, S. F. J. Am. Chem. Soc. 2000, 122, 10781– 10787. 5. Timmer, M. S. M.; Ovaa, H.; Filippov, D. V.; van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett. 2000, 41, 8635–8638. 6. Thiel, O. R. Alkene and alkyne metathesis in organic synthesis. In Transition Metals for Organic Synthesis (2nd Edn.), 2004, 1, pp 321–333. (Review). 7. Smith, A. B., III; Basu, K.; Bosanac, T. J. Am. Chem. Soc. 2007, 129, 14872–14874. 8. Hoveyda, A.H.; Zhugralin, A. R. Nature 2007, 450, 243–251. (Review). 9. Marvin, C. C.; Clemens, A. J. L.; Burke, S. D. Org. Lett. 2007, 9, 5353–5356. 10. Keck, G. E.; Giles, R. L.; Cee, V. J.; Wager, C. A.; Yu, T.; Kraft, M. B. J. Org. Chem. 2008, 73, 9675–9691. 11. Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Chem. Eur. J. 2008, 14, 5716–5726. (Review). 12. Sattely, E. S.; Meek, S. J.; Malcolmson, S. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 943–953. 468

Ritter reaction Amides from nitriles and alcohols in strong acids. General scheme:

O H 1 2 R1 R OH R CN N R2 H

e.g.: O H2SO4 OH H3CCN N H O H 2

:N H E1 OH OH2 H2O N

nitrilium ion : OH2 O OH2 H OH N N N N H

Similarly:

O H2SO4 H3CCN H O N 2 H

Example 13

H MeOCHN OH H

H2SO4

MeCN Cr Cr OC CO 89% OC CO CO CO

Example 24

CH3 CH3 t-BuOH, conc. H2SO4 O N − o N CN 70 75 C, 75 min., 97% HN

Example 35

NO2

NO2 Pt electrode, E = 2.5 V CH3CN, LiClO4 O

O H2O, 56%, dr 8:2 O2N N H OH O2N

Example 46

fuming H SO CH CN, rt, 30 min., 2 4, 3 OH

O o then H2O, 100 C, 2 h, 77% NH2

References

1. (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045−4048. (b) Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048−4050. 2. Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213–329. (Review). 3. Top, S.; Jaouen, G. J. Org. Chem. 1981, 46, 78−82. 4. Schumacher, D. P.; Murphy, B. L.; Clark, J. E.; Tahbaz, P.; Mann, T. A. J. Org. Chem. 1989, 54, 2242−2244. 5. Le Goanvic, D; Lallemond, M.-C.; Tillequin, F.; Martens, T. Tetrahedron Lett. 2001, 42, 5175−5176. 6. Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 5906−5925. 7. Nair, V.; Rajan, R.; Rath, N. P. Org. Lett. 2002, 4, 1575−1577. 8. Concellón, J. M.; Riego, E.; Suárez, J. R.; García-Granda, S.; Díaz, M. R. Org. Lett. 2004, 6, 4499−4501. 9. Penner, M.; Taylor, D.; Desautels, D.; Marat, K.; Schweizer, F. Synlett 2005, 212−216. 10. Brewer, A. R. E. Ritter reaction. In Name Reactions for Functional Group Transfor- mations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 471−476. (Review). 11. Baum, J. C.; Milne, J. E.; Murry, J. A.; Thiel, O. R. J. Org. Chem. 2009, 74, 2207−2209.

470

Robinson annulation Michael addition of cyclohexanones to methyl vinyl ketone followed by intramolecular aldol condensation to afford six-membered α,β-unsaturated ketones.

O O O base

R R

methyl vinyl ketone (MVK)

O O O enolate O Michael isomerization R addition H formation R R O : B :B HB H − H O O aldol HO 2 O O addition dehydration O R R R

Example 1, Homo-Robinson7

MVK, AcOH, BF3•OEt2 NaOMe 98% − o O 20 C, 97% O O TMSO

1.5 equiv Et2Zn 2.5 equiv LDA, TMSCl 1.1 equiv CH2I2

o THF, −78 oC Et2O, 0 C TMSO

o 1. 2.5 equiv FeCl3, 0 C 2. NaOAc, reflux

40% for 4 steps TMSO O

Example 28

O 3 equiv TfOH, P O O 4 10 O CH2Cl2, microwave 40 oC, 8 h, 57%

Example 3, Double Robinson-type cyclopentene annulation9

O OH 10 equiv CO2R

0.1 equiv FeCl3•6H2O RO2C o CH2Cl2, 60 C, 2 d OH O O O CO2R conc. H2SO4 0 oC, 1 h RO2C CO2R RO C then rt, 16 h 2 O O O

Example 410

O O O

CN DBU, tol., reflux, 20 h,16% NC

References

1. Rapson, W. S.; Robinson, R. J. Chem. Soc. 1935, 1285–1288. Robert Robinson used the Robinson annulaton in his total synthesis of cholesterol. Here is a story told by Derek Barton about Robinson and Woodward: “By pure chance, the two great men met early in a Monday morning on an Oxford train station platform in 1951. Robinson politely asked Woodward what kind of research he was doing these days; Woodward replied that he thought that Robinson would be interested in his recent total synthesis of cholesterol. Robinson, incensed and shouting ‘Why do you always steal my research topic?’, hit Woodward with his umbrella.”—An excerpt from Barton, Derek, H. R. Some Recollections of Gap Jumping, American Chemical Society, Washington, D.C., 1991. 2. Gawley, R. E. Synthesis 1976, 777–794. (Review). 3. Guarna, A.; Lombardi, E.; Machetti, F.; Occhiato, E. G.; Scarpi, D. J. Org. Chem. 2000, 65, 8093–8096. 4. Tai, C.-L.; Ly, T. W.; Wu, J.-D.; Shia, K.-S.; Liu, H.-J. Synlett 2001, 214–217. 5. Jung, M. E.; Piizzi, G. Org. Lett. 2003, 5, 137–140. 6. Singletary, J. A.; Lam, H.; Dudley, G. B. J. Org. Chem. 2005, 70, 739–741. 7. Yun, H.; Danishefsky, S. J. Tetrahedron Lett. 2005, 46, 3879–3882. 8. Jung, M. E.; Maderna, A. Tetrahedron Lett. 2005, 46, 5057–5061. 9. Zhang, Y.; Christoffers, J. Synthesis 2007, 3061–3067. 10. Jahnke, A.; Burschka, C.; Tacke, R.; Kraft, P. Synthesis 2009, 62–68. 472

Robinson–Gabriel synthesis Cyclodehydration of 2-acylamidoketones to give 2,5-di- and 2,4,5-trialkyl, aryl, heteroaryl-, and aralkyloxazoles.

R2 R − H O 2 HN 2 N R3 R R3 1 O O R1 O

R1, R2, R3 = alkyl, aryl, heteroaryl

H R2 H R2 R − 2 N N H2O N R3 R3 R R3 1 O O R1 O OH R1 O

Example 13

O O H H N Ph3P, I2, Et3N O H N O H CbzHN O 55% O CbzHN O

Example 24

OTIPS O OMe H MeO O N N H O HO

OH − 1. Dess Martin, CH2Cl2 O 2. Ph3P, BrCCl2CCl2Br OMe N R O N 3. DBU, CH3CN 4. TBAF, THF OMe H O 42% (+)-hennoxazole A

Example 3, Halogen effect9

O H 2 equiv PPh3 N O N H CCl4, MeCN O reflux, 97% N N

O H 2 equiv PPh3 N O N Br H CBr4, MeCN O reflux, 68% N N

Example 410

1. PPh3, C2Br2Cl4, CH2Cl2 N O CHO 2,6-di-tert-butylpyridine N O NaHCO , CH Cl , 0 oC OTBS OTBS 3 2 2 O N O N H o TBDPSO 2. Et3N, MeCN, 0 C to rt TBDPSO 89% for 2 steps

References

1. (a) Robinson, R. J. Chem. Soc. 1909, 95, 2167−2174. (b) Gabriel, S. Ber. 1910, 43, 134−138. (c) Gabriel, S. Ber. 1910, 43, 1283−1287. 2. Turchi, I. J. In The Chemistry of Heterocyclic Compounds, 45; Wiley: New York, 1986; pp 1−342. (Review). 3. Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604−3606. 4. Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558−559. 5. Morwick, T.; Hrapchak, M.; DeTuri, M.; Campbell, S. Org. Lett. 2002, 4, 2665−2668. 6. Nicolaou, K. C.; Rao, P. B.; Hao, J.; Reddy, M. V.; Rassias, G.; Huang, X.; Chen, D. Y.-K.; Snyder, S. A. Angew. Chem., Int. Ed. 2003, 42, 1753−1758. 7. Godfrey, A. G.; Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.; Mitchell, D. J. Org. Chem. 2003, 68, 2623−2632. 8. Brooks, D. A. Robinson–Gabriel Synthesis. In Name Reactions in Heterocyclic Chem- istry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 249−253. (Re- view). 9. Yang, Y.-H.; Shi, M. Tetrahedron Lett. 2005, 46, 6285–6288. 10. Bull, J. A.; Balskus, E. P.; Horan, R. A. J.; Langner, Martin; Ley, Steven V. Angew. Chem., Int. Ed. 2006, 45, 6714−6718. 474

Robinson−Schöpf reaction 1,4-Diketone condensations with primary amines to give tropinones.

CO2H N CHO

NH2 O 2 CO2↑ 2 H2O CHO CO2H O

H O NH : 2 HN: HO C CO H H − 2 2 imine H2O O OH formation N CHO CHO CHO O O H O HO2C CO2H HO2C CO2H − HO2C CO2H H2O : :N N H N H OH O hemiaminal O N H N O decarboxylation ↑ CO2

HO2C HO C O 2 OH

N N N ↑ CO2

O O O OH O H

Example 15

Ph MeO OMe Ph O − OH KCN, citric acid, H2O, rt, 24 48 h N O H NC NH2 then EtOH, reflux, 96 h

Example 29

O CHO CHO CO2H N THF, rt NH2 O 72 h, 51%

OH CO2H OH

References

1. Robinson, R. J. Chem. Soc. 1917, 111, 762–768. 2. Paquette, L. A.; Heimaster, J. W. J. Am. Chem. Soc. 1966, 88, 763–768. 3. Büchi, G.; Fliri, H.; Shapiro, R. J. Org. Chem. 1978, 43, 4765–4769. 4. Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H. P. J. Am. Chem. Soc. 1983, 105, 7754–7755. 5. Royer, J.; Husson, H. P. Tetrahedron Lett. 1987, 28, 6175–6178. 6. Villacampa, M.; Martínez, M.; González-Trigo, G.; Söllhuber, M. M. J. Heterocycl. Chem. 1992, 29, 1541–1544. 7. Bermudez, J.; Gregory, J. A.; King, F. D.; Starr, S.; Summersell, R. J. Bioorg. Med. Chem. Lett. 1992, 2, 519–522. 8. Langlois, M.; Yang, D.; Soulier, J. L.; Florac, C. Synth. Commun. 1992, 22, 3115– 3116. 9. Jarevång, T.; Anke, H.; Anke, T.; Erkel, G.; Sterner, O. Acta Chem. Scand. 1998, 52, 1350–1352. 10. Amedjkouh, M.; Westerlund, K. Tetrahedron Lett. 2004, 45, 5175–5177.

476

Rosenmund reduction

Hydrogenation reduction of acid chloride to aldehyde using BaSO4-poisoned palladium catalyst. Without this poisoning, the resulting aldehyde may be further reduced to the corresponding alcohol.

O H2 O R Cl − Pd BaSO4 R H

Pd Pd Pd Pd Pd Pd H Pd H HH HH HH

O Pd(0) O H Pd H Cl R Cl oxidative R Pd ligand exchange addition

O reductive O H Pd(0) R Pd elimination R H

Example 14

H2/Pd or Pd/BaSO4 O 2,6-dimethylpyridine, THF O R Cl − − R H or H2/Pd C/quinoline S, PhH 74−97%

Example 26

NBoc NBoc2 Me2N 2 Cl HO CO t-Bu CO2t-Bu Cl 2 O O

H2, 5% Pd/C NBoc2 2,6-lutidine H CO2t-Bu THF, 2 h, 78% O

Example 39

O 1. SOCl2, cat. DMF, reflux, 4 h OH 2. H2, 5% Pd/C, EtOAc, 53%

O H

References

1. Rosenmund, K. W. Ber. 1918, 51, 585–594. Karl Wilhelm Rosenmund was born in Berlin, Germany in 1884. He was a student of Otto Diels and received his Ph.D. In 1906. Rosenmund became professor and director of the Pharmaceutical Institute in Kiel in 1925. 2. Mosettig, E.; Mozingo, R. Org. React. 1948, 4, 362–377. (Review). 3. Tsuji, J.; Ono, K.; Kajimoto, T. Tetrahedron Lett. 1965, 6, 4565–4568. 4. Burgstahler, A. W.; Weigel, L. O.; Schäfer, C. G. Synthesis 1976, 767–768. 5. McEwen, A. B.; Guttieri, M. J.; Maier, W. F.; Laine, R. M.; Shvo, Y. J. Org. Chem. 1983, 48, 4436–4438. 6. Bold, V. G.; Steiner, H.; Moesch, L.; Walliser, B. Helv. Chim. Acta 1990, 73, 405– 410. 7. Yadav, V. G.; Chandalia, S. B. Org. Proc. Res. Dev. 1997, 1, 226–232. 8. Chandnani, K. H.; Chandalia, S. B. Org. Proc. Res. Dev. 1999, 3, 416–424. 9. Chimichi, S.; Boccalini, M.; Cosimelli, B. Tetrahedron 2002, 58, 4851–4858. 10. Ancliff, R. A.; Russell, A. T.; Sanderson, A. J. Chem. Commun. 2006, 3243–3245.

478

Rubottom oxidation α-Hydroxylation of enolsilanes.

O OSiR3 1. m-CPBA OH

2. K2CO3, H2O

Ar ‡ Ar R Si O 3 O O Prilezhaev O O O H R SiO O H R3SiO 3 O epoxidation H

The “butterfly” transition state

R3Si H SiR3 O :O O O K2CO3, H2O OH OH hydrolysis

Example 12

2.5 eq m-CPBA O OSiMe3 OH ClCH CH Cl CO2Me 2 2 N N CO2Me 0 oC to rt, 1 h, 80%

Example 23

o OH TMSCl, NaI 1. m-CPBA, NaHCO3, pentane, 0 C

o Et3N, rt, 91% 2. aq. K2CO3, 0 C, 20 h, 80% O OTMS O

Example 34

OTBS OTBS OTBS TMSO O O m-CPBA TMSO SiO2 HO TMSO TMSO 63% TMSO

Example 45

Me Me H Me H Me 1. LDA, TMSCl 2. m-CPBA, NaHCO3 H H HO 3. K CO , MeOH H H 2 3 72% O Me O Me

References

1. Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron Lett. 1974, 15, 4319−4322. George Rubottom discovered the Rubottom oxidation when he was an assistant professor at the University of Puerto Rico. He is now a grant officer at the National Science Foundation. 2. Andriamialisoa, R. Z.; Langlois, N.; Langlois, Y. Tetrahedron Lett. 1985, 26, 3563−2366. 3. Jauch, J. Tetrahedron 1994, 50, 12903−12912. 4. Crimmins, M. T.; Al-awar, R. S.; Vallin, I. M.; Hollis, W. G., Jr.; O’Mahoney, R.; Lever, J. G.; Bankaitis-Davis, D. M. J. Am. Chem. Soc. 1996, 118, 7513–7528. 5. Paquette, L. A.; Sun, L.-Q.; Friedrich, D.; Savage, P. B. Tetrahedron Lett. 1997, 38, 195–198. 6. Paquette, L. A.; Hartung, R. E.; Hofferberth, J. E.; Vilotijevic, I.; Yang, J. J. Org. Chem. 2004, 69, 2454−2460. 7. Christoffers, J.; Baro, A.; Werner, T. Adv. Synth. Cat. 2004, 346, 143−151. (Review). 8. He, J.; Tchabanenko, K.; Adlington, R. M.; Cowley, A. R.; Baldwin, J. E. Eur. J. Org. Chem. 2006, 4003−4013. 9. Wolfe, J. P. Rubottom oxidation. In Name Reactions for Functional Group Transfor- mations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 282−290. (Review). 10. Wang, H.; Andemichael, Y. W.; Vogt, F. G. J. Org. Chem. 2009, 74, 478−481.

480

Rupe rearrangement Acid-catalyzed rearrangement of tertiary α-acetylenic (terminal) alcohols, leading to the formation of α,β-unsaturated ketones rather than the corresponding α,β- unsaturated aldehydes. Cf. Meyer−Schuster rearrangement.

O OH + H , H2O

H OH OH2 − − H H2O H dehydration H

H O: 2 : OH O protonation H H tautomerization

H H H

Example 14

O conc. H2SO4

OH CHCl , HOAc, reflux, 1 h 3

Example 28

O OH CH3 Me Me HCO2H, reflux 15 min., 42%

Example 39 O OH H3C A-252C H+ resin H3C EtOAc, reflux H H

H H 4 h, 78% H O O

References

1. Rupe, H.; Kambli, E. Helv. Chim. Acta 1926, 9, 672. 2. Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429−438. (Review). 3. Hasbrouck, R. W.; Anderson Kiessling, A. D. J. Org. Chem. 1973, 38, 2103−2106. 4. Baran, J.; Klein, H.; Schade, C.; Will, E.; Koschinsky, R.; Bäuml, E.; Mayr, H. Tetra- hedron 1988, 44, 2181−2184. 5. Barre, V.; Massias, F.; Uguen, D. Tetrahedron Lett. 1989, 30, 7389–7392. 6. An, J.; Bagnell, L.; Cablewski, T.; Strauss, C. R.; Trainor, R. W. J. Org. Chem. 1997, 62, 2505–2511. 7. Yadav, J. S.; Prahlad, V.; Muralidhar, B. Synth. Commun. 1997, 27, 3415−3418. 8. Takeda, K.; Nakane, D.; Takeda, M. Org. Lett. 2000, 2, 1903–1905. 9. Weinmann, H.; Harre, M.; Neh, H.; Nickisch, K.; Skötsch, C.; Tilstam, U. Org. Proc. Res. Dev. 2002, 6, 216−219. 10. Mullins, R. J.; Collins, N. R. Meyer–Schuster Rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 305−318. (Review).

482

Saegusa oxidation Palladium-catalyzed conversion of enol silanes to enones, also known as the Saegusa enone synthesis.

Me Si 3 O O 0.5 Pd(OAc)2 0.5 p-benzoquinone Me benzene, rt, 3 h, 91% Me

The mechanism is similar to that of the Wacker oxidation (page 564).

AcO AcO Pd(II) OAc Me Si Me3Si O 3 O: O Pd(II) OAc Me OSiMe3

Me Me O O O H Pd(II) OAc β-hydride Pd(0) HOAc Pd OAc H elimination Me Me Me

Regenerating the Pd(II) oxidant: O OH

Pd(OAc) Pd(0) 2 HOAc 2

O OH

Larock reported regeneration of the Pd(II) oxidant using oxygen:4

O HOAc Pd(0) O2 Pd HOOPdOAc O O

OSiMe 3 HOOSiMe Pd(II)(OAc) 3 2

Example 13

OMe OMe O O O O Me3SiCl, Et3N O TMSO H H CH3OCH2CH2OCH3 rt, 3 h, 74% O O O O H H

OMe O O Pd(OAc) , p-benzoquinone 2 O o H CH3CN, rt, 60 C, 53% O O H

Example 28

O O O LDA, TBSCl Pd(OAc)2, O2 O O HMPA−THF O DMSO, 80 oC o −78 to 0 C, 93% 48 h, 77% O O OTBS

Example 310

H OTES O Me Pd(OAc)2, DMSO Me

0 oC to rt, 12 h, 81% Me Me O O

References

1. Ito, Y.; Hirao, T.; Saegusa, T.; J. Org. Chem. 1978, 43, 1011–1013. 2. Dickson, J. K., Jr.; Tsang, R.; Llera, J. M.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 5350–5356. 3. Kim, M.; Applegate, L. A.; Park, O.-S.; Vasudevan, S.; Watt, D. S. Synth. Commun. 1990, 20, 989–997. 4. Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng, D. Tetrahedron Lett. 1995, 36, 2423–2426. 5. Porth, S.; Bats, J. W.; Trauner, D.; Giester, G.; Mulzer, J. Angew. Chem., Int. Ed. 1999, 38, 2015–2016. The authors proposed a sandwiched Pd(II) as a possible alternative pathway. 6. Williams, D. R.; Turske, R. A. Org. Lett. 2000, 2, 3217–3220. 7. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596–7597. 8. Kadota, K.; Kurusu, T.; Taniguchi, T.; Ogasawara, K. Adv. Synth. Catal. 2001, 343, 618–623. 9. Sha, C.-K.; Huang, S.-J.; Zhan, Z.-P. J. Org. Chem. 2002, 67, 831–836. 10. Angeles A. R; Waters, S. P.; Danishefsky S. J. J. Am. Chem. Soc. 2008, 130, 13765– 13770.

484

Sakurai allylation reaction Lewis acid-mediated addition of allylsilanes to carbon nucleophiles. Also known as the Hosomi–Sakurai reaction. The allylsilane will add to the carbonyl compound directly if the electrophile (carbonyl group) is not part of an α,β- unsaturated system (Example 2), giving rise to an alcohol.

O O TiCl4 SiMe3

TiCl O 3 TiCl4 Cl TiCl3

: Michael complexation O O addition

SiMe3 SiMe3 Cl The β-carbocation is stabilized by the β-silicon effect

TiCl O 3 O silicon H2O Me3Si Cl cleavage workup

Example 12

TMS EtAlCl2, Tol.

0 oC, 50% O O

Example 26

OH O O CHO TiCl , CH Cl Br 4 2 2 SiMe3 Br rt, 10 min., 67% 9:1 dr OTIPS OTIPS

Example 39

SiMe3

Me H OPMB H CHO Ba(OH)2•8H2O H3C OPMB BF3•OEt2 H H OH O o 0 oC, 2 h, 62% O OC(O)CO Me −78 C, 4 h H 2 H CO2Et Me OPMB OHC H OC(O)CO2Me CO2Et H

Example 410

H HO H H O H O SiMe3 BnN NBn BnN NBn BF3•OEt2, CH2Cl2 rt, 64% O O OH

References

1. Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 1295–1298. 2. Majetich, G.; Behnke, M.; Hull, K. J. Org. Chem. 1985, 50, 3615–3618. 3. Tori, M.; Makino, C.; Hisazumi, K.; Sono, M.; Nakashima, K. Tetrahedron: Asymme- try 2001, 12, 301–307. 4. Leroy, B.; Markó, I. E. J. Org. Chem. 2002, 67, 8744–8752. 5. Itsuno, S.; Kumagai, T. Helv. Chim. Acta 2002, 85, 3185–3196. 6. Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2003, 125, 13155–13164. 7. Knepper, K.; Ziegert, R. E.; Bräse, S. Tetrahedron 2004, 60, 8591–8603. 8. Rikimaru, K.; Mori, K.; Kan, T.; Fukuyama, T. Chem. Commun. 2005, 394–396. 9. Kalidindi, S.; Jeong, W. B.; Schall, A.; Bandichhor, R.; Nosse, B.; Reiser, O. Angew. Chem., Int. Ed. 2007, 46, 6361–6363. 10. Norcross, N. R.; Melbardis, J. P.; Solera, M. F.; Sephton, M. A.; Kilner, C.; Zakharov, L. N.; Astles, P. C.; Warriner, S. L.; Blakemore, P. R. J. Org. Chem. 2008, 73, 7939– 7951.

486

Sandmeyer reaction Haloarenes from the reaction of a diazonium salt with CuX.

CuX ArN2 Y Ar X X = Cl, Br, CN

e.g.: CuCl N ↑ Ar CuCl Ar Cl CuCl ArN2 Cl 2 2

Example 14

Cl Cl Cl 1. FeCl3 DMSO, rt N Cl Cl 2 N2 CuCl4 2. CuCl2 97% 81% Cl Cl Cl 2

Example 27

CF CF3 3 CF3

1. H2SO4 CuCN, NaCN N 2. NaNO N Na CO , 50% NH2 2 2 3 CN Cl Cl Cl

Example 38

OMe OMe NaNO2, CuBr OH OH 55% H N Br 2

Example 49

1. HOAc, H O, H SO 2 2 4 O NO O NO2 reflux, 2 h 2 O o 2. NaNO2, 0 C N N 3. CuCN, 50 oC NC N H O 50−58% O

References

1. Sandmeyer, T. Ber. 1884, 17, 1633. Traugott Sandmeyer (1854−1922) was born in Wettingen, Switzerland. He apprenticed under Victor Meyer and Arthur Hantzsch although he never took a doctorate. He later spent 31 years at the company J. R. Geigy, which is now part of Novartis. 2. Suzuki, N.; Azuma, T.; Kaneko, Y.; Izawa, Y.; Tomioka, H.; Nomoto, T. J. Chem. Soc., Perkin Trans. 1 1987, 645–647. 3. Merkushev, E. B. Synthesis 1988, 923–937. (Review). 4. Obushak, M. D.; Lyakhovych, M. B.; Ganushchak, M. I. Tetrahedron Lett. 1998, 39, 9567–9570. 5. Hanson, P.; Jones, J. R.; Taylor, A. B.; Walton, P. H.; Timms, A. W. J. Chem. Soc., Perkin Trans. 2 2002, 1135–1150. 6. Daab, J. C.; Bracher, F. Monatsh. Chem. 2003, 134, 573–583. 7. Nielsen, M. A.; Nielsen, M. K.; Pittelkow, T. Org. Proc. Res. Dev. 2004, 8, 1059– 1064. 8. Kim, S.-G.; Kim, J.; Jung, H. Tetrahedron Lett. 2005, 46, 2437–2439. 9. LaBarbera, D. V.; Bugni, T. S.; Ireland, C. M. J. Org. Chem. 2007, 72, 8501–8505. 10. Gehanne, K.; Lancelot, J.-C.; Lemaitre, S.; El-Kashef, H.; Rault, S. Heterocycles 2008, 75, 3015–3024.

488

Schiemann reaction Fluoroarene formation from arylamines. Also known as the Balz−Schiemann reaction.

Ar NH2 HNO2 HBF4

Δ ↑ ArN2 BF4 Ar F N2 BF3

N N HBF4 N HO O N N HO O H2O O: H2ONO O O O

N N H : O O O H N OH : N OH 2

: O Ar N Ar N Ar N NH Ar N 2

Δ ↑ Ar Ar F BF H2O Ar N N ArN N2 FBF3 3 2 BF4

Example 14

F NH2 NaNO2, HBF4, H2O N N N N −10 to 0 oC, 25% N F N N F N R R β R = 2,3-5-tri-O-acetyl- -D-ribofuranose

Example 2, Photo-Schiemann reaction6

F F F F NHBoc 1. HBF4 2. NaNO2 HN N HN N HN N 3. hv 8% 36%

Example 3, Photo-Schiemann reaction8

BF −N + hv + − 4 2 CO2Et F CO2Et H2N CO2Et NO BF4 [bmim][BF ] [bmim][BF ] HN N 4 HN N HN N 4 0 oC, 24 h, 56%

Example 410

− + o F NH2 N2 BF4 160−200 C NaNO2

HBF sand, 67% CO2Me CO2Me 4 S CO2Me S S 93%

References

1. Balz, G.; Schiemann. G. Ber. 1927, 60, 1186−1190. Günther Schiemann was born in Breslau, Germany in 1899. In 1925, he received his doctorate at Breslau, where he became an assistant professor. In 1950, he became the Chair of Technical Chemistry at Istanbul, where he extensively studied aromatic fluorine compounds. 2. Roe, A. Org. React. 1949, 5, 193−228. (Review). 3. Sharts, C. M. J. Chem. Educ. 1968, 45, 185−192. (Review). 4. Montgomery, J. A.; Hewson, K. J. Org. Chem. 1969, 34, 1396−1399. 5. Laali, K. K.; Gettwert, V. J. J. Fluorine Chem. 2001, 107, 31−34. 6. Dolensky, B.; Takeuchi, Y.; Cohen, L. A.; Kirk, K. L. J. Fluorine Chem. 2001, 107, 147−152. 7. Gronheid, R.; Lodder, G.; Okuyama, T. J. Org. Chem. 2002, 67, 693−720. 8. Heredia-Moya, J.; Kirk, K. L. J. Fluorine Chem. 2007, 128, 674−678. 9. Gribble, G. W. Balz-Schiemann reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 552−563. (Review). 10. Pomerantz, M.; Turkman, N. Synthesis 2008, 2333−2336.

490

Schmidt rearrangement The Schmidt reactions refer to the acid-catalyzed reactions of hydrazoic acid with electrophiles, such as carbonyl compounds, tertiary alcohols and alkenes. These substrates undergo rearrangement and extrusion of nitrogen to furnish amines, nitriles, amides or imines.

O HN3 O 1 R N2↑ 1 2 2 R R + R N H H

N N O H N N H O HN3 HO N3 H HO N 2O NH 1 2 R R 1 2 R1 R2 R R 1 2 R1 R2 R R azido-alcohol

1 1 R − R 1 2 H2O R R N ↑ N: N N N2 R2 migration : H2O nitrilium ion intermediate (Cf. Ritter intermediate)

1 O HO R tautomerization R1 H N R2 N 2 R H

Example 1, A classic example3

O H NaN N CO2Et CO2Et 3 O MeSO3H 21%

Example 25

O H O N NaN3, H2SO4

CHCl , 92% 3

Example 3, Intramolecular Schmidt rearrangement6

OH TfOH, CH2Cl2 OH

o N O 0 C, 79% O N 3

Example 4, Intramolecular Schmidt rearrangement8

H O H O O N O TiCl4 H 82% Et Et

Example 5, Intermolecular Schmidt rearrangement9

O H NC O HO C HO2C N O 2 NH

N N N NaN3, CHCl3

conc. H2SO4 84% 0% OMe OMe OMe

References

1. (a) Schmidt, K. F. Angew. Chem. 1923, 36, 511. Karl Friedrich Schmidt (1887−1971) collaborated with Curtius at the University of Heidelberg, where Schmidt became a Professor of Chemistry after 1923. (b) Schmidt, K. F. Ber. 1924, 57, 704−706. 2. Wolff, H. Org. React. 1946, 3, 307−336. (Review). 3. Tanaka, M.; Oba, M.; Tamai, K.; Suemune, H. J. Org. Chem. 2001, 66, 2667−2573. 4. Golden, J. E.; Aubé, J. Angew. Chem., Int. Ed. 2002, 41, 4316−4318. 5. Johnson, P. D.; Aristoff, P. A.; Zurenko, G. E.; Schaadt, R. D.; Yagi, B. H.; Ford, C. W.; Hamel, J. C.; Stapert, D.; Moerman, J. K. Bioorg. Med. Chem. Lett. 2003, 13, 4197−4200. 6. Wrobleski, A.; Sahasrabudhe, K.; Aubé, J. J. Am. Chem. Soc. 2004, 126, 5475−5481. 7. Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260−11261. 8. Iyengar, R.; Schidknegt, K.; Morton, M..; Aubé, J. J. Org. Chem. 2005, 70, 10645−10652. 9. Amer, F. A.; Hammouda, M.; El-Ahl, A. A. S.; Abdel-Wahab, B. F. Synth. Commun. 2009, 39, 416−425. 10. Wu, Y.-J. Schmidt reactions. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 353−372. (Review). 492

Schmidt’s trichloroacetimidate glycosidation reaction Lewis acid-promoted glycosidation of trichloroacetimidates with alcohols or phenols.

HN CCl 3 Ar O OH cat. NaH O O HO Ar O O

AcO OAc Cl CCN • 3 AcO OAc BF3 OEt2 AcO OAc OCH 3 OCH OCH3 3

trichloroacetimidate

N CCl3 H O O H O O • deprotonation BF3 OEt2 ↑ H2 AcO OAc AcO OAc OCH 3 OCH 3

• BF3 OEt2

HN CCl3 neighboring O O O group assistance AcO O CH3O

H OAr: Ar O O O O O

Cl3C NH2 AcO OAc AcO O OCH CH O 3 3

Example 15

HN CCl3 I CO2Me

O O BF •OEt , 4 Å MS I CO2Me 3 2 O O OMe CH Cl , −50 oC, 95% OMe AcO OAc HO OMe 2 2 AcO OAc OCH3 OMe OCH3

Example 27

BnO O OH BnO AcO BnO BnO O O NH BF •OEt 3 2 BnO O CH2Cl2/hexane AcO CCl3 BnO −20 oC, 68%

Example 39

AcO OAc PF6 O HO AcO N H2 AcO O NH − o 0.2 equiv TMSOTf, CH2Cl2, 15 C, 5 min. CCl 3

t-Bu PF AcO OAc 6 O O N AcO t-Bu PF6 AcO O H O O 2 AcO O N AcO H2 AcO 30% 40%

References

1. (a) Grundler, G.; Schmidt, R. R. Carbohydr. Res. 1985, 135, 203−218. (b) Schmidt, R. R. Angew. Chem., Int. Ed. 1986, 25, 212−235. (Review). 2. Smith, A. L.; Hwang, C.-K.; Pitsinos, E.; Scarlato, G. R.; Nicolaou, K. C. J. Am. Chem. Soc. 1992, 114, 3134−3136. 3. Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503−1531. (Review). 4. Nicolaou, K. C. Angew. Chem., Int. Ed. 1993, 32, 1377−1385. (Review). 5. Groneberg, R. D.; Miyazaki, T.; Stylianides, N. A.; Schulze, T. J.; Stahl, W.; Schreiner, E. P.; Suzuki, T.; Iwabuchi, Y.; Smith, A. L.; Nicolaou, K. C. J. Am. Chem. Soc. 1993, 115, 7593−611. 6. Fürstner, A.; Jeanjean, F.; Razon, P. Angew. Chem., Int. Ed. 2002, 41, 2097−2101. 7. Yan, L. Z.; Mayer, J. P. J. Org. Chem. 2003, 68, 1161−1162. 8. Harding, J. R.; King, C. D.; Perrie, J. A.; Sinnott, D.; Stachulski, A. V. Org. Biomol. Chem. 2005, 3, 1501−1507. 9. Steinmann, A.; Thimm, J.; Thiem, J. Eur. J. Org. Chem. 2007, 66, 5506−5513. 10. Coutrot, F.; Busseron, E.; Montero, J.-L. Org. Lett. 2008, 10, 753−756.

494

Shapiro reaction The Shapiro reaction is a variant of the Bamford−Stevens reaction. The former uses bases such as alkyl lithium and Grignard reagents whereas the latter employs bases such as Na, NaOMe, LiH, NaH, NaNH2, etc. Consequently, the Shapiro reaction generally affords the less-substituted olefins (the kinetic products), while the Bamford−Stevens reaction delivers the more-substituted olefins (the thermodynamic products).

R1 R1 H 2 n-BuLi R2 N R2 N Ts E then E R3 R3

Bu R1 R2 N R1 H N Ts H R2 N R3 N Ts H 3 Bu R 1 R1 R 1 − R 2 N2 R2 E R N R2 N E 3 R3 R 3 R

Example 12

NNHTs MeLi, Et2O

98% 2%

Example 23

NNHTs − MeLi, Et2O PhH 75−80%

Example 37

MeO MeO OTBDPS 1. TsNHNH2, MeOH, THF OTBDPS

H H 2. n-BuLi, THF, –78 °C to rt H H O OMe 3. aqueous workup O OMe H H H H 69%

Example 48

1. n-BuLi NHTris O H Me H 2. MgBr2•OEt2 N O O Ph 3. Me HO Me Me Me Me Me O O Ph 55% yield Me one diastereomer

References

1. Shapiro, R. H.; Duncan, J. H.; Clopton, J. C. J. Am. Chem. Soc. 1967, 89, 471–472. Robert H. Shapiro was an assistant professor at the University of Colorado. He was not given tenure despite getting a reaction named after him. 2. Shapiro, R. H.; Heath, M. J. J. Am. Chem. Soc. 1967, 89, 5734–5735. 3. Dauben, W. G.; Lorber, M. E.; Vietmeyer, N. D.; Shapiro, R. H.; Duncan, J. H.; Tomer, K. J. Am. Chem. Soc. 1968, 90, 4762−4763. 4. Shapiro, R. H. Org. React. 1976, 23, 405−507. (Review). 5. Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 55–59. (Review). 6. Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 1−83. (Review). 7. Grieco, P. A.; Collins, J. L.; Moher, E. D.; Fleck, T. J.; Gross, R. S. J. Am. Chem. Soc. 1993, 115, 6078–6093. 8. Tamiya, J.; Sorensen, E. J. Tetrahedron 2003, 59, 6921–6932. 9. Wolfe, J. P. Shapiro reaction. In Name Reactions for Functional Group Transforma- tions; Li, J. J., Corey, E. J., eds, John Wiley & Sons: Hoboken, NJ, 2007, pp 405−413. 10. Bettinger, H. F.; Mondal, R.; Toenshoff, C. Org. Biomol. Chem. 2008, 6, 3000–3004.

496

Sharpless asymmetric amino-hydroxylation Osmium-mediated cis-addition of nitrogen and oxygen to olefins. Regioselectiv- ity may be controlled by ligand. Nitrogen sources (X−NClNa) include:

O R O O S O O NClNa BnO NClNa O TMS NBrLi EtO NClNa NClNa R = p-Tol; Me

chiral ligand 1 1 R K2OsO2(OH)4 R R

R ClNaN−X HO NHX t-BuOH, H2O

The catalytic cycle:

OsO4 ClN−X

R R1 O HO NHX O Os N X L* O

H2O O R O Os N X O L* O R1 O Os N R1 O N X X R

R R ClN−X O O R1 O Os O Os N N R1 O * O * L L X X

Example 11b

O O 5 mol% (DHQD)2PHAL 4 mol% K2OsO2(OH)4 NH OH BnO BnO NClNa n-PrOH/H2O (1:1), 63% ee 51%

(DHQD)2-PHAL = 1,4-bis(9-O-dihydroquinidine)phthalazine:

N NN N O O H O O

N N

Example 22

BnOCONH2 NaOH, t-BuOCl OH CO Et 2 (DHQD)2AQN CO2Et

K2OsO2(OH)4 NHCbz BnO BnO n-PrOH/H2O (1:1) rt, 12 h, 45%, 87% ee

Example 36

F F F NaOH, urethane K2OsO2(OH)4 (DHQD) PHAL 2 Me Me

1,3-dichloro-5,5-di- HO NH methyl hydantoin HN OH EtO Me n-PrOH/H O OEt 2 O O

1. Cs2CO2, MeOH

2. H SO 2 4 HN O

References

1. (a) Herranz, E.; Sharpless, K. B. J. Org. Chem. 1978, 43, 2544−2548. K. Barry Shar- pless (USA, 1941−) shared the Nobel Prize in Chemistry in 2001 with Herbert Wil- liam S. Knowles (USA, 1917−) and Ryoji Noyori (Japan, 1938−) for his work on chirally catalyzed oxidation reactions. (b) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996, 35, 2813−2817. (c) Rubin, A. E.; Sharpless, K. B. Angew. Chem., Int. Ed. 1997, 36, 2637−2640. (d) Kolb, H. C.; Sharpless, K. B. Tran- sition Met. Org. Synth. 1998, 2, 243−260. (Review). (e) Thomas, A.; Sharpless, K. B. J. Org. Chem. 1999, 64, 8379−8385. (f) Gontcharov, A. V.; Liu, H.; Sharpless, K. B. Org. Lett. 1999, 1, 783−786. 498

2. Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.; Hughes, R.; Natarajan, S.; Jain, N. F.; Ramanjulu, J. M.; Braese, S.; Solomon, M. E. Chem. Eur. J. 1999, 5, 2602−2621. 3. Lohr, B.; Orlich, S.; Kunz, H. Synlett 1999, 1139−1141. 4. Boger, D. L.; Lee, R. J.; Bounaud, P.-Y.; Meier, P. J. Org. Chem. 2000, 65, 6770−6772. 5. Demko, Z. P.; Bartsch, M.; Sharpless, K. B. Org. Lett. 2000, 2, 2221−2223. 6. Barta, N. S.; Sidler, D. R.; Somerville, K. B.; Weissman, S. A.; Larsen, R. D.; Reider, P. J. Org. Lett. 2000, 2, 2821−2824. 7. Bolm, C.; Hildebrand, J. P.; Muñiz, K. In Catalytic Asymmetric Synthesis; 2nd edn., Ojima, I., Ed.; Wiley−VCH: New York, 2000, 399. (Review). 8. Bodkin, J. A.; McLeod, M. D. J. Chem. Soc., Perkin 1 2002, 2733−2746. (Review). 9. Rahman, N. A.; Landais, Y. Cur. Org. Chem. 2000, 6, 1369−1395. (Review). 10. Nilov, D.; Reiser, O. Recent Advances on the Sharpless Asymmetric Aminohydroxyla- tion. In Organic Synthesis Highlights Schmalz, H.-G.; Wirth, T., eds.; Wiley−VCH: Weinheim, Germany 2003, 118−124. (Review). 11. Bodkin, J. A.; Bacskay, G. B.; McLeod, M. D. Org. Biomol. Chem. 2008, 2544−2553. 12. Wong, D.; Taylor, C. M. Tetrahedron Lett. 2009, 50, 1273−1275.

499

Sharpless asymmetric dihydroxylation Enantioselective cis-dihydroxylation of olefins using osmium catalyst in the presence of cinchona alkaloid ligands.

β AD-mix- HO OH (DHQD)2-PHAL R R R S M S RM K2OsO2(OH)4 RL H R R RL H K CO , K Fe(CN) S M 2 3 3 6 RL H (DHQ) -PHAL 2 HO OH AD-mix-α

(DHQ)2-PHAL = 1,4-bis(9-O-dihydroquinine)phthalazine:

N NN N O O

O O

N N

The concerted [3 + 2] cycloaddition mechanism:5

O O O O L O Os O Os Os O O O O O O L L

O [3 + 2]-like hydrolysis HO O OsO cycloaddition O HO L

Example 12

OH OH OH O K2OsO2(OH)4 O (DHQD)2PHAL EtO2C EtO2C K2CO3, MeSO2NH2 OH N N 3 t-BuOH/H2O (1:1) 3 rt, 12 h, 90% de

Example 24

β OH 1. AD-mix- , MeSO2NH2 CO Et CO2Et 2 t-BuOH/H2O (1:1), rt, 12 h ONos BnO 2. NosCl, Et3N, CH2Cl2 BnO o 0 C, 54%, 92% ee Nos = nosylate = 4-nitrobenzenesulfonyl

The catalytic cycle: (the secondary cycle is shut off by maintaining a low concen- tration of olefin): R R

O O O Os O O

R H O R L 2

Secondary cycle low ee R R OH

R R OH low ee R R L R

O R O O O Os L O Os O O O O NMM NMO

H2O

Primary cycle R R OH high ee L R

R OH

high ee

OO Os O O

Example 39

OMe OMe OH Me CO Et Me CO2Et AD-mix-α 2 OH t-BuOH/H O (1:1) O 2 O 93%, 97% ee O O

501

Example 410

K2OsO2(OH)4 OH (DHQD)2PHAL

NMO OH 70% ee acetone/H2O 89%

References

1. (a) Jacobsen, E. N.; Markó, I.; Mungall, W. S.; Schröder, G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968−1970. (b) Wai, J. S. M.; Markó, I.; Svenden, J. S.; Finn, M. G.; Jacobsen, E. N.; Sharpless, K. B. J. Am. Chem. Soc. 1989, 111, 1123−1125. 2. Kim, N.-S.; Choi, J.-R.; Cha, J. K. J. Org. Chem. 1993, 58, 7096−7699. 3. Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483−2547. (Review). 4. Rao, A. V. R.; Chakraborty, T. K.; Reddy, K. L.; Rao, A. S. Tetrahedron Lett. 1994, 35, 5043−5046. 5. Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319−329. (Mechanism). 6. DelMonte, A. J.; Haller, J.; Houk, K. N.; Sharpless, K. B.; Singleton, D. A.; Strassner, T.; Thomas, A. A. J. Am. Chem. Soc. 1997, 119, 9907−9908. (Mechanism). 7. Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024−2032. (Review, Nobel Prize Address). 8. Zhang, Y.; O’Doherty, G. A. Tetrahedron 2005, 61, 6337−6351. 9. Chandrasekhar, S.; Reddy, N. R.; Rao, Y. S. Tetrahedron 2006, 62, 12098−12107. 10. Ferreira, F. C.; Branco, L. C.; Verma, K. K.; Crespo, J. G.; Afonso, C. A. M. Tetrahedron: Asymmetry 2007, 18, 1637−1641. 11. Ramon, R.; Alonso, M.; Riera, A. Tetrahedron: Asymmetry 2007, 18, 2797−2802. 12. Krishna, P. R.; Reddy, P. S. Synlett 2009, 209−212.

502

Sharpless asymmetric epoxidation Enantioselective epoxidation of allylic alcohols using t-butyl peroxide, titanium tetra-iso-propoxide, and optically pure diethyl tartrate.

1 R1 R − − -- R R t-Bu O OH, Ti(Oi Pr)4 O OH OH L-(+)-diethyl tartrate R R2 2

1 1 R R − − R R t-Bu O OH, Ti(Oi-Pr)4 O OH OH D-(−)-diethyl tartrate R R2 2

The catalytic cycle:

Oi-Pr LnTi Oi-Pr

t-Bu−O−OH O OH OH O LnTi O O t-Bu

* O O LnTi O O * LnTi O t-Bu t-Bu

O * ** LnTi O O * O * t-Bu * * LnTi O O t-Bu

The putative active catalyst and the transition state:

EtO O CO2Et OEt EtO2C O CO2Et O O O Oi-Pr Ti Ti OO i-PrO Ti O O i-PrO OO

EtO2C Oi-Pr t-Bu

Example 13

O Ti(Oi-Pr)4, 4 Å MS, (+)-DET Me OH Me OH crude: 88% yield, 92.3 % ee t-BuOOH, CH2Cl2 recrystallization: 73% yield, > 98% ee −20 °C

Example 23

(−)-DIPT, Ti(Oi-Pr) 4 O OH OH TBHP, 3 Å MS − − 50 60%, 88 92% ee

Example 311

OEt H

O L-(+)-DIPT, Ti(Oi-Pr)4 O OH OH H (R,R) NH TBHP, EtOAc 89%, 98% ee (S,S)-reboxetine

Example 412

BnO BnO − O O D-( )-DIPT, Ti(Oi-Pr)4 BnO BnO BnO O BnO TBHP, 4 Å MS BnO BnO OH OH 70%, > 95% ee

504

References

1. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974−5976. (b) Wil- liams, I. D.; Pedersen, S. F.; Sharpless, K. B.; Lippard, S. J. J. Am. Chem. Soc. 1984, 106, 6430−6433. (c) Woodard, S. S.; Finn, M. G.; Sharpless, K. B. J. Am. Chem. Soc. 1991, 113, 106−113. 2. Pfenninger, A. Synthesis 1986, 89−116. (Review). 3. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765−5780. 4. Corey, E. J. J. Org. Chem. 1990, 55, 1693−1694. (Review). 5. Johnson, R. A.; Sharpless, K. B. In Comprehensive Organic Synthesis; Trost, B. M., Ed,; Pergamon Press: New York, 1991; Vol. 7, Chapter 3.2. (Review). 6. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., ed,; VCH: New York, 1993; Chapter 4.1, pp 103−158. (Review). 7. Schinzer, D. Org. Synth. Highlights II 1995, 3. (Review). 8. Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1−299. (Review). 9. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; 2nd ed., Ojima, I., ed.; Wiley-VCH: New York, 2000, 231−285. (Review). 10. Palucki, M. Sharpless−Katsuki Epoxidation. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 50−62. (Review). 11. Henegar, K. E.; Cebula, M. Org. Proc. Res. Dev. 2007, 11, 354−358. 12. Pu, J.; Franck, R. W. Tetrahedron 2008, 64, 8618−8629. 13. Knight, D. W.; Morgan, I. R. Tetrahedron Lett. 2009, 50, 35−38.

505

Sharpless olefin synthesis Olefin synthesis from the syn-oxidative elimination of o-nitrophenyl selenides, which may be prepared using o-nitrophenyl selenocyanate and Bu3P, among other methods.

NO2 SeCN O R R Se R OH Bu3P, THF, rt NO2

R H O Bu3P: : NO2 NO2 SN2 Se Se CN CN PBu3

NO2 Se R PBu R O 3 OPBu3 Se NO 2

NO2 O R syn-elimination Se OH Se R H O NO2

Example 13

OH H H H OH 1. Bu3P, o-O2NPhSeCN, THF, rt 2. CSA, PhH, rt to 70 oC H O

3. m-CPBA, 2,4,6-collidine N o CH2Cl2, 0 C, 42% N H MeO

Example 26

MeO 1. Bu3P, o-O2NPhSeCN MeO O THF, rt, 6 h, 97% O O O OH O O

2. m-CPBA, Et3N, OH o OH CH2Cl2, −78 C 86% OH OH

Example 39

NO2 O SeCN O O O 1. OH O O O n-Bu3P, THF, rt, 78% O H H H OH 2. aq. H O , THF, pyr. H HO 2 2 −40 oC to rt, 90% HO OMe OMe

Example 410

NO2 SeCN HO 1.

H n-Bu P, THF, rt H O 3 O O 2. aq. H O , THF, 40 oC H 2 2 O 90% 2 steps H

References

1. (a) Sharpless, K. B.; Young, M. Y.; Lauer, R. F. Tetrahedron Lett. 1973, 1979−1982. (b) Sharpless, K. B.; Young, M. Y. J. Org. Chem. 1975, 40, 947−949. 2. (a) Grieco, P. A.; Miyashita, M. J. Org. Chem. 1974, 39, 120−122. (b) Grieco, P. A.; Miyashita, M. Tetrahedron Lett. 1974, 1869−1871. (c) Grieco, P. A.; Masaki, Y.; Boxler, D. J. Am. Chem. Soc. 1977, 97, 1597−1599. (d) Grieco, P. A.; Gilman, S.; Ni- shizawa, M. J. Org. Chem. 1976, 41, 1485−1486. (e) Grieco, P. A.; Yokoyama, Y. J. Am. Chem. Soc. 1977, 99, 5210−5219. 3. Smith, A. B., III; Haseltine, J. N.; Visnick, M. Tetrahedron 1989, 45, 2431−2449. 4. Reich, H. J.; Wollowitz, S. Org. React. 1993, 44, 1−296. (Review). 5. Hsu, D.-S.; Liao, C.-C. Org. Lett. 2003, 5, 4741−4743. 6. Meilert, K.; Pettit, G. R.; Vogel, P. Helv. Chim. Acta 2004, 87, 1493−1507. 7. Siebum, A. H. G.; Woo, W. S.; Raap, J.; Lugtenburg, J. Eur. J. Org. Chem. 2004, 2905−2916. 8. Blay, G.; Cardona, L.; Collado, A. M.; Garcia, B.; Morcillo, V.; Pedro, J. R. J. Org. Chem. 2004, 69, 7294−7302. The authors observed the concurrent epoxidation of a tri-subsituted olefin, possibly by the o-nitrophenylselenic acid via an intramolecular process. 9. Paquette, L. A.; Dong, S.; Parker, G. D. J. Org. Chem. 2007, 72, 7135−7147. 10. Yokoe, H.; Yoshida, M.; Shishido, K. Tetrahedron Lett. 2008, 49, 3504−3506. 507

Simmons–Smith reaction

Cyclopropanation of olefins using CH2I2 and Zn(Cu).

CH2I2 Zn(Cu) ICH2ZnI

Zn I CH2 I ICH2ZnI Oxidative addition Simmons−Smith reagent

(ICH ) Zn 2 ICH2ZnI 2 2 ZnI2

I ZnI C I ZnI H2 ZnI2

Example 12

O O Zn/Cu [from Zn and Cu(SO4)2]

CH2I2, Et2O, reflux, 36 h, 90%

Example 2, An asymmetric version3

CONEt2

OH (1 eq) OH

OH CONEt2 OH

6 eq Zn/Cu, 3 eq CH2I2 MeO MeO o CH2Cl2, 0 C, 15 h 78%, 94% ee

Example 3, Diastereoselective Simmons−Smith cyclopropanations of allylic amines and carbamates9

I I NBn2 NBn2 Zn Et2Zn, CH2I2, TFA N Ph CH2Cl2, rt, 1 h Ph 92%, > 98% de

Example 410

O HO HO o 1. PhMe2SiH, RhCl(PPh3)3, 60 C H H o 2. Et2Zn, CH2I2, 0 C O O O 3. TsOH, MeOH O O O 83%, 3 steps

References

1. Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323−5324. Howard E. Simmons (1929−1997) was born in Norfolk, Virginia. He carried out his graduate studies at MIT under John D. Roberts and Arthur Cope. After obtaining his Ph.D. In 1954, he joined the Chemical Department of the DuPont Company, where he discovered the Simmons–Smith reaction with his colleague, R. D. Smith. Simmons rose to be the vice president of the Central Research at DuPont in 1979. His views on physical exercise were the same as those of Alexander Woollcot’s: “If I think about exercise, I know if I wait long enough, the thought will go away.” 2. Limasset, J.-C.; Amice, P.; Conia, J.-M. Bull. Soc. Chim. Fr. 1969, 3981−3990. 3. Kitajima, H.; Ito, K.; Aoki, Y.; Katsuki, T. Bull. Chem. Soc. Jpn. 1997, 70, 207−217. 4. Nakamura, E.; Hirai, A.; Nakamura, M. J. Am. Chem. Soc. 1998, 120, 5844−5845. 5. Loeppky, R. N.; Elomari, S. J. Org. Chem. 2000, 65, 96−103. 6. Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1−415. (Review). 7. Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2003, 125, 2341−2350. 8. Long, J.; Du, H.; Li, K.; Shi, Y. Tetrahedron Lett. 2005, 46, 2737−2740. 9. Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Chem. Com- mun. 2007, 4029−4031. 10. Shan, M.; O’Doherty, G. A. Synthesis 2008, 3171−3179. 11. Kim, H. Y.; Salvi, L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2009, 131, 954−962.

509

Skraup quinoline synthesis

Quinoline from aniline, glycerol, sulfuric acid and oxidizing agent (e.g. PhNO2).

HO OH H2SO4 OH NH2 PhNO2 N

H dehydration HO OH H HO OH CHO HO OH HO OH OH2

glycerol

H H O H O CHO dehydration conjugate H H2O H H addition

: N H N H 2 acrolein

O H OH OH O H intramolecular tautomerization H

: addition N N N H N H H H

OH2 H dehydration oxidation by H , − N PhNO2 H2 N H N H For an alternative mechanism, see that of the Doebner−von Miller reaction (page 196).

Example 15

F H2SO4, FeSO4 F H BO , 80 % F OH 3 3 F HO OH SO3H F NH2 F N

NO2

Example 26

O O H2SO4, H3BO3 OH FeSO4•7H2O HO OH 75 % N O N N O NH2

Example 3, A modified Skraup quinoline synthesis8

O HOAc, reflux H H 8−10 h, 78% MeO N SMe MeO NH2 MeS SMe

References

1. (a) Skraup, Z. H. Monatsh. Chem. 1880, 1, 316. Zdenko Hans Skraup (1850−1910) was born in Prague, Czechoslovakia. He apprenticed under Lieben at the University of Vienna. (b) Skraup, Z. H. Ber. 1880, 13, 2086. 2. Manske, R. H. F.; Kulka, M. Org. React. 1953, 7, 80−99. (Review). 3. Bergstrom, F. W. Chem. Rev. 1944, 35, 77−277. (Review). 4. Eisch, J. J.; Dluzniewski, T. J. Org. Chem. 1989, 54, 1269−1274. 5. Oleynik, I. I.; Shteingarts, V. D. J. Fluorine Chem. 1998, 91, 25−26. 6. Fujiwara, H.; Kitagawa, K. Heterocycles 2000, 53, 409−418. 7. Ranu, B. C.; Hajra, A.; Dey, S. S.; Jana, U. Tetrahedron 2003, 59, 813−819. 8. Panda, K.; Siddiqui, I.; Mahata, P. K.; Ila, H.; Junjappa, H. Synlett 2004, 449−452. 9. Moore, A. Skraup Doebner–von Miller Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 488−494. (Review). 10. Denmark, S. E.; Venkatraman, S. J. Org. Chem. 2006, 71, 1668−1676. Mechanistic study using 13C-labelled α,β-unsaturated ketones. 11. Vora, J. J.; Vasava, S. B.; Patel, Asha D.; Parmar, K. C.; Chauhan, S. K.; Sharma, S. S. E-J. Chem. 2009, 6, 201−206.

511

Smiles rearrangement Intramolecular nucleophilic aromatic rearrangement. General scheme:

Z X strong X Z base YH Y

X = S, SO, SO2, O, CO2 YH = OH, NHR, SH, CH2R, CONHR Z = NO2, SO2R e.g.: NO NO2 O 2 O2 2 S S OH SNAr

O OH

O2 NO2 O2S NO2 S

O O spirocyclic anion intermediate (Meisenheimer complex)

Example 17

O O O Br NH2 H N 2 O HO NaOH, DMA O

O O NaOH, H2O H2O, reflux HO 50 oC N 59%, 3 steps H H N O 2

Example 2, Microwave Smiles rearrangement9

H N O o N O K2CO3, 200 C

μ N NH2 W, NMP, 30 min. N N H 90%

Example 310

MOMO O O I(OAc)2 MOMO O O BnO I AcO OMe OH 2 equiv Na2CO3 OMe OH H2O, rt, 2 h OBn

MOMO O O

DMF, 150 oC I 87% overall OMe O OBn

References

1. Evans, W. J.; Smiles, S. J. Chem. Soc. 1935, 181−188. Samuel Smiles began his career at King’s College London as an assistant professor. He later became professor and chair there. He was elected Fellow of the Royal Society (FRS) in 1918. 2. Truce, W. E.; Kreider, E. M.; Brand, W. W. Org. React. 1970, 18, 99−215. (Review). 3. Gerasimova, T. N.; Kolchina, E. F. J. Fluorine Chem. 1994, 66, 69−74. (Review). 4. Boschi, D.; Sorba, G.; Bertinaria, M.; Fruttero, R.; Calvino, R.; Gasco, A. J. Chem. Soc., Perkin Trans. 1 2001, 1751−1757. 5. Hirota, T.; Tomita, K.-I.; Sasaki, K.; Okuda, K.; Yoshida, M.; Kashino, S. Heterocycles 2001, 55, 741−752. 6. Selvakumar, N.; Srinivas, D.; Azhagan, A. M. Synthesis 2002, 2421−2425. 7. Mizuno, M.; Yamano, M. Org. Lett. 2005, 7, 3629−3631. 8. Bacque, E.; El Qacemi, M.; Zard, S. Z. Org. Lett. 2005, 7, 3817−3820. 9. Bi, C. F.; Aspnes, G. E.; Guzman-Perez, A.; Walker, D. P. Tetrahedron Lett. 2008, 49, 1832−1835. 10. Jin, Y. L.; Kim, S.; Kim, Y. S.; Kim, S.-A.; Kim, H. S. Tetrahedron Lett. 2008, 49, 6835−6837.

513

Truce−Smile rearrangement A variant of the Smiles rearrangement where Y is carbon:

Z Z X base Y L L YH XH

Example 16

CF3 CF3 CF N 3 N N KH or NaH O O O OMe OM CO2Me MO OMe

CF3 CF3 N N

O OH O O

Example 27

NO2 N N O NaOH, H2O 2 H O2S O2S S N EtOH, reflux NO2 NO2 41% 46% O

Example 38 O

O2N K2CO3, DMF

HO reflux, 73% F

O N 2 O OH O2N O O

514

Example 410

F HO O 1. K2CO3, DMSO, rt, 85% O O NO2 O2N 2. PTSA, acetone/H2O O 50 oC, 98%

HO O K2CO3, DMSO O rt, 93% O2N O NO2

References

1. Truce, W. E.; Ray, W. J. Jr.; Norman, O. L.; Eickemeyer, D. B. J. Am. Chem. Soc. 1958, 80, 3625–3629. 2. Truce, W. E.; Hampton, D. C. J. Org. Chem. 1963, 28, 2276–2279. 3. Bayne, D. W; Nicol, A. J.; Tennant, G. J. Chem. Soc., Chem. Comm. 1975, 19, 782– 783. 4. Fukazawa, Y.; Kato, N.; Ito, S.; Tetrahedron Lett. 1982, 23, 437–438. 5. Hoffman, R. V.; Jankowski, B. C.; Carr, C. S.; Düsler, E. N J. Org. Chem. 1986, 51, 130–135. 6. Erickson, W. R.; McKennon, M. J. Tetrahedron Lett. 2000, 41, 4541–4544. 7. Kimbaris, A.; Cobb, J.; Tsakonas, G.; Varvounis, G. Tetrahedron 2004, 60, 8807– 8815. 8. Mitchell, L. H.; Barvian, N. C. Tetrahedron Lett. 2004, 45, 5669–5672. 9. Snape, T. J. Chem. Soc. Rev. 2008, 37, 2452–2458. (Review). 10. Snape, T. J. Synlett 2008, 2689–2691. 515

Sommelet reaction Transformation of benzyl halides to the corresponding benzaldehydes with the aide of hexamethylenetetramine. Cf. Delépine amine synthesis (page 171).

N N X Δ Δ CHO Ar X N N Ar Ar N N H O N CHCl3 N 2

hexamethylenetetramine

N X N : CH N N S 2 : 2 hydride N N N H Ar N N N N N transfer Ar X N Ar

N N CH CH3 N 3 Ar CH3 Ar N N CHO N N H Ar N NH N N O N :OH H 2 hemiaminal

The hydride transfer and the ring-opening of hexamethylenetetramine may occur in a synchronized fashion:

X N N CH3 H Ar N N N N N N Ar Example 13

Br CHO BnO BnO 1. HMTA, CHCl3, reflux, 6 h

S 2. 50% HOAc/H2O, reflux, 3 h S 40%

Example 24

HMTA, HOAc/H2O (11:3) reflux, 4 h CHO NH2 then 4.5 HCl, reflux, 1.5 h OH 68% OH

Example 37

F F N HOAc, H2O CHO Cl N N Δ N , 62% F F

Example 48

Br Br Br

NBS, BPO

CCl4, reflux, 15 h 38% 62%

CHO

HMTA, H2O/EtOH (1:1)

reflux, 4 h, 75%

References

1. Sommelet, M. Compt. Rend. 1913, 157, 852−854. Marcel Sommelet (1877−1952) was born in Langes, France. He received his Ph.D. In 1906 at Paris where he joined the Faculté de Pharmacie after WWI and became the chair of organic chemistry in 1934. 2. Angyal, S. J. Org. React. 1954, 8, 197–217. (Review). 3. Campaigne, E.; Bosin, T.; Neiss, E. S. J. Med. Chem. 1967, 10, 270−271. 4. Stokker, G. E.; Schultz, E. M. Synth. Commun. 1982, 12, 847−853. 5. Armesto, D.; Horspool, W. M.; Martin, J. A. F.; Perez-Ossorio, R. Tetrahedron Lett. 1985, 26, 5217−5220. 6. Kilenyi, S. N., in Encyclopedia of Reagents of Organic Synthesis, ed. Paquette, L. A., Wiley: Hoboken, NJ, 1995, Vol. 3, p. 2666. (Review). 7. Malykhin, E. V.; Shteingart, V. D. J. Fluorine Chem. 1998, 91, 19−20. 8. Karamé, I.; Jahjah, M.; Messaoudi, A.; Tommasino, M. L.; Lemaire, M. Tetrahedron: Asymmetry 2004, 15, 1569−1581. 9. Göker, H.; Boykin, D. W.; Yildiz, S. Bioorg. Med. Chem. 2005, 13, 1707−1714. 10. Li, J. J. Sommelet reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 689−695. (Re- view). 517

Sommelet–Hauser rearrangement [2,3]-Wittig rearrangement of benzylic quaternary ammonium salts upon treatment with alkali metal amides via the ammonium ylide intermediates.

NH2 N NH3 N

N N [2,3]-sigmatropic NH3 H rearrangement

NH2 ammonium ylide

HNH2

aromatization N N H

Example 13

I CsF, HMPA DMF, reflux N SiMe Ph N SiMe3 I 3 rt, 23 h, 86% 18 h, 94% N

Example 24

Br CsF, HMPA N

N SiMe3 AcO N o 10 C, 0.5 h, 32% AcO 46:54 AcO

Example 38

t-BuOK, THF

N −15 oC, 50% N Br

Example 410

N CO2R* CO R* t-BuOK, THF N 2

− o Br 60 C, 4 h CO2Me 57%, > 20:1 de CO Me R* = (−)-8-phenylmenthyl 2

References

1. Sommelet, M. Compt. Rend. 1937, 205, 56–58. 2. Shirai, N.; Sato, Y. J. Org. Chem. 1988, 53, 194–196. 3. Shirai, N.; Watanabe, Y.; Sato, Y. J. Org. Chem. 1990, 55, 2767–2770. 4. Tanaka, T.; Shirai, N.; Sugimori, J.; Sato, Y. J. Org. Chem. 1992, 57, 5034–5036. 5. Klunder, J. M. J. Heterocycl. Chem. 1995, 32, 1687–1691. 6. Maeda, Y.; Sato, Y. J. Org. Chem. 1996, 61, 5188–5190. 7. Endo, Y.; Uchida, T.; Shudo, K. Tetrahedron Lett. 1997, 38, 2113–2116. 8. Hanessian, S.; Talbot, C.; Saravanan, P. Synthesis 2006, 723–734. 9. Liao, M.; Peng, L.; Wang, J. Org. Lett. 2008, 10, 693–696. 10. Tayama, E.; Orihara, K.; Kimura, H. Org. Biomol. Chem. 2008, 6, 3673–3680.

519

Sonogashira reaction Pd/Cu-catalyzed cross-coupling of organohalides with terminal alkynes. Cf. Cadiot–Chodkiewicz coupling and Castro−Stephens reaction. The Castro– Stephens coupling uses stoichiometric copper, whereas the Sonogashira variant uses catalytic palladium and copper.

PdCl2•(PPh3)2 RX R' R R' CuI, Et3N, rt

Ph3P II Cl Pd Ph3P Cl

CuC CR' R'C CCu Ph3P II X HX-amine HX-amine Pd Ph P R Cycle B' 3 Cycle B ii RX ii CuX R'C CH i CuX R'C CH

Cycle A Ph3P II C CR' iii Pd 0 Ph3P II C CR' Pd (PPh3)2 Pd Ph3P C CR' Ph3P R

R'C CC CR' iii i. oxidative addition ii. transmetallation iii. reductive elimination RC CR'

Note that Et3N may reduce Pd(II) to Pd(0) as well, where Et3N is oxidized to the iminium ion at the same time:

NEt2 NEt H 2 PdCl NEt H Cl 2 3 Pd PdCl2 H Cl

reductive NEt2 Cl Cl Pd H HCl Pd(0) elimination

Example 12

I PdCl2•(Ph3P)2

N CO2Et CuI, Et N H 3 60 oC, 89% N CO2Et H

Example 23 Br Br SiMe3 N N Br PdCl2•(Ph3P)2, CuI Et N, rt, 65–74% SiMe 3 3

Example 38 OMe MeO OMe Pd(PPh3)4, CuI, [bmim][BF4] Et3N, 80 °C, 12 h, 11% I OMe BF4 N N MeO OMe OMe [bmim][BF ] MeO OMe 4 OMe

MeO OMe Example 49 PMPO O PMPO O OTBS O OTf OTBS O OH O O TMS O OH O TMS Cl OTBDPS Cl OTBDPS Pd(PPh3)4, CuI, MeO i-PrNEt2:DMF (1:1) MeO OMOM > 83% OMOM

References

1. (a) Sonogashira K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467−4470. Richard Heck also discovered the same transformation using palladium but without the use of copper: J. Organomet. Chem. 1975, 93, 259−263. 2. Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 2248−2252. 3. Ernst, A.; Gobbi, L.; Vasella, A. Tetrahedron Lett. 1996, 37, 7959−7962. 4. Hundermark, T.; Littke, A.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729−1731. 5. Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002, 4, 1411−1414. 6. Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.; de Mei- jere, A., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 1, 319. (Review). 7. Lemhadri, M.; Doucet, H.; Santelli, M. Tetrahedron 2005, 61, 9839−9847. 8. Li, Y.; Zhang, J.; Wang, W.; Miao, Q.; She, X.; Pan, X. J. Org. Chem. 2005, 70, 3285−3287. 9. Komano, K.; Shimamura, S.; Inoue, M.; Hirama, M. J. Am. Chem. Soc. 2007, 129, 14184−11186. 10. Gray, D. L. Sonogashira Reaction. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 100−133. (Review). 521

Staudinger ketene cycloaddition [2 + 2]-Cycloaddition of ketene and imine to form β-lactam. Other coupling part- ners for ketenes include: olefin to give cyclobutanone and carbonyl to give β- lactone.

O O X X = NR; O; CHR X

R3 R2 R3 R4 R1 R2 R4 R1

O O X R X 3 R R3 R2 4 R R R1 R2 4 1

puckered transition state:

Example 16

O O O Ot-Bu PhO PhO Ot-Bu Cl p-Tol N Et3N, CH2Cl2 N p-Tol N 10 oC to rt, 24 h O N 88%

Example 27

O AcO O Cl N N Et N, CH Cl 3 2 2 AcO −78 oC to rt, 60%

Example 39

H O PMP CO2Et CO2Et CO2Et O PMPN CHPMP O O PMP N PMP N Et N, CH Cl O COCl 3 2 2 O O −40 oC to rt H PMP major O minor 15 h, 70%

Example 410

Cl N I MeO C CO t-Bu MeO C CO t-Bu 2 2 2 2 N N Me C O CO2H CH Cl , Et N S S 2 2 3

MeO C MeO2C 2 CO2t-Bu Ph C N CH PMP CO2t-Bu 2 N H N Ph O S 62% S H 56 : 44 N Ph N O CH PMP H CH2PMP 2

References

1. Staudinger, H. Ber. 1907, 40, 1145−1146. Hermann Staudinger (Germany, 1881−1965) won the Nobel Prize in Chemistry in 1953 for his discoveries in the area of macromolecular chemistry. 2. Cooper, R. D. G.; Daugherty, B. W.; Boyd, D. B. Pure Appl. Chem. 1987, 59, 485−492. (Review). 3. Snider, B. B. Chem. Rev. 1988, 88, 793−811. (Review). 4. Hyatt, J. A.; Raynolds, P. W. Org. React. 1994, 45, 159−646. (Review). 5. Orr, R. K.; Calter, M. A. Tetrahedron 2003, 59, 3545−3565. (Review). 6. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Mugnoli, A.; Novi, M.; Petrillo, G.; San- cassan, F.; Tavani, C. Tetrahedron 2003, 59, 10195−10201. 7. Banik, I.; Becker, F. F.; Banik, B. K. J. Med. Chem. 2003, 46, 12−15. 8. Banik, B. K.; Banik, I.; Becker, F. F. Bioorg. Med. Chem. Lett. 2005, 13, 3611−3622. 9. Chincholkar, P. M.; Puranik, V. G.; Rakeeb, A.; Deshmukh, A. S. Synlett 2007, 2242−2246. 10. Cremonesi, G.; Dalla Croce, P.; Fontana, F.; La Rosa, C. Tetrahedron: Asymmetry 2008, 19, 554−561.

523

Staudinger reduction Phosphazo compounds (e.g., iminophosphoranes) from the reaction of tertiary phosphine (e.g., Ph3P) with organic azides.

PR3 N X N 2 3 XNN N PR3 XNPR3

phosphazide

N PR3 NX N N : XNN N PH2R3 XNN N PR3 PR3 N N X phosphazide

‡ PR3 PR3 N N H2O XNPR XNH2 OPR3 N N N2 3 N N X X

4-membered ring transition state

Example 12

OMe OMe Ph P, THF N O N3 3 Δ OTBDMS , 81% OTBDMS

N N

Example 23

CO2CH3

H H 1. PPh3, THF O N O CO CH 3 NH 2 3 2. NaBH4, MeOH O H O O MeO MeO 60% H

Example 34 N O 3 H N

O Br N N Br H Ts

H N O

PBu3, toluene N

reflux, 20 h, 82% Br N N Br H Ts Example 48

N3 BnO O 1.1 eq. PMe3, 2.4 eq. Boc-ON BnO N 3 N3 − o O Tol., 78 to 10 C N AcO 3 OAc N3 N3 BnO O 37% BnO O 42% BnO BnO N3 N3 N3 NHBoc O O NHBoc N AcO AcO 3 OAc OAc Example 59

F O F O PPh3, H2O O O N N N N THF, 45 °C NC N3 NC NH2 2 78% 2 R R

References

1. Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635−646. 2. Stork, G.; Niu, D.; Fujimoto, R. A.; Koft, E. R.; Bakovec, J. M.; Tata, J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123, 3239−3242. 3. Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3, 2721−2722. 4. Jiang, B.; Yang, C.-G.; Wang, J. J. Org. Chem. 2002, 67, 1369−1371. 5. Venturini, A.; Gonzalez, J. J. Org. Chem. 2002, 67, 9089−9092. 6. Chen, J.; Forsyth, C. J. Org. Lett. 2003, 5, 1281−1283. 7. Fresneda, P. M.; Castaneda, M.; Sanz, M. A.; Molina, P. Tetrahedron Lett. 2004, 45, 1655−1657. 8. Li, J.; Chen, H.-N.; Chang, H.; Wang, J.; Chang, C.-W. T. Org. Lett. 2005, 7, 3061−3064. 9. Takhi, M.; Murugan, C.; Munikumar, M.; Bhaskarreddy, K. M.; Singh, G.; Sreenivas, K.; Sitaramkumar, M.; Selvakumar, N.; Das, J.; Trehan, S.; Iqbal, J. Bioorg. Med. Chem. Lett. 2006, 16, 2391−2395. 10. Iula, D. M. Staudinger reaction. In Name Reactions for Functional Group Transfor- mations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 129−151. (Review). 525

Stetter reaction 1,4-Dicarbonyl derivatives from aldehydes and α,β-unsaturated ketones and esters. The thiazolium catalyst serves as a safe surrogate for −CN. Also known as the Michael−Stetter reaction. Cf. Benzoin condensation.

Cl Ph HO N O S RCHO R O NH3 O

Ph Bn HO N deprotonation N H H R1 S 1 S O R = HOCH2CH2CH2- :NH R 3 Bn Bn N N Michael OH OH R1 R1 S H S addition R R :NH 3 O Bn N Bn OH N tautomerization O R1 S R1 O S R O R O Ph Ph NH4 HO N HO N R O S S

Example 1, Intramolecular Stetter reaction2

Me Me N I CN CN HO S 2.3 equiv MeO2C MeO2C TEA, i-PrOH, 80 oC OHC O 67%

Example 23 Me Me N I O O HO S (cat.)

OHC CHO o O O O Et3N, EtOH, 80 C, 56% O O

Example 35

O CO2Me N H

N O

HO S CO Me Cl O 2 N N (cat.) Ph O N Et N, DMF, 100 ºC, 75% 3

Example 4, Sila-Stetter reaction9

Et Me N Br O O O 30 mol% S Ph Me HO Ph Ph Si Ph Ph Me 4 equiv i-PrOH, DBU, THF, 77% Ph O Me

References

1. (a) Stetter, H.; Schreckenberg, H. Angew. Chem. 1973, 85, 89. Hermann Stetter (1917−1993), born in Bonn, Germany, was a chemist at Technische Hochschule Aachen in West Germany. (b) Stetter, H. Angew. Chem. 1976, 88, 695−704. (Re- view). (c) Stetter, H.; Kuhlmann, H.; Haese, W. Org. Synth. 1987, 65, 26. 2. Trost, B. M.; Shuey, C. D.; DiNinno, F., Jr.; McElvain, S. S. J. Am. Chem. Soc. 1979, 101, 1284−1285. 3. El-Haji, T.; Martin, J. C.; Descotes, G. J. Heterocycl. Chem. 1983, 20, 233−235. 4. Harrington, P. E.; Tius, M. A. Org. Lett. 1999, 1, 649−651. 5. Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.; Tai, K.; Hida, T.; Yamauchi, T.; Nagai, M. J. Med. Chem. 2000, 43, 409−419. 6. Kobayashi, N.; Kaku, Y.; Higurashi, K. Bioorg. Med. Chem. Lett. 2002, 12, 1747−1750. 7. Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 6284−6289. 8. Reynolds, N. T.; Rovis, T. Tetrahedron 2005, 61, 6368−6378. 9. Mattson, A. E.; Bharadwaj, A. R.; Zuhl, A. M.; Scheidt, K. A. J. Org. Chem. 2006, 71, 5715−5724. 10. Cee, V. J. Stetter Reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 576−587. (Review). 527

Still–Gennari phosphonate reaction A variant of the Horner−Emmons reaction using bis(trifluoroethyl)phosphonate to give Z-olefins.

O KN(SiMe3)2, 18-Crown-6 Ph CO2CH3 (CF3CH2O)2P CO2CH3 then PhCH2CHO

O O O O CF3CH2O P CF3CH2O OMe CF3CH2O P CF CH O OMe H 3 2 H SiMe3 Ph N O SiMe 3

O O OCH CF OCH2CF3 2 3 PO OCH CF PO OCH CF 2 3 2 3 Ph CO2CH3 H H H H CO2CH3 CO2CH3 Ph Ph erythro isomer, kinetic adduct

Example 12

KN(SiMe3)2, 18-Crown-6 O −78 oC, THF, 30 min. Ph CO2CH3 (CF3CH2O)2P CO2CH3 then PhCH CHO, 87% 2

Example 23

N N O N CO Et O O N 2 F CH CO 3 2 P Me OEt F F3CH2CO F Sn(OSO2CF3)2, N-methylpiperidine Me CH2Cl2, 70%, E:Z = 96:4

Example 34

OTBS O O F CH CO 3 2 P N OEt O F3CH2CO CH3 S

OTBS KHMDS, THF 18-crown-6, −78 oC, 1 h O N EtO CH 89%, (Z)-isomer only 3 S

Example 49

MeO CHO P(OCH2CF3)2 O O O O O O OPMB TBS TBS TBS OTBS

NaH, THF MeO

73%, Z:E 5:1 O O O O O OPMB TBS TBS TBS OTBS

References

1. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405−4408. W. Clark Still (1946−) was born in Augusta, Georgia. He was a professor at Columbia University. 2. Nicolaou, K. C.; Nadin, A.; Leresche, J. E.; LaGreca, S.; Tsuri, T.; Yue, E. W.; Yang, Z. Chem. Eur. J. 1995, 1, 467−494. 3. Sano, S. Yokoyama, K.; Shiro, M.; Nagao, Y. Chem. Pharm. Bull. 2002, 50, 706–709. 4. Mulzer, J.; Mantoulidis, A.; Öhler, E. Tetrahedron Lett. 1998, 39, 8633–8636. 5. Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9535−9544. 6. Mulzer, J.; Ohler, E. Angew. Chem., Int. Ed. 2001, 40, 3842−3846. 7. Beaudry, C. M.; Trauner, D. Org. Lett. 2002, 4, 2221−2224. 8. Dakin, L. A.; Langille, N. F.; Panek, J. S. J. Org. Chem. 2002, 67, 6812−6815. 9. Paterson, I.; Lyothier, I. J. Org. Chem. 2005, 70, 5494−5507. 10. Rong, F. Horner–Wadsworth–Emmons reaction. In Name Reactions for Homologa- tions-Part I; Li, J. J., Corey, E. J.; Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 420−466. (Review).

529

Stille coupling Palladium-catalyzed cross-coupling reaction of organostannanes with organic halides, triflates, etc. For the catalytic cycle, see Kumada coupling on page 325.

Pd(0) 1 2 1 2 RX R Sn(R )3 RR XSn(R)3

R1 Sn(R2) oxidative R L 3 RX L2Pd(0) Pd transmetallation addition X L isomerization L L reductive 2 1 XSn(R)3 Pd R R L2Pd(0) 1 elimination R R

Example 14

SnBu PhO2S 3 N Cl N Br N Cl N SO2Ph

Cl N NH2 PdCl •(Ph P) , CuI 2 3 2 Cl N NH2 THF, reflux, 92%

Example 25

Cl (MeCN)2PdCl2

TBDPSO Br Me3Sn Cl AsPh3, NMP o 80 C, 1.5 h, 55%

Cl Cl HCl

TBDPSO Cl HN Cl

Zoloft

Example 3, π-Allyl Stille coupling8

Me Me OTBDPS Pd2(dba)3, LiCl OAc Me i-Pr2NEt, NMP OTBDPS Me Me Me SnMe 3 Me 35 °C, 1.5 h, 96% O Me O

Example 49

I Me OH Me MeO Pd(PPh3)4, CuTC O OTBS SnMe Me 3 DMF, 32% O N S MeHN O

Me MeO Me OTBS OH 18

O Me O N S MeHN O

References

1. (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636−3638. John Kenneth Stille (1930−1989) was born in Tucson, Arizona. He developed the reaction bearing his name at Colorado State University. At the height of his career, Stille unfortunately died of an airplane accident returning from an ACS meeting. (b) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992−4998. (c) Stille, J. K. Angew. Chem., Int. Ed. 1986, 25, 508−524. 2. Farina, V.; Krishnamurphy, V.; Scott, W. J. Org. React. 1997, 50, 1–652. (Review). 3. Duncton, M. A. J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1999, 1235−1249. (Review on the intramolecular Stille reaction). 4. Li, J. J.; Yue, W. S. Tetrahedron Lett. 1999, 40, 4507−4510. 5. Lautens, M.; Rovis, T. Tetrahedron, 1999, 55, 8967−8976. 6. Mitchell, T. N. Organotin Reagents in Cross-Coupling Reactions. In Metal-Catalyzed Cross-Coupling Reactions (2nd edn.) De Meijere, A.; Diederich, F. eds., 2004, 1, 125−161. Wiley-VCH: Weinheim, Germany. (Review). 7. Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245−2267. (Review). 8. Snyder, S. A.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 740−742. 9. Roethle, P. A.; Chen, I. T.; Trauner, D. J. Am. Chem. Soc. 2007, 129, 8960−8961. 10. Mascitti, V. Stille Coupling. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 133−162. (Review). 531

Stille−Kelly reaction Palladium-catalyzed intramolecular cross-coupling reaction of bis-aryl halides using ditin reagents.

Br Me3Sn SnMe3 Br Pd(Ph P) OH 3 4 OH OH OH

BrPd Me3Sn Pd Br Pd(0) Br Me3Sn SnMe3 Br Br oxidative transmetalation OH addition OH OH OH OH OH Me Sn Me3Sn 3 Pd(0) PdBr reductive Br Pd(0) elimination oxidative OH addition OH OH OH

Pd transmetallation reductive Pd(0) elimination OH OH OH OH Example 16 I II I HO Me3Sn SnMe3 N N N

Cl O PdCl2•(Ph3P)2 O NaH, DMF, reflux, 89% xylene, reflux, 92%

References

1. Kelly, T. R.; Li, Q.; Bhushan, V. Tetrahedron Lett. 1990, 31, 161−164. 2. Grigg, R.; Teasdale, A.; Sridharan, V. Tetrahedron Lett. 1991, 32, 3859−3862. 3. Iyoda, M.; Miura, M.; Sasaki, S.; Kabir, S. M. H.; Kuwatani, Y.; Yoshida, M. Hetero- cycles 1997, 38, 4581−4582. 4. Fukuyama, Y.; Yaso, H.; Nakamura, K.; Kodama, M. Tetrahedron Lett. 1999, 40, 105−108. 5. Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999, 1505−1510. 6. Yue, W. S.; Li, J. J. Org. Lett. 2002, 4, 2201−2203. 7. Olivera, R.; SanMartin, R.; Tellitu, I.; Dominguez, E. Tetrahedron 2002, 58, 3021−3037. 8. Mascitti, V. Stille Coupling. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 133−162. (Review).

Stobbe condensation Condensation of diethyl succinate and its derivatives with carbonyl compounds in the presence of bases.

CO2Et O CO2Et KOt-Bu R CO2H R R1 CO2Et HOt-Bu R1

t-BuO R CO Et O R1 O R1 2 H enolate aldol lactonization OEt O R OEt O formation addition CO2Et CO2Et EtO O

R 1 CO2Et R 1 R CO Et R 2 CO2Et CO2Et ring H O H R CO2 R CO2H O opening Ot-Bu 1 1 EtO O R R O

Example 1, Stobbe condensation and cyclization5

O O CHO CO2Me 1. t-BuOK, t-BuOH, reflux CO2Me

O CO Me 2. Ac2O, NaOAc, reflux 2 84% O O O OAc

Example 2, Stobbe condensation6

O O O O CHO aq. NaOH, EtOH O OH −10 oC, 5 h, 80−95% O O O O

Example 3, Cyclization of the Stobbe product7

BnO2C BnO2C CO2Et NaOAc, Ac2O CO2Et reflux, 57% CO2H OAc

Example 4, Two sequential Stobbe condensations9

CO2Me 1. (CH2CO2Et)2, NaOMe, MeOH then aq. NaOH, 36% F CHO CO2Me 2. MeOH, H2O4, 94% F

O I O I

O O CHO CO2Me

NaOMe, MeOH, 74% F CO2H

References

1. Stobbe, H. Ber. 1893, 26, 2312. Hans Stobbe (1860−1938) was born in Tiehenhof, Germany. He earned his Ph.D. In 1889 at the University of Leipzig where he became a professor in 1894. 2. Zerrer, R.; Simchen, G. Synthesis 1992, 922–924. 3. Yvon, B. L.; Datta, P. K.; Le, T. N.; Charlton, J. L. Synthesis 2001, 1556–1560. 4. Liu, J.; Brooks, N. R. Org. Lett. 2002, 4, 3521–3524. 5. Giles, R. G. F.; Green, I. R.; van Eeden, N. Eur. J. Org. Chem. 2004, 4416–4423. 6. Mahajan, V. A.; Shinde, P. D.; Borate, H. B.; Wakharkar, R. D. Tetrahedron Lett. 2005, 46, 1009–1012. 7. Sato, A.; Scott, A.; Asao, T.; Lee, M. J. Org. Chem. 2006, 71, 4692–4695. 8. Kapferer, T.; Brückner, R. Eur. J. Org. Chem. 2006, 2119–2133. 9. Mizufune, H.; Nakamura, M.; Mitsudera, H. Tetrahedron 2006, 62, 8539–8549. 10. Lowell, A. N.; Fennie, M. W.; Kozlowski, M. C. J. Org. Chem. 2008, 73, 1911–1918.

534

Strecker amino acid synthesis Sodium cyanide-promoted condensation of aldehyde, or ketone, with amine to afford α-amino nitrile, which may be hydrolyzed to α-amino acid.

2 2 O R R R2 NaCN HN H HN 1 H2N R H 1 1 AcOH R CN R CO2H

H R2 HN R2 O H H 1 HN O R NH R1 : NH R1 H R2 N 1 R1 N H R2 R

: NC R2 H : H OH H N H2O 2 iminium ion 2 2 R :OH 2 R HN 2 R HN R2 HN H HN NH acidic amide 1 2 1 NH3 R 1 NH2 R hydrolysis R R1 CO H O HO OH HO O 2 H H

Example 1, Soluble cyanide source2

C8H17 C H 8 17 O H H (EtO)2PCN N H H

H H pyrrolidine, THF, 62% NC O

Example 23

Cl OHC O O CN Cl Cl

NH N N acetone cyanohydrin S S S MgSO , 45 oC 4 Plavix toluene, 31%

Example 38

CN NH2 O Ph Ph NaCN, NH4Cl CN NH2 Ph i-PrOH, NH4OH H H 34% 35%

Example 49

Ph Ph F C F C NaCN, BnNH2 3 O 3 O AcOH, MeOH CN

O 98% HN Bn CF CF 3 3

References

1. Strecker, A. Ann. 1850, 75, 27−45. 2. Harusawa, S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1979, 20, 4663–4666. 3. Burgos, A.; Herbert, J. M.; Simpson, I. J. Labelled. Compd. Radiopharm. 2000, 43, 891–898. 4. Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762–766. 5. Yet, L. Recent Developments in Catalytic Asymmetric Strecker-Type Reactions, in Or- ganic Synthesis Highlights V, Schmalz, H.-G.; Wirth, T. eds.; Wiley−VCH: Wein- heim, Germany, 2003, pp 187−193. (Review). 6. Meyer, U.; Breitling, E.; Bisel, P.; Frahm, A. W. Tetrahedron: Asymmetry 2004, 15, 2029–2037. 7. Huang, J.; Corey, E. J. Org. Lett. 2004, 6, 5027–5029. 8. Cativiela, C.; Lasa, M.; Lopez, P. Tetrahedron: Asymmetry 2005, 16, 2613–2523. 9. Wrobleski, M. L.; Reichard, G. A.; Paliwal, S.; Shah, S.; Tsui, H-C.; Duffy, R. A.; La- chowicz, J. E.; Morgan, C. A.; Varty, G. B.; Shih, N-Y. Bioorg. Med. Chem. Lett. 2006, 16, 3859–3863. 10. Galatsis, P. Strecker amino acid synthesis. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 477−499. (Review). 11. Belokon, Y. N.; Hunt, J.; North, M. Tetrahedron: Asymmetry 2008, 19, 2804−2815.

536

Suzuki–Miyaura coupling Palladium-catalyzed cross-coupling reaction of organoboranes with organic halides, triflates, etc. In the presence of a base (transmetallation is reluctant to occur without the activating effect of a base). For the catalytic cycle, see Kumada coupling on page 325.

L2Pd(0) 1 2 1 RX R B(R )2 R R NaOR3

3 3 oxidative R L NaOR OR R L RX L Pd(0) R1 B(R2) 1 2 Pd 2 Pd 2 R B(R )2 addition X X L base L transmetallation L L reductive 3 2 1 R OB(R)2 Pd R R L Pd(0) R1 2 isomerization R elimination

Example 12

I Pd(OAc)2 CO2Me O Ph3P, K2CO3 CO Me B CO2Me N 2 O THF, MeOH CO Me CO2Et 70 °C, 15 h, 80% N 2 CO Et 2

Example 24

B(OH)2

I I N N N TBS I N I I N N SEM Pd(Ph3P)4, Na2CO3, 45% SEM TBS

Example 3, Intramolecular Suzuki–Miyaura coupling8

OBn OBn TBDMSO O TBDMSO O 1. BH OMOM OMOM 2 O O 2. H2O, CH2O 3. KHF2 Br Br 99% BF K 3

BnO

OH O OMOM cat. Pd(PPh3)4, Cs2CO3 O

THF/H2O, reflux, 42%

Example 49

O OMe I N O O SnBu3 H O OMe B B N 3 cat. Pd (dba) , Ph As 3 H O 2 3 3 O DMF, 84%

I O OH OMe HO N H cat. PdCl2(dppf), Ph3As K PO (aq), DMF, 71% 3 4

References

1. (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 36, 3437−3440. (b) Miyaura, N.; Suzuki, A. Chem. Commun. 1979, 866–867. 2. Tidwell, J. H.; Peat, A. J.; Buchwald, S. L. J. Org. Chem. 1994, 59, 7164–7168. 3. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457−2483. (Review). 4. (a) Kawasaki, I.; Katsuma, H.; Nakayama, Y.; Yamashita, M.; Ohta, S. Heterocycles 1998, 48, 1887–1901. (b) Kawaski, I.; Yamashita, M.; Ohta, S. Chem. Pharm. Bull. 1996, 44, 1831–1839. 5. Suzuki, A. In Metal-catalyzed Cross-coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley−VCH: Weinhein, Germany, 1998, 49–97. (Review). 6. Stanforth, S. P. Tetrahedron 1998, 54, 263−303. (Review). 7. Zapf, A. Coupling of Aryl and Alkyl Halides with Organoboron Reagents (Suzuki Re- action). In Transition Metals for Organic Synthesis (2nd edn.); Beller, M.; Bolm, C. eds., 2004, 1, 211−229. Wiley−VCH: Weinheim, Germany. (Review). 8. Molander, G. A.; Dehmel, F. J. Am. Chem. Soc. 2004, 126, 10313–10318. 9. Coleman, R. S.; Lu, X.; Modolo, I. J. Am. Chem. Soc. 2007, 129, 3826–3827. 10. Wolfe, J. P.; Nakhla, J. S. Suzuki coupling. In Name Reactions for Homologations- Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 163−184. (Review). 538

Swern oxidation

Oxidation of alcohols to the corresponding carbonyl compounds using (COCl)2, DMSO, and quenching with Et3N.

(COCl)2, DMSO o O OH CH2Cl2, −78 C 1 2 R1 R2 R R then Et3N

Cl S O O O S H O O O ↑ :O Cl S CO2 CO↑ Cl Cl S Cl Cl O O Cl R1 R2 O

H S Cl S :NEt O 3 O CH2 O ↓ (CH ) S↑ Et3N•HCl H 3 2 H R1 R1 R2 1 2 2 R R R sulfur ylide

Example 12

OMe OMe H H O o OH 1. (COCl)2, DMSO, −60 C, 45 min

2. Et N, −60 oC, 15 min. then rt OH OH 3 OMe OMe O 81% OMe OMe OH

Example 23

Cl TMSCH CH O C Swern TMSCH CH O C 2 2 2 conditions 2 2 2 NC NC HO O 80% O O O O

Example 35

OH O C H C11H23 (COCl) , DMSO 11 23 C6H13 2 C6H13 then Et N, 89% 3 OSiMe t-Bu OSiMe2t-Bu 2

Example 47

OMe OMe O N3 HO N3 (COCl)2, DMSO OTBDPS OTBDPS then Et3N, 85% N N

References

1. (a) Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1976, 41, 3329−3331. (b) Huang, S. L.; Omura, K.; Swern, D. Synthesis 1978, 4, 297−299. (c) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480−2482. 2. Ghera, E.; Ben-David, Y. J. Org. Chem. 1988, 53, 2972−2979. 3. Smith, A. B., III; Leenay, T. L.; Liu, H. J.; Nelson, L. A. K.; Ball, R. G. Tetrahedron Lett. 1988, 29, 49−52. 4. Tidwell, T. T. Org. React. 1990, 39, 297−572. (Review). 5. Chadka, N. K.; Batcho, A. D.; Tang P. C.; Courtney, L. F.; Cook C. M.; Wovliulich, P. M.; Uskoviü, M. R. J. Org. Chem. 1991, 56, 4714−4718. 6. Harris, J. M.; Liu, Y.; Chai, S.; Andrews, M. D.; Vederas, J. C. J. Org. Chem. 1998, 63, 2407−2409. (Odorless protocols). 7. Stork, G.; Niu, D.; Fujimoto, R. A.; Koft, E. R.; Bakovec, J. M.; Tata, J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123, 3239−3242. 8. Nishide, K.; Ohsugi, S.-i.; Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron Lett. 2002, 43, 5177−5179. (Another odorless protocols). 9. Kawaguchi, T.; Miyata, H.; Ataka, K.; Mae, K.; Yoshida, J.-i. Angew. Chem., Int. Ed. 2005, 44, 2413−2416. 10. Ahmad, N. M. Swern oxidation. In Name Reactions for Functional Group Transfor- mations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 291−308. (Review). 11. Lopez-Alvarado, P; Steinhoff, J; Miranda, S; Avendano, C; Menendez, J. C. Tetrahedron 2009, 65, 1660−1672.

540

Takai reaction Stereoselective conversion of an aldehyde to the corresponding E-vinyl iodide using CHI3 and CrCl2.

O CHI , CrCl 3 2 I R R H THF

R O I I H CrCl2 CrCl2 H I H I III III Cr Cl2 I Cr Cl2 H I CrIIICl 2 R III OCr Cl2 I III R Cl2Cr I

A radical mechanism was recently proposed10

I I I I O I H I III H Cr I R H H I II III Cr CrII Cr

III OCrIII OCr III I I OCr R R I H H I R I R II CrIII II Cr Cr

Example 12

CHI3, CrCl2 Ph CHO Ph I THF, 70% OTBS OTBS 20: 1 E:Z

Example 23

Et Et Et Et Et Et Et Et N N N N 25 equiv CrCl2 6 equiv CHI3 Ni Ni CHO N N I N N THF, rt, 3 h Et Et Et Et 75% Et Et Et Et

Example 34

o OTES CHI3, CrCl2, 0 C OTES

OHC CO2Me I CO2Me THF, 50%

Example 4, A Br/Cl variant9

6 equiv CrCl2, 2 equiv CHBr3 OTHP O THF, 0 oC, 2.5 h, 67%

Br OTHP Cl OTHP 1 : 1

Example 510

H 5.8 equiv anhydrous CrCl2 H CO Me CO2Me 2 2 equiv CHI3 MOMO MOMO CHO 1,4-dioxane−THF (6:1) I H H 20 oC, 72 h, 88%

References

1. Takai, K.; Nitta, Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408–7410. 2. Andrus, M. B.; Lepore, S. D.; Turner, T. M. J. Am. Chem. Soc. 1997, 119, 12159– 12169. 3. Arnold, D. P.; Hartnell, R. D. Tetrahedron 2001, 57, 1335–1345. 4. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2004, 45, 8717–8724. 5. Dineen, T. A.; Roush, W. R. Org. Lett. 2004, 6, 2043–2046. 6. Lipomi, D. J.; Langille, N. F.; Panek, J. S. Org. Lett. 2004, 6, 3533–3536. 7. Paterson, I.; Mackay, A. C. Synlett 2004, 1359–1362. 8. Concellón, J. M.; Bernad, P. L.; Méjica, C. Tetrahedron Lett. 2005, 46, 569–571. 9. Gung, B. W.; Gibeau, C.; Jones, A. Tetrahedron: Asymmetry 2005, 16, 3107–3114. 10. Legrand, F.; Archambaud, S.; Collet, S.; Aphecetche-Julienne, K.; Guingant, A.; Evain, M. Synlett 2008, 389–393.

542

Tebbe’s reagent The Tebbe’s reagent, ȝ-chlorobis(cyclopentadienyl)(dimethylaluminium)-ȝ- methylenetitanium, transforms a carbonyl compound to the corresponding exo- olefin.

H2 C CH3 Ti Al Cl CH3

Preparation:2,6

↑ Cp2Ti Al(CH3)2 Cp2TiCl2 + 2 Al(CH3)3 CH4 + Al(CH3)2Cl + Cl

Mechanism:3

Cp2Ti CH2 dissociation Cp2Ti Al(CH3)2 1 Cl Al(CH3)2 R Cl O R

[2 + 2] Cp2Ti CH2 retro-[2 + 2] 1 Cp2Ti O O R 1 cycloaddition cycloaddition R R R oxatitanacyclobutane formation of the strong Ti=O is the driving force.

Example 1, Ketone2

O Tebbe's reagent, Tol.

CO2Et CO2Et then the ketone substrate, o THF, 0 C to rt, 30 min., 67%

Example 2, Double Tebbe4

H Cp H 2.5 eq Ti Al Cp Cl O O O THF, CH2Cl2 O H −40 to 25 °C, 69%

Example 3, Double Tebbe5

3 equiv Tebbe's reagent in Tol. TBSO OBn OTBS TBSO OBn OTBS pyr., Tol./THF CHO OHC O OBn OTBS −78 oC to −15 oC, 2 h O OBn OTBS TBS 86% TBS

Example 4, N-Oxide6 Cp Ti Al Cp Cl

N THF, 0 oC to rt, 90% O N

Example 5, Amide11

CF3 CF CF3 CF 3 3 N N O 1. Tebbe's reagent OH

2. BH3, THF, H2O2, NaOH O N O − O N O 75 95%

References

1. Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978, 100, 3611−3613. 2. Pine, S. H.; Pettit, R. J.; Geib, G. D.; Cruz, S. G.; Gallego, C. H.; Tijerina, T.; Pine, R. D. J. Org. Chem. 1985, 50, 1212–1216. 3. Cannizzo, L. F.; Grubbs, R. H. J. Org. Chem. 1985, 50, 2386–2387. 4. Philippo, C. M. G.; Vo, N. H.; Paquette, L. A. J. Am. Chem. Soc. 1991, 113, 2762−2764. 5. Ikemoto, N.; Schreiber, L. S. J. Am. Chem. Soc. 1992, 114, 2524–2536. 6. Pine, S. H. Org. React. 1993, 43, 1−98. (Review). 7. Nicolaou, K. C.; Koumbis, A. E.; Snyder, S. A.; Simonsen, K. B. Angew. Chem., Int. Ed. 2000, 39, 2529–2533. 8. Straus, D. A. Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons, 2000. (Review). 9. Payack, J. F.; Hughes, D. L.; Cai, D.; Cottrell, I. F.; Verhoeven, T. R. Org. Syn., Coll. Vol. 10, 2004, p 355. 10. Beadham, I.; Micklefield, J. Curr. Org. Synth. 2005, 2, 231−250. (Review). 11. Long, Y. O.; Higuchi, R. I.; Caferro, T.s R.; Lau, T. L. S.; Wu, M.; Cummings, M. L.; Martinborough, E. A.; Marschke, K. B.; Chang, W. Y.; Lopez, F. J.; Karanewsky, D. S.; Zhi, L. Bioorg. Med. Chem. Lett. 2008, 18, 2967−2971. 12. Zhang, J. Tebbe reagent. In Name Reactions for Homolotions-Part I; Li, J. J., Corey, E. J., Eds., Wiley & Sons: Hoboken, NJ, 2009, pp 319−333. (Review). 544

TEMPO oxidation TEMPO = Tetramethyl pentahydropyridine oxide. 2,2,6,6-Tetramethylpiperi- dinyloxy is a stable nitroxyl radical, which serves in oxidations as catalyst

NaOCl, cat. TEMPO O R OH KBr, NaHCO3, CH2Cl2 R OH

: : N N 1/2 NaOCl O O N O : HO R : O Cl

O NHAc N R H OO H HR N OH O N O Cl

: O B O OH H R O R O R O Cl

Example 14

OH NaOCl, cat. TEMPO HO C 2 O O HO HO HO HO OMe KBr, NaHCO3, CH2Cl2 OMe OH 55% OH

Example 2, Trichloroisocyanuric/TEMPO Oxidation5

Cl O N O

NN Cl Cl O O R OH 0.01 mol equiv TEMPO R OH 0.05 mol equiv NaBr acetone, aq. NaHCO3, rt 1−24 h, 75−100%

Example 38

O cat. TEMPO, 2 eq. 2,6-lutidine

electrolysis in CH3CN/H2O (95:5) 95% Example 410

OH Ormosil-TEMPO, NaOCl OH OH CO2H CH3CN, NaHCO3, 5% o Cl Cl 0 C, 80% “Ormosil-TEMPO” is a sol-gel hydrophobized nanostructured silica matrix doped with TEMPO

References

1. Garapon, J.; Sillion, B.; Bonnier, J. M. Tetrahedron Lett. 1970, 11, 4905–4908. 2. de Nooy, A. E.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153–1174. (Re- view). 3. Rychnovsky, S. D.; Vaidyanathan, R. J. Org. Chem. 1999, 64, 310–312. 4. Fabbrini, M.; Galli, C.; Gentili, P.; Macchitella, D. Tetrahedron Lett. 2001, 42, 7551– 7553. 5. De Luca, L.; Giacomelli, G.; Masala, S.; Porcheddu, A. J. Org. Chem. 2003, 45, 4999– 5001. 6. Ciriminna, R.; Pagliaro, M. Tetrahedron Lett. 2004, 45, 6381–6383. 7. Tashino, Y.; Togo, H. Synlett 2004, 2010–2012. 8. Breton, T.; Liaigre, D.; Belgsir, E. M. Tetrahedron Lett. 2005, 46, 2487–2490. 9. Chauvin, A.-L.; Nepogodiev, S. A.; Field, R. A. J. Org. Chem. 2005, 47, 960–966. 10. Gancitano, P.; Ciriminna, R.; Testa, M. L.; Fidalgo, A.; Ilharco, L. M.; Pagliaro, M. Org. Biomol. Chem. 2005, 3, 2389–2392. 11. Zhang, M.; Chen, C.; Ma, W.; Zhao, J. Angew. Chem., Int. Ed. 2008, 47, 9730–9733.

546

Thorpe−Ziegler reaction The intramolecular version of the Thorpe reaction, which is base-catalyzed self- condensation of nitriles to yield imines that tautomerize to enamine.

CN CN OEt CN HOEt NH2

EtO H N H N HOEt OEt

N HOEt N

CN EtO H CN NH NH HOEt 2

Example 1, A radical Thorpe−Ziegler reaction2

Bu SnH, AIBN H N CN CN 3 2 syringe pump NC Br PhH, 80 oC, 56%

Example 25

CN LDA, THF NH2 − o 78 C to rt CN N N 2 h, 80% CN Ph Ph

Example 38

N NH2 Ph KOH, EtOH HN H N Ph O N S reflux, 5 min., 80% S O H O N O H

Example 49

NC CN NC CN NC NH2

NH Cl CN N CN N CN

Et3N, reflux 15 min., 91% OMe OMe OMe

References

1. (a) Baron, H.; Remfry, F. G. P.; Thorpe, Y. F. J. Chem. Soc. 1904, 85, 1726–1761. (b) Ziegler, K. et al. Ann. 1933, 504, 94–130. Karl Ziegler (1898−1973), born in Helsa, Germany, received his Ph.D. In 1920 from von Auwers at the University of Marburg. He became the director of the Max-Planck-Institut für Kohlenforschung at Mül- heim/Ruhr in 1943. He shared the Nobel Prize in Chemistry in 1963 with Giulio Natta (1903−1979) for their work in polymer chemistry. The Ziegler−Natta catalyst is widely used in polymerization. 2. Curran, D. P.; Liu, W. Synlett 1999, 117–119. 3. Dansou, B.; Pichon, C.; Dhal, R.; Brown, E.; Mille, S. Eur. J. Org. Chem. 2000, 1527– 1531. 4. Keller, L.; Dumas, F.; Pizzonero, M.; d’Angelo, J.; Morgant, G.; Nguyen-Huy, D. Tet- rahedron Lett. 2002, 43, 3225–3228. 5. Malassene, R.; Toupet, L.; Hurvois, J.-P.; Moinet, C. Synlett 2002, 895–898. 6. Satoh, T.; Wakasugi, D. Tetrahedron Lett. 2003, 44, 7517–7520. 7. Wakasugi, D.; Satoh, T. Tetrahedron 2005, 61, 1245–1256. 8. Dotsenko, V. V.; Krivokolysko, S. G.; Litvinov, V. P. Monatsh. Chem. 2008, 139, 271–275. 9. Salaheldin, A. M.; Oliveira-Campos, A. M. F.; Rodrigues, L. M. ARKIVOC 2008, 180–190. 10. Miszke, A.; Foks, H.; Brozewicz, K.; Kedzia, A.; Kwapisz, E.; Zwolska, Z. Heterocycles 2008, 75, 2723–2734.

548

Tsuji−Trost reaction The Tsuji–Trost reaction is the palladium-catalyzed substitution of allylic leaving groups by carbon nucleophiles. These reactions proceed via π-allylpalladium intermediates.

R1 Pd(0) (catalytic) Nu 1 R1 Nu R X (II) base Pd X 2 π-allyl complex

1 2 1 2 1 2 R1 R2 Pd(0) R R R R Pd(0) R R OR Nu Hard Nu X X Soft Nu Nu

Inversion of R1 >> R2 Retention of configuration configuration

X = OCOR, OCO2R, OCONHR, OP(O)(OR)2, OPh, Cl, NO2, SO2Ph, NR3X, SR2X, OH

The catalytic cycle: Pd(0) or Pd(II) precatalysts

R1 Nu R1 X LnPd(0)

1 R Nu R1 X L Pd(0) n LnPd(0)

D B π-allyl complex Nu R1 R1 + L

Pd(II) − X Pd(II) L L L X C

A: Coordination C: Ligand exchange B: Oxidative addition D: Substitution then (Ionization) reductive elimination

Example 1, Allylic ether3

BnO BnO Pd (dba) , dppb N 2 3 O O α:β = 90:10 N THF, 60–70 oC BnO N BnO OPh H 72% N

Example 2, Allylic acetate3

NH2 N N N NH2 N N OAc H N AcO AcO N NaH, Pd(Ph3P)4, DMF N o 60 C, 18 h, 79%

Example 3, Allylic epoxide5

N N N H O HO N Pd(Ph3P)4, THF rt, 64 h, 35%

Example 4, Intramolecular Tsuji–Trost reaction6

O O NH2 10 mol% Pd(OAc)2 10 mol% n-Bu NCl BnN NH Bn N OCO2Me 4

P(OEt) , NaHCO 3 3 S S DMF, 100 oC, 77% CO Me CO2Me 2

Example 5, Intramolecular Tsuji–Trost reaction7

Me TESO OTES TESO Me

O 10 mol% Pd2(dba)3 OTES O OMe O THF (0.005 M) O Me Me 40 oC, 80% Ot-Bu Me t-BuO Me TMSO O O OTMS

550

Example 6, Asymmetric Tsuji–Trost reaction8

O O BocO O O EtO C O EtO2C O 2 2.5 mol% (dba)3Pd2•CHCl3 I 7.5 mol% ent-cat I O 30 mol% Bu NCl MeO O O MeO OH 4 H CH2Cl2 89% yield, 95% ee

O O NH HN ent-cat =

PPh2 Ph2P

References

1. (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 6, 4387−4388. (b) Tsuji, J. Acc. Chem. Res. 1969, 2, 144−152. (Review). 2. Godleski, S. A. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., eds.; Vol. 4. Chapter 3.3. Pergamon: Oxford, 1991. (Review). 3. Bolitt, V.; Chaguir, B.; Sinou, D. Tetrahedron Lett. 1992, 33, 2481–2484. 4. Moreno-Mañas, M.; Pleixats, R. In Advances in Heterocyclic Chemistry; Katritzky, A. R., ed.; Academic Press: San Diego, 1996, 66, 73. (Review). 5. Arnau, N.; Cortes, J.; Moreno-Mañas, M.; Pleixats, R.; Villarroya, M. J. Heterocycl. Chem. 1997, 34, 233−239. 6. Seki, M.; Mori, Y.; Hatsuda, M.; Yamada, S. J. Org. Chem. 2002, 67, 5527−5536. 7. Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorenson, E. J. J. Am. Chem. Soc. 2003, 125, 5393−5407. 8. Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 3090−3100. 9. Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044−15045. 10. Fuchter, M. J. Tsuji–Trost Reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 185−211. (Review).

551

Ugi reaction Four-component condensation (4CC) of carboxylic acids, C-isocyanides, amines, and carbonyl compounds to afford diamides. Cf. Passerini reaction.

O R2 H 1 2 3 N 3 RCO2H R NH2 R CHO R N C R N R R1 O

isocyanide

H NR1 O O R2 2 HO H O H R 1 2 N: 1 N R RCO2H R C H R R 2 : R 1 H N R NH2 H 3 R imine

R3 H R3 N O R2 O N H H O N N 3 : 1 R O R O 2 R N R N R R2 R R1 O 1 R

Example 12

OMe C OMOM BnO N O I NH2 H O BocHN O OTBDPS CO H O 2

OMOM NHPMP

O MeOH, Δ NHBoc N 1 h, 90% O OMe O O TBDPSO I OBn

Example 25

O NH C CO2H O2N 2 HN N O2S N OMe OTBS CHO

O2N O2S N O MeOH, Δ OO NHt-Bu 61% N HN OMe

OTBS Example 37

O HO O NH2 N CH3 C O O OCH3 CH3 H3CO CH3 OCH3

OCH3

OCH3 O NH TFE, rt PMB N O 78% O CH O 3 CH H C H 3 3

Example 48

O OH

H3C H TBSO CH3 C O N H N NH 2 2 2 (CH2O)n

H3C H H OTBS

OH TBSO O 553

Cy NH O O N

H3C H HO CH3 O 1. MeOH, rt.

2. TBAF, THF 54%, 2 Steps H3C H O H OH

N O HO O HN Cy

References

1. (a) Ugi, I. Angew. Chem., Int. Ed. 1962, 1, 8Ȃ21; (b) Ugi, I.; Offermann, K.; Herlin- ger, H.; Marquarding, D. Liebigs Ann. Chem. 1967, 709, 1–10.; (c) Ugi, I.; Kaufhold, G. Ann. 1967, 709, 11–28; (d) Ugi, I.; Lohberger, S.; Karl, R. In Comprehensive Or- ganic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 2, 1083. (Review); (e) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (Re- view); (f) Ugi, I. Pure Appl. Chem. 2001, 73, 187Ȃ191. (Review). 2. Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552−6554. 3. Hebach, C.; Kazmaier, U. Chem. Commun. 2003, 596Ȃ597. 4. Multicomponent Reactions J. Zhu, H. Bienaymé, Eds.; Wiley-VCH, Weinheim, 2005. 5. Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7, 47Ȃ50. 6. Dömling, A. Chem. Rev. 2006, 106, 17Ȃ89. 7. Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett. 2007, 9, 3631Ȃ3634. 8. Rivera, D. G.; Pando, O.; Bosch, R.; Wessjohann, L. A. J. Org. Chem. 2008, 73, 6229Ȃ6238. 9. Bonger, K. M.; Wennekes, T.; Filippov, D. V.; Lodder, G.; van der Marel, G. A.; Overkleeft, H. S. Eur. J. Org. Chem. 2008, 3678Ȃ3688. 10. Williams, D. R.; Walsh, M. J. Ugi Reaction. In Name Reactions for Homologations- Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 786−805. (Review).

554

Ullmann coupling Homocoupling of aryl halides in the presence of Cu or Ni or Pd to afford biaryls.

Cu 2 I CuI2

Cu, single Cu(II)I I Cu(I)I electron transfer SET

I Cu(II)I CuI2

The overall transformation of PhI to PhCuI is an oxidative addition process.

Example 13

NO2 NO 2 Cu powder, DMF N N N Cl 100−105 oC, 4 h, 63% O2N

Example 2, CuTC-catalyzed Ullmann coupling4

O N S O N Cu NMP, rt, 88% I I

Example 35

OEt

O OMe O Cu-bronze − ο I 210 220 C MeO OMe OEt 72% MeO OMe MeO O

OEt

Example 48

O P(O)Ph2 Cu, DMF O P(O)Ph2 O P(O)Ph2 I I ο O P(O)Ph2 O P(O)Ph2 140 C, 88% O P(O)Ph2

70% 18%

Example 59

MeO MeO O I 0 Cu , Pd(PPh3)4 MOMO PhHN PhHNOC O MOMO ο N DMF, 100 C I NCy N 39%

References

1. (a) Ullmann, F.; Bielecki, J. Ber. 1901, 34, 2174−2185. Fritz Ullmann (1875−1939), born in Fürth, Bavaria, studied under Graebe at Geneva. He taught at the Technische Hochschule in Berlin and the University of Geneva. (b) Ullmann, F. Ann. 1904, 332, 38−81. 2. Fanta, P. E. Synthesis 1974, 9−21. (Review). 3. Kaczmarek, L.; Nowak, B.; Zukowski, J.; Borowicz, P.; Sepiol, J.; Grabowska, A. J. Mol. Struct. 1991, 248, 189−200. 4. Zhang, S.; Zhang, D.; Liebskind, L. S. J. Org. Chem. 1997, 62, 2312−2313. 5. Hauser, F. M.; Gauuan, P. J. F. Org. Lett. 1999, 1, 671−672. 6. Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4, 1623−1626. 7. Nelson, T. D.; Crouch, R. D. Org. React. 2004, 63, 265−556. (Review). 8. Qui, L.; Kwong, F. Y.; Wu, J.; Wai, H. L.; Chan, S.; Yu, W.-Y.; Li, Y.-M.; Guo, R.; Zhou, Z.; Chan, A. S. C. J Am. Chem. Soc. 2006, 128, 5955−5965. 9. Markey, M. D.; Fu, Y.; Kelly, T. R. Org. Lett. 2007, 9, 3255−3257. 10. Ahmad, N. M. Ullman coupling. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 255−267. (Review).

556

van Leusen oxazole synthesis 5-Substituted oxazoles through the reaction of p-tolylsulfonylmethyl isocyanide (TosMIC, also known as the van Leusen reagent) with aldehydes in protic solvents at refluxing temperatures.

N O O O NC S K2CO3 H O MeOH, reflux

O O O O O O S N S N N C C S C H R O B O R

H N N HHN Tos + H Tos H − TosH O O O R R H R B

Example 13

N O H O O O H H S NC Pr NaOMe Pr N N Pr MeOH, reflux Pr HN 81% HN

Example 25

O NC O N O O S K2CO3 EtO EtO H DMF, 80% O O

Example 39

N O CHO TosMIC, K2CO3

MeOH, reflux O OHC CHO 81% N O N

Example 410

O TosMIC, K2CO3 O CHO O N MeOH, reflux O O 4 h, 91%

References

1. (a) van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron Lett. 1972, 13, 2369–2381. (b) Possel, O.; van Leusen, A. M. Heterocycles 1977, 7, 77–80. (c) Sai- kachi, H.; Kitagawa, T.; Sasaki, H.; van Leusen, A. M. Chem. Pharm. Bull. 1979, 27, 793–796. (d) van Nispen, S. P. J. M.; Mensink, C.; van Leusen, A. M. Tetrahedron Lett. 1980, 21, 3723–3726. 2. van Leusen, A. M.; van Leusen, D. In Encyclopedia of Reagents of Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 7, 4973−4979. (Review). 3. Anderson, B. A.; Becke, L. M.; Booher, R. N.; Flaugh, M. E.; Harn, N. K.; Kress, T. J.; Varie, D. L.; Wepsiec, J. P. J. Org. Chem. 1997, 62, 8634–8639. 4. Kulkarni, B. A.; Ganesan, A. Tetrahedron Lett. 1999, 40, 5633–5636. 5. Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen, M. A. J. Org. Chem. 2000, 65, 1516–1524. 6. Barrett, A. G. M.; Cramp, S. M.; Hennessy, A. J.; Procopiou, P. A.; Roberts, R. S. Org. Lett. 2001, 3, 271–273. 7. Herr, R. J.; Fairfax, D. J., Meckler, H.; Wilson, J. D. Org. Process Res. Dev. 2002, 6, 677–681. 8. Brooks, D. A. van Leusen Oxazole Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 254– 259. (Review). 9. Kotha, S.; Shah, V. R. Synthesis 2007, 3653–3658. 10. Besselièvre, F.; Mahuteau-Betzer, F.; Grierson, D. S.; Piguel, S. J. Org. Chem. 2008, 73, 3278–3280.

558

Vilsmeier−Haack reaction The Vilsmeier–Haack reagent, a chloroiminium salt, is a weak electrophile. There- fore, the Vilsmeier–Haack reaction works better with electron-rich carbocycles and heterocycles.

O O O DMF, POCl3 CHO 100 oC, 24 h CHO

34% 4%

O O O Cl P Cl N O PCl2 N H N: O PCl Cl 2 O N: O H H OPCl Cl Cl Cl 2 H Vilsmeier–Haack reagent

: O O O

H Cl H N H B Cl H N N: Cl O O O aqueous

H workup : O : HO H H N CHO H N H

Example 12

OHC DMF, POCl OMe 3 OMe MeO MeO 100 oC, 14 h, 98% OH

Example 23

DMF, POCl3 N N 100 oC, 83% CHO N Cl N Cl

Example 39

CH OH CH3 Cl CH3 OH CH3 Cl 3 CHO CHO POCl3/DMF

o N CH3 N CH3 100 C, 20 h N OH N CH3 CH3 15% CH CH3 65% CH3 3 10%

Example 410 O

12 equiv POCl /DMF 3 Cl R R O O 80−100 oC, 31−71%

CHO

12 equiv POCl3/DMF Cl R R O 120−135 oC, 39−78% Cl

References

1. Vilsmeier, A.; Haack, A. Ber. 1927, 60, 119–122. 2. Reddy, M. P.; Rao, G. S. K. J. Chem. Soc., Perkin Trans. 1 1981, 2662–2665. 3. Lancelot, J.-C.; Ladureé, D.; Robba, M. Chem. Pharm. Bull. 1985, 33, 3122–3128. 4. Marson, C. M.; Giles, P. R. Synthesis Using Vilsmeier Reagents CRC Press, 1994. (Book). 5. Seybold, G. J. Prakt. Chem. 1996, 338, 392−396 (Review). 6. Jones, G.; Stanforth, S. P. Org. React. 1997, 49, 1–330. (Review). 7. Jones, G.; Stanforth, S. P. Org. React. 2000, 56, 355–659. (Review). 8. Tasneem, Synlett 2003, 138–139. (Review of the Vilsmeier–Haack reagent). 9. Nandhakumar, R.; Suresh, T.; Jude, A. L. C.; Kannan, V. R.; Mohan, P. S. Eur. J. Med. Chem. 2007, 42, 1128–1136. 10. Tang, X.-Y.; Shi, M. J. Org. Chem. 2008, 73, 8317–8320. 11. Pundeer, R.; Ranjan, P.; Pannu, K.; Prakash, O. Synth. Commun. 2009, 39, 316–324.

560

Vinylcyclopropane−cyclopentene rearrangement Transformation of vinylcyclopropane to cyclopentene via a diradical intermediate.

R2 Δ R2

R1 R1

R R 2 2 R2 R 2

R1 R1 R 1 R1

Example 11 O

340 oC, 2 h O CO2Me

50% CO2Me

Example 22

1. n-BuLi, THF−HMPT −78 to −30 oC 2. PhCH2Br SO2Ph P 3. desulfonylation h 77% overall yield

Example 39

H H O O H MOM H N H AlCl3, CH2Cl2 O O N O N MOM 0 oC, 88% MOM H N MOM O

MOM O O N MOM O H N O N O H O N MOM MOM

Example 410

O O Me CO2Me Me CO2Me 150 mol% MgI (0.2 M) Me 2 Me Me Me o CH3CN, 40 C, 6 h, 75% H H

References

1. Brule, D.; Chalchat, J. C.; Garry, R. P.; Lacroix, B.; Michet, A.; Vessier, R. Bull. Soc. Chim. Fr. 1981, 1−2, 57−64. 2. Danheiser, R. L.; Bronson, J. J.; Okano, K. J. Am. Chem. Soc. 1985, 107, 4579−4581. 3. Hudlický, T.; Kutchan, T. M.; Naqvi, S. M. Org. React. 1985, 33, 247−335. (Review). 4. Goldschmidt, Z.; Crammer, B. Chem. Soc. Rev. 1988, 17, 229−267. (Review). 5. Sonawane, H. R.; Bellur, N. S.; Kulkarni, D. G.; Ahuja, J. R. Synlett 1993, 875−884. (Review). 6. Hiroi, K.; Arinaga, Y. Tetrahedron Lett. 1994, 35, 153−156. 7. Baldwin, J. E. Chem. Rev. 2003, 103, 1197−1212. (Review). 8. Wang, S. C.; Tantillo, D. J. J. Organomet. Chem. 2006, 691, 4386−4392. 9. Zhang, F.; Kulesza, A.; Rani, S.; Bernet, B.; Vasella, A. Helv. Chim. Acta 2008, 91, 1201−1218. 10. Coscia, R. W.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131, 2496−2498.

562

von Braun reaction Different from the von Braun degradation reaction (amide to nitrile), the von Braun reaction refers to the treatment of tertiary amines with cyanogen bromide, resulting in a substituted cyanamide.

R CN Br CN N Br R 1 N 1 R R2 R R2

Br NC Br R SN2 CN R Br R N: CN N N 1 R2 R1 R2 1 R R R 2

Example 14

CF3 CF3 CF3 Br-CN KOH O O O CN MeOH/H O N N Tol. N 2 H Prozac

Example 25

CO Me CO2Me 2 CO Me CO2Me 2 Br-CN, THF, H2O Br N 75% N CN

Example 39

OTBS OTBS TBSO Br BrCN, CH2Cl2 Br NC N Ph Ph N reflux, 98% Ph N CN

References

1. von Braun, J. Ber. 1907, 40, 3914−3933. Julius von Braun (1875−1940) was born in Warsaw, Poland. He was a Professor of Chemistry at Frankfurt.

2. Hageman, H. A. Org. React. 1953, 7, 198−262. (Review). 3. Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279−1300. (Review). 4. Mody, S. B.; Mehta, B. P.; Udani, K. L.; Patel, M. V.; Mahajan, Rajendra N.. Indian Patent IN177159 (1996). 5. McLean, S.; Reynolds, W. F.; Zhu, X. Can. J. Chem. 1987, 65, 200−204. 6. Chambert, S.; Thomasson, F.; Décout, J.-L. J. Org. Chem. 2002, 67, 1898−1904. 7. Hatsuda, M.; Seki, M. Tetrahedron 2005, 61, 9908−9917. 8. Thavaneswaran, S.; McCamley, K.; Scammells, P. J. Nat. Prod. Commun. 2006, 1, 885−897. (Review). 9. McCall, W. S.; Abad Grillo, T.; Comins, D. L. Org. Lett. 2008, 10, 3255−3257.

564

Wacker oxidation Palladium-catalyzed oxidation of olefins to ketones, and aldehydes in certain cases.

cat. PdCl2, H2O O R CuCl2, O2 R

2 HCl + 2 CuCl 0.5 O 2 LnPdCl2 R

complexation H2O 2 CuCl2

L Pd HCl n reductive elimination Cl LnClPd R LnPdHCl : : O hydroxypalladation H H

O hydride shift HCl R LnClPd R L = ligand H O:: or solvent H

Example 15

O CO2H O2, 5% Pd(OAc)2 O NaOAc, DMSO, 80%

Example 27

O O O O CHO O O O H 10% Pd(OAc) , HClO H H H 2 4 H H

H H 0.5 equiv benzoquinone H H H H CH3CN 35% 45%

Example 39

O2, 20 mol% Cu(OAc)2 10 mol% PdCl2

OO OOO DMA/H2O (7:1) 84%

Example 410 O

O O O 5 eq. PdCl2, air O DMF/H O (7:1) HO 2 81% O

O O

O O O O O O

O O HO 12 : 1 HO O O CHO

References

1. Smidt, J.; Sieber, R. Angew. Chem., Int. Ed. 1962, 1, 80−88. 2. Tsuji, J. Synthesis 1984, 369−384. (Review). 3. Hegedus, L. S. In Comp. Org. Syn. Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 4, 552. (Review). 4. Tsuji, J. In Comp. Org. Syn. Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 7, 449. (Review). 5. Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298−5300. 6. Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecule 1994, University Science Books: Mill Valley, CA, pp 199−208. (Review). 7. Pellissier, H.; Michellys, P.-Y.; Santelli, M. Tetrahedron 1997, 53, 10733−10742. 8. Feringa, B. L. Wacker oxidation. In Transition Met. Org. Synth. Beller, M.; Bolm, C., eds.; Wiley−VCH: Weinheim, Germany. 1998, 2, 307−315. (Review). 9. Smith, A. B.; Friestad, G. K.; Barbosa, J.; Bertounesque, E.; Hull, K. G.; Iwashima, M.; Qiu, Y.; Salvatore, B. A.; Spoors, P. G.; Duan, J. J.-W. J. Am. Chem. Soc. 1999, 121, 10468−10477. 10. Kobayashi, Y.; Wang, Y.-G. Tetrahedron Lett. 2002, 43, 4381−4384. 11. Hintermann, L. Wacker-type Oxidations in Transition Met. Org. Synth. (2nd edn.) Bel- ler, M.; Bolm, C., eds., Wiley−VCH: Weinheim, Germany. 2004, 2, pp 379−388. (Re- view). 12. Li, J. J. Wacker−Tsuji oxidation. In Name Reactions for Functional Group Transfor- mations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 309−326. (Review). 13. Okamoto, M.; Taniguchi, Y. J. Cat. 2009, 261, 195−200. 566

Wagner–Meerwein rearrangement Acid-catalyzed alkyl group migration of alcohols to give more substituted olefins.

R 1 R1 R R H H R2 OH R2 R3 R3

R R R R1 R1 − H O R1 H H H 2 H R2 R2 R2 OH OH R3 R3 2 R3

1,2-shift

R1 − R1 R H H R2 2 3 3 R R R R

Example 13

H3CO2C OH H3C Br HN CH3SO3H O ClCH CH Cl N O N 2 2 OCH3 50 oC, 86% H3CN O HN OCH3 H CO 3

H3C CO2CH3 Br HN O

N O N OCH3 H CN 3 O HN OCH3 H CO 3

Example 2, Double Wagner–Meerwein rearrangement6

O O O O

OEt TFA, CH2Cl2 OEt HO 72 h, 76%

Example 37

OH OH O O Et AlCl, CH3 OTBS 2 CH3 OTBS CH2Cl2 HO −78 oC → rt O H MsO H 52% H BzO BzO

Example 49

BzO BzO H H H • H BF3 Et2O O benzene, 40% O OBz OBz H3C H C H CH 3 CH 3 3

References

1. Wagner, G. J. Russ. Phys. Chem. Soc. 1899, 31, 690. 2. Hogeveen, H.; Van Kruchten, E. M. G. A. Top. Curr. Chem. 1979, 80, 89–124. (Re- view). 3. Kinugawa, M.; Nagamura, S.; Sakaguchi, A.; Masuda, Y.; Saito, H.; Ogasa, T.; Kasai, M. Org. Proc. Res. Dev. 1998, 2, 344–350. 4. Trost, B. M.; Yasukata, T. J. Am. Chem. Soc. 2001, 123, 7162–7163. 5. Guizzardi, B.; Mella, M.; Fagnoni, M.; Albini, A. J. Org. Chem. 2003, 68, 1067–1074. 6. Bose, G.; Ullah, E.; Langer, P. Chem. Eur. J. 2004, 10, 6015–6028. 7. Guo, X.; Paquette, L. A. J. Org. Chem. 2005, 70, 315–320. 8. Li, W.-D. Z.; Yang, Y.-R. Org. Lett. 2005, 7, 3107–3110. 9. Michalak, K.; Michalak, M.; Wicha, J. Molecules 2005, 10, 1084–1100. 10. Mullins, R. J.; Grote, A. L. Wagner–Meerwein rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 373−394. (Review).

568

Weiss–Cook reaction Synthesis of cis-bicyclo[3.3.0]octane-3,7-dione. The product is frequently decar- boxylated.

EtO2C EtO2C R CO2Et O R aq. buffer O O O O R1 R1 EtO2C EtO2C CO2Et

R EtO C EtO2C R O EtO2C R EtO2C 2 H OH OH O O O O O O R1 O H R1 H R1 EtO C EtO2C EtO C EtO2C 2 2

H CO Et R EtO2C 2 EtO2C R CO2Et EtO2C OH R O O O HO O OH 1 H 1 H R 1 EtO2C R CO Et R CO Et H EtO2C 2 EtO2C 2

EtO C CO Et EtO2C CO2Et EtO2C R CO2Et 2 R 2 R

O O HO O HO OH H H R1 1 R1 EtO C R CO Et EtO C CO2Et EtO2C CO2Et 2 2 2

Example 12

MeO2C O O MeO2C O CO2Me pH 5.6 O MeO2C CO2Me 86% MeO2C

Example 23

CO2CH3 1. pH = 8.3 2. HOAc/HCl, Δ O O O O CHO 90% CO2CH3 H

Example 34

CO2CH3 O 1. pH = 6.8 2. HOAc/HCl O O O O 80% CO CH 2 3

Example 49

EtO2C CO2Et Et O NaHCO3 O O H2O/MeOH Me O rt, 24 h, 86% EtO C 2 CO2Et

EtO C CO Et EtO2C Et CO2Et EtO2C Et CO2Et 2 Et 2

O O HO OH HO OH Me Me EtO C Me CO Et EtO2C CO2Et EtO2C CO2Et 2 2

References

1. Weiss, U.; Edwards, J. M. Tetrahedron Lett. 1968, 9, 4885–4887. 2. Bertz, S. H.; Cook, J. M.; Gawish, A.; Weiss, U. Orga. Synth. 1986, 64, 27–38. 3. Kubiak, G.; Fu, X.; Gupta, A. K.; Cook, J. M. Tetrahedron Lett. 1990, 31, 4285–4288. 4. Wrobel, J.; Takahashi, K.; Honkan, V.; Lannoye, G.; Bertz, S. H.; Cook, J. M. J. Org Chem. 1983, 48, 139–141. 5. Gupta, A. K.; Fu, X.; Snyder, J. P.; Cook, J. M. Tetrahedron 1991, 47, 3665–3710. 6. Paquette, L. A.; Kesselmayer, M. A.; Underiner, G. E.; House, S. D.; Rogers, R. D.; Meerholz, K.; Heinze, J. J. Am. Chem. Soc. 1992, 114, 2644–2652. 7. Fu, X.; Cook, J. M. Aldrichimica Acta 1992, 25, 43–54. (Review). 8. Fu, X.; Kubiak, G.; Zhang, W.; Han, W.; Gupta, A. K.; Cook, J. M. Tetrahedron 1993, 49, 1511–1518. 9. Williams, R. V.; Gadgil, V. R.; Vij, As.; Cook, J. M.; Kubiak, G.; Huang, Q. J. Chem. Soc., Perkin Trans. 1 1997, 1425–1428. 10. van Ornum, S. G.; Li, J.; Kubiak, G. G.; Cook, J. M. J. Chem. Soc., Perkin Trans. 1 1997, 3471–3478.

570

Wharton reaction Reduction of α,β-epoxy ketones by hydrazine to allylic alcohols.

R2 NH2NH2 R1 R2 N ↑ H O R O 2 2 1 O Δ HO

R H R 2 2 R H 2 H2O N R1 N H R1 O OH O O R1 : NH NH2 NH NH O : hydrazone 2 2

: R OH2 2 H tautomerization R1 R2 R1 N H N2↑ O N HO diazene

Example 15

O OH O

NH2NH2•H2O, MeOH N N TEOC H HOAc, rt, 52% TEOC H

Example 26

TBDMSO TBDMSO CO CH CO2CH3 2 3 NH2NH2•HCl, Et3N (dimethylamino)ethanol O 32% OH O

Example 37

O O

NH2NH2, KOH

THF, reflux, 64% HO OH

OH OH

91 : 9 HO HO OH OH

Example 48

O NH NH •H O, MeOH 2 2 2 TESO OH TESO O O HOAc, rt, 59% O O

References

1. (a) Wharton, P. S.; Bohlen, D. H. J. Org. Chem. 1961, 26, 3615−3616. (b) Wharton, P. S. J. Org. Chem. 1961, 26, 4781−4782. 2. Caine, D. Org. Prep. Proced. Int. 1988, 20, 1−51. (Review). 3. Dupuy, C.; Luche, J. L. Tetrahedron 1989, 45, 3437−3444. (Review). 4. Thomas, A. F.; Di Giorgio, R.; Guntern, O. Helv. Chim. Acta 1989, 72, 767−773. 5. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003−2004. 6. Yamada, K.-i.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1998, 63, 3666−3672. 7. Di Filippo, M.; Fezza, F.; Izzo, I.; De Riccardis, F.; Sodano, G. Eur. J. Org. Chem. 2000, 3247−3249. 8. Takagi, R.; Tojo, K.; Iwata, M.; Ohkata, K. Org. Biomol. Chem. 2005, 3, 2031−2036. 9. Li, J. J. Wharton reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 152−158. (Re- view).

572

White Reagent

O O Ph S · S Ph Pd(OAc)2 White Reagent

The White Reagent 1 is a highly versatile, commercially-available catalyst for allylic C–H oxidation which allows for the construction of useful C–O, C–N, and C–C bonds directly from relatively inert allylic C–H bonds (Figure 1).1–11 The White Reagent enables novel and predictable disconnections for the synthesis of complex molecules which can streamline their synthesis.2,4,7,8 Widely available α- olefins undergo intra- and intermolecular C–H oxidation with remarkably high levels of chemo-, regio-, and stereoselectivity. Mechanistic studies provide evidence that the White Reagent promotes allylic C–H cleavage to generate π- allylpalladium intermediate 2 which can then be functionalized with an oxygen, nitrogen or carbon nucleophile (Figure 1).3

Figure 1 H

R O O Ph S · S Ph 1 Pd(OAc)2 C−C (10 mol%) C−O White Reagent CO Me OC(O)R1 R 2

NO2 R C−N 1 Pd(II)Ln OC(O)R R NR'2 R 2 R Ar

OH O

R O NR' 2

Common organic functionality such as Lewis basic phenol 3,3 acid-labile acetal 4,8 highly reactive aryl triflate 6,11 and depsipeptide 55 are well-tolerated under the mild reaction conditions (Figure 2). In all cases the products are isolated as one regioisomer and olefin isomer after column purification. Current state-of-the-art methods for constructing C–N bonds rely on functional group interconversions or C–C bond forming reactions using preoxidized materials. Allylic amination using the White Reagent can streamline the synthesis of nitrogen-containing molecules by reducing the functional group manipulations necessary for working with oxygenated intermediates. Allylic C–H amination was used to synthesize (–)-8, an intermediate in the synthesis of L- acosamine derivative 9 (Figure 3A).7 The C–H amination route to (–)-8 proceeded in half the total number of steps, no functional group manipulations, and

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_267, © Springer-Verlag Berlin Heidelberg 2009 573 comparable overall yield to the alternative C–O to C–N bond-forming route. Intermolecular C–H amination has also led to the construction of (+)- deoxynegamycin analogue 12 in five less steps and improved overall yield compared to the alternative route relying on C–O substitution (Figure 3B).8

Figure 2 O O Ph S · S Ph 1 H Pd(OAc)2 Nu Nu + pro-nucleophile (NuH) (10 mol%) or R (1.5−2.0 equiv) R R conditions branched product (B) linear product (L)

branched allylic C-H oxidation linear allylic C-H amination OH BQ (2 equiv), p-BrPhO2C O Cr(salen)Cl (6 mol%), o dioxane, 43 C O O CO Me BQ (2 equiv), TBME, N 2 45 oC Ts O OBn 3, 65% yield, > 20:1 B:L (+)-4, 63%, > 20:1 E:Z, > 20:1 L:B branched macrolactonization linear allylic C-H alkylation

O MeO2C CO2Me BQ (2 equiv) O DMBQ (1.5 equiv), o N NO AcOH (0.5 equiv), CH2Cl2, 45 C TfO 2 O dioxane:DMSO (4:1) NH HN OMe Ph O O 5 6 , 61% yield, 3:1 dr , 64% yield, > 20:1 E:Z, > 20:1 L:B

Figure 3

A. O O O Ph S · S Ph 1 OMe Pd(OAc)2 O steps O NHTs (10 mol%) O O PhBQ (1.05 equiv) NTs THF, 50 oC, 72 h Me NHAc TBSO H 78%, 9:1 dr crude TBSO OH 70% yield, 7 ( − 8 − (+)- 1 isomer ( )- ( )-N-acetyl-O-methyl ) acosamine 9

B. O O Ph S · S Ph 1 Pd(OAc)2 BocNH (10 mol%) BocNH O BocNH O Cr(salen)Cl (6 mol%) steps N OTMSE N CbzNHTs (2 equiv) 2 HBr H TMSEO C NTsCBz NH CO H 2 BQ (2 equiv.), TBME 2 2 (−)-10 (+)-11 (+)-deoxynegamycin 54%, 1 isomer 12 analogue

Similarly, allylic C–H oxidation can streamline the construction of oxygenated compounds by reducing functional group manipulations necessary for working with bisoxygenated intermediates. For example, a chiral allylic C–H oxidation/enzymatic resolution sequence furnished bisoxygenated compound 14 in 97% ee and in 42% overall yield in just 3 steps from a commercially available 574 monooxygenated precursor, 11-undecenoic acid (Figure 4).10 Alternative routes to similar molecules require protection/deprotection sequences and use a kinetic resolution giving a maximum of 50% yield.

Figure 4 2) 1 (10 mol%) (R,R)-Cr(salen)F O OAc O H 1. (MeO)NMe O H (10 mol%) MeO MeO N 7 HO 7 CDI, DCM N 7 AcOH (1.1 equiv) Me 14 Me undecenoic acid 13 BQ (2 equiv) 42% overall yield 4 Å MS, EtOAc, rt > 20:1 B:L, 97% ee 3) Novazyme 435

In addition to allylic C–H oxidation, the White Reagent also catalyzes intermolecular Heck arylations.6 Notably, the arylation uses electronically unbiased α-olefins and aryl boronic acids and occurs under acidic, oxidative conditions. A one-pot allylic C–H oxidation/vinylic C–H arylation reaction furnishes E-arylated allylic esters with high regio- and stereoselectivities (Figure 5). This three-component coupling can be used to rapidly synthesize densely functionalized products from inexpensive hydrocarbon feedstocks. N-Boc glylcine allylic ester 9 was synthesized in one step using commercially available olefin, amino acid, and boronic acid reagents. Compounds similar to 15 have been transformed into medicinally relevant dipeptidyl peptidase IV inhibitors.6

Figure 5 Branched allylic C−H esterification Oxidative Heck O O O NHBoc S · S 1 O O Ph Ph (4-Br)PhB(OH) Pd(OAc)2 2 Me (10 mol%) NHBoc o H O (1.5 equiv), 45 C 7 N-Boc-Gly (2 equiv) Me Me 15, 75% Br 7 BQ (2 equiv) o 7 > 20:1 E:Z dioxane, 45 C > 20:1 internal:terminal 1-undecene

Besides the one-pot process described above, the White Reagent catalyzes a chelate-controlled oxidative Heck arylation between a wide range of α-olefins and organoborane compounds in good yields and with excellent regio- and stereoselectivities (Figure 6).9 Unlike other Heck arylation methods, no Pd–H isomerization is observed under the mild reaction conditions. Aryl boronic acids, styrenylpinacol boronic esters, and aryl potassium trifluoroborates (activated with boric acid) are all compatible with the general reaction conditions.

575

Figure 6 O O M M = B(OH) 2 Ph S · S Ph 1 X R' = BF3K Pd(OAc)2 X (10 mol%) or R AcOH (4 equiv) R Ar n = 0−2 Bpin quinone (2 equiv) > 20:1 E:Z Ar dioxane, rt, 4 h > 20:1 internal:terminal

amino acids α,β-unsaturated carbonyls F O H N BocHN Ph

F O CO Me Bn 2 Br (+)-16, 60% (+)-17, 62% free alcohols allylic amine NHBoc HO N Ph 18, 83% Boc (+)-19, 81%

References

1. Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346–1347. 2. Fraunhoffer, K. J.; Bachovchin, D. A.; White, M. C. Org. Lett. 2005, 7, 223–226. 3. Chen. M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am. Chem. Soc. 2005, 127, 6970–6971. 4. Covell, D. J.; Vermeulen, N. A.; White, M. C. Angew. Chem. Int. Ed. 2006, 45, 8217– 8220. 5. Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White, M. C. J. Am. Chem. Soc. 2006, 128, 9032–9033. 6. Delcamp, J. H.; White, M. C. J. Am. Chem. Soc. 2006, 128, 15076–15077. 7. Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 7274–7276. 8. Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 129, 3316–3318. 9. Delcamp, J. H.; Brucks, A. P.; White, M. C. J. Am. Chem. Soc. 2008, 129, 11270– 11271. 10. Covell, D. J.; White, M. C. Angew. Chem., Int. Ed. 2008, 47, 6448–6451. 11. Young, A. J.; White, M. C. J. Am. Chem. Soc. 2008, 129, 14090–14091.

576

Willgerodt–Kindler reaction Conversion of a ketone to thioamide, with functional group migration.

S O HNR2 Me Ar NR n 2 Ar Δ n TsOH, S8, thioamide

In Carmack’s mechanism,2 the most unusual movement of a carbonyl group from methylene carbon to methylene carbon was proposed to go through an intricate pathway via a highly reactive intermediate with a sulfur-containing heterocyclic ring. The sulfenamide serves as the isomerization catalyst. e.g.: O S HN O N Δ O TsOH, S8, thioamide O

SH N: S S S S S O N S S SH S S S S S SS SS O SN S O NH O NH sulfenamide S O SN HS S

O O O : N : O S N N : N S S H N N H O thiirene O

O O O O : N N N N S H S S S :N N H N H HN O O O O

S S NO S8 N N N O O O

Example 1, The Willgerodt–Kindler reaction was a key operation in the initial synthesis of racemic Naproxen:3 O O HN O N

S S O 8 O 1. H+ OH 2. CH3OH, H2SO4 O O 3. NaH, CH3I Naproxen 4. NaOH

Example 25 S O HN O N

S8, microwave O 4 min., 40%

Example 3, A domino annulation reaction under Willgerodt–Kindler conditions:10 O

O N Cl O N HN O S S S S o S8, 130 C, 6 h, 15% 46% N 26% N N

References

1. (a) Willgerodt, C. Ber. 1887, 20, 2467−2470. Conrad Willgerodt (1841−1930), born in Harlingerode, Germany, was a son of a farmer. He worked to accumulate enough money to support his study toward his doctorate, which he received from Claus. He became a professor at Freiburg, where he taught for 37 years. (b) Kindler, K. Arch. Pharm. 1927, 265, 389−415. 2. Carmack, M.; Spielman, M. A. Org. React. 1946, 3, 83−107. (Review). 3. Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Roskowski, A.; Tomolonis, A.; Fried, J. H. J. Med. Chem. 1970, 13, 203−205. 4. Carmack, M. J. Heterocycl. Chem. 1989, 26, 1319−1323. 5. Nooshabadi, M.; Aghapoor, K.; Darabi, H. R.; Mojtahedi, M. M. Tetrahedron Lett. 1999, 40, 7549−7552. 6. Alam, M. M.; Adapa, S. R. Synth. Commun. 2003, 33, 59−63. 7. Reza Darabi, H.; Aghapoor, K.; Tajbakhsh, M. Tetrahedron Lett. 2004, 45, 4167−4169. 8. Purrello, G. Heterocycles 2005, 65, 411−449. (Review). 9. Okamoto, K.; Yamamoto, T.; Kanbara, T. Synlett 2007, 2687−2690. 10. Kadzimirsz, D.; Kramer, D.; Sripanom, L.; Oppel, I. M.; Rodziewicz, P.; Doltsinis, N. L.; Dyker, G. J. Org. Chem. 2008, 73, 4644−4649. 578

Wittig reaction Olefination of carbonyls using phosphorus ylides, typically the Z-olefin is obtained.

O R3 R1 R3 Ph3P Ph3PO R1 R2 R4 R2 R4

1 : R S 2 X 1 1 Ph3P N R R R X Ph3P H PPh3 R : R B

O R O R1 3 Ph3P R2 2 [2 + 2] 3 R R2 O R R1 R PPh cycloaddition 3 3 R R betaine “puckered” transition state, irreversible and concerted

Ph3PO R3 R1 R R3 PPh3 O R2 R1 R2 R oxaphosphetane

Example 13

NaH, Et2O; then add CHO + − CH2=CHPPh3 Br

NHTs DMF, reflux, 48 h, 50% N Ts

Example 24

1.8 N NaOEt, EtOH Cl PPh3 HO O O −30 oC to rt

CO2H

CO2H 2-cis-4-cis-vitamin A acid Accutane

Example 35

H H PhO N S PhO N Tol., 70 oC S O O O N N O PPh3 70% O CO t-Bu t-BuO C 2 2

Example 49 O OTMS H H H O O I

O O PPh3 H H O O H H H

OTBS EtS H O OTPS 1. n-BuLi, HMPA EtS 2. PPTS, 75% O O H H H O OTPS TBSO

H O EtS OTMS O O EtS H H H H O H O O H O O H H O O H H H

References 1. Wittig, G.; Schöllkopf, U. Ber. 1954, 87, 1318−1330. Georg Wittig (Germany, 1897−1987), born in Berlin, Germany, received his Ph.D. from K. von Auwers. He shared the Nobel Prize in Chemistry in 1981 with Herbert C. Brown (USA, 1912−2004) for their development of organic boron and phosphorous compounds. 2. Maercker, A. Org. React. 1965, 14, 270−490. (Review). 3. Schweizer, E. E.; Smucker, L. D. J. Org. Chem. 1966, 31, 3146–3149. 4. Garbers, C. F.; Schneider, D. F.; van der Merwe, J. P. J. Chem. Soc. (C) 1968, 1982– 1983. 5. Ernest, I.; Gosteli, J.; Greengrass, C. W.; Holick, W.; Jackman, D. E.; Pfaendler, H. R.; Woodward, R. B. J. Am. Chem. Soc. 1978, 100, 8214–8222. 6. Murphy, P. J.; Brennan, J. Chem. Soc. Rev. 1988, 17, 1−30. (Review). 7. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1988, 89, 863−927. (Review). 8. Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1–157. (Review). 9. Nicolaou, K. C. Angew. Chem., Int. Ed. 1996, 35, 589–607. 10. Rong, F. Wittig reaction in. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 588−612. (Review). 580

Schlosser modification of the Wittig reaction The normal Wittig reaction of nonstabilized ylides with aldehydes gives Z-olefins. The Schlosser modification of the Wittig reaction of nonstabilized ylides furnishes E-olefins instead.

Br PhLi PhLi t-BuOH R Ph P 1 3 R CHO t-BuOK 1 R R

Br H Ph P H 3 Ph3P Ph P H R 3 R R1 O R Ph phosphorus ylide

Br Ph3POLi Br Ph3POLi t-BuOH RR1 H 1 RRLi Ph LiBr complex of β-oxo ylide These conditions allow for the erythreo betaine to interconvert to the threo betaine

PPh3 Br R R t-BuOH LiBr LiO H Ph3PO t-BuOK R1 1 H R LiBr complex of threo betaine

Example 16

Me Ph O I O 5 equiv Et3P, DMF, rt, 30 min. N N then 0 oC, LDA, then O O O N N Ph H 66% Me EtO C EtO2C 2

581

Example 210

O PPh3Br

PhLi, Bu2O/THF 66%

References 1. (a) Schlosser, M.; Christmann, K. F. Angew. Chem., Int. Ed. 1966, 5, 126. (b) Schlosser, M.; Christmann, K. F. Ann. 1967, 708, 1−35. (c) Schlosser, M.; Christ- mann, K. F.; Piskala, A.; Coffinet, D. Synthesis 1971, 29−31. 2. van Tamelen, E. E.; Leiden, T. M. J. Am. Chem. Soc. 1982, 104, 2061−2062. 3. Parziale, P. A.; Berson, J. A. J. Am. Chem. Soc. 1991, 113, 4595−606. 4. Sarkar, T. K.; Ghosh, S. K.; Rao, P. S.; Satapathi, T. K.; Mamdapur, V. R. Tetrahe- dron 1992, 48, 6897−6908. 5. Deagostino, A.; Prandi, C.; Tonachini, G.; Venturello, P. Trends Org. Chem. 1995, 5, 103−113. (Review). 6. Celatka, C. A.; Liu, P.; Panek, J. S. Tetrahedron Lett. 1997, 38, 5449−5452. 7. Panek, J. S.; Liu, P. J. Am. Chem. Soc. 2000, 122 11090−11097. 8. Duffield, J. J.; Pettit, G. R. J. Nat. Prod. 2001, 64, 472−479. 9. Kraft, P.; Popaj, K. Eur. J. Org. Chem. 2004, 4995−5002. 10. Kraft, P.; Popaj, K. Eur. J. Org. Chem. 2008, 4806−4814. 582

[1,2]-Wittig rearrangement Treatment of ethers with bases, such as alkyl lithium, results in alcohols.

R2Li R1 R1 R 2 O 1 R 2 OH 1

The [1,2]-Wittig rearrangement is believed to proceed via a radical mechanism:

2 R Li Li deprotonation R1 homolytic H R O R1 R1 cleavage R O R O

1 1 R R1 workup R R OLi R OLi R OH

Example 1, Aza [1,2]-Wittig rearrangement2

n-BuLi workup H Ph N Li N Ph N SnBu3 Ph CH CH 83% 3 CH 3 3

Example 23

t-BuLi O 58% O OH O

Example 34

OH H H O O O TMS n-BuLi, THF, ether TMS 0 °C, 60%, > 98:2 dr OTBDPS OTBDPS

Example 46

NOMe NOMe 2 eq. LDA, THF O −78 oC, 82% OH O O

Example 58

OTBS n-BuLi, THF TBSO OH TBSO O Ph TBSO Ph −20 to 0 oC, 32%

Example 69

OMe OMe N N LDA, THF Ph O O O Ph − o 40 C, 94% OH

References

1 Wittig, G.; Löhmann, L. Ann. 1942, 550, 260–268. 2 Peterson, D. J.; Ward, J. F. J. Organomet. Chem. 1974, 66, 209–217. 3 Tsubuki, M.; Okita, H.; Honda, T. J. Chem. Soc., Chem. Commun. 1995, 2135–2136. 4 Tomooka, K.; Yamamoto, H.; Nakai, T. J. Am. Chem. Soc. 1996, 118, 3317–3318. 5 Maleczka, R. E., Jr.; Geng, F. J. Am. Chem. Soc. 1998, 120, 8551–8552. 6 Miyata, O.; Asai, H.; Naito, T. Synlett 1999, 1915–1916. 7 Katritzky, A. R.; Fang, Y. Heterocycles 2000, 53, 1783–1788. 8 Tomooka, K.; Kikuchi, M.; Igawa, K.; Suzuki, M.; Keong, P.-H.; Nakai, T. Angew. Chem., Int. Ed. 2000, 39, 4502–4505. 9 Miyata, O.; Asai, H.; Naito, T. Chem. Pharm. Bull. 2005, 53, 355–360. 10 Wolfe, J. P.; Guthrie, N. J. [1,2]-Wittig Rearrangement. In Name Reactions for Ho- mologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 226−240. (Review).

584

[2,3]-Wittig rearrangement Transformation of allyl ethers into homoallylic alcohols by treatment with base. Also known as the Still−Wittig rearrangement. Cf. Sommelet−Hauser rearrangement.

2 2 3 1 1 [2,3]-sigmatropic 3 1 X Y Y rearrangement X 2 2 1

R R 1 O R R2Li O H R1 2 R R1 = alkynyl, alkenyl, Ph, COR, CN.

R R [2,3]-sigmatropic workup

rearrangement 1 1 O R HO R

Example 12

KOt-Bu, HOt-Bu, THF O 0 oC, 26 h, 22% O HO O

Example 23

LDA, THF, −78 oC; TsO CO H O CO2H then TsCl, 87% 2 > 95% E

Example 35

H O H H O N O 1.5 equiv LiHMDS N H HO H O N O 5 equiv HMPA, THF HO H O H H H O −78 to −10 οC 94 : 6 67%

Example 46

Me Me Me OSEM OSEM n-BuLi O O Me THF-pentane 97% O Me Me HO

References

1. Cast, J.; Stevens, T. S.; Holmes, J. J. Chem. Soc. 1960, 3521−3527. 2. Thomas, A. F.; Dubini, R. Helv. Chim. Acta 1974, 57, 2084−2087. 3. Nakai, T.; Mikami, K.; Taya, S.; Kimura, Y.; Mimura, T. Tetrahedron Lett. 1981, 22, 69−72. 4. Nakai, T.; Mikami, K. Org. React. 1994, 46, 105−209. (Review). 5. Kress, M. H.; Yang, C.; Yasuda, N.; Grabowski, E. J. J. Tetrahedron Lett. 1997, 38, 2633−2636. 6. Marshall, J. A.; Liao, J. J. Org. Chem. 1998, 63, 5962−5970. 7. Maleczka, R. E., Jr.; Geng, F. Org. Lett. 1999, 1, 1111−1113. 8. Tsubuki, M.; Kamata, T.; Nakatani, M.; Yamazaki, K.; Matsui, T.; Honda, T. Tetrahe- dron: Asymmetry 2000, 11, 4725−4736. 9. Schaudt, M.; Blechert, S. J. Org. Chem. 2003, 68, 2913−2920. 10. Ahmad, N. M. [2,3]-Wittig Rearrangement. In Name Reactions for Homologations- Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 241−256. (Review). 586

Wohl–Ziegler reaction The Wohl–Ziegler reaction is the reaction of an allylic or benzylic substrate with N-bromosuccinimide (NBS) under radical initiating conditions to provide the corresponding allylic or benzylic bromide. Conditions used to promote the radical reaction are typically radical initiators, light and/or heat; carbon tetrachloride (CCl4) is typically utilized as the solvent.

O Br O CCl , reflux 4 R R Br N HN initiator O O

Initiation: Δ N ↑ 2 CN NC NN CN homolytic 2 cleavage 2,2ƍ-azobisisobutyronitrile (AIBN) O O

N Br CN N Br CN O O

Propagation: O O H abstraction N H NH

O O O O

N Br Br N

O O The succinimidyl radical is now available for the next cycle of the radical chain reaction.

Example 13

: OAc O OAc OAc OAc O

NBS, CCl4 O Br reflux, 30 min., 48% AcO AcO AcO

Example 27

CO2Me 1.2 eq. NBS, 0.1 eq. AIBN CO2Me

solvent free, 60 to 65 oC Br 89%

Example 38

Br N N NBS, CCl4 reflux, 71% N N Br

Example 49

Br NBS, AIBN (cat)

BocN CCl4, reflux, 2 h, BocN O 95% O

References

1. Wohl, A. Ber. 1919, 52, 51−63. Alfred Wohl (1863−1939), born in Graudenz, Ger- many, received his Ph.D. from A. W. Hofmann. In 1904, he was appointed Professor of Chemistry at the Technische Hochschule in Danzig. 2. Ziegler, K.; Spath, A.; Schaaf, E.; Schumann, W.; Winkelmann, E. Ann. 1942, 551, 80−119. Karl Ziegler (1898−1973), born in Helsa, Germany, received Ph.D. in 1920 from von Auwers at the University of Marburg. He became the director of the Max- Planck-Institut für Kohlenforschung at Mülheim/Ruhr in 1943 and stayed there until 1969. He shared the Nobel Prize in Chemistry in 1963 with Giulio Natta (1903−1979) for their work in polymer chemistry. The Ziegler−Natta catalyst is widely used in polymerization. 3. Djerassi, C.; Scholz, C. R. J. Org. Chem. 1949, 14, 660−663. 4. Allen, J. G.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 351−352. 5. Detterbeck, R.; Hesse, M. Tetrahedron Lett. 2002, 43, 4609−4612. 6. Stevens, C. V.; Van Heecke, G.; Barbero, C.; Patora, K.; De Kimpe, N.; Verhe, R. Synlett 2002, 1089−1092. 7. Togo, H.; Hirai, T. Synlett 2003, 702−704. 8. Marjo, C. E.; Bishop, R.; Craig, D. C.; Scudder, M. L. Mendeleev Commun. 2004, 278−279. 9. Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310−6311. 10. Curran, T. T. Wohl–Ziegler reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 661−674. (Review). 588

Wolff rearrangement Conversion of an α-diazoketone into a ketene.

1 1 O N2 Δ R H2O R O CO 2 2 1 C O R R R1 R2 N2 R2 R2 OH

α-diazoketone ketene intermediate

Step-wise mechanism:

N N O 1 O N O N N2 R C O 1 2 2 R1 R2 R1 R2 R R R

α-ketocarbene Treatment of the ketene with water would give the corresponding homologated carboxylic acid.

Concerted mechanism:

N 1 N R O N 2 C O 2 1 2 R R R

Example 12

O O O O Δ or hv H OEt EtOH, dioxane (1:1) N2 > 90%

Example 23

O CO2Me N2 hv, MeOH O N O 90% N Me Me

Example 34

1. LiHMDS, TFEA hυ

N 2. MsN3, Et3N 2 CH3OH O O OMe O

Example 49

C H C5H11 5 11 N HN HN 2 O O EtO C EtO2C O 2 O O CO2Et Rh2Oct4

C5H11CONH2 N N N Boc Boc 55% Boc 39% Wolff rearrangement N-H insertion

References

1. Wolff, L. Ann. 1912, 394, 23−108. Johann Ludwig Wolff (1857−1919) earned his doctorate in 1882 under Fittig at Strasbourg, where he later became an instructor. In 1891, Wolff joined the faculty of Jena, where he collaborated with Knorr for 27 years. 2. Zeller, K.-P.; Meier, H.; Müller, E. Tetrahedron 1972, 28, 5831−5838. 3. Kappe, C.; Fäber, G.; Wentrup, C.; Kappe, T. Ber. 1993, 126, 2357−2360. 4. Taber, D. F.; Kong, S.; Malcolm, S. C. J. Org. Chem. 1998, 63, 7953−7956. 5. Yang, H.; Foster, K.; Stephenson, C. R. J.; Brown, W.; Roberts, E. Org. Lett. 2000, 2, 2177−2179. 6. Kirmse, W. “100 years of the Wolff Rearrangement” Eur. J. Org. Chem. 2002, 2193−2256. (Review). 7. Julian, R. R.; May, J. A.; Stoltz, B. M.; Beauchamp, J. L. J. Am. Chem. Soc. 2003, 125, 4478−4486. 8. Zeller, K.-P.; Blocher, A.; Haiss, P. Mini-Reviews Org. Chem. 2004, 1, 291−308. (Re- view). 9. Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin, A. M. Z. J. Org. Chem. 2005, 70, 5840−5851. 10. Kumar, R. R.; Balasubramanian, M. Wolff Rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 257−273. (Review).

590

Wolff–Kishner reduction Carbonyl reduction to methylene using basic hydrazine.

O NH2NH2 R R1 R R1 NaOH, reflux

HO O H

NH2 : N R R1 HO N H N H R R1 1 : R R NH NH 2 2 H H O

O HO − H H 1 N2 H N R 1 N R R R R R1

Example 1, Huang Minlon modification, with loss of ethylene here5

NH2NH2•H2O o NH2NH2•2HCl KOH, 210 C O 130 oC 36%

Example 27

O H2N N 80% NH2NH2•H2O

toluene, microwave MeO2C 20 min., 75% MeO2C

KOH, microwave

30 min., 40% MeO C 2

Example 38

OH O

85% NH2NH2•H2O, KOH OH o H2O, 30 min., 165 C, 87% HO

OH OH OH OH O H H H H

1,5-hydride shift HO HO

Example 4, Huang Minlon modification10

OH N Me NH2NH2•H2O diethylene glycol HO HO reflux, 4.75 h, 75% OMe OMe

References

1. (a) Kishner, N. J. Russ. Phys. Chem. Soc. 1911, 43, 582−595. (b) Wolff, L. Ann. 1912, 394, 86. (c) Huang, Minlon J. Am. Chem. Soc. 1946, 68, 2487−2488. (d) Huang, Minlon J. Am. Chem. Soc. 1949, 71, 3301−3303. (The Huang-Minlon modification). 2. Todd, D. Org. React. 1948, 4, 378−422. (Review). 3. Cram, D. J.; Sahyun, M. R. V.; Knox, G. R. J. Am. Chem. Soc. 1962, 84, 1734−1735. 4. Murray, R. K., Jr.; Babiak, K. A. J. Org. Chem. 1973, 38, 2556−2557. 5. Lemieux, R. P.; Beak, P. Tetrahedron Lett. 1989, 30, 1353−1356. 6. Taber, D. F.; Stachel, S. J. Tetrahedron Lett. 1992, 33, 903−906. 7. Gadhwal, S.; Baruah, M.; Sandhu, J. S. Synlett 1999, 1573−1592. 8. Szendi, Z.; Forgó, P.; Tasi, G.; Böcskei, Z.; Nyerges, L.; Sweet, F. Steroids 2002, 67, 31−38. 9. Bashore, C. G.; Samardjiev, I. J.; Bordner, J.; Coe, J. W. J. Am. Chem. Soc. 2003, 125, 3268−3272. 10. Pasha, M. A. Synth. Commun. 2006, 36, 2183−2187. 11. Song, Y.-H.; Seo, J. J. Heterocycl. Chem. 2007, 44, 1439−1443. 12. Shibahara, M.; Watanabe, M.; Aso, K.; Shinmyozu, T. Synthesis 2008, 3749−3754.

592

Woodward cis-dihydroxylation Cf. Prévost trans-dihydroxylation.

1. I2, AgOAc

+ HO OH 2. H2O, H

I II I S 2 SN2 N : O O OAc cyclic iodonium ion intermediate neighboring group assistance

OO − protonation H OO HO O

H O: H O O 2 : OH2 hydrolysis HO O HO O HO OH O HO O H H

Example 11

CH CH 3 OR1 3 I2, AgOAc 1 2 HOAc, H2O R = Ac, R = H H C 1 2 H C 3 OR2 R = H, R = Ac 3 → H H 23 95 °C H H 3.5 h O O

CH 3 OH

KOH, MeOH H C 3 OH H 23 °C, 71% overall H O

Example 26

H3C CH3 NBA, AgOAc, HOAc H HO 23 °C, 75% H MeO2C

OH OH

H3C CH 3 H3C CH3

H H HO O HO OAc H H MeO C O 2 MeO2C Br Me Br

References

1. Woodward, R. B.; Brutcher, F. V., Jr. J. Am. Chem. Soc. 1958, 80, 209−211. Robert Burns Woodward (USA, 1917−1979) won the Nobel Prize in Chemistry in 1953 for his synthesis of natural products. 2. Kirschning, A.; Plumeier, C.; Rose, L. Chem. Commun. 1998, 33−34. 3. Monenschein, H.; Sourkouni-Argirusi, G.; Schubothe, K. M.; O’Hare, T.; Kirschning, A. Org. Lett. 1999, 1, 2101−2104. 4. Kirschning, A.; Jesberger, M.; Monenschein, H. Tetrahedron Lett. 1999, 40, 8999−9002. 5. Muraki, T.; Yokoyama, M.; Togo, H. J. Org. Chem. 2000, 65, 4679−4684. 6. Germain, J.; Deslongchamps, P. J. Org. Chem. 2002, 67, 5269−5278. 7. Myint, Y. Y.; Pasha, M. A. J. Chem. Res. 2004, 333−335. 8. Emmanuvel, L.; Shaikh, T. M. A.; Sudalai, A. Org. Lett. 2005, 7, 5071−5074. 9. Mergott, D. J. Woodward cis-dihydroxylation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 327−332. (Review). 10. Burlingham, B. T.; Rettig, J. C. J. Chem. Ed. 2008, 85, 959−961.

594

Yamaguchi esterification Esterification using 2,4,6-trichlorobenzoyl chloride (the Yamaguchi reagent).

Cl O Cl O O Cl Cl O R O Cl HO R1 O R OH Cl Cl R1 Et3N, CH2Cl2 DMAP, Tol., reflux R O

O O Cl Cl R O O O O Cl Cl Cl : Cl Cl Cl R O N :NEt Cl O 3 Cl Cl H R O N

DMAP (dimethylaminopyridine)

OR O Cl O Cl O N O O R N Cl Cl : N N Cl Cl R1 O H Steric hindrance of the chloro substituents blocks attack of the other carbonyl of the mixed anhydride intermediate.

OR R O 1 O N R R O 1 N

Example 1, Intermolecular coupling5

OMe OH I n-Bu3Sn CO2H ODMT OTES OMe

OMe I O 2,4,6-trichlorobenzoyl chloride OTES O DMAP, Tol., Et3N n-Bu3Sn rt, 24 h, 89% ODMT OMe

Example 2, Intramolecular coupling7

O 2,4,6-trichlorobenzoyl chloride O O O Et3N, THF HO then DMAP, toluene, 62% CO2H

O O O O O

Example 3, Dimerization8

H H H H H O OH Yamaguchi reagent O O O O O O 125 oC, 6 h, 66% BnO O H BnO OH H H

References

1. (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989−1993. (b) Kawanami, Y.; Dainobu, Y.; Inanaga, J.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1981, 54, 943−944. 2. Richardson, T. I.; Rychnovsky, S. D. Tetrahedron 1999, 55, 8977−8996. 3. Paterson, I.; Chen, D. Y.-K.; Aceña, J. L.; Franklin, A. S. Org. Lett. 2000, 2, 1513−1516. 4. Hamelin, O.; Wang, Y.; Deprés, J.-P.; Greene, A. E. Angew. Chem., Int. Ed. 2000, 39, 4314−4316. 5. Quéron, E.; Lett, R. Tetrahedron Lett. 2004, 45, 4533−4537. 6. Mlynarski, J.; Ruiz-Caro, J.; Fürstner, A. Chem., Eur. J. 2004, 10, 2214−2222. 7. Lepage, O.; Kattnig, E.; Fürstner, A. J. Am. Chem. Soc. 2004, 126, 15970−15971. 8. Smith, A. B. III.; Simov, V. Org. Lett. 2006, 8, 3315−3318. 9. Ahmad, N. M. Yamaguchi esterification. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 545−550. (Review). 10. Wender, P. A.; Verma, V. A. Org. Lett. 2008, 10, 3331−3334. 11. Carrick, J. D.; Jennings, M. P. Org. Lett. 2009, 11, 769−772.

596

Zincke reaction The Zincke reaction is an overall amine exchange process that converts N-(2,4- dinitrophenyl)pyridinium salts, known as Zincke salts, to N-aryl or N-alkyl pyridiniums upon treatment with the appropriate aniline or alkyl amine.

NH2 N O2N Cl RNH2 O2N N Cl Zincke salt R NO2 NO2

H NR

2 : Cl R R N N N N N H ring- O N H O N H 2 O2N 2 opening

NO2 NO NO2 2

R NH: 2 R R NH N NH N H H 1,6-addition/elimination O2N O2N

NO NO 2 2

R NH

: 2 N R H NH N O2N H O2N

NO2 NO 2

H H H H cis-trans N N N N R R R R inversion

6π H : R R R N N N N N N N electrocyclization Cl H H H2 R R R R

Example 15

Et Cl NO N Et 2 Acetone, Δ Cl NH O N 2 2 OH overnight (79%) Ph N NO2 NO 2

n-BuOH, Δ N 20 h, 86% Cl OH Ph

Example 26

NH Cl 2

NO2 N N OH OH N N OH Δ Cl NO H2O, , 16 h 2 OH

OEt EtO

CaCO3, H2O/THF (4:1) N N O 20 oC, 3 days 25%, 2 steps HO

Example 39

Cl NO CO t-Bu 2 MeOH, reflux N 2 11 Boc 89% N NO2

CO t-Bu CO t-Bu N 2 N 2 11 11 Boc NH2 Boc N 11 N Cl Cl O2N N 11 n-BuOH, heat, 61%

NO2 N

598

Example 410

Cl NO 2 N Cl Me NH O2N 2 then NaOH

NO2 N 58% NO2 Zincke salt

LiSnBu CHO 3 CHO Me2N Bu3Sn 50−55% Zincke aldehyde

References

1. (a) Zincke, Th. Ann. 1903, 330, 361−374. (b) Zincke, Th.; Heuser, G.; Möller, W. Ann. 1904, 333, 296−345. (c) Zincke, Th.; Würker, W. Ann. 1905, 338, 107−141. (d) Zincke, Th.; Würker, W. Ann. 1905, 341, 365−379. (e) Zincke, Th.; Weisspfenning, G. Ann. 1913, 396, 103−131. 2. Epszju, J.; Lunt, E.; Katritzky, A. R. Tetrahedron 1970, 26, 1665−1673. (Review). 3. Becher, J. Synthesis 1980, 589−612. (Review). 4. Kost, A. N.; Gromov, S. P.; Sagitullin, R. S. Tetrahedron 1981, 37, 3423−3454. (Re- view). 5. Wong, Y.-S.; Marazano, C.; Gnecco, D.; Génisson, Y.; Chiaroni, A.; Das, B. C. J. Org. Chem. 1997, 62, 729−735. 6. Urban, D.; Duval, E.; Langlois, Y. Tetrahedron Lett. 2000, 41, 9251−9256. 7. Cheng, W.-C.; Kurth, M. J. Org. Prep. Proced. Int. 2002, 34, 585−588. (Review). 8. Rojas, C. M. Zincke Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 355−375. (Review). 9. Shorey, B. J.; Lee, V.; Baldwin, J. E. Tetrahedron 2007, 63, 5587−5592. 10. Michels, T. D.; Rhee, J. U.; Vanderwal, C. D. Org. Lett. 2008, 10, 4787−4790.

599

Subject Index acyl halide, 234 acyl malonic ester, 263 A acyl transfer, 14, 322, 424, 452 abnormal Beckmann rearrangement, 34 2-acylamidoketones, 472 abnormal Chichibabin reaction, 108 acylation, 8, 51, 234, 235, 296, 322, 332, abnormal Claisen rearrangement, 121 440 acetic anhydride, 54, 167, 204, 424, 440, O-acylation, 332 442, 452 acylbenzenesulfonylhydrazines, 334 2-acetamido acetophenone, 92 acylglycine, 205 acetone cyanohydrin, 534 acylium ion, 234, 240, 253, 319 acetonitrile as a reactant, 168 acyl-o-aminobiphenyls, 371 α-acetylamino-alkyl methyl ketone, 167 α-acyloxycarboxamide, 415 acetylation, 311 α-acyloxyketone, 14 acetylenic alcohols, 100 α-acyloxythioether, 452 Į,ȕ-acetylenic esters, 225 adamantane-like structure, 432 acid chloride, 11, 461, 476 1,4-addition of a nucleophile, 355 acid scavenger, 202 addition of Pd-H, 373 acid-catalyzed acylation, 296 cis-addition, 496 acid-catalyzed alkyl group migration, 1,6-addition/elimination, 596 566 ADDP, 366 acid-catalyzed condensation, 131, 133 adduct formation, 365 acid-catalyzed cyclization, 409 adenosine, 370 acid-catalyzed electrocyclic formation of aglycon, 221 cyclopentenone, 383 AIBN, 22, 23, 24, 25, 200, 546, 586, acid-catalyzed reaction, 490 587 acid-catalyzed rearrangement, 436, 480 air oxidation, 194 acidic alcohol, 339 Al(Oi-Pr)3, 345 acidic amide hydrolysis, 534 alcohol activation, 365 acidic methylene moiety, 337 aldehyde cyanohydrin, 229 acid-labile acetal, 572 Alder ene reaction, 1, 2, 111 acid-mediated cyclization, 444 Alder’s endo rule, 184 acid-promoted rearrangement, 190 aldol addition, 470 acrolein, 30, 509 aldol condensation, 3, 42, 107, 212, 238, acrylic ester, 30 274, 284, 375, 424, 470 acrylonitrile, 30 Algar–Flynn–Oyamada reaction, 6 activated hydroxamate, 332 alkali metal amide, 517 activated methylene compounds, 315 alkali metal, 44, 517 activating agent, 440 alkaline medium, 460 activating auxiliary, 458 alkene, 1, 30, 236, 399, 417, 419, 430, activating effect of a base, 536 448, 490 activating group, 288, 351, 440 alkenyl anilines, 281 activation of the hydroxamic acid, 332 alkenylation, 277 activation step, 325 alkoxide-catalyzed oxidation, 404 α-active methylene nitrile, 254 alkoxide-catalyzed rearrangements, 214 acyclic mechanism, 159 alkoxy methylenemalonic ester, 263 acyl anhydride, 234 α-alkoxycarbonyl phosphonate, 341 acyl azides, 162 alkyl alcohol, 231 acyl derivative, 432 alkyl amine, 596 N-acyl derivative, 162 alkyl cation, 236 ortho-acyl diarylmethanes, 66 alkyl fluorosilane, 233 acyl group, 234 alkyl group migration, 566

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_BM2, © Springer-Verlag Berlin Heidelberg 2009 600 alkyl halide, 171, 236, 247, 325, 357 amide, 33, 102, 105, 123, 328, 379, 468, O-allyl hydroxylamines, 350 490, 543562 alkyl lithium, 494, 582 amidine, 438 alkyl migration, 319, 436 amination, 58, 80-82, 330, 572, 573 N-alkyl pyridinium, 596 amine exchange, 596 O-alkylating agent, 343 amine-catalyzed rearrangements, 214 alkylating agent, 236, 343 amino acid, 167, 534, 574, 575 N-alkylation, 343 α-amino acid, 167, 534 alkylation reaction, 203 α-amino ketone, 238, 385 alkyl-silane, 231 α-amino nitrile, 534 alkyne coordination, 198 aminoacetal intermediate, 444 alkyne insertion, 198 β-aminoalcohol, 177 alkyne, 98, 100, 148, 198, 236, 257, 259, gem-aminoalcohol, 330 419, 519 o-aminobiphenyls, 371 alkynyl copper reagent, 90, 98, 257, 519 β-aminocrotonate, 391 alkynyl halide, 90 aminothiophene synthesis, 254 Allan–Robinson reaction, 8, 322 ammonia, 107, 270, 274, 276, 411 allenyl enyne, 382 ammonium carbonate, 76 all-trans-retinal, 88 ammonium sulfite, 74 allyl ether, 584 ammonium ylide intermediate, 517 π -allyl Stille coupling, 529 amphotericin B, 89 allyl trimethylsilyl ketene acetal, 125 aniline, 46, 81, 102, 131, 133, 194, 251, allylic acetate, 549 263, 281, 373, 394, 509, 596 allylic alcohol, 100, 127, 363, 401, 406, anilinomethylenemalonic ester, 263 502, 570 anion-assisted Claisen rearrangement, allylic amination, 572 96 allylic amine, 426, 507 anionic oxy-Cope rearrangement, 138 allylic bromide, 586 p-anisyloxymethyl, 141 allylic carbamate, 507 α-anomer, 222, 223 allylic C–H amination, 572 β-anomer, 320 allylic C–H cleavage, 572 anomeric center, 313 allylic C–H oxidation, 572, 573, 574 anthracenes, 66 allylic epoxide, 549 AOM, 141 allylic ester enolate, 125 aprotic solvent, 16, 401 allylic ether, 549 aralkyloxazole, 472 allylic leaving group, 548 Arndt–Eistert homologation, 10 allylic substrate, 586 aromatic aldehyde, 229 allylic sulfoxide, 363 aromatic solvent, 202 allylic tertiary amine-N-oxides, 350 aromatization, 196, 234, 236, 517 allylic transformation, 222 Arthur C. Cope, 217 allylic transposition, 1 aryl aldehyde, 424 allylic trichloroacetamide, 406 aryl boronic acid, 87, 102, 574 allyloxycarbenium ions, 222 aryl diazonium salt, 262 π -allylpalladium intermediate, 548, 572 aryl groups migrate intramolecularly, allylsilane, 484 393 (R)-alpine-borane, 359, 360 aryl halide, 64, 80, 368, 531, 554 aluminum chloride, 253 aryl hydrazine, 72 aluminum hydride, 100, 235 aryl migration, 36, 165 aluminum phenolate, 240 1,2-aryl migration, 215 amalgamated zinc, 129 aryl potassium trifluoroborate, 574 N-aryl pyridinium, 596 601 aryl–acetylene, 98 aza-π-methane rearrangement, 192 Ȧ-arylamino-ketone, 46 azide, 52, 102, 162, 163, 458, 523 arylation, 102, 277, 332, 574 azido-alcohol, 52, 490 O-arylation, 332 aziridine, 52, 146, 266 arylboronates, 368 azirine intermediate, 385 β-arylethylamine, 434 N-aziridinyl imine, 16 2-aryl-3-hydroxy-4H-1benzopyran-4- azlactone, 204 ones, 6 2,2ƍ-azobisisobutyronitrile, 22, 24, 200, arylhydrazone, 227 586 O-aryliminoethers, 105 1,1'-(azodicarbonyl)dipiperidine, 366 3-arylindole, 46 aryllithium, 413 B arylmethyl ether, 202 backside displacement, 454 asymmetric [3+2]-cycloaddition, 144 Baeyer–Villiger oxidation, 12, 70, 165 asymmetric acyl Pictet–Spengler, 434 Baker–Venkataraman rearrangement, 14 asymmetric aldol condensation, 212 Balz−Schiemann reaction, 488 asymmetric amino-hydroxylation, 496 Bamford–Stevens reaction, 16, 494 asymmetric aza-Michael addition, 355 Barbier coupling reaction, 18 asymmetric Carroll rearrangement, 96 Bartoli indole synthesis, 20 asymmetric Claisen rearrangement, 118 Barton ester, 22 asymmetric construction of carbon– Barton nitrite photolysis, 26 carbon bond, 351 Barton radical decarboxylation, 22 asymmetric Diels–Alder reactions, 143 Barton–McCombie deoxygenation, 24 asymmetric dihydroxylation, 499 base-catalyzed condensation, 169, 463 asymmetric epoxidation, 300, 502 base-catalyzed self-condensation, 546 asymmetric hydroboration, 71 base-induced cleavage, 273 asymmetric hydrogenation, 399 base-mediated rearrangement, 332 asymmetric intermolecular Heck reac- base-promoted radical coupling, 262 tion, 277 base-sensitive aldehyde, 341 asymmetric Mannich reaction, 337, 338 basic condition, 203, 337, 430 asymmetric Mannich-type reaction, 337, basic hydrogen peroxide conditions, 165 338 basic oxidation, 70 asymmetric Michael addition, 355 BaSO4-poisoned palladium catalyst, 476 asymmetric Mukaiyama aldol reaction, Batcho–Leimgruber indole synthesis, 28 376 Baylis–Hillman reaction, 30 asymmetric Petasis reaction, 426 9-BBN, 359 asymmetric reduction of ketones, 359 Beckmann rearrangement, 33 asymmetric reduction, 359, 399 Belluš–Claisen rearrangement, 117 asymmetric Robinson annulation, 271 benzaldehyde, 95, 108, 515 asymmetric Simmons−Smith, 507 1,4-benzenediyl diradical formation, 40 asymmetric Tsuji–Trost reaction, 550 benzil, 36 α-attack, 6 benzilate, 36 β-attack, 6 benzilic acid rearrangement, 36 aurone derivative, 7 benzoin condensation, 38, 525 aza [1,2]-Wittig rearrangement, 582 p-benzoquinone, 391 aza-Diels–Alder reaction, 187 benzothiazole, 309 aza-Grob fragmentation, 268 benzyl halide, 171, 515, 586 aza-Henry reaction, 284 benzyl reagent, 202 azalactone, 167 benzylation, 202, 203 aza-Myers−Saito reaction, 382 benzylic bromide, 586 aza-Payne rearrangement, 421 benzylic quaternary ammonium salt, 517 602 benzylic substrate, 586 α-bromoacid, 282 Bergman cyclization, 40, 382 bromodinitrobenzene, 347 betaine, 578, 580 N-bromosuccinimide, 586, see also NBS biaryl, 554 Brook rearrangement, 68 cis-bicyclo[3.3.0]octane-3,7-dione, 568 [1,2]-Brook rearrangement, 68, 69 Biginelli pyrimidone synthesis, 42 [1,3]-Brook rearrangement, 68 biindolyl, 369 [1,4]-Brook rearrangement, 68 bimolecular elimination, 30 [1,5]-Brook rearrangement, 69 Birch reduction, 44 Brown hydroboration, 70 2,4-bis(4-methoxyphenyl)-1,3- BT, 309 dithiadiphosphetane-2,4-disulfide, 328 Bu3P, 505 bis(trifluoroethyl)phosphonate, 527 Bucherer carbazole synthesis, 72 bis-acetylene, 90 Bucherer reaction, 74 bis-aryl halide, 531 Bucherer–Bergs reaction, 76 1,4-bis(9-O-dihydroquinidine)- Büchner ring expansion, 78 phthalazine, 496, 499 Buchwald–Hartwig amination, 80, 102 Bischler indole synthesis, 46 t-BuLi, 69, 199, 390, 413, 414, 582 Bischler–Möhlau indole synthesis, 46 Burgess dehydrating reagent, 84, 339 Bischler–Napieralski reaction, 48 Burke boronates, 87 B-isopinocampheyl-9-borabicyclo- butterfly transition state, 478 [3.3.1]-nonane, 359 t-butyl peroxide, 502 bisoxygenated intermediate, 573 Blaise reaction , 50 C Blum–Ittah aziridine synthesis, 52 13C-labelled α,β-unsaturated ketone, 196 boat-like, 117 Cadiot–Chodkiewicz coupling, 90, 98, Bobbitt modification, 445 519 N-Boc glylcine allylic ester, 574 calystegine, 220 Boekelheide reaction, 54 camphorsulfonic acid, 203, see also Boger pyridine synthesis, 56, 188 CSA 9-borabicyclo[3.3.1]nonane, 359, see Camps quinoline synthesis, 92 also 9-BBN Cannizzaro reaction, 94 borane, 70, 87, 89, 143, 359, 360, 536, carbazole, 60, 70, 72 574 carbene generation, 460 Borch reductive amination, 58 carbene mechanism, 428 boric acid, 574 carbene, 10, 112, 156, 198, 428, 460, Z-(O)-boron-enolate, 212 588 boron trifluoride etherate, 222 carbocation rearrangement, 176, 177 boronate, 87, 368 β-carbocation stabilization by the silicon boronic acid-Mannich, 426 group, 231 boronic acid, 87, 88, 102,426, 574 β-carbocation stabilizationby the β- boron-mediated Reformatsky reaction, silicon effect, 484 457 carbocyclization, 220 boron-protected haloboronic acid, 87, 88 carbodiimide, 332, 370 Borsche–Drechsel cyclization, 60 carbon Ferrier reaction, 222 Boulton–Katritzky rearrangement, 62 carbon monoxide, 253, 419 Bouveault aldehyde synthesis, 64 carbon nucleophile, 222, 484, 548, 572, Bouveault–Blanc reduction, 65 see also C- nucleophile Br/Cl variant of the Takai reaction, 541 carbon tetrachloride, 586, see also CCl4 Bradsher reaction, 66 carbon–boron bond, 306, 328, 387, 430, bromine/alkoxide for Hofmann rear- 434, 436 rangement, 290 carbonyl oxide, 161 603 carbonyl, 335, 399, 456, 484, 490, 542 chloroiminium salt, 558 ȕ-carbonyl sulfide derivative, 251 α-chloromethyl ketones, 276 1,2-carbon-to-nitrogen migration, 162 2-chloro-1-methyl-pyridinium iodide, carboxylic acid, 10, 22, 94, 202, 214, 379 282, 304, 415, 551 3-chloropyridine, 112 carboxylic amide derivative, 273 N-chlorosuccinimide, 150, see also NCS Carroll rearrangement, 96 cholesterol, 321 Castro–Stephens coupling, 90, 98, 519 chromium (VI), 304 in situ Castro–Stephens reaction, 99 chromium trioxide, 304 catalytic asymmetric enamine aldol, 271 chromium trioxide-pyridine complex, catalytic asymmetric inverse-electron- 304 demand Diels–Alder reaction, 187 chromium variant of the Nicholas reac- catalytic cycle, 81, 143, 277, 288, 325, tion, 395 399, 401, 465, 496, 500, 502, 529, 536, Chugaev reaction, 110 548, 564 Chugaev syn-elimination, 110 catalytic Pauson−Khand reaction, 419 Ciamician–Dennsted rearrangement, 112 CBS reagent, 143 cinchona alkaloid ligand, 499 3CC, 415 cinnamic acid synthesis, 424 4CC, 551 Claisen condensation, 113, 182 C–C bond rotation, 277 Claisen isoxazole synthesis, 115 CCl4, 97, 298, 319, 447, 455, 473, 516, Claisen rearrangement, 16, 96, 117 586, 587 para-Claisen rearrangement, 119 Celebrex, 318 ortho-Claisen rearrangement product, CH2I2, 470, 507, 508 119 CH3OTf, 202 classical Favorskii rearrangement, 217 chair-like, 117 cleavage of primary carbon–boron bond, Chan alkyne reduction, 100 308 Chan–Lam C–X coupling reaction, 102 Clemmensen reduction, 129 Chantix, 211 C–O bond fragmentation, 240 Chapman rearrangement, 105, 393 CO insertion, 198 Chapman-like thermal rearrangement, CO, 198, 319 106 cobalt-catalyzed Alder-ene reaction, 2 chelate-controlled oxidative Heck Collins oxidation, 304 arylation, 574 Collins–Sarett oxidation, 305 chemoselective tandem acylation of the Combes quinoline synthesis, 131, 133 Blaise reaction intermediate, 51 combinatorial Doebner reaction, 195 chemoselectivity, 572 Comins modification, 64 CHI3, 540 complexation, 87, 234, 240, 296, 484, Chichibabin pyridine synthesis, 107 564 chiral allylic C–H oxidation, 573 concerted oxygen transfer, 300 chiral auxiliary, 212, 351 concerted process, 113, 117, 137, 184, chiral ligand, 496 268, 499, 578, 588 chiral oxazoline, 351 condensation, 3, 28, 38, 42, 43, 60, 92, chlorination, 332 107, 113, 131, 133, 169, 182, 196, 204, in situ chlorination, 455 212, 225, 229, 238, 254, 255, 270, 274, chloro substituent, 594 284, 286, 315, 375, 423, 434, 444, 463, chloroammonium salt, 292 470, 474, 525, 532, 534, 546, 551 ȝ-chlorobis-(cyclopentadienyl)- Aldol, 3, 424 (dimethylaluminium)-ȝ- Benzoin, 38 methylenetitanium, 542 Claisen, 113 chlorodinitrobenzene, 347 Darzens, 169 604

Dieckmann, 182 cyanamide, 562 Guareschi–Thorpe, 270 cyanide, 38 Knoevenagel, 254, 255, 315 cyanoacetic ester, 270 Stobbe, 532 cyanogen bromide, 562 conjugate addition, 42, 196, 355, 391, cyanohydrins, 76 509, see also Michael addition cyclic intermediate, 159 Conrad–Limpach reaction, 131, 133 cyclic iodonium ion intermediate, 447, coordination and deprotonation, 102, 592 345 cyclic mechanism, 159 coordination, 102, 198, 345, 404, 548 cyclic thiocarbonate, 156 Cope elimination reaction, 135, 136 cyclic transition state, 345, 404 Cope rearrangement, 119, 137 cyclization of the Stobbe product, 532 copper catalyst, 257 cyclization, 6, 40, 46, 60, 66, 115, 131, Corey’s PCC, 304 133, 173, 196, 220, 227, 255, 263, 281, Corey’s oxazaborolidine, 143 371, 382, 383, 385, 400, 413, 417, 423, Corey’s ylide, 146 434, 444, 450, 463, 532, 596 Corey–Bakshi–Shibata (CBS) reagent, Bergman, 40 143 Borsche–Drechsel, 60 Corey–Claisen, 117 Ferrier carbocyclization, 220 Corey–Fuchs reaction, 148 Myers−Saito, 382 Corey–Kim oxidation, 150 Nazarov, 383 Corey–Nicolaou double activation, 152 Parham, 423 Corey–Nicolaou macrolactonization, Pshorr, 450 152 [2+2] cycloaddition, 78, 300, 465, 521, Corey–Seebach dithiane reaction, 154 542, 578 Corey–Winter olefin synthesis, 156 [2+2+1] cycloaddition, 419 Corey–Winter reductive elimination, [3+2]-cycloaddition, 143, 499 156 [4+2]-cycloaddition reactions, 184 Corey−Chaykovsky reaction, 146 cyclobutane cleavage, 173 coumarin, 423 cyclobutanone, 521 (−)-CP-263114, 304 cyclodehydration, 472 Cp2TiMe2, 428 cyclo-dibromodi-ȝ-methylene(ȝ- Cr(CO)3-coordinated hydroquinone, 198 tetrahydrofuran)trizinc, 403 Cr(IV), 304 cyclohepta-2,4,6-trienecarboxylic acid CrCl2, 540 ester, 78 Criegee glycol cleavage, 159 cyclohexadiene, 44 Criegee mechanism of ozonolysis, 161 cyclohexanone phenylhydrazone, 60 Criegee zwitterion, 161 cyclohexanone, 60, 220, 383, 419, 470 Crimmins procedure for Evans aldol, cyclopentene, 560 212 cyclopropanation, 112, 507 Crixivan, 301 cyclopropane, 146, 192, 560 cross-coupling, 87, 88, 102, 259, 288, cyclopropanone intermediate, 214 289, 299, 325, 389, 519, 529, 531, 536 cycloreversion, 465 cross-McMurry coupling, 335, 336 C−C bond cleavage, 268 Cr−Ni bimetallic catalyst, 401 C−C bond migration, 176, 177 CSA, 203, 271, 412, 453, 505 Cu(III) intermediate, 90, 98 D Cu(OAc)2, 102, 103, 259, 260, 299, 565 Dakin oxidation, 165 cupric acetate, 102 Dakin–West reaction, 167 Curtius rearrangement, 162 Danishefsky diene, 184 CuTC-catalyzed Ullmann coupling, 554 Darzens condensation, 169 605

DBU, 15, 170, 206, 285, 290, 333, 341, dienone, 119 342, 377, 386, 406, 407, 471, 472, 526, Dienone–phenol rearrangement, 190 DCC, 23, 245, 370 dienophile, 56, 184, 186, 187 de Mayo reaction, 173 diethyl diazodicarboxylate, 365, see also DEAD, 223, 243, 248, 365, 366 DEAD decalin, 432 diethyl succinate, 532 decarboxylation, 96, 263, 315, 332, 474, diethyl tartrate, 502 568 diethyl thiodiglycolate, 286 dehydrating reagent, 339, 432 dihydroisoquinolines, 48 dehydration, 46, 108, 408, 470, 480, 509 cis-dihydroxylation, 499 dehydrative ring closure, 371 1,4-dihydropyridine, 274 Delépine amine synthesis, 171, 515 diketone, 14, 131, 173, 270, 286, 408, demetallation, 395 409, 411, 458, 474 Demjanov rearrangement, 175 α-diketone, 286 deoxygenation, 24 β-diketones, 14, 131 (+)-deoxynegamycin, 573 1,4-diketone, 408, 409, 411 deprotonation of nitroalkanes, 284 1,4-diketone condensation, 474 depsipeptide, 572 1,5-diketone, 173 Dess–Martin oxidation, 179, 180, 472 dimerization, 255, 257, 299 desulfonylation, 560 dimethylaminomethylating agent, 206 desymmetrization, 95 dimethylaminomethylation, 206 Dewar intermediate, 119 dimethylaminopyridine, 594, see also (DHQ)2-PHAL, 499 DMAP (DHQD)2-PHAL, 496 N,N-dimethylformamide dimethyl diamide, 551 acetal, 28 diaryl compound, 262 dimethylmethylideneammonium iodide, diastereomer, 311, 451, 495 206 diastereoselective glycosidation, 313 dimethylsulfide, 150 diastereoselective Simmons−Smith dimethylsulfonium methylide, 146 cyclopro-panation, 507 dimethylsulfoxonium methylide, 146 1,8-diazabicyclo[5.4.0]undec-7-ene, dimethyltitanocene, 428 341, see also DBU dinitrophenyl, 67 diazoacetic esters, 78 diol, 156, 159, 203, 250, 436, 2-diazo-1,3-diketone, 458 diosgenin, 130 α-diazoketone, 588 1,3-dioxolane-2-thione, 156 2-diazo-3-oxoester, 458 dipeptidyl peptidase IV inhibitor, 574 diazomethane, 10 diphenyl 2-pyridylphosphine, 244 diazonium salt, 177, 262, 302, 486 diphenylphosphoryl azide, 163, see also diazotization, 176, 177 DPPA diboron reagents, 368 DIPT, 503 dibromoolefin, 148 1,3-dipolar cycloaddition, 161, 458, 459 1,3-dicarbonyl compounds, 317 2,2ƍ-dipyridyl disulfide, 152 1,4-dicarbonyl derivative, 525 diradical, 40, 192, 382, 417, 560 1,3-dicyclohexylurea, 370 N,N-disubstituted acetamide, 440 dichlorocarbene, 112, 460 disubstituted azodicarboxylate, 365 Dieckmann condensation, 182 3,4-disubstituted phenols, 190 Diels–Alder adduct, 184 4,4-disubstituted cyclohexadienone, 190 Diels–Alder reaction, 56, 66, 143, 184, 3,4-disubstituted thiophene-2,5- 185, 186, 187 dicarbonyl, 42, 286, 317, 525 diene, 44, 184, 186, 188, 192 di-tert-butylazodicarbonate, 244 1,4-diene, 192 dithiane, 154 606 ditin reagent, 531 electronically unbiased α-olefin, 574 di-vinyl ketone, 383 electron-rich alkyl group, 436 di-π-methane rearrangement, 192 electron-rich carbocycle, 558, 558 2,4-dinitro-benzenesulfonyl chloride, electron-rich ligands, 80 243 electron-withdrawing substituent, 44, DMAP, 78, 103, 157, 158, 161, 167, 184, 347 245, 380, 453, 594, 595 electrophile, 30, 89, 146, 266, 325, 484, DMFDMA, 28 490, 558 DMS, 150 electrophilic site, 413 DNP, 67 electrophilic substitution, 234, 296 Doebner quinoline synthesis, 194 elemental sulfur, 254, 408 Doebner–von Miller reaction, 196, 509 elimination, 30, 80, 84, 90, 98, 102, 110, domino annulation reaction under 135, 136, 156, 229 Willgerodt–Kindler conditions, 577 α-elimination, 460 Dötz reaction, 198 β-elimination, 281, 339, 519 double Chapman rearrangement, 106 syn-elimination, 505 double imine, 227 syn-β-elimination, 277 double Robinson-type cyclopentene Emil Fischer, 222 annulation, 471 enamine formation, 271, 274 double Tebbe, 542, 543 enamine, 56, 107, 131, 442, 546 double Wagner–Meerwein enantioselective aromatic Claisen rear- rearrangement, 566 rangement, 121 Dowd–Beckwith ring expansion, 200 enantioselective borane reduction, 143 Dowtherm A, 134 enantioselective cis-dihydroxylation, DPE-Phos, 82 499 DPPA, 163, 164 enantioselective epoxidation, 502 DTBAD, 244 enantioselective ester enolate-Claisen Dudley reagent, 202 rear-rangement, 125 enantioselective Mukaiyama-aldol E reaction, 4 E/Z geometry control, 125 enantiospecific Baker−Venkataraman E1cB, 271, 339 rear-rangement, 14 E2, 30, 31, 424, 430 ene reaction, 1, 110, 121, 140 E2 anti-elimination, 430 enediyne, 40 E2 elimination, 424 ene-hydrazine, 227 E-allylic alcohols, 100 enol, 96, 458 EAN, 316 enol ether, 355, 377, 397 E-arylated allylic ester, 574 enol silane, 482 EDDA, 315 enolate, 3, 125, 182, 206, 212, 250, 274, EDG, 184 282, 355, 424, 458, 470, 532 Eglinton coupling, 259 enolates, enolsilylethers, 206 Ei, 84 enolizable hydrogens for ketones, 217 electrocyclic formation, 383 enolizable α-haloketones, 214 electrocyclic ring closure, 198 enolization, 8, 42, 282, 322, 323, 337 electrocyclic ring opening, 78 enolsilane, 478 electrocyclization, 40, 131, 133, 417, enone, 173, 323, 482 596 enophile, 1 electron transfer, 18, 44, 215, 266, 311, enzymatic resolution, 573 335, 456, 554 episulfone intermediate, 454 electron-deficient heteroaromatics, 361 epoxidation electron-donating substituent, 44, 184 Corey−Chaykovsky, 146 607

Jacobsen–Katsuki, 300 Feist–Bénary furan synthesis, 218 Payne, 421 Ferrier carbocyclization, 220 Prilezhaev, 478 Ferrier glycal allylic rearrangement, 222 Sharpless, 502 Ferrier I reaction, 222 epoxide migration, 421 Ferrier II Reaction, 220 epoxide, 146, 300, 421, 478, 502 549 Ferrier reaction, 222 cis-epoxide, 300 Ferrier rearrangement, 222 trans-epoxide, 300 Fiesselmann thiophene synthesis, 225 2,3-epoxy alcohol, 421 Fischer carbene, 198 α,β-epoxy esters, 169 Fischer indole synthesis, 60, 72, 227 α,β-epoxy ketone, 570 Fischer oxazole synthesis, 229 α,β-epoxy sulfonylhydrazones, 208 flavone, 8 1,2-epoxy-3-ol, 421 flavonol, 6 α,β-epoxyketones, 208 Fleming–Tamao oxidation, 231 − Erlenmeyer−Plöchl azlactone synthesis, Fleming Kumada oxidation, 233 204 fluoride, 288 erythreo betaine, 580 fluoroarene, 488 erythro (kinetic adduct), Horner– fluoro-Meisenheimer complex, 347 Wadsworth–Emmons reaction, 294 fluorous Corey−Kim reaction, 150 erythro isomer, 527 fluorous Mukaiyama reagent, 380 Eschenmoser hydrazone, 16 formal [2+2+1] cycloaddition, 419 Eschenmoser’s salt, 206, 337 formaldehyde, 210, 330 Eschenmoser–Claisen amide acetal rear- formamide acetal, 28 rangement, 123 formic acid, 210, 330 Eschenmoser–Tanabe fragmentation, o-formylphenol, 460 208 formylation, 64, 253 Eschweiler–Clarke reductive alkylation four-component condensation, 551 of amines, 210, 330 four-electron system, 1 6π-electrocyclization, 131, 133, 596 four-membered titanium oxide ring in- ester, 22, 26, 30, 50, 65, 78, 96, 103, termediate, 428 113, 115, 117, 125, 127, 133, 169, 214, fragmentation, 196, 208, 240, 268 225, 240, 245, 263, 270, 286, 328, 343, Friedel–Crafts acylation reaction, 234 438, 525 Friedel–Crafts alkylation reaction, 236 esterification, 379, 574, 594 Friedel–Crafts reaction, 234 + − Friedländer quinoline synthesis, 238 Et3O BF4 , 343 Fries rearrangement, 240 Et3SiH, 245 ether formation, 202, 339, 366, 584 ortho-Fries rearrangement, 241 − ethyl oxalate, 463 Fries Finck rearrangement, 240 ethylammonium nitrate, 316 Fukuyama amine synthesis, 243 ethylenediamine diacetate, 315 Fukuyama reduction, 245 ethylformate, 458 Fukuyama−Mitsunobu procedure, 243 Evans aldol reaction, 212 functional group interconversion, 572 Evans syn, 212 functional group migration, 576 evolution of CO2, 167 furan ring as the masked carbonyl, 464 EWG, 184 furan synthesis, 218, 409 exo complex, 419 fused pyridine ring, 263 extrusion of dinitrogen, 162 extrusion of nitrogen, 56, 490 G Gabriel amine synthesis, 249 F Gabriel synthesis, 171, 246 Favorskii rearrangement, 214 Gabriel–Colman rearrangement, 250 608

Garner’s aldehyde, 266 (+)-hennoxazole, 472 Gassman indole synthesis, 251 Henry nitroaldol reaction, 284 Gattermann–Koch reaction, 253 heteroaryl Heck reaction, 280 Gewald aminothiophene synthesis, 254 heteroaryl recipient, 280 Glaser coupling, 257, 299 heteroaryllithium, 413 glycerol, 509 heteroarylsulfones, 309 glycidic ester, 169 hetero-Carroll rearrangemen, 96 glycol, 159, 222, 223, 225, 334, 591 hetero-Diels–Alder reaction , 56, 187 glycosidation, 313, 320, 492 heterodiene addition, 187 β-glycoside, 320 heterodienophile addition, 187, 188 C-glycosidic product, 222 heteropoly acid catalyst, 168 glycosyl acceptor, 313 hex-5-enopyranosides, 221 Gomberg–Bachmann reaction, 262, 450 hexacarbonyldicobalt complex, 395, 419 Gould–Jacobs reaction, 263 hexacarbonyldicobalt-stabilized proper- green Dakin–West reaction, 168 gyl cation, 395 Grignard reaction, 18, 266 hexamethylenetetramine, 171, 172, 515 Grignard reagent, 16, 20, 266, 325, 490, Hinsberg synthesis of thiophene deriva- 494 tive, 286 Grob fragmentation, 268 Hiyama cross-coupling reaction, 288 Grubbs’ catalyst, 78, 465, 467 Hoch–Campbell aziridine synthesis, 266 Grubbs’ catalyst, intramolecular Hofmann degradation, 290 Buchner rea-ction, 78 Hofmann rearrangement, 290 Guareschi imide, 270 Hofmann–Löffler–Freytag reaction, 292 Guareschi–Thorpe condensation, 270 homoallylic alcohol, 584 homocoupling, 258, 299, 335, 554 H homo-Favorskii rearrangement, 215 [1,5]-H-atom shift, 121 homologated carboxylic acid, 588 Hajos–Wiechert reaction, 271 homolysis, 215 halfordinal, 230 homolytic cleavage, 22, 24, 26, 200, Haller–Bauer reaction, 273 292, 298, 334, 582, 586 N-haloamines, protonated, 292 homo-McMurry coupling, 335 o-halo-aniline, 373 homo-Robinson, 470 haloarene, 486 Horner–Wadsworth–Emmons reaction, α-halocarbohydrate, 320 294, 341 α-haloesters, 50, 169, 456 Horner−Emmons reaction, 527 halogen effect, 472 Hosomi–Sakurai reaction, 484 α-halogenation, 282 Hosomi−Miyaura borylation, 368 halogen–lithium exchange, 413 Houben–Hoesch synthesis, 296 α-haloketones, 171, 218 Huang Minlon modification, 590, 591 2-halomethyl cycloalkanones, 200 Hunsdiecker–Borodin reaction, 298 α-halosulfone, 454 hydantoin, 76, 102, 497 Hantzsch 1,4-dihydropyridines, 274, 275 hydrazine, 72, 102, 227, 249, 317, 334, Hantzsch dihydropyridine synthesis, 274 570, 590 Hantzsch pyrrole synthesis, 276 hydrazoic acid, 490 head-to-head alignment, 173 hydrazone, 16, 60, 208, 227, 302, 570 head-to-tail alignment, 173 hydride, 94, 100, 210, 330, 345, 359,

Heck arylation, 574 373, 404, 482, 515, 564, 591 Heck reaction, 277, 278, 280, 373, 574 β-hydride elimination, 373, 482 Hegedus indole synthesis, 281 hydride shift, 564, 591 Hell–Volhard–Zelinsky reaction, 282 hydride source, 210 hemiaminal, 474, 515 hydride transfer, 94, 345, 359, 404, 515 609 hydro-allyl addition, 1 Bischler–Möhlau, 46 o-hydroxyaryl ketones, 8 Fischer, 227 hydrogen atom abstraction, 24 Gassman, 251 1,5-hydrogen abstraction, 26 Hegedus, 281 1,5-hydrogen atom transfer, 292 Mori–Ban, 373 hydrogen donor, 40, 274 Nenitzescu, 391 hydrogenation, 399, 476 Reissert, 463 hydrogenolysis, 251 indole-2-carboxylic acid, 463 hydrolysis of iminium salt, 271 Ing–Manske procedure, 249 hydrolysis, 54, 162, 165, 231, 247, 266, Initiation, radical, 586 271, 282, 286, 296, 315, 385, 393, 438, inositol, 220 447, 456, 460, 463, 478, 499, 534, 592 insertion toward CH, 419 hydropalladation, 564 insertion, 198, 277, 280, 373, 419, 589 hydroxamic acid, 332 intercomponent interactions, 90 hydroxide-catalyzed rearrangements, intermolecular addition, 361, 509 214 intermolecular aldol, 4 ω-hydroxyl-acid, 152 intermolecular Bradsher cycloaddition, hydroxylamine, 115, 349 66, 67 N-hydroxyl amines, 135 intermolecular C–H amination, 573 α-hydroxylation, 478 intermolecular C–H oxidation, 572 4-hydroxy-3-carboalkoxyquinoline, 263 intermolecular Friedel–Crafts acylation, ȕ-hydroxycarbonyl, 3 234 2ƍ-hydroxychalcones, 6 intermolecular Heck arylation, 280, 574 5-hydroxylindole, 391 intermolecular Yamaguchi coupling, 3-hydroxy-isoxazoles, 115 594 2-hydroxymethylpyridine, 54 internal acetylenes, 353 β-hydroxy-β-phenylethylamine, 432 intramolecular acyl transfer, 424 4-hydroxyquinoline, 263 intramolecular Alder-ene reaction, 1 β-hydroxysilane, 203, 430 intramolecular aldol condensation, 470 3-hydroxy-2-thiophenecarboxylic acid intramolecular Baylis–Hillman reaction, deri-vatives, 225 31 hydrozinolysis, 62 intramolecular Boger pyridine synthesis, hypohalite, 251, 290 56 intramolecular Bradsher cyclization, 66 I intramolecular Büchner reaction, 78 IBX, 179, 397 intramolecular Cannizzaro reaction, 95 imide, 102, 270, 444, 474 intramolecular C–H oxidation, 572 imine, 58, 102, 107, 131, 490, 521, 546, intramolecular condensation, 205 551 intramolecular cross-coupling, 531 iminium formationhydrolysis, 315 intramolecular cyclization, 413 iminium ion, 315, 330, 440, 442, 519, intramolecular Diels–Alder reaction, 534 184, 185 imino ether, 438 intramolecular ene reaction, 110 iminochloride, 385 intramolecular Favorskii Rearrange- iminophosphorane, 523 ment, 214 indole, 20, 28, 46, 60, 72, 227, 251, 281, intramolecular Friedel–Crafts acylation, 373, 391, 463 234, 235 indole synthesis, 227, 251, 281, 373, intramolecular Heck reaction, 278, 280, 391, 463 285, 280, 373 Bartoli, 20 intramolecular Horner–Wadsworth– Batcho–Leimgruber, 28 Emmons, 295 610 intramolecular Houben−Hoesch reac- isomerization, 229, 353, 421, 470 tion, 296 isoquinoline 1,4-diol, 250 intramolecular mechanism, 304 isoquinoline, 48, 250, 432, 434, 444, intramolecular Michael addition, 356 461, 462 intramolecular Minisci reaction, 362 3-isoxazolol, 115 intramolecular Mitsunobu reaction, 366 5-isoxazolol, 115 intramolecular Mukaiyama aldol reaction, 375 J intramolecular Nicholas reaction using Jacobsen–Katsuki epoxidation, 300 chromium, 396 Japp–Klingemann hydrazone synthesis, intramolecular Nozaki–Hiyama–Kishi 60, 302 reaction, 401 Johnson–Claisen (orthoester) rearrange- intramolecular nucleophilic aromatic re- ment, 127 arrangement, 511 Jones oxidation, 304, 305 intramolecular pathway, 440 Julia olefination, 309 intramolecular Pauson−Khand reaction, Julia–Kocienski olefination, 309, 311 419 intramolecular Schmidt rearrangement, K 491 Kahne glycosidation, 313 intramolecular SN2, 169 Kazmaier–Claisen, 117 intramolecular Stetter reaction, 525 ketene, 10, 123, 125, 127, 521, 588 intramolecular Suzuki–Miyaura cou- ketene acetal, 123, 125, 127 pling, 536 ketene cycloaddition, 521 intramolecular Thorpe reaction, 546 N,O-ketene acetals, 123 intramolecular transamidation, 331 α-ketocarbene, 588 intramolecular Tsuji–Trost reaction, 549 α-ketocarbene intermediate, 10 intramolecular Yamaguchi coupling, keto-enol tautomerization, 96 594 β-ketoester, 50, 96, 113, 115, 133, 218, inverse electronic demand Diels–Alder 274, 276, 302, 423 reaction, 186 2-ketophenols, 240 cis-trans inversion, 596 4-ketophenols, 240 inversion of configuration, 548 α-keto-phosphonate, 341 iododinitrobenzene, 347 ketoximes, 266 iodosobenzene diacetate for Hofmann ketyl, 65 rear-rangement, 290 Kharasch cross-coupling reaction, 325 O-iodoxybenzoic acid, 179, 397 kinetic product, 16, 294, 494, 527 ionic liquid, 316, 343 kinetic resolution, 574 ionic liquid-promoted interrupted Feist– Kishner reduction, 1

Benary reaction, 218 Knoevenagel condensation, 254, 255, ionic mechanism, 266 315 ipso attack, 347 Knorr pyrazole synthesis, 317, 411 ipso substitution, 231, 347 Knorr thiophene synthesis, 328 Ireland–Claisen (silyl ketene acetal) Koch–Haaf carbonylation, 319 rearrangement, 125 Koenig–Knorr glycosidation, 320 iron salt-mediated Polonovski reaction, Kostanecki acylation reaction, 322 441 Kostanecki reaction, 8, 322 irreversible fragmentation, 196 Kostanecki−Robinson reaction, 322 C-isocyanide, 415, 551 Kröhnke pyridine synthesis, 333 isocyanate intermediate, 76, 162, 290, Kumada coupling, 288, 325, 529, 536 332 isoflavone, 8 611

+ − L Me3O BF4 , 343 lactam, 240, 328, 521 Meerwein reagent, 343, 361 β-lactam, 521 Meerwein’s salt, 343 lactone, 204, 328, 403, 521 Meerwein–Eschenmoser–Claisen rear- azalactone, 167, 204 rangement, 123 β-lactone, 521 Meerwein–Ponndorf–Verley reduction, lactonization, 532 345, 404 larger counterion, 309 Me-IBX, 397 Lawesson’s reagent, 328, 408 Meisenheimer complex, 243, 347, 511 lead tetraacetate for Hofmann rear- [1,2]-Meisenheimer rearrangement, 349 rangement, 291 [2,3]-Meisenheimer rearrangement, 350 lead tetraacetate, 159 Meisenheimer−Jackson salt, 347 Lebel modification of the Curtius rear- Meldrum’s acid, 116 rangement, 164 4-membered ring transition state, 523 less-substituted olefin, 494 Mes, 465 Leuckart–Wallach reaction, 210, 330, mesityl, 465 331 mesyl azide, 458 Lewis acid catalyst, 222 metal-methylation, 343 Lewis acid, 1, 212, 222, 234, 236, 240, methoxycarbonylsulfamoyl- 375, 377, 395, 423, 484, 492 triethylammonium hydroxide inner salt, Lewis acid-catalyzed aldol condensa- 84 tion, 375 o-methyl-IBX, 397 Lewis acid-catalyzed Michael addition, methyl triflate, 202 377 methyl vinyl ketone, 470 Lewis basic phenol, 572 methylenated ketones, 206 LiBr complex, 580 N-methylation, 344 ligand exchange, 80, 476, 548 N-methyliminodiacetic acid, 87 Lipitor, 411 2-methylpyridine N-oxide, 54 liquid ammonia, 44 Meyers oxazoline method, 351 long-lived radical, 26 Meyer–Schuster rearrangement, 353, Lossen rearrangement, 332 480 low-valent titanium, 335 MgO, 202 L-phenylalanine, 271, 272 Mg-Oppenauer oxidation, 404 proline, 143, 271, 337, 338 Michael addition, 107, 271, 274, 323, LTA, 159 355, 377, 423, 470, 484, 525, see also conjugate addition M Michaelis–Arbuzov phosphonate syn- macrolactonization, 152, 573 thesis, 357 magnesium metal, 266 Michael−Stetter reaction, 525 magnesium oxide, 202 microwave, 29, 33, 43, 47, 74, 210, 264, maleimidyl acetate, 250 298, 299, 334, 335, 356, 429, 470, 511, manganaoxetane intermediate, 300 577, 590 Mannich base, 337 microwave Smiles rearrangement, 511 Mannich reaction, 206, 337, 426 microwave-assisted Gould–Jacobs reac- Martin’s sulfurane dehydrating reagent, tion, 264 339, 457 microwave-assisted, solvent-free Masamune–Roush conditions, 341 Bischler-indole synthesis, 47 masked carbonyl equivalent, 154 microwave-Hunsdiecker−Borodin, 298 McFadyen–Stevens reduction, 334 microwave-indued Biginelli McMurry coupling, 335 condensation, 43 MCR, 42, 76 MIDA, 87 612

Midland reduction, 359 Nef reaction, 387 migration order, 12, 436 Negishi cross-coupling reaction, 325, migration, 12, 36, 68, 162, 165, 175, 389 177, 203, 215, 319, 393, 421, 436, 490, neighboring group assistance, 447, 492, 566, 576 592 1,3-migration of an aryl group from Nenitzescu indole synthesis, 391 oxygen to sulfur, 393 Newman−Kwart reaction, 393 migratory insertion, 277 Nicholas reaction, 395 Minisci reaction, 361 Nicholas-Pauson–Khand sequence, 395 Mislow–Evans rearrangement, 363 nickel-catalyzed cross-coupling, 325, Mitsunobu reaction, 243, 332, 365, 366 389 mixed anhydride, 205, 594 Nicolaou dehydrogenation, 397 mixed orthoester, 127 nifedipine, 274 Miyaura borylation, 368 nitrene, 162 Mn(III)salen, 300 nitrile, 2, 34, 50, 98, 254, 296, 438, 468,, Mn(III)salen-catalyzed asymmetric ep- 490, 534, 546, 562 oxidation, 300 nitrile-Alder-ene reaction, 2 modified Ireland–Claisen nitrilium ion intermediate, 468, 490 rearrangement, 126 nitrite ester, 26 modified Skraup quinoline synthesis, 2-nitroalcohol, 284 509 nitroaldol condensation, 284 Moffatt oxidation, 370 nitroalkanes, 284 monooxygenated precursor, 574 nitroarenes, 20 more-substituted olefin, 494 nitrobenzene, 371 Morgan–Walls reaction , 371 4-nitrobenzenesulfonyl, 499 Mori–Ban indole synthesis, 373 nitrogen nucleophile, 572 Morita–Baylis–Hillman reaction, 30 nitrogen radical cation, 292 morpholine-polysulfide, 255 nitrogen source, 496 MPS, 255 nitronate, 284, 347, 387 Mukaiyama aldol reaction, 4, 375, 375, nitronic acid, 284, 387 376 o-nitrophenyl selenide, 505 Mukaiyama Michael addition, 377 o-nitrophenyl selenocyanate, 505 Mukaiyama reagent, 379, 380 nitroso intermediate, 20, 26, 102 multicomponent reactions, 42, 62 o-nitrotoluene derivatives, 28, 463 MVK, 470 non-enolizable ketone, 217, 273 MWI, 43 nonstabilized ylide, 580 Myers−Saito cyclization, 382 Nos, 499 N-(2,4-dinitrophenyl)pyridinium salt, nosylate, 499 596 Noyori asymmetric hydrogenation, 399 Nozaki–Hiyama–Kishi reaction, 401 N nucleophile, 89, 154, 162, 222, 355, 365, naphthol, 72 395, 484, 548, 572, 573 β-naphthol, 74 C-nucleophile, 222, see also carbon nu- β-naphthylamines, 74 cleophile Naproxen, 577 O-nucleophile, 222 Nazarov cyclization, 383 S-nucleophile, 222 NBS variant of Hofmann rearrangement, nucleophilic addition, 50, 351, 438, 456, 290 456 NBS, 290, 298, 516, 586, 587 nucleophilic radical, 361 NCS, 100, 150, 151, 292 Nysted reagent, 403 Neber rearrangement, 385 613

O manganaoxetane, 300 octacarbonyl dicobalt, 419 γ-oximino alcohol, 26 odorless Corey−Kim reaction, 150 oxidation, 70, 107, 194, 572 olefin, 16, 66, 70, 84, 110, 135, 146, Baeyer–Villiger, 12 148, 156, 157, 173, 277, 294, 309, 319, Collins–Sarett, 305 335, 339, 373, 454, 494, 499, 500, 505, Corey–Kim, 150 507, 521, 564, 566, 572, 574, 578, 580 Dakin, 165 α-olefin, 572, 574 Dess−Martin, 179 cis-olefin, 294 Étard, 129 E-olefin, 300, 309, 311, 580 Fleming–Tamao, 231 exo-olefin, 542 Hooker, 196 trans-olefin, 294 Jacobsen–Katsuki, 300 (Z)-olefin, 300, 527, 578, 580 Jones, 304 olefin ether, 66 Moffatt, 370 olefin formation, 294, 454, 505 Oppenauer, 404 olefin silfide, 66 PCC, 306 olefination, 156, 309, 311, 335, 403, PDC, 307 428, 430, 578 Prilezhaev, 323 olefination of ketones and aldehydes, Riley, 336 403 Rubottom, 378 oleum, 446 Saegusa, 482 one-carbon homologation, 10 , 148 Sarett, 538 one-pot PCC–Wittig reactions, 306 Swern, 402 Oppenauer oxidation, 404, 345 Tamao−Kumada, 233 optically pure diethyl tartrate, 502 TEMPO, 544 organic azide, 523 Wacker, 564 organoborane, 70, 536, 574 oxidative addition, 80, 90, 98, 245, 277, organocatalyst, 4, 274 280, 288, 325, 368, 373, 389, 401, 456, organohalide, 266, 288, 325, 519, 529, 476, 507, 519, 529, 531, 536, 548, 554 536 syn-oxidative elimination, 505 organolithium, 325 oxidative cyclization, 6, 281 organomagnesium compounds, 266, oxidative demetallation, 395 325, see also Grignard reagent oxidative homo-coupling, 257, 299 organosilicon, 288 N-oxide, 54, 135, 300, 349, 350, 440, organostannane, 529 442, 543 organozinc, 389, 456 oxide-coated titanium surface, 335 Ormosil-TEMPO, 545 oxime, 33, 266, 385 osmium catalyst, 499 oxirane, 52 osmium-mediated, 496, 499 oxo-Diels–Alder reaction, 187 O-substituted glycal derivatives, 222 4-oxoform, 263 O-sulfonylation, 332 oxonium ion, 313, 320, 343 Overman rearrangement, 406 β-oxo ylide, 580 oxaphosphetane, 578 oxy-Cope rearrangement, 137, 138, 140 oxa-Pictet–Spengler, 434 oxygen nucleophile, 572 oxatitanacyclobutane, 542 oxygen transfer, 300 oxazete intermediate, 105 oxygenated compound, 572, 573 oxazole, 229, 472, 556 5-oxazolone, 205 P oxazoline intermediate, 167 P2O5, 432 π oxa- -methane rearrangement, 193 P4O10, 432 oxetane, 417 P4–t-Bu, 311 614

Paal thiophene synthesis, 408 Petasis boronic acid-Mannich reaction, Paal–Knorr furan synthesis, 409 426 Paal–Knorr pyrrole synthesis, 317, 411 Petasis reaction, 426 palladation, 281, 564 Petasis reagent, 428 palladium, 80, 98, 277, 288, 325, 368, Peterson elimination, 203 389, 476, 482, 519, 529, 531, 536, 548, Peterson olefination, 430 564, 572 Pfau−Platter azulene synthesis, 78 palladium-catalyzed alkenylation, 277 Pfitzner−Moffatt oxidation, 370 palladium-catalyzed arylation, 277 Ph3P, 52, 53, 99, 148, 149, 152, 223, palladium-catalyzed oxidation, 564 280, 288, 360, 365, 368, 373, 472, 519, palladium-promoted reaction 523, 536, 578 Buchwald–Hartwig amination, 80 PhCuI, 554 Heck, 277 phenanthridine cyclization, 371 heteroaryl Heck, 280 β-phenethylamides, 48 Hiyama, 288 phenol esters, 240 Kumada, 325 phenol, 102, 165, 190, 240, 296, 393, Miyaura borylation, 368 423, 460, 492, 572 Mori–Ban indole, 373 phenolic ether, 296 Negishi, 389 phenylhydrazine, 227 Rosenmund reduction, 476 4-phenylpyridine N-oxide, 300 Saegusa, 482 phenyltetrazolyl, 309 Sonogashira, 519 PhNO2, 509 Stille, 529 phospha-Michael addition, 355 Stille–Kelly, 531 phosphate ester, 220 Suzuki–Miyaura, 536 phosphazide, 523 Tsuji–Trost, 548 phosphazo compound, 523 Wacker, 564 phosphite, 357 palladium-catalyzed substitution, 548 phosphonate synthesis, 357 pancratistatin, 220 phosphonate, 294, 341, 357, 527 paniculide A, 220 phosphoric acid, 409 paraffin, 134 phosphorus oxychloride, 48, 49, 229, Parham cyclization, 413, 415 235, 264, 371, 432, 558, 559, Passerini reaction, 551 phosphorus pentoxide, 432 Paternò–Büchi reaction, 417 phosphorus ylide, 578, 580 Pauson–Khand reaction, 395, 419, 420 [2+2]-photochemical cyclization, 173 Payne rearrangement, 421 photochemical decomposition, 292 Pb(OAc)4, 159 photochemical rearrangement, 162 PCC oxidation, 304, 306 photo-Favorskii Rearrangement, 215 Pd(II) oxidant, 482 photo-Fries rearrangement, 241 Pd(II) reduction to Pd(0), 519 photoinduced electrocyclization, 417 Pd/C catalyst, 245 photolysis, 26, 192 Pd/Cu-catalyzed cross-coupling, 519 photo-Reimer–Tiemann reaction without PDC, 304, 307 base, 460 Pd–H isomerization, 574 photo-Schiemann reaction, 488 Pechmann coumarin synthesis, 423 phthalimide, 247, 248, 249 pentacoordinate silicon intermediate, 68 Pictet–Gams isoquinoline synthesis, 432 peracid, 231 Pictet–Spengler tetrahydroisoquinoline pericyclic reaction, 1 synthesis, 434 periodinane oxidation, 179, 180 pinacol, 436, 574 Perkin reaction, 424 pinacol rearrangement, 436 (1R)-(+)-α-pinene, 359 615

Pinner reaction, 438 pyrazolone, 317 piperidine, 292 2-pyridinethione, 152 pivalic acid, 411 2-pyridone, 270 PMB ethers, 202 pyridinium chlorochromate, 304, see PMB reagent, 202 also PCC PMB-protection, 203 pyridinium dichromate, 304, see also Polonovski reaction, 440, 442 PDC Polonovski–Potier rearrangement, 442 pyridium, 66 polyene skeleton, 89 pyridone, 102 polymer-support Hinsberg thiophene pyrimidine, 102 synthesis, 287 α-pyridinium methyl ketone salts, 323 polymer-supported Mukaiyama reagent, pyrolysis, 156 379 pyrrole, 112, 276, 317, 411 polyphosphoric acid, 34, 66, 332, see pyrrolidine, 292 also PPA pyruvic acid, 194 polysubstituted oxetane ring system, 417 Pomeranz–Fritsch reaction, 444, 446 Q potassium phthalimide, 247 quasi-axial bonds, 222 PPA, 34, 66, 132, 134, 163, 164, 235, quasi-Favorskii rearrangement, 217 PPSE, 235 quinaldic acid, 461 precatalyst, 465, 548 quinoline, 92, 131, 133, 194, 196, 238, preoxidized material, 572 263, 394, 461, 509, 510 Prévost trans-dihydroxylation, 447, 592 quinolin-4-ones, 133 Prilezhaev epoxidation, 478 quinoline-4-carboxylic acid, 194 primary alcohol, 304, 305, 339 primary amides, 290 R primary amine, 171, 178, , 210, 243, racemization, 227, 273 247, 290, 411, 474 radical, 22, 24, 26, 40, 44, 65, 129, 192, primary cycle, 500 200, 257, 262, 266, 292, 300, 335, 361, primary nitroalkane, 387 382, 417, 450, 540, 544, 546, 560, 582, primary ozonide, 161 586 Prins reaction, 448 radical anion, 44, 65, 129, 335 proline, 143, 271 radical cation, 292 (S)-(−)-proline, 271 radical chain reaction, 586 propagation, 586 radical coupling, 262 propargylated product, 395 6-exo-trig radical cyclization, 450 protic acid, 33, 202, 5-exo-trig-ring closure, 182 protic solvent, 16, 556 radical decarboxylation, 22 proton transfer, 38, 52, 131, 132, 133, radical initiating conditions, 586 458 radical intermediate, 300 protonated heteroaromatic nucleus, 361 radical mechanism, 257, 266, 540, 582 Pschorr cyclization, 450 radical reactions PT, 309 Barton radical decarboxylation, 22 puckered transition state, 521, 578 Barton–McCombie, 240 Pummerer rearrangement, 452 Barton nitrite photolysis, 26 purine, 102 Dowd–Beckwith ring expansion, 200 putative active catalyst, 502 Gomberg–Bachmann, 262 PyPh2P, 244 McFadyen–Stevens reduction, 334 PYR, 309 McMurry coupling, 335 pyrazinone, 102 TEMPO-mediated oxidation, 544 pyrazole, 317, 411 radical Thorpe−Ziegler reaction, 546 616 radical-based carbon–carbon bond for- Schmidt, 490 mation, 361 siloxy-Cope, 141 radical-mediated ring expansion, 200 Smiles, 511 Ramberg–Bäcklund reaction, 454 Sommelet–Hauser, 513 Raney nickel, 251 Tiffeneau–Demjanov, 177 Ra-Ni, 29, 155 Truce−Smile, 513 rate-limiting step, 218 Vinylcyclopropane−cyclopentene,

Rawal diene, 188 560 RCM, 465 Wagner–Meerwein, 566 real catalyst, 465 [1,2]-Wittig, 582 rearomatization, 196 [2,3]-Wittig, 584 rearrangement Wolff, 588 abnormal Claisen, 121 (S,S)-reboxetine, 503 anionic oxy–Cope, 138 Red-Al, 100 Baker–Venkataraman, 14 redox reaction, 94, 401 Beckmann, 33 reducing agent, 210, 330, 274 Benzilic acid, 36 reduction Boulton–Katritzky, 62 Birch, 44 Brook, 68 Bouveault–Blanc, 65 Carrol, 96 CBS, 143 Chapman, 105 Chan alkyne, 100 Ciamician–Dennsted, 112 Clemmensen, 129 Claisen, 117 Fukuyama, 245 para-Claisen Cope, 119 ketones, 345 Cope, 137 McFadyen–Stevens, 334 Curtius, 162 Meerwein–Ponndorf–Verley, 345 Demjanov, 175 Midland, 359 Dienone–phenol, 190 Rosenmund, 476 Di-π-methane, 192 Staudinger, 532 Eschenmoser–Claisen, 123 Wolff–Kishner, 590 Favorskii, 214 1,4-reduction, 44 Ferrier glycal allylic, 222 reduction of Pd(OAc)2 to Pd(0) using Fries, 240 Ph3P, 373 Gabriel–Colman, 250 reductive amination, 58, 330 Hofmann, 290 reductive cyclization, 463 Ireland–Claisen, 125 reductive elimination, 58, 80, 90, 98, Johnson–Claisen, 127 102, 156, 245, 277, 288, 325, 330, 368, Lossen, 332 389, 419, 476, 519, 529, 531, 536, 548, [1,2]-Meisenheimer, 349 564 [2,3]-Meisenheimer, 350 reductive Heck reaction, 278 Meyer–Schuster, 353 reductive methylation, 210 Mislow–Evans, 363 Reformatsky reaction, 456 Neber, 385 regeneration of Pd(0), 373 Overman, 406 regioisomer, 173, 572 oxy-Cope, 140 regioselectivity, 52, 496, 572 Payne, 421 Regitz diazo synthesis, 458 Pinacol, 436 Reimer–Tiemann reaction, 460 Polonovski–Potier, 442 Reissert aldehyde synthesis, 461 Pummerer, 452 Reissert compound from isoquinoline, Rupe, 480 462 quasi-Favorskii, 217 Reissert compound, 461 617

Reissert indole synthesis, 463 Schmidt’s trichloroacetimidate glycosi- retention of configuration, 231, 548 dation reaction, 492 retro-[1,4]-Brook rearrangement, 69 Schmittel cyclization, 382 retro-[2+2] cycloaddition, 542 Schönberg rearrangement, 393 retro-aldol reaction, 173 Schrock’s catalyst, 465 retro-benzilic acid rearrangement, 36 secondary alcohol, 179, 304, 339, 404 retro-Bucherer reaction, 74 secondary amine, 210, 243 retro-Claisen condensation, 60, 113 secondary cycle, 500 retro-Cope elimination, 136 secondary nitroalkane, 387 retro-Diels−Alder reaction, 56, 185 secondary ozonide, 161 retro-Henry reaction, 284 secondary α-acetylenic alcohol, 353 reverse Kahne-type glycosylation, 314 seleno-Mislow-Evans, 363 reversible conjugate addition, 196 semi-benzylic mechanism, 217 rhodium carbenoid, 78 SET, 18, 44, 65, 129, 155, 266, 311, ring expansion, 200 554, 335, 397, 554 ring opening, 532, 596 Shapiro reaction, 16, 494 6-oxo-trig ring formation, 322 Sharpless asymmetric amino hydroxyla- ring-closing metathesis, 465 tion, 496 trisubstituted phosphine, 365 Sharpless asymmetric dihydroxylation, Ritter intermediate, 490 499 Ritter reaction, 468 Sharpless asymmetric epoxidation , 502 Robinson annulation, 271, 470 Sharpless olefin synthesis, 505 Robinson–Gabriel synthesis, 472 1,3-shift, 353 Robinson–Schöpf reaction, 474 Shioiri–Ninomiya–Yamada modification room temperature Buchwald–Hartwig of Curtius rearrangement, 163 amination, 81 SIBX, 397 Rosenmund reduction, 476 [1,2]-sigmatropic rearrangement, 349 Rosenmund–von Braun synthesis of aryl [2,3]-sigmatropic rearranegment, 20, nitrile, 98 251, 350, 363, 584 rotation, 277, 430 [3,3]-sigmatropic rearranegment, 60, 72, rotaxane, 90 96, 117, 119, 121, 123, 125, 127, 137, Rubottom oxidation, 478 138, 140, 141, 227, 406 Rupe rearrangement, 353, 480 sila-Stetter reaction, 525 ruthenium(II) BINAP-complex, 399 sila-Wittig reaction, 430 silicon cleavage, 484 S β-silicon effect, 484 Saegusa enone synthesis, 482 siloxane, 102 Saegusa oxidation, 397, 482 α-silyloxy carbanions, 68 safe surrogate for cyanide, 525 siloxy-Cope rearrangement, 141 Sakurai allylation reaction, 484 silver carboxylate, 298 Sandmeyer reaction, 486 silver salt, 320 Sanger’s reagent, 347 silver-catalyzed oxidative decarboxyla- saponification, 263 tion, 361 Sarett oxidation, 304, 305 silyation, 332 Saucy–Claisen, 117 α-silyl carbanion, 430 Schiemann reaction, 488 silyl enol ether, 375, 377, 397 Schiff base, 133 α-silyl oxyanions, 68 Schlittler–Müller modification, 446 [1,2]-silyl migration, 68 Schlosser modification of the Wittig β-silylalkoxide intermediate reaction, 580 Simmons–Smith reaction , 507 Schmidt rearrangement, 490 Simmons−Smith reagent, 507 618 single electron transfer, 18, 44, 65, 129, Stetter reaction, 38, 525 155, 266, 311, 554, 335, see also SET Stille coupling, 529 single-electron process, 335 Stille–Kelly reaction, 531 singlet diradical, 417 Still–Gennari phosphonate reaction, 527 six-membered α,β-unsaturated ketone, Still−Wittig rearrangement, 584 470 Stobbe condensation and cyclization, Skraup quinoline synthesis, 196, 509 532 Skraup type, 263 Stobbe condensation, 532 SMEAH, 100 stoichiometric copper, 519 SmI2-mediated Reformatsky reaction, stoichiometric Pd(II), 281 457 Strecker amino acid synthesis, 534 Smile reaction, 393 strong acid, 319, 468, 598 Smiles rearrangement, 511, 513 styrenylpinacol boronic ester, 574 SN1, 313 substituted hydrazine, 317 SN2 inversion, 365 7-substituted indoles, 20 SN2 reaction, 52, 129, 148, 179, 229, 5-substituted oxazole, 556 247, 249, 240, 292, 357, 363, 365, 578, 2-substituted-quinolin-4-ol, 92 592 4-substituted-quinolin-2-ol, 92 SNAr, 243, 347, 379 substitution reactions, 351 sodium amalgam, 311 succinimidyl radical, 586 sodium bis(2-methoxyethoxy)aluminum sulfenamide, 576 hydride, 100 sulfinate, 102 sodium bisulfite, 72 sulfonamides, 102 sodium cyanide, 534 sulfone reduction, 309 sodium hypochlorite for Hofmann rear- sulfone, 30, 309, 311, 454 rangement, 291 sulfonium ion, 251 sodium tert-butoxide, 80 sulfonyl azide, 458 sodium, 65 sulfoxide activation, 313 solid-phase Cope elimination, 135 sulfoxide, 313, 363, 452 soluble cyanide source, 534 sulfoximines, 102 solvent-free Claisen condensation, 114 sulfur ylide, 146, 538 solvent-free Dakin oxidation, 165 sulfurane dehydrating reagent, 339, 340, Sommelet reaction, 171, 515 457 Sommelet–Hauser rearrangement, 251, sulfur-containing heterocyclic ring, 576 517, 584 sulfuric acid, 304 Sonogashira reaction, 98, 519 Suzuki, 298 (−)-sparteine, 213, 351 Suzuki–Miyaura coupling, 102, 536 spirocyclic anion intermediate, 511 Swern oxidation, 150, 538 stabilized IBX, 397 switchable molecular shuttles, 90 stable nitroxyl radical, 544 syn/anti, 377 stannane, 20, 102, 529, 531 syn-addition, 70 statin side chain, 50 synchronized fashion, 515 Staudinger ketene cycloaddition, 521 Staudinger reduction, 523 T step-wise mechanism, 588 Takai reaction, 540 stereoselective conversion, 540 Tamao−Kumada oxidation, 233 stereoselective oxidation, 231 d3-tamoxifen, 210 stereoselective reduction, 100 tautomerization, 74, 121, 133, 140, 167, stereoselectivity, 572 198, 227, 274, 353, 383, 408, 490, 509, steric hindrance, 594 525, 570 sterically-favored isomer, 419 TBABB, 377 619

TBAO, 239 thioamide, 576 TBTBTFP, 309 thiocarbonyl derivatives, 24, 328, 408 TDS, 141, 180 1,1ƍ-thiocarbonyldiimidazole, 156 Tebbe olefination, 428, 542 thioglycolic acid derivatives, 225 Tebbe’s reagent, 428 thiol, 102, 245 TEMPO oxidation, 544 thiophene, 17, 225, 254, 286, 287, 328, terminal acetylenic group, 353 329, 408 terminal alkyne, 148, 299, 257, 519 thiophene from dione, 328 tertiary alcohol, 84, 339, 490 thiophene synthesis, 225, 408 tertiary amine, 30, 206, 349, 350, 562 thiophene-2,5-dicarbonyls, 286 tertiary amine N-oxide, 349 thiophenol, 393 tertiary carbocation, 319 Thorpe−Ziegler reaction, 546 tertiary carboxylic acid formation, 319 three-component aminomethylation, 337 tertiary N-oxide, 440, 442 three-component condensation, 415 tertiary phosphine, 523 three-component coupling, 194, 426, tertiary α-acetylenic (terminal) alcohol, 574 480 threo (thermodynamic adduct), Horner– tertiary α-acetylenic alcohols, 353 Wadsworth–Emmons reaction, 294 tetrahydrocarbazole, 60 threo betaine, 580 tetrahydroisoquinoline, 434 Ti(0), 335 tetramethyl pentahydropyridine oxide, Ti=O, 542 544 TiCl3/LiAlH4, 335 tetra-n-butylammonium bibenzoate, 377 Tiffeneau–Demjanov rearrangement, 1,1,3,3-tetramethylguanidine, 95 177 2,2,6,6-tetramethylpiperi-dinyloxy, 544 titanium tetra-iso-propoxide, 502 tetrazole, 309 TMG, 95 Tf2O, 313, 314, 379 TMSO-P(OEt)2, 358 TFA, 14, 54, 287, 292, 354, 362, 375, p-tolylsulfonylmethyl isocyanide, 556 391, 415, 445, 507, 566 tosyl amide, 458 TFAA, 54, 262, 443 tosyl ketoxime, 385 thermal aliphatic Claisen rearrangement, trans-β-dimethylamino-2-nitrostyrene, 16 28 thermal aryl rearrangement, 105 transannular aldol reaction, 4 thermal Bamford–Stevens, 17 transition state, 1, 309, 345, 404, 478, thermal decomposition, 292 503, 521, 523, 578, thermal elimination, 110, 135 transmetallation, 102, 288, 325, 368, thermal rearrangement, 96, 162 389, 401, 519, 529, 531, 536, 536 thermal-catalyzed condensation, 133 trapping molecule, 90 thermal-mediated rearrangement, 332 Traxler–Zimmerman trasition state, 193 thermodynamic adduct, 294 triacetoxyperiodinane, 179 thermodynamic product, 16, 494 trialkyl orthoacetate, 127 thermodynamic sink, 140 trialkyloxonium salts, 343 thermodynamically favored, 319 1,1,1-triacetoxy-1,1-dihydro-1,2- thermolysis, 62 benziodoxol-3(1H)-one, 179 thexyldimethylsilyl, 141, 180 1,2,4-triazine, 56 thia-Fries rearrangement, 241 triazole intermediate, 458 thia-Michael addition, 355 trichloroacetimidate intermediate, 406, thiazolium catalyst, 525 492 thiazolium salt, 38 2,4,6-trichlorobenzoyl chloride, 594 thiirane, 146 trichloroisocyanuric/TEMPO oxidation, 3-thioalkoxyindoles, 251 545 620 triethyloxonium tetrafluoroborate, 343 V triflate, 202, 288, 325, 389, 529, 536, van Leusen oxazole synthesis, 556 572 van Leusen reagent, 556 trifluoroacetic anhydride, 54, 442, see varenicine, 211 also TFAA vicinal diol, 159, 436 trifluorotoluene, 202 Vilsmeier–Haack reaction, 558, 558 1,3,3-trimethyl-6-azabicyclo[3.2.1]- Vinyl azide, 162 octane, 239 vinyl boronic acid, 426 trimethyloxonium tetrafluoroborate, 343 vinyl Grignard, 20 trimethylphosphite, 156 vinyl halide, 401 trimethylsilyl chloride, 125 E-vinyl iodide, 540 trimethylsilyl polyphosphate, 235 vinyl ketones, 30, 470 tri-O-acetyl-D-glucal, 222 vinyl sulfones, 30 1, 1,2,3-trioxolane, 161 N,O-vinylation, 102 2,4-trioxolane, 161 vinylcyclopropane, 192, 560 triphenylphosphine, 365, see also Ph3P vinylcyclopropane−cyclopentene triplet diradical, 417 rearrangement, 560 n, π* triplet, 417 vinylic alkoxy pentacarbonyl chromium tropinone, 474 carbene, 198 Truce−Smile rearrangement, 513 vinylic C–H arylation, 574 Tsuji–Trost allylation, 548 vinylogous Mukaiyama aldol reaction, Two sequential Stobbe condensations, 375 532 2-cis-vitamin A acid, 578 von Braun degradation, 562 U von Braun reaction, 562 Ugi reaction, 415, 551 UHP, 12, 165 W Ullmann coupling, 554 Wacker oxidation, 281, 482, 564 umpolung, 154 Wagner–Meerwein rearrangement, 566 11-undecenoic acid, 574 Wagner–Meerwein shift, 331 α,β-unsaturation of aldehydes, 397 Weinstock variant of the Curtius rear- α,β-unsaturation of ketones, 397 rangement, 163 α,β-unsaturated aldehyde, 480 Weiss–Cook reaction, 568 γ,δ-unsaturated amides, 123 Wharton reaction, 570 α,β-unsaturated carbonyl compounds, White reagent, 572 353 Willgerodt–Kindler reaction, 576 Wittig reaction, 148, 294, 306, 430, 578, γ,δ-unsaturated carboxylic acids, 125 580 α,β-unsaturated ester, 525 γ,δ Wittig reagent, 403 -unsaturated ester, 127 [1,2]-Wittig rearrangement, 582 2,3-unsaturated glycosyl derivatives, [2,3]-Wittig rearrangement, 517, 584 222 Wohl–Ziegler reaction, 586 5,6-unsaturated hexopyranose deriva- Wolff rearrangement, 40, 588 tives, 220 Wolff–Kishner reduction, 590 α,β -unsaturated ketone, 323, 480, 525 Woodward cis-dihydroxylation, 447, γ -unsaturated ketones, 96 592 α,β-unsaturated system, 355, 377, 484 urea, 12, 42, 102, 162, 165, 332, 370 X urea-hydrogen peroxide complex, 12, xanthate, 110 165 Xphos, 82, 83, 89, 369

621

Y Yamaguchi esterification, 594, 595 Yamaguchi reagent, 594, 595 ylidene-sulfur adduct, 254, 255

Z Zimmerman rearrangement, 192 zinc amalgam, 129 zinc-carbenoid, 129 zinc chloride, 371 zinc reagent, 389, 403, 456 Zincke anhydride, 598 Zincke reaction, 596 Zincke salt, 596, 598 Zn(Cu), 507 zwitterionic peroxide, 161