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Name Reactions

A Collection of Detailed Reaction Mechanisms

Third Expanded Edition

123 Jie Jack Li, Ph.D. Pﬁzer Global Research and Development Chemistry Department 2800 Plymouth Road Ann Arbor, MI 48105 USA e-mail: jack.li@pﬁzer.com

3rd. expanded ed. ISBN-10 3-540-30030-9 Springer Berlin Heidelberg New York ISBN-13 978-3-540-30030-4 Springer Berlin Heidelberg New York e-ISBN 3-540-30031-7 ISBN-10 3-540-40203-9 2nd ed. Springer Berlin Heidelberg New York

Library of Congress Control Number: 2006925628

This work is subject to copyright. All rights 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 for prosecution under the German Copyright Law.

Springer is a part of Springer Science+Business Media springer.com

© Springer-Verlag Berlin Heidelberg 2003, 2006 Printed in Germany

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 therelevantprotectivelawsandregulationsandthereforefreeforgeneraluse.

Typesetting: By the Author Production: LE-TEX, Jelonek, Schmidt & Vöckler GbR, Leipzig Coverdesign: KünkelLopka, Heidelberg Printed on acid-free paper 2/3100 YL – 5 4 3 2 1 0 Dedicated to

Professor E. J. Corey 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 hesita- te 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 disco- verers, 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 ca- taloging 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 La Jolla, March 2006 Preface

Confucius said: “Reviewing old knowledge while learning new old knowledge, is that not, after all, a pleasure?” Indeed, name reactions are not only the fruit of pioneering organic chemists, but also our contemporaries whose combined discoveries have resulted in organic chemistry today. Since publication of this book, Barry Sharpless and Ryoji Noyori, whose name reactions have been included since the first edition, went on to win the Nobel Prizes in 2001. Recently, Richard Schrock, Robert Grubbs, and Yves Chauvin shared the 2005 Nobel Prize in chemistry for their contributions to metathesis, a name reaction that has been also included since the first edition. Therefore, I intend to keep up with the new developments in the field of organic chemistry while retaining the collection of name reactions that have withheld test of time. The third edition contains major improvements over the previous two editions. I have updated references. Each reaction is now supplemented with two to three representative examples in synthesis to showcase its synthetic utility. As Emil Fi- scher stated: “Science is not an abstraction; but as a product of human endeavor it is inseparably bound up in its development with the personalities and fortunes of those who dedicate themselves to it.” To that end, I added biographical sketches for most of the chemists who discovered or developed those name reactions. Furthemore, I have significantly beefed up the subject index to help the reader na- vigate the book more easily. In preparing this manuscript, I have incurred many debts of gratitude to Prof. Reto Mueller of Switzerland, Prof. Robin Ferrier of New Zealand, and Prof. James M. Cook of the University of Wisconsin, Milwaukee; Dr. Yike Ni of California Institute of Technology, and Dr. Shengping Zheng of Columbia University for in- valuable suggestions. I also wish to thank Dr. Gilles Chambournier, Prof. Phil S. Baran of Scripps Research Institute and his students, Narendra Ambhaikar, Ben Hafensteiner, Carlos Guerrero, and Dan O’Malley, Prof. Brian M. Stoltz of Cali- fornia Institute of Technology and his students, Kevin Allan, Daniel Caspi, David Ebner, Andrew Harned, Shyam Krishnan, Michael Krout, Qi Charles Liu, Sandy Ma, Justin Mohr, John Phillips, Jennifer Roizen, Brinton Seashore-Ludlow, Na- thaniel Sherden, Jennifer Stockdill, and Carolyn Woodroofe for proofreading the final draft of the manuscript. Their knowledge and time have tremendously en- hanced the quality of this book. Any remaining errors are, of course, solely my own responsibility. I welcome your critique.

Jack Li Ann Arbor, Michigan, March 2006 Table of Contents

Abbreviations ...... XVIII

Alder ene reaction ...... 1 Aldol condensation...... 3 Algar–Flynn–Oyamada reaction ...... 5 Allan–Robinson reaction...... 8 Appel reaction ...... 10 Arndt–Eistert homologation...... 12 Baeyer–Villiger oxidation...... 14 Baker–Venkataraman rearrangement ...... 16 Bamberger rearrangement...... 18 Bamford–Stevens reaction ...... 20 Barbier coupling reaction...... 22 Bargellini reaction...... 24 Bartoli indole synthesis ...... 26 Barton radical decarboxylation ...... 28 Barton–McCombie deoxygenation...... 30 Barton nitrite photolysis...... 32 Barton–Zard reaction ...... 34 Batcho–Leimgruber indole synthesis ...... 36 Baylis–Hillman reaction...... 39 Beckmann rearrangement...... 41 Beirut reaction...... 43 Benzilic acid rearrangement...... 45 Benzoin condensation ...... 47 Bergman cyclization...... 49 Biginelli pyrimidone synthesis...... 51 Birch reduction...... 53 Bischler–Möhlau indole synthesis...... 55 Bischler–Napieralski reaction ...... 57 Blaise reaction...... 59 Blanc chloromethylation ...... 61 Blum aziridine synthesis ...... 63 Boekelheide reaction...... 65 Boger pyridine synthesis ...... 67 Borch reductive amination ...... 69 Borsche–Drechsel cyclization ...... 71 Boulton–Katritzky rearrangement...... 73 Bouveault aldehyde synthesis ...... 75 Bouveault–Blanc reduction...... 77 Boyland–Sims oxidation ...... 79 Bradsher reaction ...... 81 Brook rearrangement...... 83 Brown hydroboration ...... 85 XII

Bucherer carbazole synthesis ...... 87 Bucherer reaction ...... 90 Bucherer–Bergs reaction...... 92 Büchner–Curtius–Schlotterbeck reaction...... 94 Büchner method of ring expansion ...... 96 Buchwald–Hartwig C–N bond and C–O bond formation reactions...... 98 Burgess dehydrating reagent ...... 100 Cadiot–Chodkiewicz coupling ...... 102 Camps quinolinol synthesis...... 104 Cannizzaro dispropotionation ...... 107 Carroll rearrangement ...... 109 Castro–Stephens coupling...... 112 Chan alkyne reduction...... 114 Chan–Lam coupling reaction ...... 116 Chapman rearrangement ...... 118 Chichibabin pyridine synthesis ...... 120 Chugaev reaction...... 123 Ciamician–Dennsted rearrangement ...... 125 Claisen condensation...... 127 Claisen isoxazole synthesis...... 129 Claisen rearrangement...... 131 Abnormal Claisen rearrangement...... 133 Eschenmoser–Claisen amide acetal rearrangement...... 135 Ireland–Claisen (silyl ketene acetal) rearrangement ...... 137 Johnson–Claisen (orthoester) rearrangement ...... 139 Clemmensen reduction...... 141 Combes quinoline synthesis...... 144 Conrad–Limpach reaction...... 147 Cope elimination reaction ...... 149 Cope rearrangement ...... 151 Oxy-Cope rearrangement ...... 152 Anionic oxy-Cope rearrangement ...... 153 Corey–Bakshi–Shibata (CBS) reduction...... 154 CoreyChaykovsky reaction...... 157 Corey–Fuchs reaction ...... 160 Corey–Kim oxidation...... 162 Corey–Nicolaou macrolactonization...... 164 Corey–Seebach dithiane reaction...... 166 Corey–Winter olefin synthesis...... 168 Criegee glycol cleavage ...... 171 Criegee mechanism of ozonolysis...... 173 Curtius rearrangement...... 175 Dakin oxidation...... 177 Dakin–West reaction...... 179 Danheiser annulation...... 181 Darzens glycidic ester condensation ...... 183 XIII

Davis chiral oxaziridine reagent...... 185 Delépine amine synthesis...... 187 de Mayo reaction...... 189 Demjanov rearrangement ...... 191 Tiffeneau–Demjanov rearrangement...... 193 Dess–Martin oxidation ...... 195 Dieckmann condensation ...... 197 Diels–Alder reaction ...... 199 Dienone–phenol rearrangement ...... 202 Di-S-methane rearrangement ...... 204 Doebner quinoline synthesis ...... 206 Dötz reaction...... 208 Dowd–Beckwith ring expansion ...... 210 ErlenmeyerPlöchl azlactone synthesis ...... 212 Eschenmoser–Tanabe fragmentation ...... 214 Eschweiler–Clarke reductive alkylation of amines ...... 216 Evans aldol reaction ...... 218 Favorskii rearrangement and quasi-Favorskii rearrangement ...... 220 Feist–Bénary furan synthesis ...... 222 Ferrier carbocyclization...... 224 Ferrier glycal allylic rearrangement ...... 227 Fiesselmann thiophene synthesis ...... 230 Fischer indole synthesis ...... 233 Fischer oxazole synthesis...... 235 Fleming–Tamao oxidation ...... 237 TamaoKumada oxidation...... 239 Friedel–Crafts reaction...... 240 Friedländer quinoline synthesis...... 243 Fries rearrangement...... 245 Fukuyama amine synthesis...... 247 Fukuyama reduction...... 249 Gabriel synthesis ...... 251 Ing–Manske procedure...... 253 Gabriel–Colman rearrangement ...... 255 Gassman indole synthesis...... 257 Gattermann–Koch reaction ...... 259 Gewald aminothiophene synthesis ...... 261 Glaser coupling ...... 263 Eglinton coupling ...... 265 Gomberg–Bachmann reaction...... 267 Gould–Jacobs reaction ...... 269 Grignard reaction ...... 271 Grob fragmentation ...... 273 Guareschi–Thorpe condensation ...... 275 Hajos–Wiechert reaction...... 277 Haller–Bauer reaction ...... 279 XIV

Hantzsch dihydropyridine synthesis...... 281 Hantzsch pyrrole synthesis...... 283 Heck reaction ...... 285 Heteroaryl Heck reaction ...... 287 Hegedus indole synthesis ...... 289 Hell–Volhard–Zelinsky reaction...... 291 Henry nitroaldol reaction ...... 293 Hinsberg synthesis of thiophene derivatives...... 295 Hiyama cross-coupling reaction...... 297 Hiyama–Denmark cross-coupling reaction ...... 299 Hofmann rearrangement...... 302 Hofmann–Löffler–Freytag reaction ...... 304 Horner–Wadsworth–Emmons reaction...... 306 Houben–Hoesch synthesis ...... 308 Hunsdiecker–Borodin reaction...... 310 Hurd–Mori 1,2,3-thiadiazole synthesis ...... 312 Jacobsen–Katsuki epoxidation ...... 314 Japp–Klingemann hydrazone synthesis ...... 316 Jones oxidation...... 318 Julia–Kocienski olefination...... 321 Julia–Lythgoe olefination...... 323 Kahne–Crich glycosidation...... 325 Keck macrolactonization...... 327 Knoevenagel condensation...... 329 Knorr pyrazole synthesis...... 331 Paal–Knorr pyrrole synthesis ...... 333 Koch–Haaf carbonylation ...... 335 Koenig–Knorr glycosidation...... 337 Kolbe–Schmitt reaction...... 339 Kostanecki reaction...... 341 Kröhnke pyridine synthesis...... 343 Kumada cross-coupling reaction...... 345 Lawesson’s reagent...... 348 Leuckart–Wallach reaction ...... 350 Lossen rearrangement ...... 352 McFadyen–Stevens reduction ...... 354 McMurry coupling ...... 356 MacMillan catalyst...... 358 Mannich reaction...... 361 Marshall boronate fragmentation ...... 363 Martin’s sulfurane dehydrating reagent ...... 365 Masamune–Roush conditions ...... 367 Meerwein–Ponndorf–Verley reduction...... 369 Meisenheimer complex ...... 371 [1,2]-Meisenheimer rearrangement...... 372 [2,3]-Meisenheimer rearrangement...... 374 XV

Meth–Cohn quinoline synthesis...... 376 Meyers oxazoline method ...... 378 Meyer–Schuster rearrangement...... 380 Michael addition...... 382 Michaelis–Arbuzov phosphonate synthesis ...... 384 Midland reduction ...... 386 Mislow–Evans rearrangement...... 388 Mitsunobu reaction...... 390 Miyaura borylation...... 392 Moffatt oxidation ...... 394 Montgomery coupling...... 396 Morgan–Walls reaction ...... 399 Pictet–Hubert reaction ...... 400 Mori–Ban indole synthesis...... 401 Mukaiyama aldol reaction...... 403 Mukaiyama Michael addition...... 405 Mukaiyama reagent...... 406 MyersSaito cyclization...... 408 Nazarov cyclization...... 410 Neber rearrangement...... 412 Nef reaction...... 414 Negishi cross-coupling reaction ...... 416 Nenitzescu indole synthesis ...... 418 Nicholas reaction...... 420 Nicolaou dehydrogenation ...... 422 Nicolaou hydroxy-dithioketal cyclization ...... 424 Nicolaou hydroxy-ketone reductive cyclic ether formation ...... 426 Nicolaou oxyselenation...... 428 Noyori asymmetric hydrogenation...... 430 Nozaki–Hiyama–Kishi reaction ...... 432 Oppenauer oxidation ...... 434 Overman rearrangement...... 436 Paal thiophene synthesis...... 438 Paal–Knorr furan synthesis ...... 440 Parham cyclization...... 442 Passerini reaction ...... 444 Paternó–Büchi reaction ...... 446 Pauson–Khand cyclopentenone synthesis ...... 448 Payne rearrangement...... 450 Pechmann coumarin synthesis ...... 452 Perkin reaction ...... 454 Petasis reaction...... 456 Peterson olefination...... 458 Pictet–Gams isoquinoline synthesis ...... 460 Pictet–Spengler tetrahydroisoquinoline synthesis...... 462 Pinacol rearrangement...... 464 XVI

Pinner reaction ...... 466 Polonovski reaction...... 468 Polonovski–Potier rearrangement ...... 470 Pomeranz–Fritsch reaction...... 472 Schlittler–Müller modification...... 473 Prévost trans-dihydroxylation...... 475 Woodward cis-dihydroxylation...... 476 Prins reaction ...... 478 Pschorr cyclization...... 480 Pummerer rearrangement...... 483 Ramberg–Bäcklund reaction...... 485 Reformatsky reaction ...... 487 Regitz diazo synthesis...... 489 Reimer–Tiemann reaction...... 492 Reissert aldehyde synthesis...... 494 Reissert indole synthesis ...... 497 Ring-closing metathesis ...... 499 Ritter reaction...... 501 Robinson annulation ...... 503 Robinson–Gabriel synthesis...... 505 Robinson–Schöpf reaction ...... 507 Rosenmund reduction ...... 509 Rubottom oxidation...... 511 Rupe rearrangement ...... 513 Saegusa oxidation ...... 515 Sakurai allylation reaction...... 518 Sandmeyer reaction...... 520 Schiemann reaction...... 522 Schmidt reaction ...... 524 Schmidt’s trichloroacetimidate glycosidation reaction ...... 526 Shapiro reaction ...... 529 Sharpless asymmetric amino hydroxylation...... 531 Sharpless asymmetric epoxidation ...... 533 Sharpless asymmetric dihydroxylation ...... 536 Sharpless olefin synthesis ...... 540 Simmons–Smith reaction ...... 543 Skraup quinoline synthesis...... 545 Doebner–von Miller reaction ...... 547 Smiles rearrangement...... 549 NewmanKwart reaction ...... 551 TruceSmile rearrangement...... 553 Sommelet reaction...... 555 Sommelet–Hauser rearrangement ...... 557 Sonogashira reaction ...... 559 Staudinger ketene cycloaddition ...... 561 Staudinger reduction ...... 563 XVII

Sternbach benzodiazepine synthesis ...... 565 Stetter reaction ...... 567 Still–Gennari phosphonate reaction ...... 569 Stille coupling ...... 571 Stille–Kelly reaction...... 573 Stobbe condensation...... 575 Stork enamine reaction...... 577 Strecker amino acid synthesis ...... 579 Suzuki coupling...... 581 Swern oxidation ...... 583 Takai iodoalkene synthesis...... 585 Tebbe olefination ...... 587 Petasis alkenylation...... 587 TEMPO-mediated oxidation ...... 589 ThorpeZiegler reaction...... 592 Tsuji–Trost allylation...... 594 Ugi reaction...... 596 Ullmann reaction...... 599 van Leusen oxazole synthesis ...... 601 Vilsmeier–Haack reaction...... 603 Vilsmeier mechanism for acid chloride formation...... 605 Vinylcyclopropanecyclopentene rearrangement ...... 606 von Braun reaction ...... 608 Wacker oxidation ...... 610 Wagner–Meerwein rearrangement...... 612 Weiss–Cook reaction ...... 614 Wharton oxygen transposition reaction...... 616 Willgerodt–Kindler reaction ...... 618 Wittig reaction...... 621 Schlosser modification of the Wittig reaction ...... 622 [1,2]-Wittig rearrangement...... 624 [2,3]-Wittig rearrangement...... 626 Wohl–Ziegler reaction ...... 628 Wolff rearrangement ...... 630 Wolff–Kishner reduction...... 632 Yamaguchi esterification...... 634 Zincke reaction...... 637

Subject Index...... 641 XVIII

Abbreviations and Acronyms

polymer support A adenosine Ac acetyl AIBN 2,2’-azobisisobutyronitrile Alpine-borane® B-isopinocampheyl-9-borabicyclo[3.3.1]-nonane Ar aryl B: generic base 9-BBN 9-borabicyclo[3.3.1]nonane [bimim]Cl•2AlCl3 1-butyl-3-methylimidazolium chloroaluminuminate (a Lewis acid ionic liquid) BINAP 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl Bn benzyl Boc tert-butyloxycarbonyl t-Bu tert-butyl Bz benzoyl Cbz benzyloxycarbonyl m-CPBA m-chloroperoxybenzoic acid 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 DEAD diethyl azodicarboxylate ' solvent heated under reflux (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 dppb 1,4-bis(diphenylphosphino)butane dppe 1,2-bis(diphenylphosphino)ethane dppf 1,1’-bis(diphenylphosphino)ferrocene dppp 1,3-bis(diphenylphosphino)propane XIX

DTBAD di-tert-butylazodicarbonate DTBMP 2,6-di-tert-butyl-4-methylpyridine E1 unimolecular elimination E2 bimolecular elimination E1cB 2-step, base-induced E-elimination via carbanion 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 Imd imidazole KHMDS potassium hexamethyldisilazide LAH lithium aluminum hydride LDA lithium diisopropylamide LHMDS lithium hexamethyldisilazide LTMP lithium 2,2,6,6-tetramethylpiperidide M metal Mes mesityl Ms methanesulfonyl MVK methyl vinyl ketone NBS N-bromosuccinimide NCS N-chlorosuccinimide NIS N-iodosuccinimide NMP 1-methyl-2-pyrrolidinone Nos nosylate (4-nitrobenzenesulfonyl) Nu nucleophile N-PSP N-phenylselenophthalimide N-PSS N-phenylselenosuccinimide PCC pyridinium chlorochromate PDC pyridinium dichromate Piv pivaloyl PMB para-methoxybenzyl PPA polyphosphoric acid PPTS pyridinium p-toluenesulfonate PyPh2P diphenyl 2-pyridylphosphine Pyr pyridine Red-Al sodium bis(methoxy-ethoxy)aluminum hydride (SMEAH) Salen N,N´-disalicylidene-ethylenediamine SET single electron transfer SM starting material XX

SMEAH sodium bis(methoxy-ethoxy)aluminum hydride (Red-Al) 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 TBDMS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl TEA triethylamine TEOC trimethysilylethoxycarbonyl Tf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid TFAA trifluoroacetic anhydride TFP tri-2-furylphosphine THF tetrahydrofuran TIPS triisopropylsilyl TMEDA N,N,N’,N’-tetramethylethylenediamine TMG tetramethylguanidine TMP tetramethylpiperidine TMS trimethylsilyl TMSCl trimethylsilyl chloride TMSCN trimethylsilyl cyanide TMSI trimethylsilyl iodide TMSOTf trimethylsilyl triflate Tol toluene or tolyl Tol-BINAP 2,2’-bis(di-p-tolylphosphino)-1,1’-binaphthyl TosMIC (p-tolylsulfonyl)methyl isocyanide Ts tosyl TsO tosylate UHP urea-hydrogen peroxide 1

Alder ene reaction Addition of an enophile to an alkene via allylic transposition. Also known as hy- droallyl addition.

O O ' O O

O O enophile

O O O O ene O H reaction O

Example 113

O H2N N KOH, Pt/Clay, 35% O H (Kishner reduction) H

O H O O O O o O 0 C, CH2Cl2, 89% OH (Alder ene reaction)

Example 214

O H O O H Tol., reflux N N 5 h, 95% O 2

References

1. Alder, K.; Pascher, F.; Schmitz, A. Ber. Dtsch. Chem. Ges. 1943, 76, 27. Kurt Alder (Germany, 19021958) shared the Nobel Prize in Chemistry in 1950 with his teacher Otto Diels (Germany, 18761954) for development of the diene synthesis. 2. Oppolzer, W. Pure Appl. Chem. 1981, 53, 1181. (Review). 3. Oppolzer, W. Angew. Chem. 1984, 96, 840. 4. Mackewitz, T. W.; Regitz, M. Synthesis 1998, 125138. 5. Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325335. (Review). 6. Stratakis, M.; Orfanopoulos, M. Tetrahedron 2000, 56, 15951615. 7. Mikami, K.; Nakai, T. In Catalytic Asymmetric Synthesis; 2nd edn.; Ojima, I., ed.; WileyVCH: New York, 2000, 543568. (Review). 8. Leach, A. G.; Houk, K. N. Chem. Commun. 2002, 1243. 9. Lei, A.; He, M.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 8198. 10. Shibata, T.; Takesue, Y.; Kadowaki, S.; Takagi, K. Synlett 2003, 268. 11. Suzuki, K.; Inomata, K.; Endo, Y. Org. Lett. 2004, 6, 409. 12. Brummond, K. M.; McCabe, J. M. The Rhodium(I)-catalyzed Alder-ene Reaction. In Modern Rhodium-Catalyzed Organic Reactions 2005, 151172. (Book chapter). 13. Miles, W. H.; Dethoff, E. A.; Tuson, H. H.; Ulas, G. J. Org. Chem. 2005, 70, 2862. 14. Pedrosa, R.; Andres, C.; Martin, L.; Nieto, J.; Roson, C. J. Org. Chem. 2005, 70, 4332. 3

Aldol condensation Condensation of a carbonyl with an enolate or an enol. A simple case is addition of an enolate to an aldehyde to afford an alcohol, thus the name aldol.

2 O O 1. base R OH R 3 1 R1 R R 2. O R R2 R3

O O R deprotonation R 1 condensation R1 R 3 2 H R R

B: O

2 2 R O O acidic R OH O 3 1 R3 R1 R R workup R R

Example 13

o O LDA, THF, then MgBr2, 110 C, then OTMS

OOBn OHC

OH O OTMS 85% yield BnO O 4

Example 212

LDA, THF, 78 to 40 oC, then aldehyde, 1 h, 83%, 3:2 de CO2H OOTBS

H

O

HO

CO2H OOTBS

References

1. Wurtz, C. A. Bull. Soc. Chim. Fr. 1872, 17, 436. Charles Adolphe Wurtz (18171884) was born in Strasbourg, France. After his doctoral training, he spent a year under Liebig in 1843. In 1874, Wurtz became a 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 is no longer considered synthetically useful, although the aldol reaction that Wurtz discovered in 1872 has become a staple in organic synthesis. 2. Nielsen, A. T.; Houlihan, W. J. Org. React. 1968, 16, 1438. (Review). 3. Still, W. C.; McDonald, J. H., III. Tetrahedron Lett. 1980, 21, 1031, 1035. 4. Mukayama, T. Org. React. 1982, 28, 203331. (Review). 5. Mukayama, T.; Kobayashi, S. Org. React. 1994, 46, 1103. (Review on Tin(II) enolates). 6. Saito, S.; Yamamoto, H. Chem. Eur. J. 1999, 5, 19591962. (Review). 7. Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325335. (Review). 8. Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432440. (Review). 9. Nicolaou, K. C.; Ritzén, A.; Namoto, K. Chem. Commun. 2001, 1523. 10. Palomo, C.; Oiarbide, M.; García, J. M. Chem. Eur. J. 2002, 8, 3644. (Review). 11. Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002, 15951601. (Review). 12. Wei, H.-X.; Hu, J.; Purkiss, D. W.; Paré, P. W. Tetrahedron Lett. 2003, 44, 949. 13. Bravin, F. M.; Busnelli, G.; Colombo, M.; Gatti, F.; Manzoni, L.; Scolastico, C. Syn- thesis 2004, 353. 14. Mahrwald, R. (ed.) Modern Aldol Reactions, WileyVCH: Weinheim, Germany, 2004. (Book). 5

AlgarFlynnOyamada Reaction Conversion of 2’-hydroxychalcones to 2-aryl-3-hydroxy-4H-1benzopyran-4-ones (flavonols) by alkaline hydrogen peroxide oxidation.

R1 OH Ar R1 O Ar H2O2, NaOH

OH

R2 O R2 O

R1 O Ar

OH

R2 O

OH O E-attack HO , H2O2 D E O O O

O O O OH OH O O flavonol

A side reaction:

O D-attack O D E then dehydration O O O aurone 6

Example 15

OH 1. PhCHO, NaOH, EtOH, rt OPh

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

Example 25

CHO

1. , aq. NaOH, EtOH O OH OMe

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

OMe

O O

OH O

References

1. Algar, J.; Flynn, J. P. Proc. Roy. Irish. Acad. 1934, 42B, 1. 2. Oyamada, T. J. Chem. Soc. Japan 1934, 55, 1256. 3. Oyamada, T. Bull. Chem. Soc. Jpn. 1935, 10, 182. 4. Wheeler, T.S. Rec. of Chem. Prog. 1957, 18, 133. (Review) 5. Smith, M. A.; Neumann, R. M.; Webb, R. A. J. Heterocycl. Chem. 1968, 5, 425. 6. Rao, A. V. S.; Rao, N. V. S. Current Science 1974, 43, 477. 7. Cullen, W. P.; Donnelly, D. M. X.; Keenan, A. K.; Kennan, P. J.; Ramdas, K. J. Chem. Soc., Perkin Trans. 1 1975, 1671. 8. Wagner, H.; Farkas, L. In The Flavonoids; Harborne, J. B.; Mabry, T. J.; Mabry H., Eds.; Academic Press: New York, 1975; p 127. (Review). 9. Wollenweber, E. In The Flavonoids: Advances in Research; Harborne, J. B.; Mabry, T. J., Eds; Chapman and Hall: New York, 1982; p 189. (Review). 10. Jain, A. C.; Gupta, S. M.; Sharma, A. Bull. Chem. Soc. Jpn. 1983, 56, 1267. 11. Prasad, K. J. Rajendra; Iyer, C. S. Rukmani; Iyer, P. R. Indian J. Chem., Sect. B 1983, 22B, 693. 7

12. Wollenweber, E. In The Flavonoids: Advances in Research since 1986; Harborne, J. B., Ed.; Chapman and Hall: New York, 1994, p 259. (Review). 13. Bennett, M.; Burke, A. J.; O'Sullivan, W. I. Tetrahedron 1996, 52, 7163. 14. Sobottka, A. M.; Werner, W.; Blaschke, G.; Kiefer, W.; Nowe, U.; Dannhardt, G.; Schapoval, E. E. S.; Schenkel, E. P.; Scriba, G. K. E. Arch. Pharm. 2000, 333, 205. 15. Bohm, B. A.; Stuessy, T. F. Flavonoids of the Sunflower Family (Asteraceae); Springer-Verlag: New York, 2001. (Review). 8

Allan–Robinson reaction Synthesis of flavones or isoflavones.

OO OH O R1 R1 OR1

R 1 R R CO2Na, ' O O

OH R1 O OH enolization O O acylation R R O R1 O H 1 R CO2

OH R1 OH R1 O O O CR1 enolization OCOR 2 1 H R R O 1 O O2CR

R1 H O O: R1 OH O R R O H OH 1 O2CR

O R1

R O 9

Example 16

OMe OO HO OH O

OMe MeO OMe OMe O

OMe OMe o PhCO2Na, 170180 C HO O

8 h, 45% OMe OMe O

References

1. Allan, J.; Robinson, R. J. Chem. Soc. 1924, 125, 2192. Robert Robinson (United Kingdom, 18861975) 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. J. 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. 3. Wagner, H.; Maurer, I.; Farkas, L.; Strelisky, J. Tetrahedron 1977, 33, 1405. 4. Dutta, P. K.; Bagchi, D.; Pakrashi, S. C. Indian J. Chem., Sect. B 1982, 21B, 1037. 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. 7. Horie, T.; Tsukayama, M.; Kawamura, Y.; Yamamoto, S. Chem. Pharm. Bull. 1987, 35, 4465. 8. Horie, T.; Kawamura, Y.; Tsukayama, M.; Yoshizaki, S. Chem. Pharm. Bull. 1989, 37, 1216. 10

Appel reaction

The reaction between triphenylphosphine and tetrahalomethane (CCl4, CBr4) forms a salt known as Appel’s salt. Treatment of alcohols with Appel’s salt gives rise to the corresponding halides.

OH X CX4, PPh3

RR1 RR1

X X X Ph PX,CX X 3 3 Ph3P: Appel’s salt

Ph3PX Ph3PX,X3C H O X3CH O R R 1 R R1

PPh O 3 X Ph3PO RR1 RR1 X

Example 17

AcO AcO CBr4, PPh3 BnO O BnO O BnO BnO DMF, 24 h, 96% BnO BnO OH Br 11

Example 2, Appel’s salt is often used as a dehydrating agent8

CO2Me CO2Me

NH N CCl , PPh , Et N N 4 3 3 N O NH N CH2Cl2, reflux, 5 h, 63%

References

1. Appel, R.; Kleinstueck, R.; Ziehn, K. D. Angew. Chem., Int. Ed. Engl. 1971, 10, 132. Rolf Appel was a professor at Anorganisch-Chemisches Institut der Universität in Bonn, Germany. 2. Appel, R.; Kleinstück, R.; Ziehn, K.-D. Chem. Ber. 1971, 104, 1335. 3. Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801. (Review). 4. Beres, J.; Bentrude, W. G.; Parkanji, L.; Kalman, A.; Sopchik, A. E. J. Org. Chem. 1995, 50, 1271. 5. Lee, K. J.; Kim, S. Heon; K., Jong H. Synthesis 1997, 1461. 6. Lee, K.-J.; Kwon, H.-T.; Kim, B.-G. J. Heterocycl. Chem. 1997, 34, 1795. 7. Lim, J.-S.; Lee, K.-J. J. Heterocycl. Chem. 2002, 39, 975. 8. Nishida, Y.; Shingu, Y.; Dohi, H.; Kobayashi, K. Org. Lett. 2003, 5, 2377. 9. Cho, H. I.; Lee, S. W.; Lee, K.-J. J. Heterocycl. Chem. 2004, 41, 799. 12

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

SOCl O O 2 1. CH2N2 O R ROH RCl2. H2O, hv OH

O N N O O R RCl HH RCl Cl N H CNN N 2 H2CNN

O O N N N CH3N2 N N 2n R R hv H H

O H R : CCO H R :OH2 D-ketocarbene intermediate ketene intermediate

H OH O C R ROH OH side reaction:

Cl CH3Cln N n H3CNN 2 13

Example 110

o BnO CO2H 1. ClCO2Et, Et3N, THF, 10 C, 15 min HN BnO Boc o 2. CH2N2, Et2O, 0 C to rt, 18 h, 78%

O AgOBz, Et3N, MeOH/THF, dark BnO N2

HN 25 oC to rt, 3 h, 61% BnO Boc

BnO CO2Me HN BnO Boc

References

1. Arndt, F.; Eistert, B. Ber. Dtsch. Chem. Ges. 1935, 68, 200. Fritz Arndt (18851969) was born in Hamburg, Germany. He discovered the ArndtEistert 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 (19021978), born in Ohlau, Silesia, was Arndt’s Ph.D. student. Eistert later joined I. G. Farbenindustrie, which became BASF after the Allies broke the conglomerate up after WWII. 2. Kuo, Y. C.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1982, 30, 899. 3. Podlech, J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1995, 34, 471. 4. Matthews, J. L.; Braun, C.; Guibourdenche, C.; Overhand, M.; Seebach, D. in Enanti- oselective Synthesis of E-Amino Acids Juaristi, E. ed. Wiley-VCH, New York, N. Y. 1997, pp 105126. (Review). 5. Katritzky, A. R.; Zhang, S.; Fang, Y. Org. Lett. 2000, 2, 3789. 6. Cesar, J.; Sollner Dolenc, M. Tetrahedron Lett. 2001, 42, 7099. 7. Katritzky, A. R.; Zhang, S.; Hussein, A. H. M.; Fang, Y.; Steel, P. J. J. Org. Chem. 2001, 66, 5606. 8. Vasanthakumar, G.-R.; Babu, V. V. S. Synth. Commun. 2002, 32, 651. 9. 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. 10. Gaucher, A.; Dutot, L.; Barbeau, O.; Hamchaoui, W.; Wakselman, M.; Mazaleyrat, J.- P. Tetrahedron: Asymmetry 2005, 16, 857. 14

Baeyer–Villiger oxidation General scheme:

O O O H OR3 O O 2 1 2 1 R 3 R R or H2O2 R O HO R

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:

O O O m-CPBA Cl HO O

H O AcO O HOAc O :O Cl H O

Cl O O H O alkyl Cl O HO O migration O O 15

Example 210

OH O OH m-CPBA, O Ph Ph NH CH2Cl2, rt NH O O O

OH O OH O m-CPBA, O NH CH2Cl2, rt NH O O

References

1. v. Baeyer, A.; Villiger, V. Ber. Dtsch. Chem. Ges. 1899, 32, 3625. Adolf von Baeyer (18351917) was one of the most illustrious organic chemists in history. He contributed in many areas of the field. The Baeyer-Drewson indigo synthesis made possible the commercialization of synthetic indigo. Baeyer’s other claim of fame is his synthesis of barbituric acid, named after his 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 (18681934), born in Switzerland, went to Munich to work with Adolf von Baeyer for eleven years. 2. Krow, G. R. Tetrahedron 1981, 37, 2697. 3. Krow, G. R. Org. React. 1993, 43, 251798. (Review). 4. Renz, M.; Meunier, B. Eur. J. Org. Chem. 1999, 4, 737. (Review). 5. Bolm, C.; Beckmann, O. Compr. Asymmetric Catal. I-III 1999, 2, 803. (Review). 6. Crudden, C. M.; Chen, A. C.; Calhoun, L. A. Angew. Chem., Int. Ed. 2000, 39, 2851. 7. Fukuda, O.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2001, 42, 3479. 8. Watanabe, A.; Uchida, T.; Ito, K.; Katsuki, T. Tetrahedron Lett. 2002, 43, 4481. 9. Kobayashi, S.; Tanaka, H.; Amii, H.; Uneyama, K. Tetrahedron 2003, 59, 1547. 10. Laurent, M.; Ceresiat, M.; Marchand-Brynaert, J. J. Org. Chem. 2004, 69, 3194. 11. Reetz, M. T.; Brunner, B.; Schneider, T.; Schulz, F.; Clouthier, C. M.; Kayser, M. M. Angew. Chem., Int. Ed. 2004, 43, 4075. 16

Baker–Venkataraman rearrangement Base-catalyzed acyl transfer reaction that converts D-acyloxyketones to E- 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 H+ Ph Ph workup transfer

Example 17

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

Example 28

O NEt2 O 2.5 eq. NaH, PhMe, reflux, 2 h then 6 eq. TFA, reflux, 1 h, 93% MeO O 17

OO

MeO OH

References

1. Baker, W. J. Chem. Soc. 1933, 1381. Wilson Baker (19002002) was born in Run- corn, England. He studied chemistry at Manchester under Arthur Lapworth and at Ox- ford under Robinson. In 1943, Baker was the first one who confirmed that penicillin 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. 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. 4. Bowden, K.; Chehel-Amiran, M. J. Chem. Soc., Perkin Trans. 2 1986, 2039. 5. Makrandi, J. K.; Kumari, V. Synth. Commun. 1989, 19, 1919. 6. Reddy, B. P.; Krupadanam, G. L. D. J. Heterocycl. Chem. 1996, 33, 1561. 7. Kalinin, A. V.; da Silva, A. J. M.; Lopes, C. C.; Lopes, R. S. C.; Snieckus, V. Tetrahe- dron Lett. 1998, 39, 4995. 8. Kalinin, A. V.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4999. 9. Thasana, N.; Ruchirawat, S. Tetrahedron Lett. 2002, 43, 4515. 10. Santos, C. M. M.; Silva, A. M. S.; Cavaleiro, J. A. S. Eur. J. Org. Chem. 2003, 4575. 18

Bamberger rearrangement Acid-mediated rearrangement of N-phenylhydroxylamines to 4-aminophenols.

H NH N H2SO4 2 OH H2O HO

H H H + N H N H OH O H

H2O:

NH2 NH2 H O H H HSO4 H HO HSO4

NH2

HO

Example 15

NH2 o NHOH HClO4, 40 C

96% OH

References

1. Bamberger, E. Ber. Dtsch. Chem. Ges. 1894, 27, 1548. Eugen Bamberger (18571932) was born in Berlin. He taught in Munich and at ETH in Zurich. He in- troduced sodium and amyl alcohol as a reducing agent. Bamberger also engaged in a long (18941900) and acrimonious controversy with Arthur Hantzsch on the structure of diazo-compounds. 2. Shine, H. J. in Aromatic Rearrangement Elsevier: New York, 1967, pp 182190. (Re- view). 3. Buckingham, J. Tetrahedron Lett. 1970, 11, 2341. 19

4. Sone, T.; Tokuda, Y.; Sakai, T.; Shinkai, S.; Manabe, O. J. Chem. Soc., Perkin Trans. 2 1981, 298. 5. Fishbein, J. C.; McClelland, R. A. J. Am. Chem. Soc. 1987, 109, 2824. 6. Zoran, A.; Khodzhaev, O.; Sasson, Y. J. Chem. Soc., Chem. Commun. 1994, 2239. 7. Tordeux, M.; Wakselman, C. J. Fluorine Chem. 1995, 74, 251. 8. Fishbein, J. C.; McClelland, R. A. Can. J. Chem. 1996, 74, 1321. 9. Naicker, K. P.; Pitchumani, K.; Varma, R. S. Catal. Lett. 1999, 58, 167. 10. Pirrung, M. C.; Wedel, M.; Zhao, Y. Synlett 2002, 143. 11. Qiu, X.; Jiang, J.-J.; Wang, X.-Y.; Shen, Y.-J. Youji Huaxue 2005, 25, 561. 20

Bamford–Stevens reaction The BamfordStevens 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 BamfordStevens reaction furnishes more-substituted olefins as the thermodynamic products, while the Shapiro reaction generally affords less-substituted olefins as the kinetic products.

1 R1 R H 2 R2 N NaOMe R N Ts H 3 R3 R

MeO R1 R1 1 R H R2 N R2 2 R N N: Ts N N Ts H 3 HN3 H R R R3

In protic solvent:

1 S H R R1 2 H N R R2 2 N N HN3 HN R R3

1 R1 R1 R 3 R2 R2 R SH H H H 2 H 3 3 R S R R

In aprotic solvent:

1 R1 R 2 N R2 R 2 N N HN HN3 R3 R 21

1 1 R1 R1 R R H O 3 2 R2 2 R2 R R : H H H 3 3 R2 R3 R R

Example 1, thermal Bamford–Stevens5

NPh Tol., 145 oC N Me3Si Ph

Me3Si Ph sealed tube, 65% E : Z = 90 : 10

Example 29

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

References

1. Bamford, W. R.; Stevens, T. S. M. J. Chem. Soc. 1952, 4735. Thomas Stevens (19002000), a chemist centenarian, was born in Renfrew, Scotland. He and his student W. R. Bamford published this paper at the University of Sheffield, UK. Stevens also contributed to another name reaction, the McFadyenStevens reaction (page 354). 2. Shapiro, R. H. Org. React. 1976, 23, 405507. (Review). 3. Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 5559. (Review on the Shapiro reaction). 4. Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 183. (Review). 5. Sarkar, T. K.; Ghorai, B. K. J. Chem. Soc., Chem. Commun. 1992, 17, 1184. 6. Nickon, A.; Stern, A. G.; Ilao, M. C. Tetrahedron Lett. 1993, 34, 1391. 7. Olmstead, K. K.; Nickon, A. Tetrahedron 1998, 54, 12161. 8. Olmstead, K. K.; Nickon, A. Tetrahedron 1999, 55, 7389. 9. Chandrasekhar, S.; Rajaiah, G.; Chandraiah, L.; Swamy, D. N. Synlett 2001, 1779. 10. May, J. A.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 12426. 11. Zhu, S.; Liao, Y.; Zhu, S. Org. Lett. 2004, 6, 377. 22

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.

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 R X RX M 3 MX

SET-2 R RM RM

Ionic mechanism,

2 R G G 1 2 1 2 O R R H R R R1 RMgX ROMgX ROH G G

Single electron transfer mechanism,

2 R R2 1 O O R R1 MgX RMgX R

R1 R2 H R1 R2 ROMgX ROH 23

Example 18

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

Example 211

O OH Zn, THF, aq. NH Cl 4 Ph Ph Br o NHCO2Et 0 C, 82%, 95% de NHCO2Et

References

1. Barbier, P. C. R. Hebd. Séances Acad. Sci. 1899, 128, 110. Phillippe Barbier (18481922) 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. 3. Molle, G.; Bauer, P. J. Am. Chem. Soc. 1982, 104, 3481. 4. Moyano, A.; Pericás, M. A.; Riera, A.; Luche, J.-L. Tetrahedron Lett. 1990, 31, 7619. (Theoretical study). 5. Alonso, F.; Yus, M. Rec. Res. Dev. Org. Chem. 1997, 1, 397. (Review). 6. Russo, D. A. Chem. Ind. 1996, 64, 405. (Review). 7. Curran, D. P.; Gu, X.; Zhang, W.; Dowd, P. Tetrahedron 1997, 53, 9023. 8. Basu, M. K.; Banik, B. Tetrahedron Lett. 2001, 42, 187. 9. Sinha, P.; Roy, S. Chem. Commun. 2001, 1798. 10. Lambardo, M.; Gianotti, K.; Licciulli, S.; Trombini, C. Tetrahedron 2004, 60, 11725. 11. Resende, G. O.; Aguiar, L. C. S.; Antunes, O. A. C. Synlett 2005, 119. 24

Bargellini reaction Synthesis of hindered morpholinones or piperazinones from ketones (such as acetone) and 2-amino-2-methyl-1-propanol or 1,2-diaminopropanes.

H NH N 2 O NaOH, CHCl3 X = O, NR XH CH2Cl2, BnEt3NCl XO

O O deprotonation H CCl3 HO CCl2 Cl CCl3

O Cl H N

: Cl NH2 H HX Cl O Cl XH

H H N N

HX Cl O XO

Example 12

NH 2 O NaOH, CHCl3 NH CH2Cl2, BnNEt3Cl

H H N N O

NO N

67% 15% 25

Example 26

H H2N 1. NaOH, CHCl3, acetone N

2. CSA, toluene, 66% HO O O

References

1. Bargellini, G. Gazz. Chim. Ital. 1906, 36, 329. 2. Lai, J. T. J. Org. Chem. 1980, 45, 754. 3. Lai, J. T. Synthesis 1981, 754. 4. Lai, J. T. Synthesis 1984, 122. 5. Lai, J. T. Synthesis 1984, 124. 6. Rychnovsky, S. D.; Beauchamp, T.; Vaidyanathan, R.; Kwan, T. J. Org. Chem. 1998, 63, 6363. 7. Cvetovich, R. J.; Chung, J. Y. L.; Kress, M. H.; Amato, J. S.; Zhou, G.; Matty, L.; Tsay, F. R.; Li, Z. Abstracts of Papers, 226th ACS National Meeting, New York, NY, United States, September 711, 2003 (2003), ORGN-078. 26

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

1. MgBr N NO2 2. H O+ H R 2 R

BrMg

O O OMgBr N N R O R OMgBr

BrMg [3,3]-sigmatropic O O N N rearrangement R R MgBr nitroso intermediate

BrMg O H H+ H N OMgBr N workup R MgBr R

H

OH + 2 N N H H R R

Example 13

1. MgBr (3 eq) 40 oC, THF N NO2 2. aq. NH4Cl, 67% H 27

Example 28

Me Me MgCl

THF, 40 oC NO2 N Br 67% Br H

References

1. Bartoli, G.; Leardini, R.; Medici, A.; Rosini, G. J. Chem. Soc., Perkin Trans. 1 1978, 892. 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. 3. Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30, 2129. 4. Bosco, M.; Dalpozzo, R.; Bartoli, G.; Palmieri, G.; Petrini, M. J. Chem. Soc., Perkin Trans. 2 1991, 657. Mechanistic studies. 5. Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.; Marcantoni, E. J. Chem. Soc., Perkin Trans. 1 1991, 2757. 6. Dobson, D. R.; Gilmore, J.; Long, D. A. Synlett 1992, 79. 7. Dobbs, A. P.; Voyle, M.; Whittall, N. Synlett 1999, 1594. 8. Dobbs, A. J. Org. Chem. 2001, 66, 638. 9. Pirrung, M. C.; Wedel, M.; Zhao, Y. Synlett 2002, 143. 10. Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 13179. 11. Knepper, K.; Braese, S. Org. Lett. 2003, 5, 2829. 12. Li, J.; Cook, J. M. Bartoli indole synthesis In Name Reactions in Heterocyclic Chemis- try, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 100103. (Review). 13. Dalpozzo, R.; Bartoli, G. Current Org. Chem. 2005, 9, 163178. (Review). 28

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

S O O HO n-Bu3SnH N N H RCl RO AIBN, ' R S Barton ester

' NC NN CN N2n 2 CN homolytic cleavage 2,2’-azobisisobutyronitrile (AIBN)

n-Bu3Sn H CN n-Bu3SnH CN

O N O RO N S RO S Bu3Sn SnBu3

CO H 2n R H SnBu3 R Bu3Sn

Example 13

OAc

OAc H

H 1. (COCl)2 S 2. O NaO N O N S CO2H 29

OAc OAc H 1. m-CPBA, 78 oC ' H

98% 2. 100 oC, 78% S N

Example 211

S 2 Ph N O HO2COTBDPS Bu3P, THF, PhH

Ph Me3SiH, AIBN N O OTBDPS Ph OTBDPS O PhH, 80 oC, 75% S

References

1. Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1983, 939. Derek Barton (United Kingdom, 19181998) studied under Ian Heilbron at Im- perial 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 at Austin. 2. Barton, D. H. R.; Zard, S. Z. Pure Appl. Chem. 1986, 58, 675. 3. Barton, D. H. R.; Bridon, D.; Zard, S. Z.; Fernandaz-Picot, I. Tetrahedron 1987, 43, 2733. 4. Cochane, E. J.; Lazer, S. W.; Pinhey, J. T.; Whitby, J. D. Tetrahedron Lett. 1989, 30, 7111. 5. Barton, D. H. R. Aldrichimica Acta 1990, 23, 3. (Review). 6. Gawronska, K.; Gawronski, J.; Walborsky, H. M. J. Org. Chem. 1991, 56, 2193. 7. Eaton, P. E.; Nordari, N.; Tsanaktsidis, J.; Upadhyaya, S. P. Synthesis 1995, 501. 8. Crich, D.; Hwang, J.-T.; Yuan, H. J. Org. Chem. 1996, 61, 6189. 9. Attardi, M. E.; Taddei, M. Tetrahedron Lett. 2001, 42, 3519. 10. Materson, D. S.; Porter, N. A. Org. Lett. 2002, 4, 4253. 11. Yamaguchi, K.; Kazuta, Y.; Abe, H.; Matsuda, A.; Shuto, S. J. Org. Chem. 2003, 68, 9255. 12. Zard, S. Z. Radical Reactions in Organic Synthesis Oxford University Press: Oxford, UK, 2003. (Book). 13. 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. 30

Barton–McCombie deoxygenation Deoxygenation of alcohols by means of radical scission of their corresponding thiocarbonyl derivatives.

1 1 R S n-Bu3SnH, AIBN R n-Bu3SnSMe O CSn 2 R2 OS PhH, reflux R H

' 2 NC NN CN N2n CN 2,2’-azobisisobutyronitrile (AIBN)

n-Bu3Sn H CN n-Bu3SnH CN

n-Bu Sn 3 SnBu R1 S 3 R1 S R2 OS R2 OS

1 n-Bu3Sn R E-scission S R2 OS

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

n-Bu Sn 3 S n-Bu3SnSMe O CSn OS

Example 15

O O O O AIBN, ', 74%

O O (CH2)4Bu2SnH Ph S 31

O O O O

O

Example 29

O OH O

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

OO 2. Bu3SnH, AIBN, 70% OO

References

1. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574. Stuart McCombie, a Barton student, now works at ScheringPlough. 2. Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672. 3. Lopez, R. M.; Hays, D. S.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 6949. 4. Hansen, H. I.; Kehler, J. Synthesis 1999, 1925. 5. Boussaguet, P.; Delmond, B.; Dumartin, G.; Pereyre, M. Tetrahedron Lett. 2000, 41, 3377. 6. Cai, Y.; Roberts, B. P. Tetrahedron Lett. 2001, 42, 763. 7. Clive, D. L. J.; Wang, J. J. Org. Chem. 2002, 67, 1192. 8. Rhee, J. U.; Bliss, B. I.; RajanBabu, T. V. J. Am. Chem. Soc. 2003, 125, 1492. 9. Gómez, A. M.; Moreno, E.; Valverde, S.; López, J. C. Eur. J. Org. Chem. 2004, 1830. 32

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

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

O O O

OAc OAc ONCl NO O O O HO HCl

O O

OAc hQ homolytic O O 1,5-hydrogen H cleavage abstraction ON•

O

OAc OAc O ON O OOH HO H N

O O Nitric oxide radical is a stable, nitroso intermediate and therefore, long-lived radical 33

OAc

O HOH OH tautomerization N

O Example11

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

References

1. Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet, M. M. J. Am. Chem. Soc. 1960, 82, 2640. In 1960, Derek Barton took a “vacation” in Cambridge, Massachusetts; 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 Beaton, 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 sat- isfying piece of work. 2. Barton, D. H. R.; Beaton, J. M. J. Am. Chem. Soc. 1960, 82, 2641. 3. Barton, D. H. R.; Beaton, J. M. J. Am. Chem. Soc. 1961, 83, 4083. 4. Kabasakalian, P.; Townley, E. J. Am. Chem. Soc. 1962, 84, 2723. 5. Barton, D. H. R.; Lier, E. F.; McGhie, J. M. J. Chem. Soc., C 1968, 1031. 6. Suginome, H.; Sato, N.; Masamune, T. Tetrahedron 1971, 27, 4863. 7. Barton, D. H. R.; Hesse, R. H.; Pechet, M. M.; Smith, L. C. J. Chem. Soc., Perkin Trans. 1 1979, 1159. 8. Barton, D. H. R. Aldrichimica Acta 1990, 23, 3. (Review). 9. Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095. (Review). 10. Herzog, A.; Knobler, C. B.; Hawthorne, M. F. Angew. Chem., Int. Ed. 1998, 37, 1552. 11. Anikin, A.; Maslov, M.; Sieler, J.; Blaurock, S.; Baldamus, J.; Hennig, L.; Findeisen, M.; Reinhardt, G.; Oehme, R.; Welzel, P. Tetrahedron 2003, 59, 5295. 12. Suginome, H. CRC Handbook of Organic Photochemistry and Photobiology 2nd edn. 2004, 102/1102/16. (Review). 34

Barton–Zard reaction Base-induced reaction of nitroalkenes with alkyl D-isocyanoacetates to afford pyrroles.

R2 R1 NO2 Base C=NCH2CO2R3 N CO2R3 R1 R2 H R1 = H, alkyl, aryl R2 = H, alkyl R3 = Me, Et, t-Bu Base = KOt-Bu, DBU, guanidine bases

Example 1

Base CO R NO2 C=NCH2CO2R3 N 2 H

O B N O H C=N CO2R Michael addition C=N CO2R H B

OO N O2N H B H C N CO2R N CO2R

O2N HNO2 [1,5] CO R N CO2R N 2 N CO2R H 35

Example 25

CNCH2CO2Et DBU, THF rt, 8 h, 75% CO2Et O2N N H

Example 37

NO2 CNCH2CO2Et DBU N NNCO2Et THF, rt, 20 h H SO2Ph PhO2S 85%

References

1. Barton, D. H. R.; Zard, S. Z. J. Chem. Soc., Chem. Commun. 1985, 1098. Samir Z. Zard, a Barton student, emigrated from Lebanon to the UK in 1975. He is a professor at CNRS and École Polytechnique in France. 2. van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van Leusen, D. Tetrahedron Lett. 1972, 5337. 3. Barton, D. H. R.; Kervagoret, J.; Zard, S. Z. Tetrahedron 1990, 46, 7587. 4. Sessler, J. L.; Mozaffari, A.; Johnson, M. R. Org. Synth. 1991, 70, 68. 5. Ono, N.; Hironaga, H.; Ono, K.; Kaneko, S.; Murashima, T.; Ueda, T.; Tsukamura, C.; Ogawa, T. J. Chem. Soc., Perkin Trans. 1 1996, 417. 6. Murashima, T.; Fujita, K.; Ono, K.; Ogawa, T.; Uno, H.; Ono, N. J. Chem. Soc., Perkin Trans. 1 1996, 1403. 7. Pelkey, E. T.; Chang, L.; Gribble, G. W. Chem. Commun. 1996, 1909. 8. Uno, H.; Ito, S.; Wada, M.; Watanabe, H.; Nagai, M.; Hayashi, A.; Murashima, T.; Ono, N. J. Chem. Soc., Perkin Trans. 1 2000, 4347. 9. Murashima, T.; Tamai, R.; Nishi, K.; Nomura, K.; Fujita, K.; Uno, H.; Ono, N. J. Chem. Soc., Perkin Trans. 1 2000, 995. 10. Fumoto, Y.; Uno, H.; Tanaka, K.; Tanaka, M.; Murashima, T.; Ono, N. Synthesis 2001, 399. 11. Lash, T. D.; Werner, T. M.; Thompson, M. L.; Manley, J. M. J. Org. Chem. 2001, 66, 3152. 12. Ferreira, V. F.; de Souza, M. C. B. V.; Cunha, A. C.; Pereira, L. O. R.; Ferreira, M. L. G. Org. Prep. Proc. Int. 2001, 33, 411. (Review). 13. Murashima, T.; Nishi, K.; Nakamoto, K.; Kato, A.; Tamai, R.; Uno, H.; Ono, N. Het- erocycles 2002, 58, 301. 14. Gribble, G. W. BartonZard Reaction in Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 7078. (Review). 36

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

R OR3 1 R1 N C OR3 R2 H N R2 R R NO2 DMF, ' NO2

1. Pd/C, H2 R N 2. 5% HCl H

Example 1 NMe DMFDMA 2

NO2 DMF, ' NO2

DMFDMA = N,N-dimethylformamide dimethyl acetal, Me2NCH(OMe)2

Pd/C, H2 N H

MeO MeO + N N OMe MeO 37

OMe

H MeO CH2 + CH2 N O N N O O O

MeO NMe2 MeOH NMe2

H NO2 NO2 :

[H] NMe2 NMe2

reduction NH2 NH

H NHMe2 N N NMe2 H H

Example 25

CO Me CO2H 1. MeI, NaHCO3 2 NMe2 2. Me2NCH(OMe)2 DMF, ' NO NO2 2 80%, 2 steps

CO2Me

Pd/C, H2, PhH, 82%

N H 38

Example 314

OBn Me2NCH(OMe)2 OBn OBn pyrrolidine NMe2

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

OBn OBn Ni, NH NH NMe2 2 2

THF, MeOH N NO2 96% 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 HoffmannLa Roche in Nutley, NJ, USA. 2. Leimgruber, W.; Batcho, A. D. US 3732245 1973. 3. Abdulla, R. F.; Brinkmeyer, R. S. Tetrahedron 1979, 35, 1675. 4. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York & London, 1970. (Review). 5. Kozikowski, A. P.; Ishida, H.; Chen, Y.-Y. J. Org. Chem. 1980, 45, 3550. 6. Maehr, H.; Smallheer, J. M. J. Org. Chem. 1981, 46, 1752. 7. Ferguson, W. J. J. Heterocycl. Chem. 1982, 19, 845. 8. Gupton, J. T.; Lizzi, M. J.; Polk, D. Synth. Commun. 1982, 12, 939. 9. Repke, D. B.; Ferguson, W. J. J. Heterocycl. Chem. 1982, 19, 845. 10. Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195. (Review). 11. Clark, R. D.; Repke, D. B. J. Heterocycl. Chem. 1985, 22, 121. 12. Feldman, P. L.; Rapoport, H. Synthesis 1986, 735. 13. Kozikowski, A. P.; Greco, M. N.; Springer, J. P. J. Am. Chem. Soc. 1982, 104, 7622. 14. Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51, 5106. 15. Toste, F. D.; Still, I. W. J. Org. Prep. Proced. Int. 1995, 27, 576. 16. Coe, J. W.; Vetelino, M. G.; Bradlee, M. J. Tetrahedron Lett. 1996, 37, 6045. 17. Grivas, S. Current Org. Chem. 2000, 4, 707. 18. Siu, J.; Baxendale, I. R.; Ley, S. V. Org. Biomolecular Chem. 2004, 2, 160. 19. Li, J.; Cook, J. M. Batcho–Leimgruber Indole Synthesis in Name Reactions in Hetero- cyclic Chemistry, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 104109. (Review). 20. Batcho, A. D.; Leimgruber, W. Org. Synth. 1984, 63, 214. 39

Baylis–Hillman reaction Also known as Morita–Baylis–Hillman reaction, and occasionally known as Rauhut–Currier reaction. It is a carboncarbon 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, D-alkoxycarbonyl ketones, aldimines, and Michael acceptors.

General scheme:

1 XEWGcatalytic R XH EWG R2 R1 R2 tertiary amine

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

Example 1:

N O OH O O N Ph Ph H

O O Ph H O conjugate aldol

addition N: N N N

O O OH O

Ph Ph H

N N N N 40

OH O N Ph N

E2 (bimolecular elimination) mechanism is also operative here:

OH O

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

Example 210 O O

H OMe Cl

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

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 at Celanese Corp. USA. 2. Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653. 3. Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001. (Review). 4. Ciganek, E. Org. React. 1997, 51, 201. (Review). 5. Shi, M.; Feng, Y.-S. J. Org. Chem. 2001, 66, 406. 6. Yu, C.; Hu, L. J. Org. Chem. 2002, 67, 219. 7. Wang L.-C.; Luis A. L.; Agapiou K.; Jang H.-Y.; Krische M. J. J. Am. Chem. Soc. 2002, 124, 2402. 8. Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404. 9. Shi, M.; Li, C.-Q.; Jiang, J.-K. Tetrahedron 2003, 59, 1181. 10. Mi, X.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2005, 70, 2338. 11. Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T. Org. Lett. 2005, 7, 147. A novel mechanism involving a hemiacetal intermediate is proposed. 41

Beckmann rearrangement Acid-mediated isomerization of oximes to amides.

In protic acid: OH O N H 1 R 2 1 2 N R R R H

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

1

R R1 R1 : N N N H R2 O 2 2 R R :OH2 H

1 1 + R R H N tautomerization HN 2 R OH R2 O

With PCl5:

OH O PCl N 5 1 R 2 1 2 N R R R H

Cl PCl4 OPCl : HCl N 4 O N H R1 R2 R1 R2 the substituent trans to the leaving group migrates 42

1

R R1 R1 : N N N H R2 O 2 2 R R :OH2 H

1 1 + R R H N tautomerization HN 2 R OH R2 O

Example 112

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

PPA = polyphosphoric acid

References

1. Beckmann, E. Chem. Ber. 1886, 89, 988. Ernst Otto Beckmann (18531923) 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. 2. Mazur, R. H. J. Org. Chem. 1961, 26, 1289. 3. Chatterjea, J. N.; Singh, K. R. R. P. J. Indian Chem. Soc. 1982, 59, 527. 4. Gawley, R. E. Org. React. 1988, 35, 1420. (Review). 5. Catsoulacos, P.; Catsoulacos, D. J. Heterocycl. Chem. 1993, 30, 1. 6. Anilkumar, R.; Chandrasekhar, S. Tetrahedron Lett. 2000, 41, 7235. 7. Khodaei, M. M.; Meybodi, F. A.; Rezai, N.; Salehi, P. Synth. Commun. 2001, 31, 2047. 8. Torisawa, Y.; Nishi, T.; Minamikawa, J.-i. Bioorg. Med. Chem. Lett. 2002, 12, 387. 9. Sharghi, H.; Hosseini, M. Synthesis 2002, 1057. 10. Chandrasekhar, S.; Copalaiah, K. Tetrahedron Lett. 2003, 44, 755. 11. Wang, B.; Gu, Y.; Luo, C.; Yang, T.; Yang, L.; Suo, J. Tetrahedron Lett. 2004, 45, 3369. 12. Hilmey, D. G.; Paquette, L. A. Org. Lett. 2005, 7, 2067. 13. Li, D.; Shi, F.; Guo, S.; Deng, Y. Tetrahedron Lett. 2005, 46, 671. 14. Fernández, A. B.; Boronat, M.; Blasco, T.; Corma, A. Angew. Chem., Int. Ed. 2005, 44, 2370. 43

Beirut reaction Synthesis of quinoxaline-1,4-dioxides from benzofurazan oxide.

O O O O N Et3N Ph N Ph O EtOH N CO2Et N O CO Et 2 O

O O O N H O Ph Et3N: Ph N

O CO2Et O CO2Et

O O O O N Ph N Ph O O N N CO2Et O CO2Et : OH

:NEt3 O O O O H N N Ph Ph N CO2Et N CO Et OH 2 O O

Example 13

O O O morpholine, N N O O OEt O H C OEt o N 3 0 C, 10 h, 82% N CH3 O 44

Example 27

O O O OO N Ph silica gel N N Ph H O Ph N MeOH, 90% N Ph N H O

References

1. Haddadin, M. J.; Issidorides, C. H. Heterocycles 1976, 4, 767. The authors named the reaction after the city where it was discovered, Beirut, the capital of Lebanon. 2. Gaso, A.; Boulton, A. J. In Advances in Heterocyclic Chem.; Vol. 29, Katritzky, A. R.; Boulton, A. J., eds.; Academic Press: New York, 1981, 251. (Review). 3. Vega, A. M.; Gil, M. J.; Fernández-Alvarez, E. J. Heterocycl. Chem. 1984, 21, 1271 4. Atfah, A.; Hill, J. J. Chem. Soc., Perkin Trans. 1 1989, 221. 5. Haddadin, M. J.; Issidorides, C. H. Heterocycles 1993, 35, 1503. 6. El-Abadelah, M. M.; Nazer, M. Z.; El-Abadla, N. S.; Meier, H. Heterocycles 1995, 41, 2203. 7. Takabatake, T.; Miyazawa, T.; Kojo, M.; Hasegawa, M. Heterocycles 2000, 53, 2151. 8. Panasyuk, P. M.; Mel’nikova, S. F.; Tselinskii, I. V. Russ. J. Org. Chem. 2001, 37, 892. 9. Turker, L.; Dura, E. Theochem 2002, 593, 143. 10. Tinsley, J. M. Beirut reaction in Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 504509. (Review). 45

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

O O KOH Ar Ar Ar OH Ar O OH

Ar O OH Ar Ar Ar O O O OH

O O O acidic Ar Ar Ar OH O OH Ar Ar workup Ar O OH H+ OH Final deprotonation of the carboxylic acid drives the reaction forward.

Example 13

O H C 3 O KOH, MeOH/H2O H3C H

H H 130140 oC, 3 h, 32% O

CO2H H3C OH H3C H

H H O

References

1. Liebig, J. Ann. 1838, 27. Justus von Liebig (18031873) pursued his Ph.D. in organic chemistry in Paris under the tutelage of Joseph Louis Gay-Lussac (17781850). 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. 46

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. 4. Trost, B. M.; Hiemstra, H. Tetrahedron 1986, 42, 3323. 5. Rajyaguru, I.; Rzepa, H. S. J. Chem. Soc., Perkin Trans. 2 1987, 1819. 6. Askin, D.; Reamer, R. A.; Jones, T. K.; Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1989, 30, 671. 7. Toda, F.; Tanaka, K.; Kagawa, Y.; Sakaino, Y. Chem. Lett. 1990, 373. 8. Robinson, J. M.; Flynn, E. T.; McMahan, T. L.; Simpson, S. L.; Trisler, J. C.; Conn, K. B. J. Org. Chem. 1991, 56, 6709. 9. Hatsui, T.; Wang, J.-J.; Ikeda, S.-y.; Takeshita, H. Synlett 1995, 35. 10. Fohlisch, B.; Radl, A.; Schwetzler-Raschke, R.; Henkel, S. Eur. J. Org. Chem. 2001, 4357. 47

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 Ar H Ar H O O

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

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

Example 111

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

Example 211

O CH3 N O HO Br S o Et3N, DMF, 60 C, 24 h, 90% 48

O O OH O O2 (air)

References

1. Lapworth, A. J. J. Chem. Soc. 1903, 83, 995. Arthur Lapworth (18721941) 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. Ide, W. S.; Buck, J. S. Org. React. 1948, 4, 269304. (Review). 3. Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407496. (Review). 4. Kluger, R. Pure Appl. Chem. 1997, 69, 1957. 5. Demir, A. S.; Dunnwald, T.; Iding, H.; Pohl, M.; Muller, M. Tetrahedron: Asymmetry 1999, 10, 4769. 6. Davis, J. H., Jr.; Forrester, K. J. Tetrahedron Lett. 1999, 40, 1621. 7. White, M. J.; Leeper, F. J. J. Org. Chem. 2001, 66, 5124. 8. Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743. 9. Duenkelmann, P.; Kolter-Jung, D.; Nitsche, A.; Demir, A. S.; Siegert, P.; Lingen, B.; Baumann, M.; Pohl, M.; Mueller, M. J. Am. Chem. Soc. 2002, 124, 12084. 10. Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc. 2003, 125, 8432. 11. Enders, D.; Niemeier, O. Synlett 2004, 2111. 12. Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 13261328. (Review). 49

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

' or hydrogen donor hv

electrocyclization H H reversible

enediyne 1,4-benzenediyl diradical

Example 114

S S Ph S S Ph

DMF, 180 oC, 24 h, 60% S SPh S SPh

Example 215

H3C H3C N hv N

N THF, 45% N

References

1. Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660. Robert G. Bergman (1942) is a professor at the University of California, Berkeley. 2. Bergman, R. G. Acc. Chem. Res. 1973, 6, 25. (Review). 3. Myers, A. G.; Proteau, P. J.; Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212. 4. Evenzahav, A.; Turro, N. J. J. Am. Chem. Soc. 1998, 120, 1835. 50

5. McMahon, R. J.; Halter, R. J.; Fimmen, R. L.; Wilson, R. J.; Peebles, S. A.; Kuczkowski, R. L.; Stanton, J. F. J. Am. Chem. Soc. 2000, 122, 939. 6. Rawat, D. S.; Zaleski, J. M. Chem. Commun. 2000, 2493. 7. Clark, A. E.; Davidson, E. R.; Zaleski, J. M. J. Am. Chem. Soc. 2001, 123, 2650. 8. Alabugin, I. V.; Manoharan, M.; Kovalenko, S. V. Org. Lett. 2002, 4, 1119. 9. Stahl, F.; Moran, D.; Schleyer, P. von R.; Prall, M.; Schreiner, P. R. J. Org. Chem. 2002, 67, 1453. 10. Eshdat, L.; Berger, H.; Hopf, H.; Rabinovitz, M. J. Am. Chem. Soc. 2002, 124, 3822. 11. Yus, M.; Foubelo, F. Rec. Res. Dev. Org. Chem. 2002, 6, 205. (Review). 12. Feng, L.; Kumar, D.; Kerwin, S. M. J. Org. Chem. 2003, 68, 2234. 13. Basak A.; Mandal S.; Bag S. S. Chem. Rev. 2003, 103, 4077. (Review). 14. Bhattacharyya, S.; Pink, M.; Baik, M.-H.; Zaleski, J. M. Angew. Chem., Int. Ed. Engl. 2005, 44, 592. 15. Zhao, Z.; Peacock, J. G.; Gubler, D. A.; Peterson, M. A. Tetrahedron Lett. 2005, 46, 1373. 51

Biginelli pyrimidone synthesis One-pot condensation of an aromatic aldehyde, urea, and ethyl acetoacetate 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

R OO O ' R CHO O H2NNH2 HCl, EtOH HN NH O H OO H OO enolization O aldol R O addition H H O H

H H H OO OO OO H H+ O O O

ROH ROH ROH2

H OO OH O

O conjugate O

HN R R : addition H2N NH2 ONH2 O

H O O OO HO H

H+ R : O H2N N R HN NH H O O 52

OO O O H O H + 2 H R H2O R HN NH HN NH

O O Example9

OMe

OO O MeO + + H2N NH2 OH

OMe

CeCl3.7H2O MeOOC NH EtOH, ', 2.5 h 95% N O H References

1. Biginelli, P. Ber. Dtsch. Chem. Ges. 1891, 24, 1317. Pietro Biginelli was at Lab. chim. della Sanita pubbl. Roma, Italy. 2. Sweet, F.; Fissekis, J. D. J. Am. Chem. Soc. 1973, 95, 8741. 3. Kappe, C. O. Tetrahedron 1993, 49, 6937. (Review). 4. Kappe, C. O. Acc. Chem. Res. 2000, 33, 879. (Review). 5. Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043. (Review). 6. Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Ma, H. Tetrahedron Lett. 2000, 41, 9075. 7. Lu, J.; Bai, Y. Synthesis 2002, 466. 8. Perez, R.; Beryozkina, T.; Zbruyev, O. I.; Haas, W.; Kappe, C. O. J. Comb. Chem. 2002, 4, 501. 9. Bose, D. S.; Fatima, L.; Mereyala, H. B. J. Org. Chem. 2003, 68, 587. 10. Kappe, C. O.; Stadler, A. Org. React. 2004, 68, 1116. (Review). 11. Limberakis, C. Biginelli Pyrimidone Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 509520. (Review). 53

Birch reduction The Birch reduction is the 1,4-reduction of aromatics to their corresponding cyclohexadie- nes 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:

CO H CO2H 2 Na, liq. NH3

CO CO H 2 2 CO e 2 e

H radical anion 54

CO2 CO2 CO2H H

H HNH2 HH Example 18

OMe OMe

o 1. Na, NH3, THF78 C N N O O 2. MeI, 98%, 30:1 dr O O OMe OMe Example 214

Na, NH3, THF N N 78 oC, quant.

References

1. Birch, A. J. J. Chem. Soc. 1944, 430. Arthur Birch (19151995), 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, 1334. (Review). 3. Birch, A. J. Pure Appl. Chem. 1996, 68, 553. (Review). 4. Schultz, A. G. Chem. Commun. 1999, 1263. 5. Ohta, Y.; Doe, M.; Morimoto, Y.; Kinoshita, T. J. Heterocycl. Chem. 2000, 37, 751. 6. Labadie, G. R.; Cravero, R. M.; Gonzalez-Sierra, M. Synth. Commun. 2000, 30, 4065. 7. Guo, Z.; Schultz, A. G. J. Org. Chem. 2001, 66, 2154. 8. Donohoe, T. J.; Guillermin, J.-B.; Calabrese, A. A.; Walter, D. S. Tetrahedron Lett. 2001, 42, 5841. 9. Yamaguchi, S.; Hamade, E.; Yokoyama, H.; Hirai, Y.; Shiotani, S. J. Heterocycl. Chem. 2002, 39, 335. 10. Pellissier, H.; Santelli, M. Org. Prep. Proced. Int. 2002, 34, 611642. (Review). 11. Jiang, J.; Lai, Y.-H. Tetrahedron Lett. 2003, 44, 1271. 12. Subba Rao, G. S. R. Pure Appl. Chem. 2003, 75, 14431451. (Review). 13. Zvilichovsky, G.; Gbara-Haj-Yahia, I. J. Org. Chem. 2004, 69, 5490. 14. Kim, J. T.; Gevorgyan, V. J. Org. Chem. 2005, 70, 2054. 55

Bischler–Möhlau indole synthesis 3-Arylindoles from the cyclization of Ȧ-arylamino-ketones and anilines.

Br H N O 2

' N O H N H

H2N : : SN2 N O H Br H O

HH dehydration HO H N N HH

N H 56

Example 15

O O NaHCO3, EtOH Br NH2 reflux, 4 h

230250 oC O O

N silicone oil, 1015 min N H H O 3580%

Example 29

F OMe OTBS

N O H2NNHN 2

N

OMe

DME, H2SO4 F reflux, 53% H N N N 2 H

References

1. Möhlau, R. Ber. Dtsch. Chem. Ges. 1881, 14, 171. 2. Bischler, A.; Fireman, P. Ber. Dtsch. Chem. Ges. 1893, 26, 1346. 3. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970, p 164. (Book). 4. Buu-Hoï, N. P.; Saint-Ruf, G.; Deschamps, D.; Bigot, P. J. Chem. Soc. (C) 1971, 2606. 5. The Chemistry of Heterocyclic Compounds, Indoles (Part 1), Houlihan, W. J., ed.; Wiley & Sons: New York, 1972. (Review). 6. Bigot, P.; Saint-Ruf, G.; Buu-Hoi, N. P. J. Chem. Soc., J. Chem. Soc., Perkin 1 1972, 2573. 7. Bancroft, K. C. C.; Ward, T. J. J. Chem. Soc., Perkin 1 1974, 1852. 8. Coic, J. P.; Saint-Ruf, G. J. Heterocycl. Chem. 1978, 15, 1367. 9. Henry, J. R.; Dodd, J. H. Tetrahedron Lett. 1998, 39, 8763. 57

Bischler–Napieralski reaction Dihydroisoquinolines from E-phenethylamides using phosphorus oxychloride.

POCl3 HN O N

R R

O Cl P Cl Cl HN O Cl HN O POCl2 R R

NH N H R H ROPOCl2 OPOCl2 Cl

O N HCl + H N + HCl +O P O ROP Cl Cl R Cl

Example 16

Bn MeO POCl MeO N 3 N CO2Me Bn P2O5, 96% O 58

Example 210

O O N HN O O O POCl3 toluene, 95% MeO OMe MeO OMe OMe OMe

References

1. Bischler, A.; Napieralski, B. Ber. Dtsch. Chem. Ges. 1893, 26, 1903. Augustus Bis- chler (18651957) was born in South 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. Fodor, G.; Nagubandi, S. Heterocycles 1981, 15, 165. 3. Rozwadowska, M. D. Heterocycles 1994, 39, 903. 4. Sotomayor, N.; Dominguez, E.; Lete, E. J. Org. Chem. 1996, 61, 4062. 5. Doi, S.; Shirai, N.; Sato, Y. J. Chem. Soc., Perkin Trans. 1 1997, 2217. 6. Wang, X.-j.; Tan, J.; Grozinger, K. Tetrahedron Lett. 1998, 39, 6609. 7. Sanchez-Sancho, F.; Mann, E.; Herradon, B. Synlett 2000, 509. 8. 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. 9. Miyatani, K.; Ohno, M.; Tatsumi, K.; Ohishi, Y.; Kunitomo, J.-I.; Kawasaki, I.; Ya- mashita, M.; Ohta, S. Heterocycles 2001, 55, 589. 10. Capilla, A. S.; Romero, M.; Pujol, M. D.; Caignard, D. H.; Renard, P. Tetrahedron 2001, 57, 8297. 11. Nicoletti, M.; O’Hagan, D.; Slawin, A. M. Z. J. Chem. Soc., Perkin Trans. 1 2002, 116. 12. 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, 376385. (Re- view). 59

Blaise reaction E-Ketoesters from nitriles and D-haloesters using Zn.

O Br CO R2 1. Zn, THF, reflux 2 CO R2 RCN R 2 R1 + 2. H3O R1

R N 2 Br CO R 2 nucleophilic 2 Zn(0) OR R1 ZnBr addition O R1

H2OH H H ZnBr N N workup 2 2 CO2R CO2R R R 1 H2O: R R1

H2OH O H NHO 2 2 CO2R CO R2 R R 2 R1 R1

Example 1, preparation of the statin side chain10

OTMS Cl CN Br CO2t-Bu

1. cat. Zn, THF, reflux OH O

Cl CO2t-Bu + 2. H3O , 85% 60

Example 211

FCN Zn, MeSO3H Br CO2Et ClN Cl THF, reflux, 2.5 h

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

References

1. Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 478, 978. Blaise was at Insti- tut Chimique de Nancy, France. 2. Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833. 3. Krepski, L. R.; Lynch, L. E.; Heilmann, S. M.; Rasmussen, J. K. Tetrahedron Lett. 1985, 26, 981. 4. Beard, R. L.; Meyers, A. I. J. Org. Chem. 1991, 56, 2091. 5. Syed, J.; Forster, S.; Effenberger, F. Tetrahedron: Asymmetry 1998, 9, 805. 6. Narkunan, K.; Uang, B.-J. Synthesis 1998, 1713. 7. Erian, A. W. J. Prakt. Chem. 1999, 341, 147. 8. Deutsch, H. M.; Ye, X.; Shi, Q.; Liu, Z.; Schweri, M. M. Eur. J. Med. Chem. 2001, 36, 303. 9. Creemers, A. F. L.; Lugtenburg, J. J. Am. Chem. Soc. 2002, 124, 6324. 10. Shin, H.; Choi, B. S.; Lee, K. K.; Choi, H.-W.; Chang, J. H.; Lee, Kyu W.; Nam, D. H.; Kim, N.-S. Synthesis 2004, 2629. 11. 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. 61

Blanc chloromethylation Lewis acid-promoted chloromethyl group installation onto the aromatics rings with 1,3,5-trioxane and HCl.

O ZnCl2 Cl HCl H2O OO 1,3,5-trioxane

H O O + H HH OO

H + H+ HO H HO

Cl SN2 Cl H2O OH2

Example 112

NH3Cl NH3Cl CH3 CH (OCH ) , HCl, PhCl 3 2 n O O o 20 C, 2 h, 71% O O Cl

References

1. Blanc, G. Bull. Soc. Chim. Fr. 1923, 33, 313. Gustave Louis Blanc (18721927), born in Paris, France, studied under Charles Friedel in Paris. He developed the chloromethylation of aromatic hydrocarbons while he was a director at the Intendance mili- taire aux Invalides. 62

2. Fuson, R. C.; McKeever, C. H. Org. React. 1942, 1, 63. (Review). 3. Olah, G.; Tolgyesi, W. S. In FriedelCrafts and Related Reactions vol. II, Part 2, Olah, G., Ed.; Interscience: New York, 1963, pp 659784. (Review). 4. Franke, A.; Mattern, G.; Traber, W. Helv. Chim. Acta 1975, 58, 283. 5. Sekine, Y.; Boekelheide, V. J. Am. Chem. Soc. 1981, 103, 1777. 6. Mallory, F. B.; Rudolph, M. J.; Oh, S. M. J. Org. Chem. 1989, 54, 4619. 7. Witiak, D. T.; Loper, J. T.; Ananthan, S.; Almerico, A. M.; Verhoef, V. L.; Filppi, J. A. J. Med. Chem. 1989, 32, 1636. 8. De Mendoza, J.; Nieto, P. M.; Prados, P.; Sanchez, C. Tetrahedron 1990, 46, 671. 9. Tashiro, M.; Tsuge, A.; Sawada, T.; Makishima, T.; Horie, S.; Arimura, T.; Mataka, S.; Yamato, T. J. Org. Chem. 1990, 55, 2404. 10. Miller, D. D.; Hamada, A.; Clark, M. T.; Adejare, A.; Patil, P. N.; Shams, G.; Romstedt, K. J.; Kim, S. U.; Intrasuksri, U.; et al. J. Med. Chem. 1990, 33, 1138. 11. Ito, K.; Ohba, Y.; Shinagawa, E.; Nakayama, S.; Takahashi, S.; Honda, K.; Nagafuji, H.; Suzuki, A.; Sone, T. J. Heterocycl. Chem. 2000, 37, 1479. 12. Harms, A.; Ulmer, E.; Kovar, K.-A. Archiv. Pharmazie 2003, 336, 155. 63

Blum aziridine synthesis Ring opening of oxiranes using azide is followed by Staudinger reduction of the intermediate azido alcohol to give aziridines.

N O 3 H 1 PPh NaN3 R 3 N R2 R1 R2 OH Staudinger R1 R2

N3 O 1 SN2 R R2 1 2 R R 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 R HO HO NNN NNNPPh3 :PPh3 2 R2 R

R1 PR HO N 3 N NNNPR3 N R2 X

PR 3 PR3 N N 1 N2 R 2 HO R R2 OH R1

1 R P NH R NH H proton 3 N :O 2 R 2 transfer O R 1 2 1 R R R PPh3 64

Example 13

1. NaN3, NH4Cl, MeOH, reflux, 4 h OTr O HN OTr 2. Ph3P, CH3CN, reflux, 30 min, 6075%

Example 25

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

OH N3 OTBS OTBS OH N3

Ph3P, CH3CN NH OTBS reflux, 99%

References

1. Ittah, Y.; Sasson, Y.; Shahak, I.; Tsaroom, S.; Blum, J. J. Org. Chem. 1978, 43, 4271. Jochanan Blum is a professor at The Hebrew University in Jerusalem, Israel. 2. Tanner, D.; Somfai, P. Tetrahedron Lett. 1987, 28, 1211. 3. Wipf, P.; Venkatraman, S.; Miller, C. P. Tetrahedron Lett. 1995, 36, 3639. 4. Fürmeier, S.; Metzger, J. O. Eur. J. Org. Chem. 2003, 649. 5. Oh, K.; Parson, P. J.; Cheshire, D. Synlett 2004, 2771. 6. Serafin, S. V.; Zhang, K.; Aurelio, L.; Hughes, A. B.; Morton, T. H. Org. Lett. 2004, 6, 1561. 65

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

TFAA N OH O N TFAA, trifluoroacetic anhydride

O2CCF3 N acyl H N O N O O transfer O O F COCF 3 3 CF CF3 3 OO

hydrolysis OCF N 3 OH N O

Example 16

Ac2O, CH2Cl2

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

Example 29

OtBu OtBu

1. TFAA, CH2Cl2

N 2. Na2CO3, 3 h N 89% O OH 66

References

1. Boekelheide, V.; Linn, W. J. J. Am. Chem. Soc. 1954, 76, 1286. Virgil Boekelheide (19192003) was a professor at the University of Oregon. 2. Boekelheide, V.; Harrington, D. L. Chem. Ind. 1955, 1423. 3. Boekelheide, V.; Lehn, W. L. J. Org. Chem. 1961, 26, 428. 4. Katritzky, A. R.; Lagowski, J. M. Chemistry of the Heterocylic N-Oxides Academic Press, NY, 1971. (Review). 5. Bell, T. W.; Firestone, A. J. Org. Chem. 1986, 51, 764. 6. Newkome, G. R.; Theriot, K. J.; Gupta, V. K.; Fronczek, F. R.; Baker, G. R. J. Org. Chem. 1989, 54, 1766. 7. Goerlitzer, K.; Schmidt, E. Arch. Pharm. 1991, 324, 359. 8. Katritzky, A. R.; Lam, J. N. Heterocycles 1992, 33, 10111049. (Review). 9. Fontenas, C.; Bejan, E.; Haddon, H. A.; Balavoine, G. G. A. Synth. Commun. 1995, 25, 629. 10. Goerlitzer, K.; Bartke, U. Pharmazie 2002, 57, 804. 11. Higashibayashi, S.; Mori, T.; Shinko, K.; Hashimoto, K.; Nakata, M. Heterocycles 2002, 57, 111. 12. Galatsis, P. Boekelheide Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 340349. (Review). 67

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

N N H NN O N

H

H2O O OH

: N HN

N N N Hetero-Diels-Alder N N N N reaction N

:B Retro-Diels-Alder H N N reaction, N2 N

Example 14

EtO2C N CO2Et N + O N EtO2C N

o CHCl3, 60 C EtO2C N CO2Et

26 h, 92% EtO2C 68

References

1. Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179. Dale Boger is a professor at the Scripps Research Institute. 2. Boger, D. L.; Panek, J. S.; Meier, M. M. J. Org. Chem. 1982, 47, 895. 3. Boger, D. L. Tetrahedron 1983, 39, 28692939. (Review). 4. Boger, D. L. Chem. Rev. 1986, 86, 781793. (Review). 5. Boger, D. L.; Panek, J. S.; Yasuda, M. Org. Synth. 1987, 66, 142. 6. Boger, D. L. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 451512. (Review). 7. Golka, A.; Keyte, P. J.; Paddon-Row, M. N. Tetrahedron 1992, 48, 7663. 8. Behforouz, M.; Ahmadian, M.Tetrahedron 2000, 56, 52595288. (Review). 9. Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 60996138. (Review). 10. Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379471. (Re- view). 11. Rykowski, A.; Olender, E.; Branowska, D.; Van der Plas, H. C. Org. Prep. Proced. Int. 2001, 33, 501. 12. Stanforth, S. P.; Tarbit, B.; Watson, M. D. Tetrahedron Lett. 2003, 44, 693. 13. Galatsis, P. Boger Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 323339. (Review). 69

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 OH R R 1 2 R R 1 N: 2 H R R N 3 4 R3 R4

H H R1 R2 R1 R2 N N R3 R4 R3 R4

Example 14

O

CH3

NH2

1. TiCl , Et N, CH Cl , rt, 48 h 4 3 2 2 HN

2. NaCNBH3, MeOH, rt, 15 min. CH 94% 3 70

Example 25

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

References

1. Borch, R. F. J. Am. Chem. Soc. 1969, 91, 3996. Richard F. Borch was born in Cleve- land, Ohio. He 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. 3. Borch, R. F.; J. Chem. Soc., Perkin I 1984, 717. 4. Barney, C. L.; Huber, E. W.; McCarthy, J. R. Tetrahedron Lett. 1990, 31, 5547. 5. Mehta, G.; Prabhakar, C. J. Org. Chem. 1995, 60, 4638. 6. Lewin, G.; Schaeffer, C. Heterocycles 1998, 48, 171. 7. Lewin, G.; Schaeffer, C.; Hocquemiller, R.; Jacoby, E.; Leonce, S.; Pierre, A.; Atassi, G. Heterocycles 2000, 53, 2353. 71

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

HCl

N N N H H

H [3,3]-sigmatropic

N NH rearrangement N N H + H H

H H+

NH NH2 NH NH

H

N NH2 N H H+ H

Example 18

CH3 H CO HCl, NaNO2, AcONa 3 HO

H2O, MeOH, 54% NH2 O 72

CH3 CH3

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

References

1. Drechsel, E. J. Prakt. Chem. 1858, 38, 69. 2. Borsche, W.; Feise, M. Ber. Dtsch. Chem. Ges. 1904, 20, 378. 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 contemporaries. Borsche and his colleague at Frankfurt, Julius von Braun, both suf- fered under the Nazi regime for their independent minds. 3. Atkinson, C. M.; Biddle, B. N. J. Chem. Soc. (C) 1966, 2053. 4. Bruck, P. J. Org. Chem. 1970, 35, 2222. 5. Gazengel, J. M.; Lancelot, J. C.; Rault, S.; Robba, M. J. Heterocycl. Chem. 1990, 27, 1947. 6. Abramovitch, R. A.; Bulman, A. Synlett 1992, 795. 7. Murakami, Y.; Yokooa, H.; Watanabe, T. Heterocycles 1998, 49, 127. 8. Lin, G.; Zhang, A. Tetrahedron 2000, 56, 7163. 9. Ergun, Y.; Bayraktar, N.; Patir, S.; Okay, G. J. Heterocycl. Chem. 2000, 37, 11. 10. Rebeiro, G. L.; Khadilkar, B. M. Synthesis 2001, 370. 73

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 17

N: o N 150 C H+ H H N N N N O O Ph Ph

N O N N Ph H

Example 211

O Ph NH2NH2, DMF N Ph N N rt, 1 h N NH2 F C N F3C 3 O O

HO F3C N NH Ph Ph O N N N N N F3C N H H 5% 92% 74

O NH2NH2, DMF N Ph F C N rt, 1 h 7 3 O

HO F7C3 N NH Ph Ph O N N N N N F7C3 N H H 24% 70%

References

1. Boulton, A. J.; Katritzky, A. R.; Hamid, A. M. J. Chem. Soc. (C) 1967, 2005. Alan Katritzky, a professor at the University of Florida, is best known for his series Ad- vances of Heterocyclic Chemistry, now in its 87th volume. 2. Ruccia, M.; Vivona, N.; Spinelli, D. Adv. Heterocyl. Chem. 1981, 29, 141. (Review). 3. Butler, R. N.; Fitzgerald, K. J. J. Chem. Soc., Perkin Trans. 1 1988, 1587. 4. Takakis, I. M.; Hadjimihalakis, P. M.; Tsantali, G. G. Tetrahedron 1991, 47, 7157. 5. Takakis, I. M.; Hadjimihalakis, P. M. J. Heterocycl. Chem. 1992, 29, 121. 6. Vivona, N.; Buscemi, S.; Frenna, V.; Cusmano, C. Adv. Heterocyl. Chem. 1993, 56, 49. 7. Katayama, H.; Takatsu, N.; Sakurada, M.; Kawada, Y. Heterocycles 1993, 35, 453. 8. Rauhut, G. J. Org. Chem. 2001, 66, 5444. 9. Crampton, M. R.; Pearce, L. M.; Rabbitt, L. C. J. Chem. Soc., Perkin Trans. 2 2002, 257. 10. Pena-Gallego, A.; Rodriguez-Otero, J.; Cabaleiro-Lago, E. M. J. Org. Chem. 2004, 69, 7013. 11. Buscemi, S.; Pace, A.; Piccionello, A. P.; Macaluso, G.; Vivona, N.; Spinelli, D.; Giorgi, G. J. Org. Chem. 2005, 70, 3288. 75

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 R CHO 3. H+

O

Me NH 2 OM M H+ RX RM Me2N R CHO R

A modification by Comins:7

N O Li NN LiO N H H

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

Example 16

Li, DMF, THF, 10 oC Br CHO

ultrasound 5 min, 85% 76

References

1. Bouveault, L. Bull. Soc. Chim. Fr. 1904, 31, 1306, 1322. Louis Bouveault (18641909) was born in Nevers, France. He devoted his short yet very productive life to teaching and to working in science. 2. Maxim, N.; Mavrodineanu, R. Bull. Soc. Chim. Fr. 1935, 2, 591. 3. Maxim, N.; Mavrodineanu, R. Bull. Soc. Chim. Fr. 1936, 3, 1084. 4. Smith, L. I.; Bayliss, M. J. Org. Chem. 1941, 6, 437. 5. Sicé, J. J. Am. Chem. Soc. 1953, 75, 3697. 6. Pétrier, C.; Gemal, A. L.; Luche, J. L. Tetrahedron Lett. 1982, 23, 3361. 7. Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078. 8. Einhorn, J.; Luche, J. L. Tetrahedron Lett. 1986, 27, 1791. 9. Einhorn, J.; Luche, J. L. Tetrahedron Lett. 1986, 27, 1793. 10. Denton, S. M.; Wood, A. Synlett 1999, 55. 11. Meier, H.; Aust, H. J. Prakt. Chem. 1999, 341, 466. 77

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

O Na, EtOH ROH ROEt

O single-electron O H OEt ROEt transfer (SET) ROEt e ketyl (radical anion)

OEt OH H OH e O ROEt ROEt ROEt H OEt

O e O H OEt

RH RH

OH OH e RH ROH RH H OEt

Example 18

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

References

1. Bouveault, L.; Blanc, G. Compt. Rend. 1903, 136, 1676. 2. Bouveault, L.; Blanc, G. Bull. Soc. Chim. 1904, 31, 666. 3. Ruehlmann, K.; Seefluth, H.; Kiriakidis, T.; Michael, G.; Jancke, H.; Kriegsmann, H. J. Organomet. Chem. 1971, 27, 327. 4. Castells, J.; Grandes, D.; Moreno-Manas, M.; Virgili, A. An. Quim. 1976, 72, 74. 78

5. Sharda, R.; Krishnamurthy, H. G. Indian J. Chem., Sect. B 1980, 19B, 405. 6. Banerji, J.; Bose, P.; Chakrabarti, R.; Das, B. Indian J. Chem., Sect. B 1993, 32B, 709. 7. Seo, B. I.; Wall, L. K.; Lee, H.; Buttrum, J. W.; Lewis, D. E. Synth. Commun. 1993, 23, 15. 8. Singh, S.; Dev, S. Tetrahedron 1993, 49, 10959. 9. Schopohl, Matthias C.; Bergander, Klaus; Kataeva, Olga; Froehlich, Roland; Waldvo- gel, Siegfried R. Synthesis 2003, 2689. 79

Boyland–Sims oxidation Oxidation of anilines to phenols using alkaline persulfate.

NR NR2 2 NR2 K S O + + 2 2 8 OSO3 K H OH aq. KOH

O O O O O SSOO O S O O ipso-attack R2N O O NR2 SO4

O O O O S S : R2N O: O R2N O O

H

O O S NR2 R2N O O + OSO3 K H OH

Another pathway is also operative:

O O O NR2 S O S O + R2N E2 OSO K R2N O O O 3 H OH 80

Example 13

NH2 + NH2 NH2 OSO K + 3 K2S2O8 OSO3 K aq. KOH OSO K+ 50-55% 3

References

1. Boyland, E.; Manson, D.; Sims, P. J. Chem. Soc. 1953, 3623. Eric Boyland and Peter Sims were at the Royal Cancer Hospital in London, UK. 2. Boyland, E.; Sims, P. J. Chem. Soc. 1954, 980. 3. Behrman, E. J. J. Am. Chem. Soc. 1967, 89, 2424. 4. Krishnamurthi, T. K.; Venkatasubramanian, N. Indian J. Chem., Sect. A 1978, 16A, 28. 5. Behrman, E. J.; Behrman, D. M. J. Org. Chem. 1978, 43, 4551. 6. Srinivasan, C.; Perumal, S.; Arumugam, N. J. Chem. Soc., Perkin Trans. 2 1985, 1855. 7. Behrman, E. J. Org. React. 1988, 35, 421511. (Review). 8. Behrman, E. J. J. Org. Chem. 1992, 57, 2266. 81

Bradsher reaction Anthracenes from ortho-acyl diarylmethanes via acid-catalyzed cyclodehydration.

HBr R CH3CO2H O R anthracene

H+ R R O O H

H+

H R O R OH H

H

H+

R OH2 R

Example5

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

References

1. Bradsher, C. K. J. Am. Chem. Soc. 1940, 62, 486. Charles K. Bradsher was a professor at Duke University. 2. Bradsher, C. K.; Smith, E. S. J. Am. Chem. Soc. 1943, 65, 451. 82

3. Bradsher, C. K.; Vingiello, F. A. J. Org. Chem. 1948, 13, 786. 4. Bradsher, C. K.; Sinclair, E. F. J. Org. Chem. 1957, 22, 79. 5. Vingiello, F. A.; Spangler, M. O. L.; Bondurant, J. E. J. Org. Chem. 1960, 25, 2091. 6. Brice, L. K.; Katstra, R. D. J. Am. Chem. Soc. 1960, 82, 2669. 7. Saraf, S. D.; Vingiello, F. A. Synthesis 1970, 655. 8. Ashby, J.; Ayad, M.; Meth-Cohn, O. J. Chem. Soc., Perkin Trans. 1 1974, 1744. 9. Nicolas, T. E.; Franck, R. W. J. Org. Chem. 1995, 60, 6904. 10. Magnier, E.; Langlois, Y. Tetrahedron Lett. 1998, 39, 837. 83

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

SiR OH O 3 RLi R1 R1 SiR3 Li R2 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

Example 111

O 1. 4 eq. NaHMDS, 78 to 15 oC CN t-BuMe2Si o Ph 2. PhCH2Br, 10 C, 75%

CN t-BuMe2SiO Ph Ph 84

Example 214

t-BuLi, Et2O Br Ph Li Ph 78 oC

O Ph O Me3Si Ph Ph 78 oC to rt, 30 min. SiMe3 then NH4Cl, H2O, 44%

References

1. Brook, A. G. J. Am. Chem. Soc. 1958, 80, 1886. Adrian G. Brook (1924) was born in Toronto, Canada. He is a professor in Lash Miller Chemical Laboratories, Univer- sity of Toronto, Canada. 2. Brook, A. G. Acc. Chem. Res. 1974, 7, 77. (Review). 3. Page, P. C. B.; Klair, S. S.; Rosenthal, S. Chem. Soc. Rev. 1990, 19, 147. (Review). 4. Takeda, K.; Nakatani, J.; Nakamura, H.; Yosgii, E.; Yamaguchi, K. Synlett 1993, 841. 5. Fleming, I.; Ghosh, U. J. Chem. Soc., Perkin Trans. 1 1994, 257. 6. Takeda, K.; Takeda, K.; Ohnishi, Y. Tetrahedron Lett. 2000, 41, 4169. 7. Sumi, K.; Hagisawa, S. J. Organomet. Chem. 2000, 611, 449. 8. Moser, W. H. Tetrahedron 2001, 57, 2065. (Review). 9. Takeda, K.; Sawada, Y.; Sumi, K. Org. Lett. 2002, 4, 1031. 10. Takeda, K.; Haraguchi, H.; Okamoto, Y. Org. Lett. 2003, 5, 3705. 11. Okugawa, S.; Takeda, K. Org. Lett. 2004, 6, 2973. 12. Matsumoto, T.; Masu, H.; Yamaguchi, K.; Takeda, K. Org. Lett. 2004, 6, 4367. 13. Tanaka, K.; Takeda, K. Tetrahedron Lett. 2004, 45, 7859. 14. Clayden, J.; Watson, D. W.; Chambers, M. Tetrahedron 2005, 61, 3195. 15. Nahm, M. R.; Xin, L.; Potnick, J. R.; Yates, C. M.; White, P. S.; Johnson, J. S. Angew. Chem., Int. Ed. Engl. 2005, 44, 2377. 85

Brown hydroboration Addition of boranes to olefins, followed by basic oxidation of the organoborane adducts, resulting in alcohols.

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

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

H R' BaeyerVilliger- O R' R' R B OOH B OH R O like reaction R'

O OR' OH R B OH B(OH) R 3 OR'

Example 12

1. BH3•SMe3, THF H 2. NaOOH H H

H

H OH HO H H H H H H H 35% 40% 86

Example 213

OMe OMe

MeO MeO NO 2 BH3•SMe3, NaOOH NO2 OMe OMe Me THF, 85%, dr 8-11:1 Me OBn OBn HO

HO HO

Example 314

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

References

1. Brown, H. C.; Tierney, P. A. J. Am. Chem. Soc. 1958, 80, 1552. Herbert C. Brown (USA, 19122004) 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, 18971987) for their development of organic boron and phosphorous compounds. 2. Nussium, M.; Mazur, Y.; Sondheimer, F. J. Org. Chem. 1964, 29, 1120. 3. Nussium, M.; Mazur, Y.; Sondheimer, F. J. Org. Chem. 1964, 29, 1131. 4. Streitwieser, A., Jr.; Verbit, L.; Bittman, R. J. Org. Chem. 1967, 32, 1530. 5. Herz, J. E.; Marquez, L. A. J. Chem. Soc. (C) 1971, 3504. 6. Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents Academic Press: New York, 1972. (Review). 7. Brewster, J. H.; Negishi, E. Science 1980, 207, 44. (Review). 8. Brown, H. C.; vara Prasad, J. V. N. Heterocycles 1987, 25, 641. 9. Fu, G. C.; Evans, D. A.; Muci, A. R. Advances in Catalytic Processes 1995, 1, 95121. (Review). 10. Hayashi, T. Comprehensive Asymmetric Catalysis IIII 1995, 1, 351364. (Review). 11. Morrill, T. C.; D’Souza, C. A.; Yang, L.; Sampognaro, A. J. J. Org. Chem. 2002, 67, 2481. 12. Hupe, E.; Calaza, M. I.; Knochel, P. Tetrahedron Lett. 2001, 42, 8829. 13. Carter K. D; Panek J. S. Org. Lett. 2004, 6, 55. 14. Clay, J. M.; Vedejs, E. J. Am. Chem. Soc. 2005, 127, 5766. 87

Bucherer carbazole synthesis Carbazoles from naphthols and aryl hydrazines promoted by sodium bisulfite.

OH NaHSO3 NH NHNH2

+ H H H H H H+ O OH OH

OSO H OSO2H 2

H H H+ O

:NH2NHPh

OSO2H

+ H H H OH NHNHPh NHNHPh :B H

OSO2H OSO2H

+ NH H NH [3,3]-sigmatropic rearrangement 88

+ NH2 H NH2 H H NH NH NH

Example 13

OH

NHNH CO2H 2

o NaHSO3, NaOH, ', 130 C

several days, 46% N H

Example 24

OH

1) aq. NaHSO3, ' N 2) H H2NHN H

References

1. Bucherer, H. T. J. Prakt. Chem. 1904, 69, 49. Hans Th. Bucherer (18691949) was born in Ehrenfeld, Germany. He shuttled between industry and academia all through his career. 2. Bucherer, H. T.; Seyde, F. J. Prakt. Chem. 1908, 77, 403. 3. Bucherer, H. T.; Schmidt, M. J. Prakt. Chem. 1909, 79, 369. 4. Bucherer, H. T.; Sonnenburg, E. F. J. Prakt. Chem. 1909, 81, 1. 5. Friedländer, P. Chem. Ztg. 1916, 40, 918. 6. Fuchs, W.; Niszel, F. Chem. Ber. 1927, 60, 209. 7. Drake, N. L. Org. React. 1942, 1, 105. (Review). 8. Buu-Hoï, N. P.; Hoán, N.; Khôi, N. H. J. Org. Chem. 1949, 14, 492. 9. Buu-Hoï, N. P.; Royer, R.; Eckert, B.; Jacquignon, P. J. Chem. Soc. 1952, 4867. 10. Zander, M.; Franke, W. Chem. Ber. 1963, 96, 699. 11. Seeboth, H.; Bärwolff, D.; Becker, B. Justus Liebigs Ann. Chem. 1965, 683, 85. 12. Seeboth, H. Angew. Chem., Int. Ed. Engl. 1967, 6, 307. 13. Thang, D. C.; Can, C. X.; Buu-Hoï, N. P.; Jacquignon, P. J. Chem. Soc., Perkin Trans. 1 1972, 1932. 89

14. Robinson, B. The Fischer Indole Synthesis, Wiley-Interscience, New York, 1982. (Book). 15. Hill, J. A.; Eaddy, J. F. J. Labeled. Compd. Radiopharm. 1994, 34, 697. 16. Pischel, I.; Grimme, S.; Kotila, S.; Nieger, M.; Vögtle, F. Tetrahedron: Asymmetry 1996, 7, 109. 90

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

OH(NH4)2SO3•NH3 NH2

o H2O, 150 C

H H H+ H H H+ O O O H H

OSO NH OSO2NH4 2 4

OH O tautomerization NH2 :NH3

OSO NH OSO2NH4 2 4

H OH2 NH2 + NH2 H NH2 H

OSO2NH4 OSO2NH4

Example2

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

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

microwave 30 min. 93%

References

1. Bucherer, H. T. J. Prakt. Chem. 1904, 69, 49. 2. Drake, N. L. Org. React. 1942, 1, 105. (Review). 3. Reiche, A.; Seeboth, H. Justus Liebigs Ann. Chem. 1960, 638, 66. 4. Seeboth, H.; Reiche, A. Justus Liebigs Ann. Chem. 1964, 671, 77. 91

5. Gilbert, E. E. Sulfonation and Related Reactions Wiley: New York, 1965, p166. (Re- view). 6. Seeboth, H. Angew. Chem., Int. Ed. Engl. 1967, 6, 307. 7. Gruszecka, E.; Shine, H. J. J. Labelled. Compd. Radiopharm. 1983, 20, 1257. 8. Belica, P. S.; Manchand, P. S. Synthesis 1990, 539. 9. Cañete, A.; Meléndrez, M. X.; Saitz, C.; Zanocco, A. L. Synth. Commun. 2001, 31, 2143. 92

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 reaction (MCR).

H 1 1 R KCN R N O O 2 R NH R2 (NH ) CO 4 2 3 O

(NH4)CO2 ļ 2 NH3 + CO2 + H2O O CO 1 OH

R : 1 O R CN NH 2 2 2 R R 1

: R N NC 2 H3N R cyanohydrin

: H OH 1 H R N 1 R N O 2 O R 2 R O N HN

H+ O H C R1 1 N O R N 2 : R NH R2 NH2 O O isocyanate intermediate

Example 110

CH3O KCN, (NH4)2CO3 N CH3O 48 h, 60 oC, 83%

O 93

CH3O CH3O

N N CH O CH O 3 HH3 O HN O NH NH HN O O Example 211

O H KCN, (NH4)2CO3 O CO2Et O H EtOH/H O, 70 oC, 50% H 2

O HN NH O H O CO2Et O H H

References

1. Bergs, H. Ger. Pat. 566, 094, 1929. Hermann Bergs worked at I. G. Farben in Ger- many. 2. Bucherer, H. T., Fischbeck, H. T. J. Prakt. Chem. 1934, 140, 69. 3. Bucherer, H. T., Steiner, W. J. Prakt. Chem. 1934, 140, 291. (Mechanism). 4. E. Ware, Chem. Rev. 1950, 46, 403. (Review). 5. Wieland, H. et al., in HoubenWeyl's Methoden der organischen Chemie, Vol. XI/2, 1958, p 371. 6. Chubb, F. L.; Edward, J. T.; Wong, S. C. J. Org. Chem. 1980, 45, 2315. 7. Rousset, A.; Laspéras, M.; Taillades, J.; Commeyras, A. Tetrahedron 1980, 36, 2649. 8. Bowness, W. G.; Howe, R.; Rao, B. S. J. Chem. Soc., Perkin Trans. 1 1983, 2649. 9. Haroutounian, S. A.; Georgiadis, M. P.; Polissiou, M. G. J. Heterocycl. Chem. 1989, 26, 1283. 10. Menéndez, J. C.; Díaz, M. P.; Bellver, C.; Söllhuber, M. M. Eur. J. Med. Chem. 1992, 27, 61. 11. Domínguez, C.; Ezquerra, A.; Prieto, L.; Espada, M.; Pedregal, C. Tetrahedron: Asymmetry 1997, 8, 511. 12. Micǂvá, J.; Steiner, B.; Kóoš, M.; Langer, V.; Gyepesova, D. Synlett 2002, 1715. 13. Li, J. J. Bucherer–Bergs Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 266274. (Review). 94

Büchner–Curtius–Schlotterbeck reaction Reaction of carbonyl compounds with aliphatic diazo compounds to deliver homologated ketones.

O 1 H R R1 2 R R N2 RO R2

R1

RO H H H 2 R2 N R N2 N R2 N N

N O nucleophilic N 1 rearrangement R H R R N2n 2 O addition R 2 R R1 Example 13

O O CH2N2 Cl N2CH2 Et2O O O H3C O O

O HCl Cl

H3C O O

Example 26

NC CN NC CN CH2N2, Et2O

Ph H rt, 100% Ph CH3 95

33% aq. NaOH O

Ph CH 45 oC, 99% 3

References

1. Büchner, E.; Curtius, T. Ber. Dtsch. Chem. Ges. 1885, 18, 2371. Eduard Büchner (Germany, 18601917) won the Nobel Prize in Chemistry in 1907 for biochemical studies and discovery of fermentation without cells. 2. Schlotterbeck, F. Ber. Dtsch. Chem. Ges. 1907, 40, 479. 3. Fried, J.; Elderfield, R. C. J. Org. Chem. 1941, 6, 577. 4. Gutsche, C. D. Org. React. 1954, 8, 364. (Review). 5. Bastús, J. B. Tetrahedron Lett. 1963, 955. 6. Kirmse, W.; Horn, K. Tetrahedron Lett. 1967, 1827. 96

Büchner method of ring expansion Reaction of benzene with diazoacetic esters to give cyclohepta-2,4,6- trienecarboxylic acid esters. Cf. PfauPlatter azulene synthesis.

N2 CO2CH3 CO2CH3 [Rh]

[Rh] N2 CO2CH3 N2n [Rh] CO2CH3 Rhodium carbenoid

CO2CH3 [2 + 2] CO2CH3

[Rh] cycloaddition [Rh]

electrocyclic CO2CH3 ring opening

Example 17

O Rh (OAc) N2 2 4

CH2Cl2, 98% H O

Example 28

I Br I cat. Rh2(OCOt-Bu)4, DMAP

O Ac2O, CH2Cl2, 73% OAc

N2

References

1. Büchner, E. Ber. Dtsch. Chem. Ges. 1896, 29, 106. 2. Dev, S. J. Indian Chem. Soc. 1955, 32, 513. 3. von Doering, W.; Knox, L. H. J. Am. Chem. Soc. 1957, 79, 352. 97

4. Marchard, A. P.; Brockway, N. M. Chem. Rev. 1974, 74, 431. (Review). 5. Anciaux, A. J.; Demonceon, A.; Noels, A. F.; Hubert, A. J.; Warin, R.; Teyssié, P. J. Org. Chem. 1981, 46, 873. 6. Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001, 3, 933. 7. Manitto, P.; Monti, D.; Speranza, G. J. Org. Chem. 1995, 60, 484. 8. Crombie, A. L; Kane, J. L. Jr.; Shea, K. M.; Danheiser, R. L. J. Org. Chem. 2004, 69, 8652. 98

Buchwald–Hartwig C–N and C–O bond formation reactions Direct Pd-catalyzed C–N and C–O bond formation from aryl halides and amines in the presence of stoichiometric amount of base.

Br N Pd(OAc)2, dppf

N NaOt-Bu, Tol., ' H

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

Pd(II) N reductive N

elimination Pd(0)

The C–O bond formation reaction follows a similar mechanistic pathway.79

Example 111

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

i-Bu P N i-Bu i-Bu N ONOligand = N

N 99

Example 212

NH2 CO2Me Pd(OAc)2, Cs2CO3 I DPE-Phos, Tol., 95 oC 95% OCF3

PPh PPh MeO2C H 2 2 N O DPE-Phos =

OCF3

References

1. Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969. John Hartwig earned his Ph.D. under Bergman and Anderson. He has moved from Yale University to the University of Illinois at Urbana-Champaign in 2006. Hartwig and Buchwald independently discovered this chemistry. 2. Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901. Steve Buchwald is a professor at MIT. 3. Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333. 4. Mann, G.; Hartwig, J. F. J. Org. Chem. 1997, 62, 5413. 5. Mann, G.; Hartwig, J. F. Tetrahedron Lett. 1997, 38, 8005. 6. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (Review). 7. Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (Review). 8. Frost, C. G.; Mendonça, P. J. Chem. Soc., Perkin Trans. 1 1998, 2615. (Review). 9. Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125. (Review). 10. Ferreira, I. C. F. R.; Queiroz, M.-J. R. P.; Kirsch, G. Tetrahedron 2003, 59, 975. 11. Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 9135. 12. Csuk, R.; Barthel, A.; Raschke, C. Tetrahedron 2004, 60, 5737. 13. Li, C. S.; Dixon, D. D. Tetrahedron Lett. 2004, 45, 4257. 14. Gooßen, L. J.; Paetzold, J.; Briel, O.; Rivas-Nass, A.; Karch, R.; Kayser, B. Synlett 2005, 275. 100

Burgess dehydrating reagent Burgess dehydrating reagent is efficient at generating olefins from secondary and tertiary alcohols where the first-order thermolytic Ei (during the elimination, the two groups leave at about the same time and bond to each other concurrently) mechanism prevails.

Reagen formation,

O CH O CNSNEt 3 2 3 1 1 R H R CH3 O N O CH O C S HNEt OH 2 3 2 3 R2 Burgess reagent R O O

O O O NSCl CH O CNSCl O 3 2 O :NEt3 H3COH

O

CH3O2CNS NEt3 O Reaction,

O CH O CNSNEt 3 2 3 H CO2CH3 SN2 O N CH3 1 1 R SO2 R HNEt3 2 O 2 OH R R

H R1 Ei N O CH O C S HNEt 2 3 2 3 R O O

Example 14 O

CH3O2CNSNEt3 OH O tol., 95 oC, 2 h, 80% 101

CO CH N 2 3 [SO3] SO NHCO2Me O 2

Example 25 O H CH O CNSNEt H N 3 2 3 N N N O O O N N DMF, 80 oC, 18 h, 87% OH

Example 310

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

N Si O

References

1. Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744. Edward M. Bur- gess earned his Ph.D. at MIT under George Büchi. He discovered the Burgess reagent at Georgia Institute of Technology, Atlanta, Georgia. 2. Burgess, E. M.; Penton, H. R.; Taylor, E. A., Jr. J. Am. Chem. Soc. 1970, 92, 5224. 3. Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1972, 94, 6135. 4. Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Org. Chem. 1973, 38, 26. 5. Stalder, H. Helv. Chim. Acta 1986, 69, 1887. 6. Claremon, D. A.; Phillips, B. T. Tetrahedron Lett. 1988, 29, 2155. 7. Creedon, S. M.; Crowley, H. K.; McCarthy, D. G. J. Chem. Soc., Perkin Trans. 1 1998, 1015. 8. Lamberth, C. J. Prakt. Chem. 2000, 342, 518. 9. Burekhardt, S.; Svenja, B. Synlett. 2000, 559. 10. Miller, C. P.; Kaufman, D. H. Synlett 2000, 1169. 11. Nicolaou, K. C.; Huang, X.; Snyder, S. A.; Rao, P. B.; Reddy, M. V. Angew. Chem., Int. Ed. 2002, 41, 834. 12. Jose, B.; Unni, M. V. V.; Prathapan, S.; Vadakkan, J. J. Synth. Commun. 2002, 32, 2495. 102

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

R1 X Cu R2 R1 R2

oxidative X 1 2 R X Cu R R1 Cu R2 addition Cu(III) intermediate

reductive CuX R1 R2 elimination

Example 16

Br OH

cat. CuCl, NH2OH•HCl

o OH EtNH2, MeOH, 040 C, 7080%

Example 211

TBS Br OH

cat. CuCl, NH2OH•HCl TBS OH 30% n-BuNH2, H2O, 92%

References

1. Chodkiewicz, W.; Cadiot, P. C. R. Hebd. Seances Acad. Sci. 1955, 241, 1055. Paul Cadiot (1923) and Wladyslav Chodkiewicz (1921) are both French chemists. 2. Cadiot, P.; Chodkiewicz, W. In Chemistry of Acetylenes; Viehe, H. G., ed.; Dekker: New York, 1969, 597647. (Review). 3. Eastmond, R.; Walton, D. R. M. Tetrahedron 1972, 28, 4591. 4. Ghose, B. N.; Walton, D. R. M. Synthesis 1974, 890. 5. Hopf, H.; Krause, N. Tetrahedron Lett. 1985, 26, 3323. 103

6. Gotteland, J.-P.; Brunel, I.; Gendre, F.; Désiré, J.; Delhon, A.; Junquéro, A.; Oms, P.; Halazy, S. J. Med. Chem. 1995, 38, 3207. 7. Bartik, B.; Dembinski, R.; Bartik, T.; Arif, A. M.; Gladysz, J. A. New J. Chem. 1997, 21, 739. 8. Montierth, J. M.; DeMario, D. R.; Kurth, M. J.; Schore, N. E. Tetrahedron 1998, 54, 11741. 9. Negishi, E.-i.; Hata, M.; Xu, C. Org. Lett. 2000, 2, 3687. 10. Steffen, W.; Laskoski, M.; Collins, G.; Bunz, U. H. F. J. Organomet. Chem. 2001, 630, 132. 11. Marino, J. P.; Nguyen, H. N. J. Org. Chem. 2002, 67, 6841. 12. Utesch, N. F.; Diederich, F. Org. Biomol. Chem. 2003, 1, 237. 13. Utesch, N. F.; Diederich, F.; Boudon, C.; Gisselbrecht, J.-P.; Gross, M. Helv. Chim. Acta 2004, 87, 698. 104

Camps quinolinol 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 OH R1 R1 NaOR R2 NH ROH N R2 O 1 2

1 O R R1 2 NaOR R

NH ROH N OH R2 O 13

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

O OH 1 1 R H R 2 R2 R N N H OH 2 105

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

1 R1 R HO 2 R2 H R

N O N OH H 3

Example 11,2

O OH

NaOH, H2O

NH 104 °C NOH N

O 69% 20%

Example 28

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

References

1. Camps, R. Chem. Ber. 1899, 32, 3228. Rudolf Camps worked under Professor Engler from 1899 to 1902 at the Technische Hochschule in Karlsruhe, Germany. 2. Camps, R. Arch. Pharm. 1899, 237, 659. 3. Clemence, F.; LeMartret, O.; Collard, J. J. Heterocycl. Chem. 1984, 21, 1345. 4. Elderfield, R. C.; Todd, W. H.; Gerber, S. Heterocyclic Compounds Vol. 6, R. C. Elderfield, ed. Wiley and Sons, New York, 1957, 576. (Review). 106

5. Hino, K.; Kawashima, K.; Oka, M.; Nagai, Y.; Uno, H.; Matsumoto, J. Chem. Pharm. Bull. 1989, 37, 110. 6. Witkop, B.; Patrick, J. B.; Rosenblum, M. J. Am. Chem. Soc. 1951, 73, 2641. 7. Barret, R.; Ortillon, S.; Mulamba, M.; Laronze, J. Y.; Trentesaux, C.; Lévy, J. J. Hete- rocycl. Chem. 2000, 37, 241. 8. 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, 386389. (Re- view). 107

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

O OH O 2 ROH RH ROH

O HO O OH O O RH RH RH OH

Pathway A:

O hydride O RH RO H H O transfer RO ROH

O ROH RO Final deprotonation of the carboxylic acid drives the reaction forward.

Pathway B:

O O RH hydride RO H O transfer RO RO

acidic O ROH ROH workup 108

Example 111

OH CHO CO H KOH powder 2

100 oC, 5 min solvent-free

Example 213

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

References

1. Cannizzaro, S. Justus Liebigs Ann. Chem. 1853, 88, 129. Stanislao Cannizzaro (18261910) was born in Palermo, Sicily, Italy. In 1847, he had to escape to Paris for participating in the Sicilian Rebellion. Upon his return to Italy, he discovered benzyl alcohol synthesis by the action of potassium hydroxide on benzaldehyde. Political interests brought Cannizzaro to the Italian Senate and he later became its vice president. 2. Geissman, T. A. Org. React. 1944, I, 94. (Review). 3. Hazlet, S. E.; Stauffer, D. A. J. Org. Chem. 1962, 27, 2021. 4. Hazlet, S. E.; Bosmajian, G., Jr.; Estes, J. H.; Tallyn, E. F. J. Org. Chem. 1964, 29, 2034. 5. Sen Gupta, A. K. Tetrahedron Lett. 1968, 5205. 6. Swain, C. G.; Powell, A. L.; Sheppard, W. A.; Morgan, C. R. J. Am. Chem. Soc. 1979, 101, 3576. 7. Mehta, G.; Padma, S. J. Org. Chem. 1991, 56, 1298. 8. Sheldon, J. C.; et al. J. Org. Chem. 1997, 62, 3931. 9. Thakuria, J. A.; Baruah, M.; Sandhu, J. S. Chem. Lett. 1999, 995. 10. Russell, A. E.; Miller, S. P.; Morken, J. P. J. Org. Chem. 2000, 65, 8381. 11. Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983. 12. Reddy, B. V. S; Srinvas, R.; Yadav, J. S.; Ramalingam, T. Synth. Commun. 2002, 32, 219. 13. Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983. 14. Curini, M.; Epifano, F.; Genovese, S.; Marcotullio, M. C.; Rosati, O. Org. Lett. 2005, 7, 1331. 109

Carroll rearrangement Thermal rearrangement of E-ketoesters followed by decarboxylation to yield J-unsaturated ketones via anion-assisted Claisen rearrangement. It is a variant of the Claisen rearrangement (page 131).

R1 R1 OO base 2 OH R O

R1 O 2 R OH CO2n R1

1 1 1 1 OO R R base R R 2 OH O R O

1 1 1 1 O R R OO R R O ester O O exchange H OR2 :B

OO OO anion-assisted O O 1 R Claisen rearrangement R1 1 R R1

O 1 acidic R O R1 CO2n 1 workup R R1 110

Example 19

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

O Carroll OO rearrangement H TESO

CO2H

CO 2 O O

H H TESO TESO

Example 210

O O

o O LDA, THF, 78 C to rt

MeO OMe

Me HO2C Me O O CCl4, reflux, 86%

MeO OMe MeO OMe 111

References

1. Carroll, M. F. J. Chem. Soc. 1940, 704. Michael F. Carroll worked at A. Boake, Rob- erts and Co. Ltd., in London, UK. 2. Carroll, M. F. J. Chem. Soc. 1941, 507. 3. Wilson, S. R.; Price, M. F. J. Org. Chem. 1984, 49, 722. 4. Gilbert, J. C.; Kelly, T. A. Tetrahedron 1988, 44, 7587. 5. Ziegler, F. E. Chem. Rev. 1988, 88, 1423. (Review). 6. Ouvrard, N.; Rodriguez, J.; Santelli, M. Tetrahedron Lett. 1993, 34, 1149. 7. Enders, D.; Knopp, M.; Runsink, J.; Raabe, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 2278. 8. Enders, D.; Knopp, M.; Runsink, J.; Raabe, G. Liebigs Ann. 1996, 1095. 9. Hatcher, M. A.; Posner, G. H. Tetrahedron Lett. 2002, 43, 5009. 10. Jung, M. E.; Duclos, B. A. Tetrahedron Lett. 2004, 45, 107. 11. Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 2603. 112

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 Ar X Cu R Ar R reflux

L Ar X L3Cu R ArX Cu R L

X Ar Cu CuX Ar R

R

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

oxidative X Ar X Cu R Ar Cu R addition Cu(III) intermediate

reductive CuX Ar R elimination

Example7

O O cat. CuI, Ph P, K CO 3 2 3 O O o I DMF, 120 C, 37% 113

References

1. Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28, 2163. Castro and Stephens were in the Department of Nematology and Chemistry at University of California, Riverside. 2. Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28, 3313. 3. Staab, H. A.; Neunhoeffer, K. Synthesis 1974, 424. 4. Kabbara, J.; Hoffmann, C.; Schinzer, D. Synthesis 1995, 299. 5. von der Ohe, F.; Brückner, R. New J. Chem. 2000, 24, 659. 6. White, J. D.; Carter, R. G.; Sundermann, K. F.; Wartmann, M. J. Am. Chem. Soc. 2001, 123, 5407. 7. Coleman, R. S.; Garg, R. Org. Lett. 2001, 3, 3487. 8. Rawat, D. S.; Zaleski, J. M. Synth. Commun. 2002, 32, 1489. 114

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, 20 h, 83% RR1 R 2

R R OH H Al AlH2R2 O H R1 2n R1 R R

R R Al OH H O workup

RR1 R R1

Example 13

OH OH LiAlH4

77%

Example 24

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

OH I

Ph CO2Me 115

References

1. Chan, K.-K.; Cohen, N.; De Noble, J. P.; Specian, A. C., Jr.; Saucy, G. J. Org. Chem. 1976, 41, 3497. Ka-Kong Chan was a chemist at HoffmannLa Roche, Inc., 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. 3. Midland, M. M.; Gabriel, J. J. Org. Chem. 1985, 50, 1143. 4. Meta, C. T.; Koide, K. Org. Lett. 2004, 6, 1785. 5. Yamazaki, T.; Ichige, T.; Kitazume, T. Org. Lett. 2004, 6, 4073. 116

Chan–Lam coupling reaction N-Arylation of a wide range of NH substrates by reaction with boronic acid in the presence of cupric acetate and either triethylamine or pyridine at room temperature. The reaction works even for poorly nucleophilic substrates such as aryla- mide.

R B(OH)2, Cu(OAc)2 R XH X

CH2Cl2, rt, Et3N or pyridine X = NR'2, OR"

Example 11

H3C B(OH)2

NH NCH3 Cu(OAc)2, pyridine rt, 48 h, 74%

Mechanism:

LLII Cu(OAc) , pyridine Cu 2 N OAc NH coordination and pyridium acetate deprotonation Ph

LLII H C B(OH) Cu 3 2 N AcOB(OH) 2 CH transmetallation 3 Ph

reductive NCH3 elimination 117

Example 23

Cl S CO2Me Cl B(OH)2 S CO2Me NO

N O Cu(OAc)2, Et3N, MS 4 Å H CH2Cl2, rt, 48 h, 29%

References

1. Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933. Dominic M. T. Chan and Patrick Y. S. Lam were both chemists at DuPont Pharmaceuticals Company, Wilmington, DE, USA. 2. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941. 3. Mederski, W. W. K. R.; Lefort, M.; Germann, M.; Kux, D. Tetrahedron 1999, 55, 12757. 4. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett 2000, 674. 5. Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415. 6. Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077. 7. Combs, A. P.; Tadesse, S.; Rafalski, M.; Haque, T. S.; Lam, P. Y. S. J. Comb. Chem. 2002, 4, 179. 8. Chan, D. M. T.; Monaco, K. L.; Li, R.; Bonne, D.; Clark, C. G.; Lam, P. Y. S. Tetra- hedron Lett. 2003, 44, 3863. 9. Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397. 10. Chiang, G. C. H.; Olsson, T. Org. Lett. 2004, 6, 3079. 118

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

Ar1 O N ' Ar1 Ar N Ar OPh Ph

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

Example 12

Cl MeO NaOEt, EtOH/Et2O MeO2C Cl

0 oC to rt, 48 h NaO NPh

Cl o MeO2C 210215 C, 70 min MeO O 28% for 2 steps NPh

Cl MeO2C Cl MeO HO2C MeO

N N H O Ph 119

Example 24

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

References

1. Chapman, A. W. J. Chem. Soc. 1925, 127, 1992. Arthur William Chapman was born in 1898 in London, England. He was 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. 3. Schulenberg, J. W.; Archer, S. Org. React. 1965, 14, 151. (Review). 4. Relles, H. M. J. Org. Chem. 1968, 33, 2245. 5. Wheeler, O. H.; Roman, F.; Rosado, O. J. Org. Chem. 1969, 34, 966. 6. Shawali, A. S.; Hassaneen, H. M. Tetrahedron 1972, 28, 5903. 7. Kimura, M. J. Chem. Soc., Perkin Trans. 2 1987, 205. 8. Kimura, M.; Okabayashi, I.; Isogai, K. J. Heterocycl. Chem. 1988, 25, 315. 9. Farouz, F.; Miller, M. J. Tetrahedron Lett. 1991, 32, 3305. 10. Dessolin, M.; Eisenstein, O.; Golfier, M.; Prange, T.; Sautet, P. J. Chem. Soc., Chem. Commun. 1992, 132. 11. Shohda, K.-I.; Wada, T.; Sekine, M. Nucleosides Nucleotides 1998, 17, 2199. 120

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 H H3N: H NH2 enamine imine

H :NH3 H R H H O Aldol R R O O R H condensation R OH H H O

H R R H2O O Michael O H R R R addition R

: N HN

H3N H H OH O R R R H

: R R R N N H H

H OH H R R R R autoxidation R R H R R R N [O] N N H 121

Example 14

O CHO NH4OH, NH4OAc

o N N 250 C, autoclave, 32%

N

N N

N

Example 25

O CHO NH4OAc, HOAc

reflux, 1 h, 68%

N

References

1. Chichibabin, A. E. J. Russ. Phys. Chem. Soc. 1906, 37, 1229. Alexei E. Chichibabin (18711945) was born in Kuzemino, Russia. He was Markovnikov’s favorite student. Markovnikov’s successor, Zelinsky (of Hell–Volhard–Zelinsky reaction fame) did not 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, 297338. (Review). 3. Frank, R. L.; Seven, R. P. J. Am. Chem. Soc. 1949, 71, 2629. 4. Frank, R. L.; Riener, E. F. J. Am. Chem. Soc. 1950, 72, 4182. 5. Weiss, M. J. Am. Chem. Soc. 1952, 74, 200. 6. Herzenberg, J.; Boccato, G. Chem. Ind. 1950, 80, 248. 122

7. Levitt, L. S.; Levitt, B. W. Chem. Ind. 1963, 1621. 8. Kessar, S. V.; Nadir, U. K.; Singh, M. Indian J. Chem. 1973, 11, 825. 9. Shimizu, S.; Abe, N.; Iguchi, A.; Dohba, M.; Sato, H.; Hirose, K.-I. Microporous Mesoporous Materials 1998, 21, 447. 10. Galatasis, P. Chichibabin (Tschitschibabin) Pyridine Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 308309. (Review). 123

Chugaev elimination Thermal elimination of xanthates to olefins.

1. CS2, NaOH OS OH R R 2. CH3I S xanthate

' R OCS CH3SH

R O S ' R H O S S S

O O CS CH SH R S n 3 n H S

Example 16

O O H H H H O O H CS2, MeI, NaH H THF, rt, 2 h, 51% S O O HO O S O O 124

O H H O o dodecane, reflux (216 C) H

48 h, 74% O O

Example 2, Chugaev syn-elimination is followed by an intramolecular ene reac- tion7

S OH O S O CS2, MeI, NaH O O N THF, 92% O Cbz N Cbz

NaHCO3, diphenyl ether O

reflux, 45 min. 72% NO Cbz References

1. Chugaev, L. Ber. Dtsch. Chem. Ges. 1899, 32, 3332. Lev A. Chugaev (18731922) was born in Moscow, Russia. He was a Professor of Chemistry at Petrograd, a posi- tion 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 to 5 a.m. 2. Chande, M. S.; Pranjpe, S. D. Indian J. Chem. 1973, 11, 1206. 3. Kawata, T.; Harano, K.; Taguchi, T. Chem. Pharm. Bull. 1973, 21, 604. 4. Harano, K.; Taguchi, T. Chem. Pharm. Bull. 1975, 23, 467. 5. Ho, T.-L.; Liu, S.-H. J. Chem. Soc., Perkin Trans. 1 1984, 615. 6. Meulemans, T. M.; Stork, G. A.; Macaev, F. Z.; Jansen, B. J. M.; de Groot, A. J. Org. Chem. 1999, 64, 9178. 7. Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 2, 3181. 8. Nakagawa, H.; Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 2001, 42, 4523. 125

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 N H

Cl Cl3CH CCl2 H2O :CCl2 OH Cl carbene

Cl Cl CCl Cl 2 N H N N H HO

Example 18

2 eq. PhHgCCl3 Cl

PhH, '54% N N H 126

Example 210

Cla Clb

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

Clb Cla

References

1. Ciamician, G. L.; Dennsted, M. Ber. Dtsch. Chem. Ges. 1881, 14, 1153. Giacomo Luigi Ciamician (18571922) was born in Trieste, Italy. After his Ph.D. training at Giessen, Germany, Ciamician carried out most of his work at the University of Bolo- gna, Italy. Ciamician is considered the father of modern organic photochemistry. 2. Cantor, P. A.; VanderWerf, C. A. J. Am. Chem. Soc. 1958, 80, 970. 3. Krauch, H.; Kunz, W. Chemiker-Ztg. 1959, 83, 815. 4. Vogel, E. Angew. Chem., Int. Ed. 1960, 72, 4. 5. Wynberg, H. Chem. Rev. 1960, 60, 169. (Review). 6. Wynberg, H. and Meijer, E. W. Org. React. 1982, 28, 1. (Review). 7. Josey, A. D.; Tuite, R. J.; Snyder, H. R. J. Am. Chem. Soc. 1960, 82, 1597. 8. Parham, W. E.; Davenport, R. W.; Biasotti, J. B. J. Org. Chem. 1970, 35, 3775. 9. De Angelis, F.; Inesi, A.; Feroci, M.; Nicoletti R. J. Org. Chem. 1995, 60, 445. 10. Král, V.; Gale, P. A.; Anzenbacher, P. Jr.; K. Jursíková; Lynch, V.; Sessler, J. L. J. Chem. Soc., Chem. Comm. 1998, 9. 11. Pflum, D. A. Ciamician–Dennsted Rearrangement In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 350354. (Review). 127

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

O O O O 2 3 base R OR 2 1 R R OR OR1 R

O O R 1 deprotonation R OR OR1 condensation H R2 OR3

B: O

R2 O O O O R3O OR1 R2 OR1 R R

Example 19

O t-BuOK, solvent-free O O Ph Ph OPh OPh o 90 C, 20 min., 84% Ph

Example 212

H NCOMe O Cbz 2 t-Bu O Ph

3.5 eq. LDA, THF O O o H 45 to 50 C N t-Bu Cbz O + then H , 97% Ph 128

References

1 Claisen, R. L.; Lowman, O. Ber. Dtsch. Chem. Ges. 1887, 20, 651. Rainer Ludwig Claisen (18511930), 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, 266302. (Review). 3 Thaker, K. A.; Pathak, U. S. Indian J. Chem. 1965, 3, 416. 4 Schäfer, J. P.; Bloomfield, J. J. Org. React. 1967, 15, 1203. (Review). 5 Tanabe, Y. Bull. Chem. Soc. Jpn. 1989, 62, 1917. 6 Leijonmarck, H. K. E. Chem. Commun. Stockhol. 1992, 33, 1. (Review). 7 Kashima, C.; Takahashi, K.; Fukusaka, K. J. Heterocycl. Chem. 1995, 32, 1775. 8 Tanabe, Y.; Hamasaki, R.; Funakoshi, S. Chem. Commun. 2001, 1674. 9 Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983. 10 Mogilaiah, K.; Kankaiah, G. Indian J. Chem., Sect. B 2002, 41B, 2194. 11 Heath, R. J.; Rock, C. O. Nat. Prod. Rep. 2002, 19, 581. (Review). 12 Honda, Y.; Katayama, S.; Kojima, M.; Suzuki, T.; Izawa, K. Org. Lett. 2002, 4, 447. 13 Mogilaiah, K.; Reddy, N. V. Synth. Commun. 2003, 33, 73. 14 Linderberg, M. T.; Moge, M.; Sivadasan, S. Org. Pro. Res. Dev. 2004, 8, 838. 129

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

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

OO O O OR OO R OH R N OH R1 O 1 R N H 1 R2 H R2 R2

:NH2OH

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

A side reaction:

OO H HONOH O R NH OH R1 O 2 R R O R2 1 R2 :NH2OH

H

O: R2 R1 NO N O H2O OH R R R O 1 OR N 1 O O R R2 2 5-isoxazolone 130

Example20

OO

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

References

1. Claisen, L; Lowman, O. E. Ber. Dtsch. Chem. Ges. 1888, 21, 784. 2. Claisen, L.; Zedel, W. Ber. 1891, 24, 140. 3. Hantzsch Ber. 1891, 24, 495. 4. Barnes, R.A. In Heterocyclic Compounds; Elderfield, R. C., Ed.; Wiley: New York, 1957; Vol. 5, p 474 ff. (Review). 5. Loudon, J. D. In Chemistry of Carbon Compounds; Rodd, E. H., Ed.; Elsevier: Am- sterdam, 1957; Vol. 4a, p. 345ff. (Review). 6. Boulton, A. J.; Katritzky, A. R. Tetrahedron 1961, 12, 41. 7. Boulton, A. J.; Katritzky, A. R. Tetrahedron 1961, 12, 51. 8. Katritzky, A.R.; Oksne, S.; Boulton, A. J. Tetrahedron 1962, 18, 777. 9. Katritzky, A. R.; Oksne, S. Proc. Chem. Soc. 1961, 387. 10. Jacquier, R.; Petrus, C.; Petrus, F.; Verducci, J. Bull. Soc. Chem. Fr. 1970, 2685. 11. Cocivera, M.; Effio, A.; Chen, H. E.; Vaish, S. J. Am. Chem. Soc. 1976, 98, 7362. 12. Jacobsen, N.; Kolind-Andersen, H.; Christensen, J. Can. J. Chem. 1984, 62, 1940. 13. Katritzky, A. R.; Barczynski, P.; Ostercamp, D. L.; Yousaf, T. I. J. Org. Chem. 1986, 51, 4037. 14. Krogsgaard-Larsen, K.; Sorensen, U. S. Org. Prep. Proc. Int. 2001, 33, 515. 15. Sorensen, U. S.; Falch, E.; Krogsgaard-Larsen, K. J. Org. Chem. 2000, 65, 1003. 16. Chen, B.-C. Heterocycles, 1991, 32, 529. 17. McNab, H. Chem. Soc. Rev. 1978, 7, 345. (Review). 18. Frølund, B.; Kristiansen, U.; Brehm, L.; Hansen, A.B.; Krogsgaard-Larsen, K.; Falch, E. J. Med. Chem. 1995, 38, 3287. 19. Frølund, B.; Tagmose, L.; Liljefors, T.; Stensbøl, T. B.; Engblom, C.; Kristiansen, U.; Krogsgaard-Larsen, K. J. Med. Chem. 2000, 43, 4930. 20. 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. 21. Brooks, D. A. Claisen Isoxazole Synthesis In Name Reactions in Heterocyclic Chemis- try, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 220224. (Re- view). 131

Claisen rearrangements The Claisen, Johnson–Claisen, Ireland–Claisen, para-Claisen rearrangements, 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 ', [3,3]-sigmatropic R 1 3 R

O O O 3 rearrangement 3 1 1 2 2

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 2

78 oC, 81% O

O

OH

References

1. Claisen, L. Ber. Dtsch. Chem. Ges. 1912, 45, 3157. 2. Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1252. (Review). 132

3. Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Perga- mon, 1991, Vol. 5, 827873. (Review). 4. Ganem, B. Angew. Chem., Int. Ed. Engl. 1996, 35, 936. 5. Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 4350. (Review). 6. Castro, A. M. M. Chem. Rev. 2004, 104, 29393002. (Review). 7. Jürs, S.; Thiem, J. Tetrahedron: Asymmetry 2005, 16, 1631. 8. Vyvyan, J. R.; Oaksmith, J. M.; Parks, B. W.; Peterson, E. M. Tetrahedron Lett. 2005, 46, 2457. 133

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

O OH '

D D E O E [3,3]-sigmatropic O rearrangement G tautomerization G "normal Claisen" H

H D H D OH O E ene O E [1,5]-H-atom E G reaction G D shift G

Example 14

MeO CHO

O

MeO OMe

CHO

PhNEt2 MeO O OMe 180 oC 40% MeO kodsurenin M 134

Example 25

O (R)-(+)-BINOL-Me•FeCl3

o CH2Cl2, 78 C, 76%

OH

Example 36

O O Tol. 180 oC O O O O 24 h, 65%

References

1. Hansen, H.-J. In Mechanisms of Molecular Migrations; vol. 3, Thyagarajan, B. S., ed.; Wiley-Interscience: New York, 1971, pp 177236. (Review). 2. Shah, R. R.; Trivedi, K. N. Curr. Sci. 1975, 44, 226. 3. Kilenyi, S. N.; Mahaux, J.-M.; van Durme, E. J. Org. Chem. 1991, 56, 2591. 4. Yi, W. M.; Xin, W. A.; Fu, P. X. J. Chem. Soc., (S), 1998, 168. 5. Nakamura, S.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 8131. 6. Schobert, R.; Siegfried, S.; Gordon, G.; Mulholland, D.; Nieuwenhuyzen, M. Tet- rahedron Lett. 2001, 42, 4561. 7. Puranik, R.; Rao, Y. J.; Krupadanam, G. L. D. Indian J. Chem., Sect. B 2002, 41B, 868. 135

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

MeO OMe OMe OMe

NMe2 NMe2

OMe H NMe Me N: OMe 2 OMe NMe2 2 H H H O: O O 1 1 RR RR1 RR

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

Example 17

F C CH3C(OMe)2NMe2 3 OPh OH PhH, 100 oC, 2 h, 60%

CF3 O Ph O NMe2

Example 29

O

NMe2 5 eq. CH3C(OMe)2NMe2

xylene, reflux, 48 h, 50% HO CO2Me CO2Me 136

References

1. Meerwein, H.; Florian, W.; Schön, N.; Stopp, G. Justus Liebigs Ann. Chem. 1961, 641, 1. 2. Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. Helv. Chim. Acta 1964, 47, 2425. 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. 3. Felix, D.; Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A. Helv. Chim. Acta 1969, 52, 1030. 4. Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Perga- mon, 1991, Vol. 5, 827873. (Review). 5. Coates, B.; Montgomery, D.; Stevenson, P. J. Tetrahedron Lett. 1991, 32, 4199. 6. Ganem, B. Angew. Chem., Int. Ed. Engl. 1996, 35, 936. 7. Konno, T.; Nakano, H.; Kitazume, T. J. Fluorine Chem. 1997, 86, 81. 8. Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 4350. (Review). 9. Loh, T.-P.; Hu, Q.-Y. Org. Lett. 2001, 3, 279. 10. Gradl, S. N.; Kennedy-Smith, J. J.; Kim, J.; Trauner, D. Synlett 2002, 411. 11. Khaledy, M. M.; Kalani, M. Y. S.; Khuong, K. S.; Houk, K. N.; Aviyente, V.; Neier, R.; Soldermann, N.; Velker, J. J. Org. Chem. 2003, 68, 572. 12. Castro, A. M. M. Chem. Rev. 2004, 104, 29393002. (Review). 13. Gilbert, M. W.; Galkina, A.; Mulzer, J. Synlett 2004, 2558. 137

Ireland–Claisen (silyl ketene acetal) rearrangement Rearrangement of allyl trimethylsilyl ketene acetal, prepared by reaction of allylic ester enolates with trimethylsilyl chloride, to yield JG-unsaturated carboxylic a- cids. 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 OSiMe3 LDA, then O O Me3SiCl

OSiMe3 CO H ', [3,3]-sigmatropic H+ 2 O rearrangement

Example 13

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

Example 2, a modified Ireland–Claisen rearrangement10

F

O F O F

O BBr3, Et3N, PhMe F chiral ligand HO F 78 to rt, 79%, > 99% ee

F 138

Example 314

OPMP PMPO KHMDS, TMSCl, THF CO2Me O O 78 to 25 oC, 1 h, 81% O O

References

1. Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897. Also J. Am. Chem. Soc. 1976, 98, 2868. 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. Cha, J. K.; Lewis, S. C. Tetrahedron Lett. 1984, 25, 5263. 3. Corey, E. J.; Lee, D.-H. J. Am. Chem. Soc. 1991, 113, 4026. (Enantioselective variant of the Ireland–Claisen rearrangement). 4. Pereira, S.; Srebnik, M. Aldrichimica Acta 1993, 26, 1729. (Review). 5. Ganem, B. Angew. Chem., Int. Ed. Engl. 1996, 35, 936. 6. Mohamed, M.; Brook, M. A. Tetrahedron Lett. 2001, 42, 191. 7. Hong, S.-p.; Lindsay, H. A.; Yaramasu, T.; Zhang, X.; McIntosh, M. C. J. Org. Chem. 2002, 67, 2042. 8. Chai, Y.; Hong, S.-p.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron 2002, 58, 29052928. (Review). 9. Khaledy, M. M.; Kalani, M. Y. S.; Khuong, K. S.; Houk, K. N.; Aviyente, V.; Neier, R.; Soldermann, N.; Velker, J. J. Org. Chem. 2003, 68, 572. 10. 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. 11. Höck, S.; Koch, F.; Borschberg, H.-J. Tetrahedron: Asymmetry 2004, 15, 1801. 12. Hutchison, J. M.; Hong, S.-p.; McIntosh, M. C. J. Org. Chem. 2004, 69, 4185. 13. Gilbert, J. C.; Yin, J.; Fakhreddine, F. H.; Karpinski, M. L. Tetrahedron 2004, 60, 51. 14. Fujiwara, K.; Goto, A.; Sato, D.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2005, 46, 3465. 139

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 to give a mixed orthoester. The orthoester loses ethanol to generate the ketene acetal, which undergoes [3,3]-sigmatropic rearrangement to give a JG-unsaturated ester.

H 2 2 2 OR CH(OR2) R O: OR :B OH 3 H H O 1 O RR+ H 1 RR1 RR

2 OR 2 [3,3]-sigmatropic CO2R O rearrangement RR1 RR1

Example 12

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

Example 27

OMe OMe N CH C(OCH ) 3 3 3 N cat. CH3CH2CO2H O reflux, 77% OMe OH

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. William S. Johnson (19131995) 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- 140

sin for 20 years before moving to Stanford University, where he was credited with building the modern-day Stanford Chemistry Department. 2. Schlama, T.; Baati, R.; Gouverneur, V.; Valleix, A.; Falck, J. R.; Mioskowski, C. An- gew. Chem., Int. Ed. 1998, 37, 2085. 3. Giardiná, A.; Marcantoni, E.; Mecozzi, T.; Petrini, M. Eur. J. Org. Chem. 2001, 713. 4. Funabiki, K.; Hara, N.; Nagamori, M.; Shibata, K.; Matsui, M. J. Fluorine Chem. 2003, 122, 237. 5. Montero, A.; Mann, E.; Herradón, B. Eur. J. Org. Chem. 2004, 3063. 6. Scaglione, J. B.; Rath, N. P.; Covey, D. F. J. Org. Chem. 2005, 70, 1089. 7. 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. 141

Clemmensen reduction Reduction of aldehydes and ketones to the corresponding methylene compounds using amalgamated zinc and hydrogen chloride.

O Zn(Hg) H H 1 RR HCl RR1

The zinc-carbenoid mechanism:6

O Zn(Hg), HCl O ZnCl Ph CH 3 SET Ph CH3 radical anion

OZnCl Zn

Ph CH Ph CH Zn 3 3 Zinc-carbenoid

H H+ Ph CH H 3

The radical anion mechanism:

O Zn(Hg) H H

Ph CH3 HCl Ph CH3

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

H OZnCl + H H S 2 Ph CH3 N H Ph CH Cl 3 Cl 142

H + e e; H H H

Ph CH3 Ph CH3

Example 18

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

Example 210

H O H Zn(Hg), HCl

N N H o Et2O, 5 C, 57% H O Ph O Ph

References

1. Clemmensen, E. Ber. Dtsch. Chem. Ges. 1913, 46, 1837. Erik C. Clemmensen (18761941) 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 (now part of Pfizer) 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 Corpora- tion in Newark, New York. 2. Martin, E. L. Org. React. 1942, 1, 155209. (Review). 3. Brewster, J. H. J. Am. Chem. Soc. 1954, 76, 6361. 4. Vedejs, E. Org. React. 1975, 22, 401422. (Review). 5. Elphimoff-Felkin, I.; Sarda, P. Tetrahedron Lett. 1983, 24, 4425. 6. Burdon, J.; Price, R. C. Chem. Commun. 1986, 893. 7. Talpatra, S. K.; Chakrabarti, S.; Mallik, A. K.; Talapatra, B. Tetrahedron 1990, 46, 6047. 8. Martins, F. J. C.; Viljoen, A. M.; Coetzee, M.; Fourie, L.; Wessels, P. L. Tetrahedron 1991, 47, 9215. 9. Ni, Y.; Kim, H. S.; Wilson, W. K.; Kisic, A.; Schroepfer, G. J., Jr. Tetrahedron Lett. 1993, 34, 3687. 10. Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Chem. Soc., Perkin Trans. 1 1996, 1113. 11. Cheng, L.; Ma, J. Org. Prep. Proc. Int. 1995, 27, 224. 143

12. Kappe, T.; Aigner, R.; Roschger, P.; Schnell, B.; Stadlbauer, W. Tetrahedron 1995, 51, 12923. 13. Kohara, T.; Tanaka, H.; Kimura, K.; Fujimoto, T.; Yamamoto, I.; Arita, M. Synthesis 2002, 355. 14. Alessandrini, L.; Ciuffreda, P.; Santaniello, E.; Terraneo, G. Steroids 2004, 69, 789. 144

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

R2 H SO OO 2 4

1 2 ' 1 NH2 R R NR

O NH : 2 R2 proton O R1 transfer N 1OH 2 R R O H2 H

O O O 2 R 2 R R2 : N OH 1 1 2 N R 1 H R NR H imine

R2 H R2 O O H+ : N R1 N R1 H H enamine

H H O O 2 HR2 R H+

1 NR1 N R H H+ 145

H H 2 2 O R R R2

: 1 1 N R1 NR NR H H

An electrocyclization mechanism is also possible:

2 H R H R2 O O 6S-electrocyclization : 1 N R NR1 H

HO R2 2 OH R proton H 2 R2 1 transfer N R 1 N R1 NR H

Example 110

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

Example 211

O O CO Et Ph 2 CO2Et Ph N N H H N NH cat. p-TsOH, 220 °C 2 neat, 38% 146

References

1. Combes, A. Bull. Soc. Chim. Fr. 1888, 49, 89. Alphonse-Edmond Combes (18581896) was born in St. Hippolyte-du-Fort, France. He apprenticed with Wurtz at Paris. He also collaborated with Charles Friedel of the FriedelCrafts 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. (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. Coscia, A. T.; Dickerman, S. C. J. Am. Chem. Soc. 1959, 81, 3098. 6. Claret, P. A.; Osborne, A. G. Org. Prep. Proced. Int. 1970, 2, 305. 7. Born, J. L. J. Org. Chem. 1972, 37, 3952. 8. Jones, G. In Chemistry of Heterocyclic Compounds, Jones, G., ed.; Wiley & Sons, New York, 1977, Quinolines Vol. 32, pps.119–125. (Review). 9. Ruhland, B.; Leclerc, G. J. Heterocycl. Chem. 1989, 26, 469. 10. Alunni-Bistocchi, G.; Orvietani, P., Bittoun, P., Ricci, A.; Lescot, E. Pharmazie 1993, 48, 817. 11. El Ouar, M.; Knouzi, N.; Hamelin, J. J. Chem. Research (S) 1998, 92. 12. Curran, T. T. Combes Quinoline Synthesis In Name Reactions in Heterocyclic Chemis- try, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 390397. (Re- view). 147

Conrad–Limpach reaction Thermal or acid-catalyzed condensation of anilines with E-ketoesters leads to quinolin-4-ones. Cf. Combes quinoline synthesis. O Ph O OO 2

NH OEt 2 260 oC N H

O CO2Et proton H2O

NH : : 2 transfer N OH EtO2C H

OEt HO CO2Et 6S electron tautomerize electrocyclization N N Schiff base

H O O H HOEt HOEt

N N HOEt

O OH proton

transfer N N H Example 13

NH2 OO CHCl3, HCl (cat.)

N OEt 60% 148

HN N Ph2O, reflux CO2Et OH N 60% N Example 212

NH2 MeO C NHPhNO O N 2 2 HO CO2Me HCl, MeOH 2 2 + N CO Me MeO2C O 64% 2 H NO2

O H Dowtherm A O2N N NO2

250 °C, 55% N CO2Me H References

1. Conrad, M.; Limpach, L. Ber. Dtsch. Chem. Ges. 1887, 20, 944. Max Conrad (18481920), born in Munich, Germany, was a professor of the University of Würz- burg, where he collaborated with Leonhard Limpach (18521933) 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. 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. Heindel, N. D.; Bechara, I. S.; Kennewell, P. D.; et al. J. Med. Chem. 1968, 11, 1218. 7. Perche, J. C.; Saint-Ruf, G. J. Heterocycl. Chem. 1974, 11, 93. 8. Jones, G. In Heterocyclic Compounds, Jones, G., ed.; John Wiley & Sons, New York, 1977, Quinolines, Vol 32, 137–151. (Review). 9. Barker, J. M.; Huddleston, P. R.; Jones, A. W.; Edwards, M. J. Chem. Res., (S) 1980, 4. 10. Guay, V.; Brassard, P. J. Heterocycl. Chem. 1987, 24, 1649. 11. Deady, L. W.; Werden, D. M. J. Org. Chem. 1987, 52, 3930. 12. Kemp, D. S.; Bowen, B. R. Tetrahedron Lett. 1988, 29, 5077. 13. Hormi, O. E. O.; Peltonen, C.; Heikkila, L. J. Org. Chem. 1990, 55, 2513. 14. Billah, M.; Buckley, G. M.; Cooper, N; et al. Bioorg. Med. Chem. 2002, 12, 1617. 15. 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, 398406. (Re- view). 149

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

O R R3 H N ' OH 3 1 2 N R 1 2 R R R R R

O 3 R R H N ' OH 1 2 N R R Ei R R R1 R2 3

Example 17

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

OH

O O HO H O N O N O

OH OH 150

Example 211

N m-CPBA, CH Cl N O 2 2 O O

rt, 100% NC H CN

N OH O CN

References

1. Cope, A. C.; Foster, T. T.; Towle, P. H. J. Am. Chem. Soc. 1949, 71, 3929. Arthur Clay Cope (19091966) 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 American Chemical Society. 2. Cope, A. C.; Trumbull, E. R. Org. React. 1960, 11, 317493. (Review). 3. DePuy, C. H.; King, R. W. Chem. Rev. 1960, 60, 431457. (Review). 4. Gallagher, B. M.; Pearson, W. H. Chemtracts: Org. Chem. 1996, 9, 126130. (Re- view). 5. Vidal, T.; Magnier, E.; Langlois, Y. Tetrahedron 1998, 54, 5959. 6. Gravestock, M. B.; Knight, D. W.; Malik, K. M. A.; Thornton, S. R. J. Chem. Soc., Perkin 1 2000, 3292. 7. Sammelson, R. E.; Kurth, M. J. Tetrahedron Lett. 2001, 42, 3419. 8. Bagley, M. C.; Tovey, J. Tetrahedron Lett. 2001, 42, 351. 9. Remen, L.; Vasella, A. Helv. Chim. Acta 2002, 85, 1118. 10. Garcia Martinez, A.; Teso Vilar, E.; Garcia Fraile, A.; de la Moya Cerero, S.; Lora Maroto, B. Tetrahedron: Asymmetry 2002, 13, 17. 11. 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. 151

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. Cf. Claisen rearrangement.

R ', [3,3]-sigmatropic R R

rearrangement

Example 15

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

Example 28

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

References

1. Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441. 2. Frey, H. M.; Walsh, R. Chem. Rev. 1969, 69, 103124. (Review). 3. Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1252. (Review). 4. Hill, R. K. In Comprehensive Organic Synthesis Trost, B. M.; Fleming, I., Eds., Per- gamon, 1991, Vol. 5, 785826. (Review). 5. Chou, W.-N.; White, J. B.; Smith, W. B. J. Am. Chem. Soc. 1992, 114, 4658. 6. Davies, H. M. L. Tetrahedron 1993, 49, 52035223. (Review). 7. Miyashi, T.; Ikeda, H.; Takahashi, Y. Acc. Chem. Res. 1999, 32, 815824. (Review). 8. Von Zezschwitz, P.; Voigt, K.; Lansky, A.; Noltemeyer, M.; De Meijere, A. J. Org. Chem. 1999, 64, 3806. 9. Nakamura, H.; Yamamoto, Y. In Handbook of Organopalladium Chemistry for Or- ganic Synthesis 2002, 2, 29192934. (Review). 10. Clive, D. L. J.; Ou, L. Tetrahedron Lett. 2002, 43, 4559. 11. Hrovat, D. A.; Brown, E. C.; Williams, R. V.; Quast, H.; Borden, W. T. J. Org. Chem. 2005, 70, 2627. 152

Oxy-Cope rearrangement

OH ', [3,3]-sigmatropic OH R R rearrangement

O OH tautomerize R R

Example 12

PhMe SiO O 2 t-Bu 1. 170 oC

PhMe2Si 2. p-TsOH-H O O O 2 6575%

PhMe2SiO O t-Bu OHC

O O

Example 24

OH xylene, Ace® tube O

225 oC, 24 h, 49%

References

1. Paquette, L. A. Angew. Chem., Int. Ed. Engl. 1990, 29, 609626. (Review). 2. Schneider, C.; Rehfeuter, M. Chem. Eur. J. 1999, 5, 2850. 3. Schneider, C. Synlett 2001, 10791091. (Review on siloxy-Cope rearrangement). 4. DiMartino, G.; Hursthouse, M. B.; Light, M. E.; Percy, J. M.; Spencer, N. S.; Tolley, M. Org. Biomol. Chem. 2003, 1, 4423. 153

Anionic oxy-Cope rearrangement

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

OK OK H2O R R

O OH tautomerize R R

Example 11

OH O KH, THF, rt

then H2O, 88%

Example 26

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

References

1. Wender, P. A.; Sieburth, S. M.; Petraitis, J. J.; Singh, S. K. Tetrahedron 1981, 37, 3967. 2. Wender, P. A.; Ternansky, R. J.; Sieburth, S. M. Tetrahedron Lett. 1985, 26, 4319. 3. Paquette, L. A. Tetrahedron 1997, 53, 1397114020. (Review). 4. Voigt, B.; Wartchow, R.; Butenschon, H. Eur. J. Org. Chem. 2001, 2519. 5. Hashimoto, H.; Jin, T.; Karikomi, M.; Seki, K.; Haga, K.; Uyehara, T. Tetrahedron Lett. 2002, 43, 3633. 6. Gentric, L.; Hanna, I.; Huboux, A.; Zaghdoudi, R. Org. Lett. 2003, 5, 3631. 154

Corey–Bakshi–Shibata (CBS) reduction Enantioselective borane reduction of ketones catalyzed by chiral oxazaborolidines.

Ph H Ph

O cat. O OH N B H

BH3, THF, rt, 97% ee

Ph H Ph Ph Ph O H Ph H Ph O BH3 RL RS N O O B H R N N H2B S B B H O H H3B H RL

Ph H Ph Ph H Ph O HOBH N BH3 2 B H O H B N 2 O B RS RL H H3B H RL RS

HOBH HOH H2O R R R R S L 2 S L

The catalytic cycle is shown on the next page. 155

The catalytic cycle: Ph H Ph

O N B H R O H2B S H O

RL RS RL

Ph Ph H Ph H Ph BH3 O O N N Ph B B H Ph H H3B H O N B OBH H B 2 2 H O RS RL RS BH3 RL

Example 19

0.1 eq. (S)-CBS O 1.0 eq. i-Pr(Et)NPh•BH3 SO2C6H4CH3-p THF, rt, syringe pump O 1.5 h, 98%, 97% ee

Ph OH H Ph SO2C6H4CH3-p O (S)-CBS = N O B CH3

Example 214

O O O HO O BH3•SMe2, cat. (R)-CBS O

o O CH2Cl2, 30 C, 84%, > 99% ee O 156

References

1. Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551. Elias J. Corey (1928) was born in Methuen, Massachusetts. After earning his Ph.D. at MIT from John Sheehan at age 22, he began his independent academic career at the Univer- sity of Illinois in 1950 and moved to Harvard University in 1959. Corey won the No- bel Prize in Chemistry in 1990 for development of novel methods for the synthesis of complex natural compounds and retrosynthetic analysis. He is still carrying out active research at Harvard. Prof. Corey has been a consultant to Pfizer for more than 50 years. 2. Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925. 3. Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861. 4. Cho, B. T.; Chun, Y. S. Tetrahedron: Asymmetry 1992, 3, 1583. 5. Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837. 6. 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. 7. Itsuno, S. Org. React. 1998, 52, 395576. (Review). 8. Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 19862012. (Review). 9. Cho, B. T.; Kim, D. J. Tetrahedron: Asymmetry 2001, 12, 2043. 10. de Koning, C. B.; Giles, R. G. F.; Green, I. R.; Jahed, N. M. Tetrahedron Lett. 2002, 43, 4199. 11. Price, M. D.; Sui, J. K.; Kurth, M. J.; Schore, N. E. J. Org. Chem. 2002, 67, 8086. 12. Fu, X.; McAllister, T. L.; Thiruvengadam, T. K.; Tann, C.-H.; Su, D. Tetrahedron Lett. 2003, 44, 801. 13. Degni, S.; Wilen, C.-E.; Rosling, A. Tetrahedron: Asymmetry 2004, 15, 1495. 14. Watanabe, H.; Iwamoto, M.; Nakada, M. J. Org. Chem. 2005, 70, 4652. 157

CoreyChaykovsky reaction The CoreyChaykovsky 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.

CH2 X X CH2 S O 1 or 2 1 H3C S RR1 RR CH3 H3C CH3 4 1 2 3

2 3 X = O, CH2, NR , S, CHCOR , 3 CHCO2R , CHCONR2, CHCN

O O O R S S 1 H C CH 1 RR 3 2 H3C CH3 O R CH3

O OR 1 O RR S R1 H C 3 O S CH3 H3C CH2 CH3

O R S 1 H3C CH3 O R

Example 112

BF4

Ph2S R20 R20 CHO KOH, DMSO, rt, 62% O 158

Example 214

O

N + (CH3)3S(O) I , NaH, DMSO O

F 60 oC, 3.5 h, 79% Cl

O

N

O

F Cl

References

1 Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867. Michael Chaykovsky last published from Prospect Pharma, USA 2 Corey, E. J.; Chaykovsky, M. Tetrahedron Lett. 1963, 4, 169. 3 Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1964, 86, 1640. 4 Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353. 5 Trost, B. M.; Melvin, L. S., Jr. Sulfur Ylides Academic Press: New York, 1975. (Re- view). 6 Block, E. Reactions of Organosulfur Compounds Academic Press: New York, 1978. (Review). 7 Johnson, C. R. Aldrichimica Acta 1985, 18, 310. (Review). 8 Gololobov, Y. G.; Nesmeyanov, A. N., Iysenko, V. P.; Boldeskul, I. E. Tetrahedron 1987, 43, 26092651. (Review). 9 Aubé, J. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Ed.; Perga- mon: Oxford, 1991, Vol. 1, pp 820825. (Review). 10 Okazaki, R.; Tokitoh, N. In Encyclopedia of Reagents in Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995, pp 213941. (Review). 11 Ng, J. S.; Liu, C. In Encyclopedia of Reagents in Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995, 215965. (Review). 12 Corey, E. J.; Cheng, H.; Baker, C. H.; Matsuda, S. P. T.; Li, D.; Song, X. J. Am. Chem. Soc. 1997, 119, 1277. 13 Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 23412372. (Review). 14 Vacher, B.; Bonnaud, B.; Funes, P.; et al. J. Med. Chem. 1999, 42, 1648. 15 Shea, K. J. Chem. Eur. J. 2000, 6, 11131119. (Review). 16 Saito, T.; Sakairi, M.; Akiba, D. Tetrahedron Lett. 2001, 42, 5451. 17 Mae, M.; Matsuura, M.; Amii, H.; Uneyama, K. Tetrahedron Lett. 2002, 43, 2069. 159

18 Chandrasekhar, S.; Narasihmulu, Ch.; Jagadeshwar, V.; Reddy, K. V. Tetrahedron Lett. 2003, 44, 3629. 19 Li, J. J. CoreyChaykovsky Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 114. (Review). 160

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

CBr4, PPh3 R Br n-BuLi R CHO RH ZnH Br

S 2 N Br3CBr :PPh3 CBr3 Br PPh3

Br Br PPh3 SN2 Br SN2

Br PPh3 CBr3 Br

O

Br RH R Br Br2 PPh3 OPPh3 Br H Br Wittig reaction (see page 621 for the mechanism)

Br2 Zn ZnBr2

R Br

Bu H Br RBr

Bu

acidic R RH workup

Example 13

OMe O O CBr4, Ph3P, CH2Cl2 OHC rt, 35 min., 90% OTBS 161

Br OMe O o 2.0 eq. THF•BH3, THF, 15 C, 26 h O Br OTBS then CH3OH, 3 N NaOH, 30% H2O2 rt, 2 h, 85%

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

o OTBS 78 C, 1 h; rt, 1 h, 99% OH Example 28

1. CBr4, Ph3P, Zn, CH2Cl2 CHO OTBS 2. n-BuLi, then NH4Cl, 90%

OTBS

References

1 Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769. Phil Fuchs is a professor at Purdue University. 2 For the synthesis of 1-bromalkynes see Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron Lett. 1994, 35, 3529. 3 Gilbert, A. M.; Miller, R.; Wulff, W. D. Tetrahedron 1999, 55, 1607. 4 Muller, T. J. J. Tetrahedron Lett. 1999, 40, 6563. 5 Serrat, X.; Cabarrocas, G.; Rafel, S.; Ventura, M.; Linden, A.; Villalgordo, J. M. Tetra- hedron: Asymmetry 1999, 10, 3417. 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. 7 Falomir, E.; Murga, J.; Carda, M.; Marco, J. A. Tetrahedron Lett. 2003, 44, 539. 8 Zeng, X.; Zeng, F.; Negishi, E.-i. Org. Lett. 2004, 6, 3245. 9 Quéron, E.; Lett, R. Tetrahedron Lett. 2004, 45, 4527. 162

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 R1 R2 1 2 then NEt3 R R NCS = N-Chlorosuccinimide; DMS = Dimethylsulfide.

O O

S Cl N Cl N :S O O

Cl O Cl O H S :NEt N S H NH O 3 :O H 1 2 O O R R R1 R2

S Et N·HCl O 3 O (CH3)2Sn R1 R2 R1 H R2

Example 1, fluorous CoreyKim reaction5

NO2 S NO2 C6F13 CHO OH NCS, toluene, 25 oC, 2 h

then Et3N, 86% 163

Example 2, odorless CoreyKim reaction8

S N O

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

SD N O 86% O 45%

References

1 Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586. 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. 3 Shapiro, G.; Lavi, Y. Heterocycles 1990, 31, 2099. 4 Pulkkinen, J. T.; Vepsäläinen, J. J. J. Org. Chem. 1996, 61, 8604. 5 Crich, D.; Neelamkavil, S. Tetrahedron 2002, 58, 3865. 6 Nishide, K.; Ohsugi, S.-I.; Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron Lett. 2002, 43, 5177. 7 Ohsugi, S.-I.; Nishide, K.; Oono, K.; Okuyama, K.; Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron 2003, 59, 8393. 8 Nishide, K.; Patra, P. K.; Matoba, M.; Shanmugasundaram, K.; Node, M. Green Chem. 2004, 6, 142. 164

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

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

H N HS N N S N S PPh S 3

Ph3P:

N N H PPh S S 3 PPh3 O O H O O n n OH OH

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

O

N S n O N S H H O n O 2-pyridinethione 165

Example 13

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

Example 26

OH OMOM OO (2-pyr-S)2, PPh3 OH

O AgClO4, ', 33%

O

Dowex, MeOH O

58% HO OH OH

References

1. Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614. 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. 4. Barbour, R. H.; Robins, D. J. J. Chem. Soc., Perkin Trans. 1 1985, 2475. 5. Barbour, R. H.; Robins, D. J. J. Chem. Soc., Perkin Trans. 1 1988, 1169. 6. Andrus, M. B.; Shih, T.-L. J. Org. Chem. 1996, 61, 8780. 7. Lu, S.-F.; O'yang, Q. Q.; Guo, Z.-W.; Yu, B.; Hui, Y.-Z. J. Org. Chem. 1997, 62, 8400. 8. Sasaki, T.; Inoue, M.; Hirama, M. Tetrahedron Lett. 2001, 42, 5299. 166

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

1. BuLi SH CH2(OMe)2 S

2. Cl-(CH2)4-I SH Et2O•BF3 S 80%

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

I Bu Cl S H S H S S

S

S Cl

Example 16

n-BuLi, THF CHO S S Ph 0 oC, 30 min. 99%

PhI(O CCCl ) HO O HO SS 2 3 2 CH CN, H O, rt, 5 min. 95% Ph Ph Ph Ph 3 2 167

Example 28

Ph S O CHO S

n-BuLi, THF, 78 to 0 oC

OH S O S Ph

References

1. Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. 1965, 4, 1075, 1077. Dieter Seebach is a professor at ETH in Zürich, Switzerland. 2. Corey, E. J.; Seebach, D. J. Org. Chem. 1966, 31, 4097. 3. Seebach, D.; Jones, N. R.; Corey, E. J. J. Org. Chem. 1968, 33, 300. 4. Seebach, D.; Corey, E. J. Org. Synth. 1968, 50, 72. 5. Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231. 6. Stowell, M. H. B.; Rock, R. S.; Rees, D. C.; Chan, S. I. Tetrahedron Lett. 1996, 37, 307. 7. Hassan, H. H. A. M.; Tamm, C. Helv. Chim. Acta 1996, 79, 518. 8. Lee, H. B.; Balasubramanian, S. J. Org. Chem. 1999, 64, 3454. 9. Bräuer, M.; Weston, J.; Anders, E. J. Org. Chem. 2000, 65, 1193. 168

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

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

S N NN N N N N N S H : R O R OH

R1 OH R1 OH

S R O R O S Imd Imd R1 O R1 OH

R O R O :P(OMe)3 S SP(OMe)3 1 R O R1 O 1,3-dioxolane-2-thione (cyclic thiocarbonate)

:P(OMe)3 R R O S O SP(OMe) P(OMe) P(OMe) 3 3 R1 O 3 R1 O

R H O P(OMe)3 O COn P(OMe)3 R1 H O 169

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

R O R O :P(OMe)3 S SP(OMe)3 R1 O R1 O

R O :P(OMe)3 SP(OMe)3 R1 O

R O R H P(OMe)3 1 O R R1 H

O P(OMe)3 :P(OMe)3 O COn O

Example 17

O O

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

O

P(OMe)3 N OMe 92% F3C OMOM One olefin isomer Example 211

OMe TBSO H CSCl , DMAP HO OAc 2 CH Cl , rt, 96% HO 2 2 H 170

OMe TBSO H O OAc S O H

OMe TBSO H (EtO)3P OAc

reflux, 76% H

References

1. Corey, E. J.; Winter, R. A. E. J. Am. Chem. Soc. 1963, 85, 2677. Roland A. E. Winter is at Ciba Specialty Chemicals Corporation, USA. 2. Horton, D.; Tindall, C. G., Jr. J. Org. Chem. 1970, 35, 3558. 3. Hartmann, W.; Fischler, H.-M.; Heine, H.-G. Tetrahedron Lett. 1972, 13, 853. 4. Block, E. Org. React. 1984, 30, 457. (Review). 5. Dudycz, L. W. Nucleosides Nucleotides 1989, 8, 35. 6. Carr, R. L. K.; Donovan, T. A., Jr.; Sharma, M. N.; Vizine, C. D.; Wovkulich, M. J. Org. Prep. Proced. Int. 1990, 22, 245. 7. Kaneko, S.; Nakajima, N.; Shikano, M.; Katoh, T.; Terashima, S. Tetrahedron 1998, 54, 5485. 8. Crich, D.; Pavlovic, A. B.; Wink, D. J. Synth. Commun. 1999, 29, 359. 9. Palomo, C.; Oiarbide, M.; Landa, A.; Esnal, A.; Linden, A. J. Org. Chem. 2001, 66, 4180. 10. Saito, Y.; Zevaco, T. A.; Agrofoglio, L. A. Tetrahedron 2002, 58, 9593. 11. Araki, H.; Inoue, M.; Katoh, T. Synlett 2003, 2401. 171

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

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

AcO Pb(OAc) 3 OAc

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

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

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

O

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

O HOAc OH O H

AcO

O II Pb (OAc)2 HOAc O 172

Example 17

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

Example 29

Pb(OAc)4, CH2Cl2, K2CO3 H o OH 15 C to rt, 1 h, then HO

H Ph3P=CHCO2Me, CH3CN, 80% PhO2S

H CO2Me E:Z = 10:1 H PhO2S

References

1 Criegee, R. Ber. Dtsch. Chem. Ges. 1931, 64, 260. Rudolf Criegee (19021975) was born in Düsseldorf, 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. 4 Danielmeier, K.; Steckhan, E. Tetrahedron: Asymmetry 1995, 6, 1181. 5 Masuda, T.; Osako, K.; Shimizu, T.; Nakata, T. Org. Lett. 1999, 1, 941. 6 Lautens, M.; Stammers, T. A. Synthesis 2002, 1993. 7 Hartung, I. V.; Eggert, U.; Haustedt, L. O.; Niess, B.; Schäfer, P. M.; Hoffmann, H. M. R. Synthesis 2003, 1844. 8 Gaul, C.; Njardarson, J. T.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 6042. 9 Gorobets, E.; Stepanenko, V.; Wicha, J. Eur. J. Org. Chem. 2004, 783. 10 Mori, K.; Rikimaru, K.; Kan, T.; Fukuyama, T. Org. Lett. 2004, 6, 3095. 173

Criegee mechanism of ozonolysis

O3 O O O

O O 1,3-dipolar : O O O O cycloaddition primary ozonide (1,2,3-trioxolane)

O O O O 1,3-dipolar O O cycloaddition zwitterionic peroxide secondary ozonide (1,2,4-trioxolane) (Criegee zwitterion) also known as “carbonyl oxide”

Example 114

H HO o O3, EtOAc, 78 C, then O O OAc HO Ac O, Et N, DMAP, O 2 3 H 78 oC to rt, 75%

Example 215

O O O3, CH2Cl2 MeOH CO2Me O o CHOMe 70 C quant. CO2Me O

References

1. Criegee, R.; Wenner, G. Justus Liebigs Ann. Chem. 1949, 564, 9. 2. Criegee, R. Rec. Chem. Prog. 1957, 18, 111. 3. Criegee, R. Angew. Chem. 1975, 87, 765. 4. Klopman, G.; Joiner, C. M. J. Am. Chem. Soc. 1975, 97, 5287. 5. Bailey, P. S.; Ferrell, T. M. J. Am. Chem. Soc. 1978, 100, 899. 174

6. Schreiber, S. L.; Liew, W.-F. Tetrahedron Lett. 1983, 24, 2363. 7. Wojciechowski, B. J.; Pearson, W. H.; Kuczkowski, R. L. J. Org. Chem. 1989, 54, 115. 8. Bunnelle, W. H. Chem. Rev. 1991, 91, 335362. (Review). 9. Kuczkowski, R. L. Chem. Soc. Rev. 1992, 21, 7983. (Review). 10. Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58, 3675. 11. Ponec, R.; Yuzhakov, G.; Haas, Y.; Samuni, U. J. Org. Chem. 1997, 62, 2757. 12. Anglada, J. M.; Crehuet, R.; Maria Bofill, J. Chem. Eur. J. 1999, 5, 1809. 13. Dussault, P. H.; Raible, J. M. Org. Lett. 2000, 2, 3377. 14. Jiang, L.; Martinelli, J. R.; Burke, S. D. J. Org. Chem. 2003, 68, 1150. 15. Schank, K.; Beck, H.; Pistorius, S. Helv. Chim. Acta 2004, 87, 2025. 175

Curtius rearrangement Thermal or photochemical rearrangement of acyl azides into amines via isocyanate intermediates. While the thermal rearrangement is a concerted process, the photochemical rearrangement goes through a nitrene intermediate.

The thermal rearrangement:

O NaN3 O '

RCl RN3

H2O N2n RNCO RNH2 CO2n

O O N3 O O RCl RCl RN3 RNNN N3

H+ O ' RNCO N2n RNNN :OH2 isocyanate intermediate

H NO R H RNH2 CO2n O :B

The photochemical rearrangement:

O hQ O N2n RNNN R N: nitrene

O RNC O RNH CO n R N 2 2 176

Example 19

O O CO Me CO2Me 2 DPPA, Et3N, t-BuOH BocHN HO2C O O O 80 oC, 16 h, 64% O

Example 211

EtO(CO)Cl, then NaN3 CO2H NHCO2Et O O EtOH, PhH, reflux, 55% O O

References

1. Curtius, T. Ber. Dtsch. Chem. Ges. 1890, 23, 3023. Theodor Curtius (18571928) was born in Duisburg, 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 com- posed music. 2. Chen, J. J.; Hinkley, J. M.; Wise, D. S.; Townsend, L. B. Synth. Commun. 1996, 26, 617. 3. am Ende, D. J.; DeVries, K. M.; Clifford, P. J.; Brenek, S. J. Org. Process Res. Dev. 1998, 2, 382. 4. Braibante, M. E. F.; Braibante, H. S.; Costenaro, E. R. Synthesis 1999, 943. 5. Migawa, M. T.; Swayze, E. E. Org. Lett. 2000, 2, 3309. 6. El Haddad, M.; Soukri, M.; Lazar, S.; Bennamara, A.; Guillaumet, G.; Akssira, M. J. Heterocycl. Chem. 2000, 37, 1247. 7. Moore, J. D.; Sprott, K. T.; Hanson, P. R. J. Org. Chem. 2002, 67, 8123. 8. Mamouni, R.; Aadil, M.; Akssira, M.; Lasri, J.; Sepulveda-Arques, J. Tetrahedron Lett. 2003, 44, 2745. 9. 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. 10. Kedrowski, B. L. J. Org. Chem. 2003, 68, 5403. 11. Dussault, P. H.; Xu, C. Tetrahedron Lett. 2004, 45, 7455. 12. Holt, J.; Andreassen, T.; Bakke, J. M.; Fiksdahl, A. J. Heterocycl. Chem. 2005, 42, 259. 177

Dakin oxidation Oxidation of aryl aldehydes or aryl ketones to phenols using basic hydrogen peroxide conditions. Cf. Baeyer–Villiger oxidation.

H2O2, NaOH HO CHO HO OH HCO2H 4550 oC

O O H aryl HO HO O H migration HO O H O

OH HO O hydrolysis HO O O H OH O H

HO2CH HO O HO OH CHO2

Example 16

OBn CHO

2.5 eq. 30% H2O2

4% (PhSe)2, CH2Cl2, 18 h CO2H

NHCO2t-Bu

OBn OBn O OH CHO NH3, MeOH, 1 h

78% CO2H CO2H

NHCO2t-Bu NHCO2t-Bu 178

Example 27

CHO urea-hydrogen peroxide (UHP) OH

o HO solvent-free, 55 C, 3 h, 83% HO

References:

1. Dakin, H. D. J. Am. Chem. Soc. 1909, 42, 477. Henry D. Dakin (18801952) 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. 3. Matsumoto, M.; Kobayashi, H.; Hotta, Y. J. Org. Chem. 1984, 49, 4740. 4. Zhu, J.; Beugelmans, R.; Bigot, A.; Singh, G. P.; Bois-Choussy, M. Tetrahedron Lett. 1993, 34, 7401. 5. Guzmán, J. A.; Mendoza, V.; García, E.; Garibay, C. F.; Olivares, L. Z.; Maldonado, L. A. Synth. Commun. 1995, 25, 2121. 6. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553. 7. Varma, R. S.; Naicker, K. P. Org. Lett. 1999, 1, 189. 8. Roy, A.; Reddy, K. R.; Mohanta, P. K.; Ila, H.; Junjappa, H. Synth. Commun. 1999, 29, 3781. 9. Lawrence, N. J.; Rennison, D.; Woo, M.; McGown, A. T.; Hadfield, J. A. Bioorg. Med. Chem. Lett. 2001, 11, 51. 179

DakinWest reaction The direct conversion of an D-amino acid into the corresponding D-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 evo- lution of CO2.

O RCOH 2 Ac2O R CO2n NH 2 NHAc

O + RCO2H H R OH O

NH: 2 R HN OH O H O N O O O H O O 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 112

O Me CO2H Ac2O, AcOH, Et3N Me Me NH2 o DMAP, 50 C, 14 h, > 90% NHAc 180

Example 214

Me HO O O OO Ac2O, pyr. OO N OBn N OBn o H 90 C, 2 h, 58% H

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 D-amino acids with acetic anhydride to give D-acetamido ketones via azalactone intermediates. Interestingly, one year before this paper by Dakin and West, Levene and Steiger had observed both tyrosine and D-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. Levene, P. A.; Steiger, R. E. J. Biol. Chem. 1927, 74, 689. 3. Levene, P. A.; Steiger, R. E. J. Biol. Chem. 1928, 79, 95. 4. Cornforth, J. W.; Elliott, D. F. Science 1950, 112, 534. 5. Allinger, N. L.; Wang, G. L.; Dewhurst, B. B. J. Org. Chem. 1974, 39, 1730. 6. Buchanan, G. L. Chem. Soc. Rev. 1988, 17, 91. (Review). 7. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553. 8. Kawase, M.; Hirabayashi, M.; Koiwai, H.; Yamamoto, K.; Miyamae, H. Chem. Com- mun. 1998, 641. 9. Kawase, M.; Okada, Y.; Miyamae, H. Heterocycles 1998, 48, 285. 10. Kawase, M.; Hirabayashi, M.; Kumakura, H.; Saito, S.; Yamamoto, K. Chem. Pharm. Bull. 2000, 48, 114. 11. Kawase, M.; Hirabayashi, M.; Saito, S. Recent Res. Dev. Org. Chem. 2001, 4, . (Review). 12. Fischer, R. W.; Misun, M. Org. Proc. Res. Dev. 2001, 5, 581. 13. Orain, D.; Canova, R.; Dattilo, M.; Klöppner, E.; Denay, R.; Koch, G.; Giger, R. Synlett 2002, 1443. 14. Godfrey, A. G.; Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.; Mitchell, D. J. Org. Chem. 2003, 68, 2623. 15. Khodaei, M. M.; Khosropour, A. R.; Fattahpour, P. Tetrahedron Lett. 2005, 46, 2105. 181

Danheiser annulation Trimethylsilylcyclopentene annulation from an DE-unsaturated ketone and trimethylsilylallene in the presence of a Lewis acid.

O O TiCl4, CH2Cl2 SiMe3 SiMe3 75 oC, 82%

Cl Cl Ti 3 O Cl Cl Ti 3 O

SiMe3 SiMe3

Cl Ti 3 O 1,2-shift of

SiMe3 silyl group

Transition State

Cl Cl Ti O 3 O

SiMe3

SiMe3 182

Example 17

O TiCl , CH Cl SiMe3 4 2 2

OMe o 78 C O

O O O

OMe OMe OMe OH O O 48% 6% 15% Me3Si

Example 28 O TiCl , CH Cl SiMe3 4 2 2

75 oC, 91%

O O H H (1:1) Me Si Me3Si 3 H H

References

1. Danheiser, R. L.; Carini, D. J.; Basak, A. J. Am. Chem. Soc. 1981, 103, 1604. Rick L. Danheiser earned his Ph.D. at Harvard under E. J. Corey. He is a professor at MIT. 2. Danheiser, R. L.; Carini, D. J.; Fink, D. M.; Basak, A. Tetrahedron 1983, 39, 935. 3. Danheiser, R. L.; Kwasigroch, C. A.; Tsai, Y.-M. J. Am. Chem. Soc. 1985, 107, 7233. 4. Danheiser, R. L.; Carini, D. J.; Kwasigroch, C. A. J. Org. Chem. 1986, 51, 3870. 5. Danheiser, R. L.; Tsai, Y.-M.; Fink, D. M. Org. Synth. 1988, 66, 1. 6. Danheiser, R. L.; Dixon, B. R.; Gleason, R. W. J. Org. Chem. 1992, 57, 6094. 7. Engler, T. A.; Agrios, K.; Reddy, J. P.; Iyengar, R. Tetrahedron Lett. 1996, 37, 327. 8. Friese, J. C.; Krause, S.; Schäfer, H. J. Tetrahedron Lett. 2002, 43, 2683. 183

Darzens glycidic ester condensation DE-Epoxy esters (glycidic esters) from base-catalyzed condensation of D-haloesters with carbonyl compounds.

O X O OEt R1 R 1 2 2 RCO2Et R R R CO2Et

O OEt X R1 R2 H X OEt R OEt R O O

1 O O R intramolecular 1 2 R R R R 2 CO Et R CO2Et X 2 SN2

Example 14

O O t-BuOK, t-BuOH CO2Et + Cl CO2Et 10°C, 85–95%

Example 29

O H O LDA, THF, O –78 °C then H3C Ph H3CBr PhCHO, –90 °C t-BuMe2Si H t-BuMe2Si 66%, 90% de

References

1 Darzens, G. A. Compt. Rend. Acad. Sci. 1904, 139, 1214. George Auguste Darzens (18671954) 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). 184

3 Ballester, M. Chem. Rev. 1955, 55, 283–300. (Review). 4 Hunt, R. H.; Chinn, L. J.; Johnson, W. S. Org. Syn. Coll. 1963, 4, 459. 5 Bauman, J. G.; Hawley, R. C.; Rapoport, H. J. Org. Chem. 1984, 49, 3791. 6 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). 7 Takahashi, T.; Muraoka, M.; Capo, M.; Koga, K. Chem. Pharm. Bull. 1995, 43, 1821. 8 Ohkata, K.; Kimura, J.; Shinohara, Y.; Takagi, R.; Hiraga, Y. Chem. Commun. 1996, 2411. 9 Enders, D.; Hett, R. Synlett 1998, 961. 10 Takagi, R.; Kimura, J.; Shinohara, Y.; Ohba, Y.; Takezono, K.; Hiraga, Y.; Kojima, S.; Ohkata, K. J. Chem. Soc., Perkin Trans. 1 1998, 689. 11 Hirashita, T.; Kinoshita, K.; Yamamura, H.; Kawai, M.; Araki, S. J. Chem. Soc., Perkin Trans. 1 2000, 825. 12 Shinohara, Y.; Ohba, Y.; Takagi, R.; Kojima, S.; Ohkata, K. Heterocycles 2001, 55, 9. 13 Arai, A.; Suzuki, Y.; Tokumaru, K.; Shioiri, T. Tetrahedron Lett. 2002, 43, 833. 14 Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad, K. R. J. Org. Chem. 2003, 68, 2410. 15 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, 1521. (Review). 185

Davis chiral oxaziridine reagents Chiral N-sulfonyloxaziridines employed for asymmetric hydroxylation, etc.

Cl O Cl Ar N e.g. N RSO 2 S O O O

O 1 Ar R N O M R RSO 1 2 R O R M O

SO2R N RSO2 Ar N O Ar O 1 R 1 R R R O O M

O M 1 R SO2R R Ar N O

Example 12

1. NaHMDS, THF, 78 oC O O O O o O 2. THF, 78 C Ph N Ph N O PhSO Ph N O 2 OH 3. camphor sulfonic acid, THF

85%, 90% de 186

Example 25

o NaHMDS, THF, 78 C O O 61%, 95% ee Ph Ph Cl OH Cl N S O O O

References

1 Davis, F. A.; Vishwakarma, L. C.; Billmers, J. M.; Finn, J. J. Org. Chem. 1984, 49, 3241. Franklin A. Davis developed this methodology while teaching at Drexel Uni- versity, now he is at Temple University. 2 Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J. Am. Chem. Soc. 1985, 107, 4346. 3 Davis, F. A.; Billmers, J. M.; Gosciniak, D. J.; Towson, J. C.; Bach, R. D. J. Org. Chem. 1986, 51, 4240. 4 Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703. (Review). 5 Davis, F. A.; Weismiller, M. C. J. Org. Chem. 1990, 55, 3715. 6 Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919934. (Review). 7 Davis, F. A.; Thimma Reddy, R.; Weismiller, M. C. J. Am. Chem. Soc. 1989, 111, 5964. 8 Davis, F. A.; Kumar, A.; Chen, B.-C. J. Org. Chem. 1991, 56, 1143. 9 Davis, F. A.; Reddy, R. T.; Han, W.; Carroll, P. J. J. Am. Chem. Soc. 1992, 114, 1428. 10 Tagami, K.; Nakazawa, N.; Sano, S.; Nagao, Y. Heterocycles 2000, 53, 771. 11 Takeda, K.; Sawada, Y.; Sumi, K. Org. Lett. 2002, 4, 1031. 12 Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek, E. Org. React. 2003, 62, 1356. (Re- view). 187

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 amine and Sommelet reaction, where the product is aldehyde. The Delépine works well for active halides such as benzyl, allyl halides, and D-halo-ketones.

N N X HX Ar NH3 Ar X N N Ar N N X N N hexamethylenetetramine

- + [ArCH2 C6H12N4] X + 3HCl + 6H2O

= ArCH2NH2•HX + 6CH2O+3NH4Cl

N : N N N: N SN2 Ar N N N Ar X X

H2O: H O H N N Ar Ar N N N N N N

H N O Ar NH Ar 3 CH N N 2 N X

Example 14

1. (CH ) N , NaHCO 2 6 4 3 O O 15 h, EtOH, H2O H NOH Br OH 2. HCl, EtOH, reflux, 15 h, 85% 2 188

Example 28

hexamethylenetetramine N Br N

Br CH2Cl2, refux, 5 h, then 30 oC

N Br N + N4C6H12 Br

conc. HCl, EtOH N Br N reflux, 1 d 78%, 2 steps NH2

References

1. Delépine, M. Bull. Soc. Chim. Paris 1895, 13, 355; 1897, 17, 290. Stephe Marcel Delépine (18711965) 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. Delépine, M. Compt. Rend. Acad. Sci. 1895, 120, 501. 1897, 124, 292. 3. Galat, A.; Elion, G. J. Am. Chem. Soc. 1939, 61, 3585. 4. Wendler, N. L. J. Am. Chem. Soc. 1949, 71, 375. 5. Quessy, S. N.; Williams, L. R.; Baddeley, V. G. J. Chem. Soc., Perkin Trans. 1 1979, 512. 6. Blažzeviü, N.; Kolnah, D.; Belin, B.; Šunjiü, V.; Kafjež, F. Synthesis 1979, 161. (Re- view). 7. Henry, R. A.; Hollins, R. A.; Lowe-Ma, C.; Moore, D. W.; Nissan, R. A. J. Org. Chem. 1990, 55, 1796. 8. Charbonnière, L. J.; Weibel, N.; Ziessel, R. Synthesis 2002, 1101. 189 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 CO Me CO2Me hQ 2

OH OH OCO2Me

O O hQ, [2 + 2]

cycloaddition CO2Me CO2Me OH OH head-to-tail alignment

O H O O retro-aldol

cyclobutane cleavage CO Me O 2 OCO2Me OCO2Me H

Minor regioisomer:

O O hQ, [2 + 2] CO2Me CO2Me

cycloaddition OH OH head-to-head alignment

H O O O CO Me 2 retro-aldol

cyclobutane cleavage CO2Me CO2Me O H O O 190

Example 15 O O

Ph O 1. hQ, cyclohexane, 83%

2. H2 (3 atm), Pd/C (10%) HOAc, rt, 18 h, 83% O O Example 29 O hQ, MeOH

> 90% OH

O O H H

HO H H O References

1. 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, Uni- versity of London. He later became a professor at the University of Western Ontario in London, Ontario, Canada, where he discovered the de Mayo reaction. 2. Corey, E. J.; Bass, J. D.; LeMahieu, R.; Mitra, R. B. J. Am. Chem. Soc. 1964, 86, 5570. 3. Challand, B. D.; Hikino, H.; Kornis, G.; Lange, G.; de Mayo, P. J. Org. Chem. 1969, 34, 794. 4. de Mayo, P. Acc. Chem. Res. 1971, 4, 49. (Review). 5. Oppolzer, W.; Godel, T. J. Am. Chem. Soc. 1978, 100, 2583. 6. Oppolzer, W. Pure Appl. Chem. 1981, 53, 1181. (Review). 7. Pearlman, B. A. J. Am. Chem. Soc. 1979, 101, 6398. 8. Kaczmarek, R.; Blechert, S. Tetrahedron Lett. 1986, 27, 2845. 9. Disanayaka, B. W.; Weedon, A. C. J. Org. Chem. 1987, 52, 2905. 10. Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297588. (Review). 11. Quevillon, T. M.; Weedon, A. C. Tetrahedron Lett. 1996, 37, 3939. 12. Blaauw, R. H.; Brière, J.-F.; de Jong, R.; Benningshof, J. C. J.; van Ginkel, A. E.; Fraanje, J.; Goubitz, K.; Schenk, H.; Rutjes, F. P. J. T.; Hiemstra, H. J. Org. Chem. 2001, 66, 233. 13. Minter, D. E.; Winslow, C. D. J. Org. Chem. 2004, 69, 1603. 14. Kemmler, M.; Herdtweck, E.; Bach, T. Eur. J. Org. Chem. 2004, 4582. 191

Demjanov rearrangement Carbocation rearrangement of primary amines via diazotization to give alcohols through CC 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

: NNO NH2 H

+ H H2O

NNOH NNOH: 2 NN

H + N2 O H : H N OH N

H O : H N2 or + H OH N N

Example 17

H NH HOH 2 NaNO2, AcOH/H2O

100110 oC, 2 h, 61% 192

Example 29

O O o O NaNO2, 04 C

0.25 M H2SO4/H2O OH HO NH2

References

1. Demjanov, N. J.; Lushnikov, M. J. Russ. Phys. Chem. Soc. 1903, 35, 26. Nikolai J. Demjanov (18611938) was a Russian chemist. 2. Smith, P. A. S.; Baer, D. R. Org. React. 1960, 11, 157188. (Review). 3. Kotani, R. J. Org. Chem. 1965, 30, 350. 4. Diamond, J.; Bruce, W. F.; Tyson, F. T. J. Org. Chem. 1965, 30, 1840. 5. Alam, S. N.; MacLean, D. B. Can. J. Chem. 1965, 43, 3433. 6. Cooper, C. N.; Jenner, P. J.; Perry, N. B.; Russell-King, J.; Storesund, H. J.; Whiting, M. C. J. Chem. Soc., Perkin Trans. 2 1982, 605. 7. Nakazaki, M.; Naemura, K.; Hashimoto, M. J. Org. Chem. 1983, 48, 2289. 8. Uyehara, T.; Kabasawa, Y.; Furuta, T.; Kato, T. Bull. Chem. Soc. Jpn. 1986, 59, 539. 9. Fattori, D.; Henry, S.; Vogel, P. Tetrahedron 1993, 49, 1649. 193

Tiffeneau–Demjanov rearrangement Carbocation rearrangement of E-aminoalcohols via diazotization to afford carbonyl compounds through CC bond migration.

O OH NaNO2

NH + 2 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 NO :

NH2 H

OH OH OH H O H+ 2 + N NNOH NNOH: 2 N

Step 3, Ring-expansion via rearrangement

: O OH N O H + N N2 H

Example 110

o NaNO2, AcOH/H2O, 0 C, 1 h OH then reflux 1 h, 98% NH2 O 194

Example 212

O O HO NH2 NaNO2 SiMe3 AcOH SiMe3 72% SiMe3 28%

References

1. Tiffeneau, M.; Weill, P.; Tehoubar, B. Compt. Rend. 1937, 205, 54. 2. Smith, P. A. S.; Baer, D. R. Org. React. 1960, 11, 157. (Review). 3. Jones, J. B.; Price, P. J. Chem. Soc.,D. 1969, 1478. 4. Parham, W. E.; Roosevelt, C. S. J. Org. Chem. 1972, 37, 1975. 5. McKinney, M. A.; Patel, P. P. J. Org. Chem. 1973, 38, 4059. 6. Jones, J. B.; Price, P. Tetrahedron 1973, 29, 1941. 7. Dave, V.; Stothers, J. B.; Warnhoff, E. W. Can. J. Chem. 1979, 57, 1557. 8. Haffer, G.; Eder, U.; Neef, G.; Sauer, G.; Wiechert, R. Justus Liebigs Ann. Chem. 1981, 425. 9. Thomas, R. C.; Fritzen, E. L. J. Antibiotics 1988, 41, 1445. 10. Stern, A. G.; Nickon, A. J. Org. Chem. 1992, 57, 5342. 11. Fattori, D.; Henry, S.; Vogel, P. Tetrahedron 1993, 49, 1649. 12. Chow, L.; McClure, M.; White, J. Org. Biomol. Chem. 2004, 2, 648. 195

DessMartin periodinane oxidation Oxidation of alcohols to the corresponding carbonyl compounds using triacetoxyperiodinane.

AcO OAc I OAc O OH O O R1 R2 R1 R2

AcO OAc H AcO OAc I OAc :O I O 2 H O R O 2 1 R OAc R1 R O O

OAc H I O O O O R1 R2 O

Example 19

AcO OAc I OAc O OH O O O O O O O O CH2Cl2, 2 h, 67% O O

Example 215 AcO OAc I OAc O O CHO O N3 N NaN3, CH2Cl2 o N 0 C, 3 h, 86% 196

References

1. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. James Cullen (J. C.) Martin (19281999) had a distinguished career spanning 36 years both at the University of Il- linois at Urbana-Champaign and Vanderbilt University. J. C.’s formal training in physical organic chemistry with Don Pearson at Vanderbilt and P. D. Bartlett at Har- vard prepared him well for his early studies on carbocations and radicals. However, it was his interest in understanding the limits of chemical bonding that led to his land- mark investigations into hypervalent compounds of the main group elements. Over a 20-year period the Martin laboratories successfully prepared unprecedented 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 widespread 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 biography is kindly supplied by Prof. Scott E. Denmark). 2. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. 3. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. 4. Speicher, A.; Bomm, V.; Eicher, T. J. Prakt. Chem. 1996, 338, 588590. (Review). 5. Chaudhari, S. S.; Akamanchi, K. G. Synthesis 1999, 760. 6. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 622. 7. Jenkins, N. E.; Ware, R. W., Jr.; Atkinson, R. N.; King, S. B. Synth. Commun. 2000, 30, 947. 8. Promarak, V.; Burn, P. L. J. Chem. Soc., Perkin 1 2001, 14. 9. Bach, T.; Kirsch, S. Synlett 2001, 1974. 10. Wavrin, L.; Viala, J. Synthesis 2002, 326. 11. Wellner, E.; Sandin, H.; Pääkkönen, L. Synthesis 2003, 223. 12. Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 5, 575. 13. Bose, D. S.; Reddy, A. V. N. Tetrahedron Lett. 2003, 44, 3543. 14. Tohma, H.; Kita, Y. Adv. Synth. Catal. 2004, 346, 111124. (Review). 15. Deng, G.; Xu, B.; Liu, C. Tetrahedron 2005, 61, 5818. 197

Dieckmann condensation The Dieckmann condensation is the intramolecular version of the Claisen condensation.

NaOEt O CO2Et CO2Et CO2Et

CO2Et O OEt enolate 5-exo-trig OEt O H formation OEt ring closure O OEt

O O OEt

CO Et CO2Et 2

Example 17

OBn H OBn H NaHMDS, THF OTBS MeO C OTBS O 2 N N 78 oC, 58% MeO2C MeO2C

Example 29

EtO2C

MeO2C O 1. t-BuOK, Tol. reflux, 5 min.

2. 18 N, H SO , THF, 4 h 2 4 N O N O 61% for two steps 198

References

1. Dieckmann, W. Ber. Dtsch. Chem. Ges. 1894, 27, 102. Walter Dieckmann (18691925), born in Hamburg, Germany, studied with E. Bamberger at Munich. Af- ter 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, 795863. (Review). 3. Toda, F.; Suzuki, T.; Higa, S. J. Chem. Soc., Perkin Trans. 1 1998, 3521. 4. Shindo, M.; Sato, Y.; Shishido, K. J. Am. Chem. Soc. 1999, 121, 6507. 5. Balo, C.; Fernández, F.; García-Mera, X.; López, C. Org. Prep. Proced. Int. 2000, 32, 563. 6. Deville, J. P.; Behar, V. Org. Lett. 2002, 4, 1403. 7. Rabiczko, J.; UrbaĔczyk-Lipkowska, Z.; Chmielewski, M. Tetrahedron 2002, 58, 1433. 8. Ho, J. Z.; Mohareb, R. M.; Ahn, J. H.; Sim, T. B.; Rapoport, H. J. Org. Chem. 2003, 68, 109. 9. de Sousa, A. L.; Pilli, R. A. Org. Lett. 2005, 7, 1617. 199

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.

Normal Diels–Alder reaction

EDG EDG EWG ' EWG

diene dienophile adduct

EDG = electron-donating group; EWG = electron-withdrawing group

Example 113

OMe OMe CO2Et hydroquinone Me3SiO

AcO o Me3SiO 180 C, 1.5 h, 62% CO2Et H

OAc Danishefsky diene Alder’s endo rule

OMe OMe

CO2Et EtO2C CO2Et

Me3SiO AcO AcO OSiMe3 4:1 D-OMe : E-OMe Example 217

O O F Br4-BIPOL, AlMe3 O O F CH2Cl2, rt, 8 h, 65% H 200

Inverse electronic demand Diels–Alder reaction

EWG EWG EDG ' EDG

diene dienophile adduct

Example 12

CO Me CO Me 2 N 2 ' N

Hetero-Diels–Alder reaction

Heterodiene addition to dienophile

SO Ph SO2Ph EtO C 2 2 SO Ph EtO C N 2 EtO2COEtN 2 OEt N

Ph OEt Ph H Ph

Example 1, the Boger pyridine synthesis (see page 67)8

CO2Me OMe CHCl , reflux MeO N N 3 NN OMe 5 days, 65% MeO CO2Me

MeO2C N MeO N MeO CO2Me MeO2CCO2Me NN 201

Heterodienophile addition to diene2

MeO toluene MeO CO2Et CO2Et O O 110 oC, 60%

Example 2, using the Rawal diene9

NMe2 o CHCl , 40 C O O 3 Me O Me CO Me 71% MeO2C 2 OTBS References

1. Diels, O.; Alder, K. Justus Liebigs Ann. Chem. 1928, 460, 98. Otto Diels (Germany, 18761954) and his student, Kurt Alder (Germany, 19021958), shared the Nobel Prize in Chemistry in 1950 for development of the diene synthesis. In this article they claimed their territory in applying the Diels–Alder reaction in total synthesis: “We ex- plicitly reserve for ourselves the application of the reaction developed by us to the solution of such problems.” 2. Wender, P. A.; Keenan, R. M.; Lee, H. Y. J. Am. Chem. Soc. 1987, 109, 4390. 3. Boger, D. L.; Panek, J. S.; Yasuda, M. Org. Synth. 1988, 66, 142. 4. Oppolzer, W. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 315399. (Review). 5. Boger, D. L. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 451512. (Review). 6. Weinreb, S. M. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 401449. (Review). 7. Wasserman, H. H.; DeSimone, R. W.; Boger, D. L.; Baldino, C. M. J. Am. Chem. Soc. 1993, 115, 8457. 8. Boger, D. L.; Baldino, C. M. J. Am. Chem. Soc. 1993, 115, 11418. 9. Huang, Y.; Rawal, V. H. Org. Lett. 2000, 2, 3321. 10. Mehta, G.; Uma, R. Acc. Chem. Res. 2000, 33, 278. (Review). 11. Yli-Kauhaluoma, J. Tetrahedron 2001, 57, 7053. (Review). 12. Ghosh, A. K.; Shirai, M. Tetrahedron Lett. 2001, 42, 6231. 13. Wang, J.; Morral, J.; Hendrix, C.; Herdewijn, P. J. Org. Chem. 2001, 66, 8478. 14. JØrgensen, K. A. Eur. J. Org. Chem. 2004, 2093. (Review). 15. Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650. (Review). 16. Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668. (Review). 17. Saito, A.; Yanai, H.; Sakamoto, W.; Takahashi, K.; Taguchi, T. J. Fluorine Chem. 2005, 126, 709. 202

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 H shift R R RR R R RR

Example 14

O O

O O 50% aq. H2SO4

reflux, 80% HO O

Example 25

O OH HO HO conc. H2SO4

Et2O, 95%

References

1. Shine, H. J. In Aromatic Rearrangements; Elsevier: New York, 1967, pp 55ҟ68. (Re- view). 2. Schultz, A. G.; Hardinger, S. A. J. Org. Chem. 1991, 56, 1105. 203

3. Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1992, 114, 1824. 4. Hart, D. J.; Kim, A.; Krishnamurthy, R.; Merriman, G. H.; Waltos, A.-M. Tetrahedron 1992, 48, 8179. 5. Frimer, A. A.; Marks, V.; Sprecher, M.; Gilinsky-Sharon, P. J. Org. Chem. 1994, 59, 1831. 6. Oshima, T.; Nakajima, Y.-i.; Nagai, T. Heterocycles 1996, 43, 619. 7. Draper, R. W.; Puar, M. S.; Vater, E. J.; Mcphail, A. T. Steroids 1998, 63, 135. 8. Banerjee, A. K.; Castillo-Melendez, J. A.; Vera, W.; Azocar, J. A.; Laya, M. S. J. Chem. Res., (S) 2000, 324. 9. Kumar, V. S.; Nagaraja, B. M.; Shashikala, V.; Seetharamulu, P.; Padmasri, A. H.; Raju, B. D.; Rao, K. S. R. J. Mol. Catal. A: Chemical 2004, 223, 283. 10. Kodama, S.; Takita, H.; Kajimoto, T.; Nishide, K.; Node, M. Tetrahedron 2004, 60, 4901. 204

Di-S-methane rearrangement Conversion of 1,4-dienes to vinylcyclopropanes under photolysis. Also known as the Zimmerman rearrangement.

1 R R 2 R 1 2 R R R hQ 3 4 R R4 R3 R 1,4-diene vinylcyclopropane

R R1 R R1 R2 hQ R2

R4 R3 R4 R3 diradical

R R1 R 2 R1 R2 R

3 4 R R4 R3 R diradical

Example 19

CN CN hQ, acetone CN 90% CN

Example 2, aza-S-methane rearrangement2

hQ, acetophenone Ph N N OAc Ph OAc benzene, 86% Ph Ph 205

References

1. Zimmerman, H. E.; Grunewald, G. L. J. Am. Chem. Soc. 1966, 88, 183. Howard E. Zimmerman is a professor at the University of Wisconsin at Madison. 2. Armesto, D.; Horspool, W. M.; Langa, F.; Ramos, A. J. Chem. Soc. Perkin Trans. I 1991, 223. 3. Zimmerman, H. E.; Armesto, D. Chem. Rev. 1996, 96, 3065. (Review). 4. Janz, K. M.; Scheffer, J. R. Tetrahedron Lett. 1999, 40, 8725. 5. Zimmerman, H. E.; Církva, V. Org. Lett. 2000, 2, 2365. 6. Tu, Y. Q.; Fan, C. A.; Ren, S. K.; Chan, A. S. C. J. Chem. Soc., Perkin 1 2000, 3791. 7. Jiménez, M. C.; Miranda, M. A.; Tormos, R. Chem. Commun. 2000, 2341. 8. Ihmels, H.; Mohrschladt, C. J.; Grimme, J. W.; Quast, H. Synthesis 2001, 1175. 9. Ünaldi, N. S.; Balci, M. Tetrahedron Lett. 2001, 42, 8365. 10. Altundas, R.; Dastan, A.; Ünaldi, N. S.; Güven, K.; Uzun, O.; Balci, M. Eur. J. Org. Chem. 2002, 526. 11. Zimmerman, H. E.; Chen, W. Org. Lett. 2002, 4, 1155. 12. Tanifuji, N.; Huang, H.; Shinagawa, Y.; Kobayashi, K. Tetrahedron Lett. 2003, 44, 751. 13. Singh, V.; Vedantham, P.; Sahu, P. K. Tetrahedron 2003, 60, 8161. 14. Frutos, L. M.; Sancho, U.; Castano, O. J. Phys. Chem. A 2005, 109, 2993. 206

Doebner quinoline synthesis Three-component coupling of an aniline, pyruvic acid, and an aldehyde to provide a quinoline-4-carboxylic acid.

CO2H

O

CO H N NH2 OHC 2

O H OH 2 H2O NH H : : 2 N H

H O + H O CO2H CO2H

N N H H

B: HO CO2H H H2O CO2H + H H

N N H H

CO2H CO2H air oxidation H2O N 2 H N H 207

Example 12 H MeO O NO O 2 CO2H NH2

CO2H MeO EtOH, , 95% ' NO N 2

Example 26 O H O CO2H NH2

CO2H

EtOH, reflux N 3 h, 20%

References

1. Doebner, O. G. Justus Liebigs Ann. Chem. 1887, 242, 265. Oscar Gustav Doebner (18501907) was born in Meiningen, Germany. After studying under Liebig, he ac- tively 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. 3. Allen, C. F. H.; Spangler, F. W.; Webster, E. R. J. Org. Chem. 1951, 16, 17. 4. 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. 2529. (Review). 5. Jones, G. in Chemistry of Heterocyclic Compounds, Jones, G., ed.; John Wiley & Sons, Inc.: New York, 1977, Vol. 32; Quinolines, pp. 125131. (Review). 6. Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1989, 32, 396. 7. Herbert, R. B.; Kattah, A. E.; Knagg, E. Tetrahedron 1990, 46, 7119. 8. Pflum, D. A. Doebner Quinoline Synthesis In Name Reactions in Heterocyclic Chem- istry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 407410. (Re- view). 208

Dötz reaction

Cr(CO)3-coordinated hydroquinone from vinylic alkoxy pentacarbonyl chromium carbene (Fischer carbene) complex and alkynes.

OH 2 OR R RL ' (OC)5Cr RL RS R1 R 1 2 S R R OR Cr(CO)3

OR OR alkyne CO (OC) Cr (OC)5Cr 4 coordination 1 2 R1 R2 R R

R1 2 R OR RL RS alkyne OR insertion 3 R (OC)4Cr R L RS

1 2 R R Cr OC CO OC CO

R1 2 R OR electrocyclic CO insertion O C R S ring closure RL Cr CO OC CO

O OH 2 2 R R R R L L tautomerization 1 1 R RS R RS OR OR Cr(CO)3 Cr(CO)3 209

Example 17 OMe NO2 (OC) Cr Se 5

O 1. THF, reflux Se

2. CAN, 22% NO2 O

Example 211 BnO

Cr(CO)5

MOMO MeO OMOM OMe BnO OH THF, 50 oC, 61%

MeO OMe

References

1. Dötz, K. H. Angew. Chem., Int. Ed. 1975, 14, 644. Karl H. Dötz (1943) was a professor at the University of Munich in Germany. 2. Wulff, W. D.; Tang, P.-C.; McCallum, J. S. J. Am. Chem. Soc. 1981, 103, 7677. 3. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., ed.; JAI Press, Greenwich, CT; 1989; Vol. 1. (Review). 4. 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). 5. Torrent, M. Chem. Commun. 1998, 999. 6. Torrent, M.; Solá, M.; Frenking, G. Chem. Rev. 2000, 100, 439. (Review). 7. Caldwell, J. J.; Colman, R.; Kerr, W. J.; Magennis, E. J. Synlett 2001, 1428. 8. Jackson, T. J.; Herndon, J. W. Tetrahedron 2001, 57, 3859. 9. 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, A. eds.; Kluwer Academic: Boston; 2002, 269287. (Re- view). 10. Pulley, S. R.; Czakó, B. Tetrahedron Lett. 2004, 45, 5511. 11. White, J. D; Smits, H. Org. Lett. 2005, 7, 235. 210

DowdBeckwith ring expansion Radical-mediated ring expansion of 2-halomethyl cycloalkanones.

O O Br Bu3SnH, AIBN CO CH 2 3 PhH, reflux CO2CH3

' NC NN CN N2n 2 CN homolytic cleavage

2,2’-azobisisobutyronitrile (AIBN)

n-Bu3Sn H CN n-Bu3SnH CN

SnBu3 O O Br Bu3SnBr CO2CH3 CO2CH3

O O

H SnBu3 CO2CH3 CO2CH3

O

Bu3Sn CO2CH3 211

Example 19

H

1.2 eq. Bu3SnH, cat. AIBN O H Tol., reflux, 23 h CO2Et I

H H O O H H CO2Et CO2Et H 86% 13%

References

1. Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1987, 109, 3493. Paul Dowd (19361996) was a professor at the University of Pittsburgh. 2. Beckwith, A. L. J.; O’Shea, D. M.; Gerba, S.; Westwood, S. W. J. Chem. Soc., Chem. Commun. 1987, 666. Athelstan L. J. Beckwith is a professor at University of Ade- laide, Adelaide, Australia. 3. Beckwith, A. L. J.; O’Shea, D. M.; Westwood, S. W. J. Am. Chem. Soc. 1988, 110, 2565. 4. Dowd, P.; Choi, S.-C. Tetrahedron 1989, 45, 77. 5. Dowd, P.; Choi, S.-C. Tetrahedron Lett. 1989, 30, 6129. 6. Dowd, P.; Choi, S.-C. Tetrahedron 1991, 47, 4847. 7. Bowman, W. R.; Westlake, P. J. Tetrahedron 1992, 48, 4027. 8. Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091. (Review). 9. Banwell, M. G.; Cameron, J. M. Tetrahedron Lett. 1996, 37, 525. 10. Wang, C.; Gu, X.; Yu, M. S.; Curran, D. P. Tetrahedron 1998, 54, 8355. 11. Hasegawa, E.; Kitazume, T.; Suzuki, K.; Tosaka, E. Tetrahedron Lett. 1998, 39, 4059. 12. Hasegawa, E.; Yoneoka, A.; Suzuki, K.; Kato, T.; Kitazume, T.; Yanagi, K. Tetrahe- dron 1999, 55, 12957. 13. Studer, A.; Amrein, S. Angew. Chem., Int. Ed. 2000, 39, 3080. 14. Kantorowski, E. J.; Kurth, M. J. Tetrahedron 2000, 56, 4317. (Review). 15. Sugi, M.; Togo, H. Tetrahedron 2002, 58, 3171. 16. Ardura, D.; Sordo, T. L. Tetrahedron Lett. 2004, 45, 8691. 212

ErlenmeyerPlöchl azlactone synthesis Formation of 5-oxazolones (or ‘azlactones’) by intramolecular condensation of acylglycines in the presence of acetic anhydride.

HN Ac2O N CO H 2 O R1 O R1 O

AcO OO H N HN O O O R O R 1 O O 1 O O H mixed anhydride

N O 2 AcOH R1 O

Example14

O

HN H CO2H Ph O O O

NaOAc, Ac2O O N 110 oC, 6973% O O Ph O

References

1. Plöchl, J. Ber. Dtsch. Chem. Ges. 1884, 17, 1616. 2. Erlenmeyer, E., Jr. Ann. 1893, 275, 1. Emil Erlenmeyer, Jr. (18641921) was born in Heidelberg, Germany to Emil Erlenmeyer (18251909), a famous chemistry professor at the University of Heidelberg. He investigated the ErlenmeyerPlöchl azlactone synthesis while he was a Professor of Chemistry at Strasburg. 3. Carter, H. E. Org. React. 1946, 3, 198239. (Review). 4. Baltazzi, E. Quart. Rev. Chem. Soc. 1955, 9, 150. (Review). 213

5. Filler, R.; Rao, Y. S. New Development in the Chemistry of Oxazolines, In Adv. Het- erocyclic Chem; Katritzky, A. R. and Boulton, A. J., Eds; Academic Press, Inc: New York, 1977, Vol. 21, pp. 175206. (Review). 6. Kumar, P.; Mishra, H. D.; Mukerjee, A. K. Synthesis 1980, 10, 836. 7. Mukerjee, A. K.; Kumar, P. Heterocycles 1981, 16, 1995. (Review). 8. Mukerjee, A. K. Heterocycles 1987, 26, 1077. (Review). 9. Cornforth, J.; Ming-hui, D. J. Chem. Soc. Perkin Trans. I 1991, 2183. 10. Ivanova, G. G. Tetrahedron 1992, 48, 177. 11. Combs, A. P.; Armstrong, R. W. Tetrahedron Lett. 1992, 33, 6419. 12. Monk, K. A.; Sarapa, D.; Mohan, R. S. Synth. Commun. 2000, 30, 3167. 13. Konkel, J. T.; Fan, J.; Jayachandran, B.; Kirk, K. L. J. Fluorine Chem. 2002, 115, 27. 14. Buck, J. S.; Ide, W.S. Org. Synth. Coll. 1943, 2, 55. 15. Brooks, D. A. ErlenmeyerPlöchl Azlactone Synthesis in Name Reactions in Hetero- cyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 229233. (Review). 214

EschenmoserTanabe fragmentation Fragmentation of DE-epoxyketones via the intermediacy of DE-epoxy sulfonylhydrazones.

O 1. H2O2, OH

+ 2. H2NNHSO2Ar, H O 3. OH

OOH OH O O

O O O

O O + H2NNHSO2Ar, H OH

N N NSOAr N SO2Ar 2 H

O O

SO2Ar N2n

N NSO2Ar

Example 14

Tol-SO2NHNH2 CHCl3-AcOH (1:1) O rt, 5 h, 73% AcO O 215

O

AcO

Example 27

Me Me 1. TsNHNH2, rt

O Me 2. 55 oC, 2 h, 50% O Me O

References

1. Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta 1967, 50, 708. Albert 2. 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. 3. Tanabe, M.; Crowe, D. F.; Dehn, R. L. Tetrahedron Lett. 1967, 3943. 4. Felix, D.; Müller, R. K.; Horn, U.; Joos, R.; Schreiber, J.; Eschenmoser, A. Helv. Chim. Acta 1972, 55, 1276. 5. Batzold, F. H.; Robinson, C. H. J. Org. Chem. 1976, 41, 313. 6. Covey, D. F.; Parikh, V. D. J. Org. Chem. 1982, 47, 5315. 7. 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. 8. Dai, W.; Katzenellenbogen, J. A. J. Org. Chem. 1993, 58, 1900. 9. Abad, A.; Arno, M.; Agullo, C.; Cuñat, A. C.; Meseguer, B.; Zaragoza, R. J. J. Nat. Prod. 1993, 56, 2133. 10. Mück-Lichtenfeld, C. J. Org. Chem. 2000, 65, 1366. 216

Eschweiler–Clarke reductive alkylation of amines Reductive methylation of primary or secondary amines using formaldehyde and formic acid. Cf. Leuckart–Wallach reaction.

HCO H RN RNH2 CH2O 2 formic acid is the hydrogen source as a reducing agent

H O OH + H H OH2 RN RN : H H H RNH2

H O H H RN O O COn : H HO RNH

H H+ : OH2 RN RN O HO

H+ O COn RNH RN

Example 17

O Pd/C/Na2SO4, H2 40 bar N O N O H EtOAc, 100 oC, 98% 217

Example 211

O NH DCOD, DCO2D, DMSO H3C CH3 microwave (120 W), 1-3 min.

O CD N 3

H3C CH3

d3-tamoxifen

References

1 Eschweiler, W. Chem. Ber. 1905, 38, 880. Wilhelm Eschweiler (18601936) was born in Euskirchen, Germany. 2 Clarke, H. T.; Gillespie, H. B.; Weisshaus, S. Z. J. Am. Chem. Soc. 1933, 55, 4571. Hans T. Clarke (18871927) was born in Harrow, England. 3 Moore, M. L. Org. React. 1949, 5, 301. (Review). 4 Pine, S. H.; Sanchez, B. L. J. Org. Chem. 1971, 36, 829. 5 Bobowski, G. J. Org. Chem. 1985, 50, 929. 6 Alder, R. W.; Colclough, D.; Mowlam, R. W. Tetrahedron Lett. 1991, 32, 7755. 7 Fache, F.; Jacquot, L.; Lemaire, M. Tetrahedron Lett. 1994, 35, 3313. 8 Bulman Page, P. C.; Heaney, H.; Rassias, G. A.; Reignier, S.; Sampler, E. P.; Talib, S. Synlett 2000, 104. 9 Torchy, S.; Barbry, D. J. Chem. Res. Synop. 2001, 292. 10 Rosenau, T.; Potthast, A.; Röhrling, J.; Hofinger, A.; Sixta, H.; Kosma, P. Synth. Commun. 2002, 32, 457. 11 Harding, J. R.; Jones, J. R.; Lu, S.-Y.; Wood, R. Tetrahedron Lett. 2002, 43, 9487. 12 Chen, F.-L.; Sung, K. J. Heterocycl. Chem. 2004, 41, 697. 218

Evans aldol reaction Asymmetric aldol condensation of aldehyde and chiral acyl oxazolidinone, the Evans chiral auxiliary.

O O O OH O

1. Bu2BOTf, R3N Ph N O N O

2. PhCHO, 78 oC

Bu Bu Bu BOT 2 f B O O O O Z-(O)-boron enolate PhCHO N O N O formation H

R3N:

Bu Bu B O O O O H aldol O N Bu Ph N O H B OBucondensation H O Ph

OH O O workup Ph N O

Example 17

MeO O O

N O NOMe

CO2Me 219

O O

N N O TiCl4, DIPEA o MeO2C CH2Cl278 C, 1.5 h

then rt, overnight, 52%

OMe

Example 213

S O O O N OBn OTES Bn

S 1 eq. Bu2BOTf, 1.1 eq. Et3N O OH OTES O N o PhMe, 0.15 M, 50 to 30 C OBn 2 h, 72% Bn

References

1. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127. David Ev- ans is a professor at Harvard University. 2. Evans, D. A.; McGee, L. R. J. Am. Chem. Soc. 1981, 103, 2876. 3. Allin, S. M.; Shuttleworth, S. J. Tetrahedron Lett. 1996, 37, 8023. 4. Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3. (Review). 5. Braddock, D. C.; Brown, J. M. Tetrahedron: Asymmetry 2000, 11, 3591. 6. Lu, Y.; Schiller, P. W. Synthesis 2001, 1639. 7. Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki, T. Tetrahedron 2000, 56, 7411. 8. Williams, D. R.; Patnaik, S.; Clark, M. P. J. Org. Chem 2001, 66, 8463. 9. Matsushima, Y.; Itoh, H.; Nakayama, T.; Horiuchi, S.; Eguchi, T.; Kakinuma, K. J. Chem. Soc., Perkin 1 2002, 949. 10. Guerlavais, V.; Carroll, P. J.; Joullié, M. M. Tetrahedron: Asymmetry 2002, 13, 675. 11. Hein, J. E.; Hultin, P. G. Synlett 2003, 635. 12. Li, G.; Xu, X.; Chen, D.; Timmons, C.; Carducci, M. D.; Headley, A. D. Org. Lett. 2003, 5, 329. 13. Zhang, W.; Carter, R. G.; Yokochi, A. F. T. J. Org. Chem 2004, 69, 2569. 220

Favorskii rearrangement and quasi-Favorskii rearrangement

Favorskii rearrangement Transformation of enolizable D-haloketones to esters, carboxylic acids, or amides via alkoxide-, hydroxide-, or amine-catalyzed rearrangements, respectively.

O OOR Cl OR

enolizable D-haloketone

O O H Cl Cl HOR OR

OR O O OR Cl

cyclopropanone intermediate

OOR OOR HOR HOR OR

Example 1, homo-Favorskii rearrangement3

O OO TsO O 1.96 eq. NaOH H

dioxane/H2O 90 oC, 3 h, 86% 51:40:9 221

Quasi-Favorskii rearrangement

O OH OH O

CO H Br 2 Br non-enolizable ketone

Example 111

Li

Br o O O THF, 78 to 30 C, 90%

References

1. Favorskii, A. E. J. Prakt. Chem. 1895, 51, 533. Aleksei E. Favorskii (18601945), born in Selo Pavlova, Russia, studied at St. Petersburg State University, where he became a professor in 1900. 2. Favorskii, A. E. J. Prakt. Chem. 1913, 88, 658. 3. Wenkert, E.; Bakuzis, P.; Baumgarten, R. J.; Leicht, C. L.; Schenk, H. P. J. Am. Chem. Soc. 1971, 93, 3208. 4. Chenier, P. J. J. Chem. Educ. 1978, 55, 286291. (Review). 5. Barreta, A.; Waegell, B. In Reactive Intermediates; Abramovitch, R. A., ed.; Plenum Press: New York, 1982, 2, pp 527585. (Review). 6. Gambacorta, A.; Turchetta, S.; Bovicelli, P.; Botta, M. Tetrahedron 1991, 47, 9097. 7. Dhavale, D. D.; Mali, V. P.; Sudrik, S. G.; Sonawane, H. R. Tetrahedron 1997, 53, 16789. 8. Braverman, S.; Cherkinsky, M.; Kumar, E. V. K. S.; Gottlieb, H. E. Tetrahedron 2000, 56, 4521. 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. Zhang, L.; Koreeda, M. Org. Lett. 2002, 4, 3755. 11. Harmata, M.; Wacharasindhu, S. Org. Lett. 2005, 7, 2563. (quasi-Favorskii rearrangement). 222

Feist–Bénary furan synthesis D-Haloketones react with E-ketoesters in the presence of base to fashion furans.

O O OO Et3N, 0 °C, 52 h Cl OEt 5457% CO2Et

Et N: 3 Et3NH H CO2Et O rate-determining CO2Et Cl step O O

OH Cl CO2Et HO H O CO2Et 2 CO2Et H Et3NH O :NEt3

O O:

CO Et 2 CO2Et

H O O Et3N:

Example 14,5

O OO + OEt OCH3 Cl O

O KOH, MeOH H3CO2C

OCH3 57% O

Example 26 223

O O OO pyridine, rt to 50 °C, 4 h Cl + H OEt then rt, overnight, 86% CO2Et

References

1. Feist, F. Ber. Dtsch. Chem. Ges. 1902, 35, 1537. 2. Bénary, E. Ber. Dtsch. Chem. Ges. 1911, 44, 489. 3. Bisagni, É.; Marquet, J.-P.; André-Louisfert, J.; Cheutin, A.; Feinte, F. Bull. Soc. Chim. Fr. 1967, 2796. 4. Gopalan, A.; Magnus, P. J. Am. Chem. Soc. 1980, 102, 1756. 5. Gopalan, A.; Magnus, P. J. Org. Chem. 1984, 49, 2317. 6. Padwa, A.; Gasdaska, J. R. Tetrahedron 1988, 44, 4147. 7. 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, 167238. (Review). 8. Cambie, R. C.; Moratti, S. C.; Rutledge, P. S.; Woodgate, P. D. Synth. Commun. 1990, 20, 1923. 9. 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, 351393. (Review). 10. König, B. Product Class 9: Furans. In Science of Synthesis: HoubenWeyl Methods of Molecular Transformations; Maas, G., Ed.; Georg Thieme Verlag: New York, 2001; Cat. 2, Vol. 9, 183278. (Review). 11. Calter, M.; Zhu, C. Org. Lett. 2002, 4, 205. 12. Calter, M.; Zhu, C.; Lachicotte, R. J. Org. Lett. 2002, 4, 209. 13. 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, 160167. (Re- view). 224

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 While attempting to find a route from carbohydrates to functionalized cyclopentanes (and hence prostaglandins), Robin Ferrier converted alkene 1 to the standard product of methoxymercuration, but was unable to proceed to cyclopentanes by causing C-6 of the C-6-mercurated product to displace the tosyloxy group from C-2. However, hydroxymercuration of 1 with mercury(II) chloride in refluxing aqueous acetone afforded the unstable hemiacetal 2 from which aldehydoke- tone 3 and hence the hydroxyketone 4 were formed spontaneously, the latter crys- tallizing in 83% yield on cooling of the solution.3 The high yield can be increased to 89% by addition of a trace of acetic acid,4 and even higher yields have been reported in similar examples. Catalytic amounts of mercury(II) trifluoroacetate5 and sulfate6 can promote the reaction, and chelation control has been held responsible for the high stereoselectivity usually observed, the favored epimers having the trans-relationship between the hydroxyl groups at the new chiral centers and the substituents at C-3.1,2 General examples: HgCl HgCl

HgCl2, Me2CO, H2O BzO O BzO O+ BzO O BzO BzO BzO reflux, 4.5 h HO O OMe TsOOMe TsOOMe Ts 1 2

HgCl O BzO BzO BzO BzO O 83%3 O O TsOOH 3 Ts 4

OBz O BzO O BzO O BzO BzO OBz BzO BzO OBz BzO OMe OMe O O O OBz BzO BzO BzO OH BzO BzO 6 83% OBz 6 BzO 4 80% OH 93% OH 225

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 7 8 OC H OMe(p) 83% 75%7 86% (2:1) 6 4

Complex bioactive compounds made following the application of the reaction

OH HO OH HO OH H NH O HO OH HO O H O NH HO O O 9 OH O 10 11 Paniculide A Pancratistatin Calystegine B2

Modified hex-5-enopyranosides and reactions OAc HO BnO OAc BnO O BnO BnO BnO OH BnO a,b OMe 85%14

BnO H BnO c HO O 13 BnOMe BnO O 79% BnO O BnO OMe d BnO BnO BnO OMe 98%13 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). 226

References

1. Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 27792831. (Review). 2. Ferrier, R. J. Top. Curr. Chem. 2001, 215, 277291 (Review). 3. Ferrier, R. J. J. Chem. Soc., Perkin Trans. 1 1979, 1455. The discovery (1977) was made in the Pharmacology Department, University of Edinburgh, while R. J. Ferrier was on leave from Victoria University of Wellington, New Zealand where he was Pro- fessor 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. 5. Chida, N.; Ohtsuka, M.; Ogura, K.; Ogawa, S. Bull. Chem. Soc. Jpn. 1991, 64, 2118. 6. Machado, A. S.; Olesker, A.; Lukacs, G. Carbohydr. Res. 1985, 135, 231. 7. Sato, K.-i.; Sakuma, S.; Nakamura, Y.; Yoshimura, J.; Hashimoto, H. Chem. Lett. 1991, 17. 8. Ermolenko, M. S.; Olesker, A.; Lukacs, G. Tetrahedron Lett. 1994, 35, 711. 9. Amano, S.; Takemura, N.; Ohtsuka, M.; Ogawa, S.; Chida, N. Tetrahedron 1999, 55, 3855. 10. Park, T. K.; Danishefsky, S. J. Tetrahedron Lett. 1995, 36, 195. 11. Boyer, F.-D.; Lallemand, J.-Y. Tetrahedron 1994, 50, 10443. 12. Das, S. K.; Mallet, J.-M.; Sinaÿ, P. Angew. Chem. Int. Ed. Engl. 1997, 36, 493. 13. Sollogoub, M.; Mallet, J.-M.; Sinaÿ, P. Tetrahedron Lett. 1998, 39, 3471. 14. Bender, S. L.; Budhu, R. J. J. Am. Chem. Soc. 1991, 113, 9883. 15. Estevez, V. A.; Prestwich, E. D. J. Am. Chem. Soc. 1991, 113, 9885. 227

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 ii) HSPh7 AcO O + Lewis acid AcO + AcO O AcO 4 OAc iii)

R = i) OCH CCH6 OAc 2 7 O ii) SPh 4 iii) AcO R General examples4

OAc SnBr4, C6H14, EtOAc AcO O AcO rt, 5 min, 94% OAc AcO O H 228

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 OO By spontaneous sigmatropic In PhCOCH CO Et, 2 2 rearrangement of the glycal In benzene, BF .OEt BF3.OEt2, 3 2, 3-trichloroacetimidate made 5 oC, 10 min, (67%, rt, 15 min, with NaH, Cl3CCN, 8 9 D-anomer). (81% D-anomer). 10 (78% Danomer).

Products formed without acid catalysts

HO OO OMe AcO OO

Promoter: DEAD, Ph3P DDQ D-anomer)11 (88%, mainly D)12 C-3 leaving group of glycal: hydroxy acetoxy

O O O O O O O O O N-iodonium dicollidine perchlorate (65%, mainly D)13 pent-4-enoyloxy 229

Modified glycals and their reactions: OBn OH O Me O O N N OBn + Ph + BnO O N N OAc I H OBn O Cl O O N N O Ph BnO O N N H

o BF3•OEt2, CH2Cl2, 0 C AgNO3, Na2CO3, reflux MeNO2, 15 (70%, mainly D 14 6 h (58%, DE References

1. Ferrier, R. J.; Zubkov, O. A. Transformation of glycals into 2,3-unsaturated glycosyl derivatives, In Org. React. 2003, 62, 569736. (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, 175. (Review). 3. Fischer, E. Chem. Ber. 1914, 47, 196. 4. Herscovici, J.; Muleka, K.; Boumaïza, L.; Antonakis, K. J. Chem. Soc., Perkin Trans. 1 1990, 1995. 5. Ferrier, R. J.; Prasad, N. J. Chem. Soc. (C) 1969, 581. 6. Moufid, N.; Chapleur, Y.; Mayon, P. J. Chem. Soc., Perkin Trans. 1 1992, 999. 7. Whittman, M. D.; Halcomb, R. L.; Danishefsky, S. J.; Golik, J.; Vyas, D. J. Org. Chem. 1990, 55, 1979. 8. Klaffke, W.; Pudlo, P.; Springer, D.; Thiem, J. Liebigs Ann. Chem. 1991, 509. 9. Yougai, S.; Miwa, T. J. Chem. Soc., Chem. Commun. 1983, 68. 10. Armstrong, P. L.; Coull, I. C.; Hewson, A. T.; Slater, M. J. Tetrahedron Lett. 1995, 36. 4311. 11. Sobti, A.; Sulikowski, G. A. Tetrahedron Lett. 1994, 35. 3661. 12. Toshima, K.; Ishizuka, T.; Matsuo, G.; Nakata, M.; Kinoshita, M. J. Chem. Soc., Chem. Commun. 1993, 704. 13. López, J. C.; Gómez, A. M.; Valverde, S.; Fraser-Reid, B. J. Org. Chem. 1995, 60, 3851. 14. Booma, C.; Balasubramanian, K. K. Tetraherdron Lett. 1993, 34, 6757. 15. Tam, S. Y.-K.; Fraser-Reid, B. Can. J. Chem. 1977, 55, 3996. 16. Ferrier, R. J.; Overend, W. G.; Ryan, A. E. J. Chem. Soc. (C) 1962, 3667. 17. Ferrier, R. J. J. Chem. Soc.1964, 5443. 230

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.

O MeO C CO Me HS 2 2 OMe

CO2Me NaOMe S OH

MeO2C

O O MeO C 2 O HS OCH3 OMe + O S OMe H CO S 3 OMe O

O MeO2C MeO2C OMe O S OMe S S MeO2C O CO Me MeO C 2 S 2 OMe

OMe O H O MeO O HS OMe S OMe NaOMe S CO2Me MeO2C 231

OCH3 CO2Me O O O S OMe S OMe S MeO2C S CO2Me CO2Me MeO2C

CO Me H 2 HOMe S O OMe H MeO2C S CO2Me

CO Me MeO CO Me 2 H 2 OH S O S

MeO2C MeO2C

Example 16

O HS N S NCl OEt CO2Et CN NaH, DMSO, 89% NH2

Example 28

S CO Me HSCH2CO2Me 2 CN NaOMe, 68% NH2

References

1. Fiesselmann, H.; Schipprak, P. Chem. Ber. 1954, 87, 835; Fiesselmann, H.; Schipprak, P.; Zeitler, L. Chem. Ber. 1954, 87, 841; Fiesselmann, H.; Pfeiffer, G. Chem. Ber. 1954, 87, 848; Fiesselmann, H.; Thoma, F. Chem. Ber. 1956, 89, 1907; Fiesselmann, H.; Schipprak, P. Chem. Ber. 1956, 89, 1897. 2. Gronowitz, S. In Thiophene and Its Derivatives, Part 1, Gronowitz, S., Ed.; Wiley & Sons: New York, 1985, 88125. (Review). 232

3. Nicolaou, K. C.; Skokotas, G.; Furuya, S.; Suemune, H.; Nicolaou, D. C. Angew. Chem. Int. Ed. Engl. 1990, 29, 1064. 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. 5. Ram, V. J.; Goel, A.; Shukla, P. K.; Kapil, A. Bioorg. Med. Chem. Lett. 1997, 7, 3101. 6. Showalter, H. D. H.; Bridges, A. J.; Zhou, H.; Sercel, A. D.; McMichael, A.; Fry, D. W. J. Med. Chem. 1999, 42, 5464. 7. Shkinyova, T. K.; Dalinger, I. L.; Molotov, S. I.; Shevelev, S. A. Tetrahedron Lett. 2000, 41, 4973 8. Redman, A. M.; Johnson, J. S.; Dally, R.; Swartz, S.; et al. Bioorg. Med. Chem. Lett. 2001, 11, 9. 9. Migianu, E.; Kirsch, G. Synthesis, 2002, 1096. 10. 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, 184192. (Review). 233

Fischer indole synthesis Cyclization of arylhydrazones to indoles.

R1 1 R1 R R2 2 NH R H 2 N 2 N R H O N NH3 N H H phenylhydrazine phenylhydrazone

R1 R1 H R2 R2 [3,3]-sigmatropic

N NH rearrangement N N 2 + H H H protonation ene-hydrazine

1 R R1 H 2 R R2 tautomerization

NH2 NH N N 2 H H H+ 2 double imine

R1 H R1 H R1 2 R R2 NH3 R2 N NH2 N NH3 N H H H H

Example 18,12

O O N Ph + NH2 N NN H H 234

N

1) neat, 160 oC, 24 h HN o 2) NH2NH2, 120 C, 12 h N 71% N H Example 213 O AcOH, '5 h

NH2 CN 57% NH CO2Et

CN N H CO2Et References

1. Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16, 2241. H. Emil Fischer (18521919) 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 Chemistry in 1902 (three years ahead of his master, von Baeyer) for his synthetic studies in the area of sugar and purine groups. 2. Fischer, E.; Hess, O. Ber. Dtsch. Chem. Ges. 1884, 17, 559. 3. Shriner, R. L.; Ashley, W. C.; Welch, E. Org. Synth. 1955, Coll. Vol. 3, 725. 4. Robinson, B. Chem. Rev. 1963, 63, 373401. (Review). 5. Robinson, B. Chem. Rev. 1969, 69, 227250. (Review). 6. Ishii, H. Acc. Chem. Res. 1981, 14, 275283. (Review). 7. Robinson, B. The Fisher Indole Synthesis, John Wiley & Sons, New York, NY, 1982. (Book). 8. Hughes, D. L. Org. Prep. Proc. Int. 1993, 25, 607-632. (Review). 9. Bosch, J.; Roca, T.; Armengol, M.; Fernández-Forner, D. Tetrahedron 2001, 57, 1041. 10. Pete, B.; Parlagh, G. Tetrahedron Lett. 2003, 44, 2537. 11. 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, 100103. (Re- view). 235

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 + OH H O R2 OR2 R N 1 OH : R1 N NH HO R Cl 1 Cl Cl

H R2 O R2 H R1 O HCl SN2 N R N H2O 1 Cl Cl

R2 O R2 H N elimination isomerization O R N 1 HCl Cl R1

Example 16

OH TsOH, Tol.

NH2 H3C reflux CHO O

o POCl3, 8085 C O O CH HN 3 CH3 15 min., 40% N O 236

Example 210

Cl OH dry HCl gas NH CN Cl SOCl2, ether HO HO

N N

CHO O OH N dry HCl gas, 16.5% halfordinal

References

1. Fischer, E. Ber. 1896, 29, 205. 2. Ingham, B. H. J. Chem. Soc. 1927, 692. 3. Minovici, S.; Nenitzescu, C. D.; Angelescu, B. Bull Soc. Chem. Romania 1928, 10, 149; Chem. Abstracts 1929, 23, 2716. 4. Ladenburg, K.; Folkers, K.; Major, R. T. J. Am. Chem. Soc. 1936, 58, 1292. 5. Wiley, R. H. Chem. Rev. 1945, 37, 401442. (Review). 6. Cornforth, J. W.; Cornforth, R. H. J. Chem. Soc. 1949, 1028. 7. Cornforth, J. W. In Heterocyclic Compounds 5; Elderfield, R. C. Ed.; Wiley & Sons: New York, 1957, 5, 309312. (Review). 8. Crow, W. D.; Hodgkin, J. H. Tetrahedron Lett. 1963, 2, 85; Austr. J. Chem. 1964, 17, 119. 9. Brossi, A.; Wenis, E. J. Heterocyclic Chem. 1965, 2, 310. 10. Onaka, T. Tetrahedron Lett. 1971, 4393. 11. Brooks, D. A. Fisher Oxazole Synthesis in Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 234236. (Review). 237

FlemingKumada oxidation Stereoselective oxidation of alkyl-silanes into the corresponding alkyl-alcohols using peracids.

1. HX SiMe Ph 2 2. ArCO3H, base OH 1 1 RR 3. hydrolysis RR retention of configuration

ipso H Si + Si H substitution X 1 RR1 RR the E-carbocation is stabilized by the silicon group

Ar X H Ar Si HX O ArCO2 :O Si O O 1 O O RR RR1

H O H O OAr O :O O : OAr ArCO2 OAr Si O Si O O Si O O 1 RR1 RR RR1

O OAr O O Ar Si O O O O Si O O RR1 RR1 238

O HO O O Ar hydrolysis O Ar O O Si Si O O OH O O 1 RR RR1

O

HO Ar O OH 1 RR1 RR

Example 17

O O OH O C8H18 m-CPBA, KHF2, DMF NBoc 0 to 25 oC, 55 70% (EtO)2PhSi OTBS

O O OH O C8H18 NBoc HO OTBS

Example 212

SiMe (OMe) OH 2 KF, KHCO MeO2C 3 MeO2C THF-MeOH

30% H2O2, 77% CO2Me CO2Me 239

TamaoKumada oxidation15 Oxidation of alkyl fluorosilanes to the corresponding alcohols. A variant of the FlemingKumada oxidation.

F F KF, H2O2 2 ROH Si R R KHCO3, DMF

F F F R F F F Si F RSi RSiF Si R O R O R F R R F F HO : HO H H F O H H O

F F F OSiF OSi 2 ROH R O R R F F R

References

1. Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem. Commun. 1984, 29. 2. Fleming, I.; Sanderson, P. E. J. Tetrahedron Lett. 1987, 28, 4229. 3. Fleming, I.; Dunoguès, J.; Smithers, R. Org. React. 1989, 37, 57576. (Review). 4. Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599. 5. Hunt, J. A.; Roush, W. R. J. Org. Chem. 1997, 62, 1112. 6. Knölker, H.-J.; Jones, P. G.; Wanzl, G. Synlett 1997, 613. 7. 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. 8. Lee, T. W.; Corey, E. J. Org. Lett. 2001, 3, 3337. 9. Rubin, M.; Schwier, T.; Gevorgyan, V. J. Org. Chem. 2002, 67, 1936. 10. Boulineau, F. P.; Wei, A. Org. Lett. 2002, 4, 2281. 11. Jung, M. E.; Piizzi, G. J. Org. Chem. 2003, 68, 2572. 12. Clive, D. L. J.; Cheng, H.; Gangopadhyay, P.; Huang, X.; Prabhudas, B. Tetrahedron 2004, 60, 4205. 13. Sanganee, M. J.; Steel, P. G.; Whelligan, D. K. Org. Biomol. Chem. 2004, 2, 2393. 14. Ko, C. H.; Jung, D. Y.; Kim, M. K.; Kim, Y. H. Synlett 2005, 304. 15. Tamao, K.; Ishida, N.; Kumada, M. J. Org. Chem. 1983, 48, 2120. 240

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 RCl R HCl AlCl3

O: O complexation AlCl AlCl3 3 RCl: RCl

O O electrophilic R AlCl4 R substitution

acylium ion

Cl Cl Al Cl O Cl aromatization O R AlCl3 H HCl R

Example 116

F

O F O Cl F N CHO AlCl3, CH2Cl2 N 88% F CHO 241

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.

AlCl AlCl R 3 R 3 R Cl: Cl AlCl4

Cl Cl Al Cl R Cl aromatization H R HCl

alkyl cation

Example 27

O

O O

O Br

O

SnCl4, CH2Cl2 O O

0 oC, 1 h, 84% O

References

1. Friedel, C.; Crafts, J. M. Compt. Rend. 1877, 84, 1392. Charles Friedel (18321899) 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 (18391917) was born in Boston, Mas- sachusetts. 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 242

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 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. 3. Gore, P. H. Chem. Ind. 1974, 727. 4. Chevrier, B.; Weiss, R. Angew. Chem., Int. Ed. Engl. 1974, 13, 1. 5. Schriesheim, A.; Kirshenbaum, I. Chemtech 1978, 8, 310314. (Review). 6. Hermecz, I.; Mészáros, Z. Adv. Heterocyclic Chem. 1983, 33, 241. 7. Patil, M. L.; Borate, H. B.; Ponde, D. E.; Bhawal, B. M.; Deshpande, V. H. Tetrahe- dron Lett. 1999, 40, 4437. 8. Ottoni, O.; Neder, A. de V. F.; Dias, A. K. B.; Cruz, R. P. A.; Aquino, L. B. Org. Lett. 2001, 3, 1005. 9. Fleming, I. Chemtracts: Org. Chem. 2001, 14, 405. (Review). 10. Metivier, P. Friedel-Crafts Acylation In Friedel-Crafts Reaction Sheldon, R. A.; Bek- kum, H. eds., Wiley-VCH: New York. 2001, pp161172. (Review). 11. Meima, G. R.; Lee, G. S.; Garces, J. M. Friedel-Crafts Alkylation In FriedelCrafts Reaction Sheldon, R. A.; Bekkum, H. eds. Wiley-VCH: New York. 2001, pp550556. (Review). 12. Le Roux, C.; Dubac, J. Synlett 2002, 181. 13. Sefkow, M.; Buchs, J. Org. Lett. 2003, 5, 193. 14. Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. Engl. 2004, 43, 550556. (Review). 15. Fakhraian, H.; Zarinehzad, M.; Ghadiri, H. Org. Prep. Proced. Int. 2005, 37, 377. 16. Ba Sappa; Mantelingu, K.; Sadashira, M. P.; Rangappa, K. S. Indian J. Chem. B. 2004, 43, 1954. 243

Friedländer quinoline synthesis The Friedländer quinoline synthesis combines an D-amino aldehyde or ketone with another aldehyde or ketone with at least one methylene D adjacent to the carbonyl to furnish a substituted quinoline. The reaction can be promoted by acid, base, or heat.

CHO OOH R R R1 1 NH2 N R

O O R R 1 R1 R Aldol O H condensation H HO NH2

OH R R OH 1 H R COR1 : O NH2 NH2

R R OH N 1 R 1 H N R HO

Example 15

CHO NBnNaOMe, EtOH NBn

NH2 O reflux, 3 h, 90% N 244

Example 215

H N O NO O AcOH, 100 °C N O 88% NHBoc OBn OBn

References

1. Friedländer, P. Ber. Dtsch. Chem. Ges. 1882, 15, 2572. Paul Friedländer (18571923), 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, 181–191. (Review). 4. Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37. (Review). 5. Shiozawa, A.; Ichikawa, Y.-I.; Komuro, C.; Kurashige, S.; Miyazaki, H.; Yamanaka, H.; Sakamoto, T. Chem. Pharm. Bull. 1984, 32, 2522. 6. Thummel, R. P. Synlett 1992, 1. 7. Riesgo, E. C.; Jin, X.; Thummel, R. P. J. Org. Chem. 1996, 61, 3017. 8. Mori, T.; Imafuku, K.; Piao, M.-Z.; Fujimori, K. J. Heterocycl. Chem. 1996, 33, 841. 9. Ubeda, J. I.; Villacampa, M.; Avendaño, C. Synthesis 1998, 1176. 10. Bu, X.; Deady, L. W. Synth. Commun. 1999, 29, 4223. 11. Strekowski, L.; Czarny, A.; Lee, H. J. Fluorine Chem. 2000, 104, 281. 12. Chen, J.; Deady, L. W.; Desneves, J.; Kaye, A. J.; Finlay, G. J.; Baguley, B. C.; Denny, W. A. Bioorg. Med. Chem. 2000, 8, 2461. 13. Gladiali, S.; Chelucci, G.; Mudadu, M. S.; Gastaut, M.-A.; Thummel, R. P. J. Org. Chem. 2001, 66, 400. 14. Hsiao, Y.; Rivera, N. R.; Yasuda, N.; Hughes, D. L.; Reider, P. J. Org. Lett. 2001, 3, 1101; and 2002, 4, 1243. 15. Henegar, K. E.; Baughman, T. A. J. Heterocycl. Chem. 2003, 40, 601. 16. Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.; McWilliams, J. C.; Reider, P. J.; Sager, J. W.; Volante, R. P. J. Org. Chem. 2003, 68, 467. 17. Pflum, D. A. Friedländer Quinoline Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 411415. (Review). 245

Fries rearrangement Lewis acid-catalyzed rearrangement of phenol esters and lactams to 2- or 4- ketophenols. Also known as the FriesFinck rearrangement.

O OH OH O OR AlCl 3 and/or R

OR

AlCl3 Cl Al O: 3 O AlCl O 3 complexation CO bond O OR OR

fragmentation R

aluminum phenolate, acylium ion

H+ AlCl3 OH O O O O H O R R R

H+ AlCl3 OH O O

OR H O OR R 246

Example 111

Br OH O OH OMe O ZrCl4, PhCl

O Br o 160 C, 3 h, 63% Br Br

Example 212

O OH O O 10% Bi(OTf)3, PhMe

110 oC, 15 h, 64% OAc OAc

References

1. Fries, K.; Finck, G. Ber. Dtsch. Chem. Ges. 1908, 41, 4271. Karl Theophil Fries (18751962) was born in Kiedrich near Wiesbaden on the Rhine. He earned his doctorate under Theodor 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 FriesFinck rearrangement. 2. Martin, R. Bull. Soc. Chim. Fr. 1974, 983988. (Review). 3. Martin, R. Org. Prep. Proced. Int. 1992, 24, 369-435. (Review). 4. Trehan, I. R.; Brar, J. S.; Arora, A. K.; Kad, G. L. J. Chem. Educ. 1997, 74, 324. 5. Boyer, J. L.; Krum, J. E.; Myers, M. C.; Fazal, A. N.; Wigal, C. T. J. Org. Chem. 2000, 65, 4712. 6. Harjani, J. R.; Nara, S. J.; Salunkhe, M. M. Tetrahedron Lett. 2001, 42, 1979. 7. Focken, T.; Hopf, H.; Snieckus, V.; Dix, I.; Jones, P. G. Eur. J. Org. Chem. 2001, 2221. 8. Kozhevnikova, E. F.; Derouane, E. G.; Kozhevnikov, I. V. Chem. Commun. 2002, 1178. 9. Clark, J. H.; Dekamin, M. G.; Moghaddam, F. M. Green Chem. 2002, 4, 366. 10. Sriraghavan, K.; Ramakrishnan, V. T. Tetrahedron 2003, 59, 1791. 11. Tisserand, S.; Baati, R.; Nicolas, M.; Mioskowski, C. J. Org. Chem. 2004, 69, 8982. 12. Ollevier, T.; Desyroy, V.; Asim, M.; Brochu, M.-C. Synlett 2004, 2794. 13. Easwaramurthy, M.; Ravikumar, R.; Lakshmanan, A. J.; Raju, G. J. Indian J. Chem., Sect. B 2005, 44B, 635. 247

Fukuyama amine synthesis Transformation of a primary amine to a secondary amine using 2,4-dinitrobenzenesulfonyl chloride and an alcohol. Also known as FukuyamaMitsunobu procedure.

SO Cl 1 2 1. R NH2, pyr. S CO2H NO2 2 2. R OH, PPh3, DEAD H NO2 N R1 R2 SO2 3. HSCH2CO2H NO 2 NO2

Cl 1 1 2 SO2NHR SO2NR R SO 2 : 2 + NO2 R OH, PPh3 NO2 1 H R NH2 NO2 DEAD

NO2 NO2 NO2

See page 390 for mechanism of the Mitsunobu reaction.

H SCOH : 2 NR1R2 SO NR1R2 2 S SO2 SNAr NO2 HO2C NO2 H+

NO2 NO2 Meisenheimer complex

S CO2H H NO2 N SO2 R1 R2

NO2 248

Example 19

H2N SO2 PyPh2P, DTBAD OH NO2 CH2Cl2, 84%

PyPh2P = diphenyl 2-pyridylphosphine; DTBAD = di-tert-butylazodicarbonate

HN K2CO3, PhSH SO2

NO2 CH3CN, 80% NH2

References

1. Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373. Tohru Fu- kuyama moved to the University of Tokyo from Rice University in 1995. 2. Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5831. 3. Yang, L.; Chiu, K. Tetrahedron Lett. 1997, 38, 7307. 4. Piscopio, A. D.; Miller, J. F.; Koch, K. Tetrahedron Lett. 1998, 39, 2667. 5. Bolton, G. L.; Hodges, J. C. J. Comb. Chem. 1999, 1, 130. 6. Lin, X.; Dorr, H.; Nuss, J. M. Tetrahedron Lett. 2000, 41, 3309. 7. Amssoms, K.; Augustyns, K.; Yamani, A.; Zhang, M.; Haemers, A. Synth. Commun. 2002, 32, 319. 8. 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. 9. Guisado, C.; Waterhouse, J. E.; Price, W. S.; JØrgensen, M. R.; Miller, A. D. Org. Biomol. Chem. 2005, 3, 1049. 10. Olsen, C. A.; Witt, M.; Hansen, S. H.; Jaroszewski, J. W.; Franzyk, H. Tetrahedron 2005, 61, 6046. 249

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 RH

Path A:

O O Pd(0) Et3SiH SEt R SEt oxidative RPd Et Si SEt addition 3

O reductive O H Pd(0) RPd elimination RH

Path B:

Et3SiH Pd(0) Et3SiPdH

O OSiEt3 Et3SiPdH R SEt RSEt Pd Pd(0) H

OSiEt3 O

RSEt RH Et3Si SEt

Example 11

CO Me CO2Me 2 O O

Et3SiH, 10% Pd/C OO OO CHO COSEt acetone, rt, 92% 250

Example 23

EtSH, DCC, DMAP EtS HO2CCO2Me CO2Me O NHBoc NHBoc CH3CN, rt, 1 h, > 70%

Et3SiH, 10% Pd/C H CO2Me acetone, rt, 30 min., >74% O NHBoc

References

1. Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112, 7050. 2. Kanda, Y.; Fukuyama, T. J. Am. Chem. Soc. 1993, 115, 8451. 3. Fujiwara, A.; Kan, T.; Fukuyama, T. Synlett 2000, 1667. 4. Tokuyama, H.; Yokoshima, S.; Lin, S.-C.; Li, L.; Fukuyama, T. Synthesis 2002, 1121. 5. Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002, 41, 4569. 6. Shimada, K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 4048. 7. Kimura, M.; Seki, M. Tetrahedron Lett. 2004, 45, 3219. (Possible mechanisms were proposed in this paper). 8. Miyazaki, T.; Han-ya, Y.; Tokuyama, H.; Fukuyama, T. Synlett 2004, 477. 251

Gabriel synthesis Synthesis of primary amines using potassium phthalimide and alkyl halides.

O 1. RX CO2H N K+ H2NR 2. OH CO2H O

O RX O OH S 2 hydrolysis N K+ N N R

O O

OH H O O OH O N R H N R O O OH

CO2 CO H 2 N H2NR R CO OOH 2 252

Example 110

O O CO Et Br CO Et 2 NK 2 N

DMF, 90 oC, 3 h, 77% O O

O O O O O 6 M HCl, reflux O OH

N

14 h, 93% HCl•H2N

O

References

1. Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224. Siegmund Gabriel (18511924), born in Berlin, 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. Press, J. B.; Haug, M. F.; Wright, W. B., Jr. Synth. Commun. 1985, 15, 837. 3. Slusarska, E.; Zwierzak, A. Justus Liebigs Ann. Chem. 1986, 402. 4. Han, Y.; Hu, H. Synthesis 1990, 122. 5. Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1991, 24, 285–289. (Review). 6. Toda, F.; Soda, S.; Goldberg, I. J. Chem. Soc., Perkin Trans. 1 1993, 2357. 7. Khan, M. N. J. Org. Chem. 1996, 61, 8063. 8. Lávová, M.; Chovancová, J.; Veverková, E.; Toma, Š. Tetrahedron 1996, 52, 14995. 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. 10. Iida, K.; Tokiwa, S.; Ishii, T.; Kajiwara, M. J. Labelled. Compd. Radiopharm. 2002, 45, 569. 253

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 K+ H NR 2 NH 2. NH2NH2 O O

:NH NH O RX O 2 2

SN2 N K+ N R

O O

O O NHNH 2 NHNH: 2 N R NH O O R

O O

NH NH H2NR NH NH ONH O R

Example6

NPht NH2

1. NH2NH2•H2O, THF, reflux, 8 h

2. Pd/C, H2, THF, 95%, 2 steps NPht NH2 254

References

1. Ing, H. R.; Manske, R. H. F. J. Chem. Soc. 1926, 2348. 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. Manske 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. 3. Khan, M. N. J. Org. Chem. 1995, 60, 4536. 4. Hearn, M. J.; Lucas, L. E. J. Heterocycl. Chem. 1984, 21, 615. 5. Khan, M. N. J. Org. Chem. 1996, 61, 8063. 6. Tanyeli, C.; Özçubukçu, S. Tetrahedron: Asymmetry 2003, 14, 1167. 7. Ariffin, A.; Khan, M. N.; Lan, L. C.; May, F. Y.; Yun, C. S. Synth. Commun. 2004, 34, 4439. 255

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 Ar G ROH NH G G = CO, SO2

O OMe O OMe

N N R R O O O O

O O OMe OMe OH N N R O O O

O O OH O O O O R R R NH N NH O OH O

Example11

O O OH O Oi-Pr 4 equiv i-PrONa Oi-Pr N S i-PrOH, reflux NH O S O 5 min., 85% O O 256

References

1. Gabriel, S.; Colman, J. Chem. Ber. 1900, 33, 980. 2. Gabriel, S.; Colman, J. Chem. Ber. 1900, 33, 2630. 3. Gabriel, S.; Colman, J. Chem. Ber. 1902, 35, 1358. 4. Allen, C. F. H. Chem. Rev. 1950, 47, 275305. (Review). 5. Hauser, C.R. and Kantor, S. W. J. Am. Chem. Soc. 1951, 73, 1437. 6. Gensler, W. J. Heterocyclic Compounds, Vol. 4, R. C. Elderfield, Ed., Wiley & Sons., New York, N.Y., 1952, 378. (Review). 7. Albert, A. and Hampton, A. J. Chem. Soc. 1952, 4985. 8. Koelsch, C. F.; Lindquist, R. M. J. Org. Chem. 1956, 21, 657. 9. Hill, J. H. M.; J. Org. Chem. 1965, 30, 620. (Mechanism). 10. Lombardino, J. G.; Wiseman, E. H.; McLamore, W. M. J. Med. Chem. 1971, 14, 1171. 11. Schapira, C. B.; Perillo, I. A.; Lamdan, S. J. Heterocycl. Chem. 1980, 17, 1281. 12. Schapira, C. B.; Abasolo, M. I.; Perillo, I. A. J. Heterocycl. Chem. 1985, 22, 577. 13. Groutas, W. C.; Chong, L. S.; Venkataraman, R.; Epp, J. B.; Kuang, R.; Houser- Archield, N.; Hoidal, J. R. Bioorg. Med. Chem. 1995, 3, 187. 14. Lazer, E. S.; Miao, C. K.; Cywin, C. L.; et al. J. Med. Chem. 1997, 40, 980. 15. Pflum, D. A. GabrielColman Rearrangement In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 416422. (Review). 257

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.

S

t-BuOCl R Et3N S R NH2 NH O N Cl H

Et3N : R S O : SN2 O H NH R S Cl N H sulfonium ion

O Et3N: S [2,3]-sigmatropic H H NEt R O 3 S rearrangement N R H (Sommelet-Hauser) NH

Et3N: S H S 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) Et3N, 69% 258

Example 21

SCH3 1) t-BuOCl

O SCH N NH2 2) 3

3) Et3N

LiAlH4, Et2O 0 oC, 48% overall N H

References

1. Gassman, P. G.; van Bergen, T. J.; Gilbert, D. P.; Cue, B. W., Jr. J. Am. Chem. Soc. 1974, 96, 5495. Paul G. Gassman (19351993) was a professor at the University of Minnesota (19741993). 2. Gassman, P. G.; van Bergen, T. J. J. Am. Chem. Soc. 1974, 96, 5508. 3. Gassman, P. G.; Gruetzmacher, G.; van Bergen, T. J. J. Am. Chem. Soc. 1974, 96, 5512. 4. Wierenga, W. J. Am. Chem. Soc. 1981, 103, 5621. 5. Ishikawa, H.; Uno, T.; Miyamoto, H.; Ueda, H.; Tamaoka, H.; Tominaga, M.; Naka- gawa, K. Chem. Pharm. Bull. 1990, 38, 2459. 6. Smith, A. B., III; Sunazuka, T.; Leenay, T. L.; Kingery-Wood, J. J. Am. Chem. Soc. 1990, 112, 8197. 7. Smith, A. B., III; Kingery-Wood, J.; Leenay, T. L.; Nolen, E. G.; Sunazuka, T. J. Am. Chem. Soc. 1992, 114, 1438. 8. Savall, B. M.; McWhorter, W. W.; Walker, E. A. J. Org. Chem. 1996, 61, 8696. 9. 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, 128131. (Review). 259

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 :

:: AlCl :C O :CO 3 :CO: AlCl3

Cl : Cl HCl : CO :C O AlCl3 AlCl3 H+

AlCl : O: O O 3 Cl Al AlCl4 3 Cl H Cl H H acylium ion

Cl O CHO H CHO AlCl4 AlCl H 3

CHO HCl AlCl3

Example, a more practical variant4

OH OH Zn(CN)2, AlCl3 NH2 o Cl HO HCl (g), 0 C; HO orcinol 260

OH o H2O, 0 to 100 C CHO

95% HO

References

1. Gattermann, L.; Koch, J. A. Ber.1897, 30, 1622. Ludwig Gattermann (18601920) 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, 290300. (Review). 3. Truce, W. E. Org. React. 1957, 9, 3772. (Review). 4. Solladié, G.; Rubio, A.; Carreño, M. C.; García Ruano, J. L. Tetrahedron: Asymmetry 1990, 1, 187. 5. Tanaka, M.; Fujiwara, M.; Ando, H. J. Org. Chem. 1995, 60, 2106. 6. Tanaka, M.; Fujiwara, M.; Ando, H.; Souma, Y. Chem. Commun. 1996, 159. 7. Tanaka, M.; Fujiwara, M.; Xu, Q.; Souma, Y.; Ando, H.; Laali, K. K. J. Am. Chem. Soc. 1997, 119, 5100. 8. Tanaka, M.; Fujiwara, M.; Xu, Q.; Ando, H.; Raeker, T J. J. Org. Chem. 1998, 63, 4408. 9. Kantlehner, W.; Vettel, M.; Gissel, A; Haug, E.; Ziegler, G.; Ciesielski, M.; Scherr, O.; Haas, R. J. Prakt. Chem. 2000, 342, 297. 10. Doana, M. I.; Ciuculescu, A.; Bruckner, A.; Pop, M.; Filip, P. Rev. Roum. Chim. 2002, 46, 345. 261

Gewald aminothiophene synthesis Base-promoted aminothiophene formation from ketone, D-active methylene nitrile and elemental sulfur.

2 R O 2 R CO2R CO2R Base S8 1 R1 R CN S NH2

O O 2 Knoevenagel OR2 O R OR BH H condensation B: 1 CN R CN

1 OOR2 R R O R1 HO R 2 BH O R NC OR CN H HO NC OR2 R1 H :B :B

OOR2 OOR2 R H B CN R N

1 : R S S 1 S S R S SS 6 S S SS

2 R O2C NH 2 R R CO2R S S S S7 B 1 S 1 R H S R NH2 S S S S 262

Example 18

H CCH 3 N 3 CO2Et

CO2Et S8 NH2 + S CN morpholine N 82% N

Example 213

Me CO2Et OO CO2Et S8, EtOH, morpholine + O o CN 60 C, 5 h, 74% t-BuO2C S NH2

References

1. Gewald, K. Z. Chem. 1962, 2, 305. 2. Gewald, K.; Schinke, E.; Böttcher, H. Chem. Ber. 1966, 99, 94. 3. Gewald, K.; Neumann, G.; Böttcher, H. Z. Chem. 1966, 6, 261. 4. Gewald, K.; Schinke, E. Chem. Ber. 1966, 99, 2712. 5. Mayer, R.; Gewald, K. Angew. Chem., Int. Ed. Engl. 1967, 6, 294306. (Review). 6. Gewald, K. Chimia 1980, 34, 101110. (Review). 7. Peet, N. P.; Sunder, S.; Barbuch, R. J.; Vinogradoff, A. P. J. Heterocycl. Chem. 1986, 23, 129. 8. Bacon, E. R.; Daum, S. J. J. Heterocycl. Chem. 1991, 28, 1953. 9. Sabnis, R. W. Sulfur Reports 1994, 16, 1. (Review). 10. Guetschow, M.; Schroeter, H.; Kuhnle, G.; Eger, K. Monatsh. Chem. 1996, 127, 297. 11. Zhang, M.; Harper, R. W. Bioorg. Med. Chem. Lett. 1997, 7, 1629. 12. Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J. Heterocycl. Chem. 1999, 36, 333. (Review). 13. Gütschow, M.; Kuerschner, L.; Neumann, U.; Pietsch, M.; Löser, R.; Koglin, N.; Eger, K. J. Med. Chem. 1999, 42, 5437. 14. Baraldi, P. G.; Zaid, A. N.; Lampronti, I.; Fruttarolo, F.; Pavani, M. G.; Tabrizi, M. A.; Shryock, J. C.; Leung, E.; Romagnoli, R. Bioorg. Med. Chem. Lett. 2000, 10, 1953. 15. Pinto, I. L.; Jarvest, R. L.; Serafinowska, H. T. Tetrahedron Lett. 2000, 41, 1597. 16. Buchstaller, H.-P.; Siebert, C. D.; Lyssy, R. H.; Frank, I.; Duran, A.; Gottschlich, R.; Noe, C. R. Monatsh. Chem. 2001, 132, 279. 17. Hoener, A. P. F.; Henkel, B.; Gauvin, J.-C. Synlett 2003, 63. 18. Tinsley, J. M. Gewald Aminothiophene Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 193198. (Review). 263

Glaser coupling Oxidative homo-coupling of terminal alkynes using copper catalyst in the presence of oxygen.

CuCl, O2 H NH4OH, EtOH

Base H CuCl Cu(I)

O2 Cu(II) Cu(I)

dimerization

Example 11

O2 2 Cu NH4OH, EtOH 90%

Example 2, homo-coupling2

Cu, NH4Cl

HO O2, 90% HO OH

References

1. Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422. 2. Bowden, K.; Heilbron, I.; Jones, E. R. H.; Sondheimer, F. J. Chem. Soc. 1947, 1583. 3. Hoeger, S.; Meckenstock, A.-D.; Pellen, H. J. Org. Chem. 1997, 62, 4556. 4. Li, J.; Jiang, H. Chem. Commun. 1999, 2369. 5. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632. (Review). 6. Setzer, W. N.; Gu, X.; Wells, E. B.; Setzer, M. C.; Moriarity, D. M. Chem. Pharm. Bull. 2001, 48, 1776. 264

7. Kabalka, G. W.; Wang, L.; Pagni, R. M. Synlett 2001, 108. 8. Youngblood, W. J.; Gryko, D. T.; Lammi, R. K.; Bocian, D. F.; Holten, D.; Lindsey, J. S. J. Org. Chem. 2002, 67, 2111. 9. Yadav, J. S.; Reddy, B. V. S.; Reddy, K. B.; Gayathri, K. U.; Prasad, A. R. Tetrahe- dron Lett. 2003, 44, 6493. 10. Moriarty, R. M.; Pavlovic, D. J. Org. Chem. 2004, 69, 5501. 11. Wang, L.; Yan, J.; Li, P.; Wang, M.; Su, C. J. Chem. Res. 2005, 112. 265

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 RH RR pyridine/MeOH

AcOCu OAc pyridine RH R N H

RCuOAc

R dimerization RR R

Example 1, homo-coupling6

Cl NC N NC N Cu(OAc)2, pyridine N MeOH, 1.5 h, 68% CN Cl Cl

Example 2, cross-coupling4

SPh Cu(OAc)2 pyridine/MeOH (1:1)

rt, 72%

Ph CO2Me 266

SPh

CO2Me Ph

References

1. Eglinton, G.; Galbraith, A. R. Chem. Ind. 1956, 737. Geoffrey Eglinton (1927) was born in Cardiff, Wales. 2. Behr, O. M.; Eglinton, G.; Galbraith, A. R.; Raphael, R. A. J. Chem. Soc. 1960, 3614. 3. Eglinton, G.; McRae, W. Adv. Org. Chem. 1963, 4, 225. (Review). 4. Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E.; Uenishi, J. J. Am. Chem. Soc. 1982, 104, 5558. 5. Altmann, M.; Friedrich, J.; Beer, F.; Reuter, R.; Enkelmann, V.; Bunz, U. H. F. J. Am. Chem. Soc. 1997, 119, 1472. 6. Srinivasan, R.; Devan, B.; Shanmugam, P.; Rajagopalan, K. Indian J. Chem., Sect. B 1997, 36B, 123. 7. Nakanishi, H.; Sumi, N.; Aso, Y.; Otsubo, T. J. Org. Chem. 1998, 63, 8632. 8. Müller, T.; Hulliger, J.; Seichter, W.; Weber, E.; Weber, T.; Wübbenhorst, M. Chem. Eur. J. 2000, 6, 54. 9. Märkl, G.; Zollitsch, T.; Kreimeier, P.; Prinzhorn, M.; Reithinger, S.; Eibler, E. Chem. Eur. J. 2000, 6, 3806. 10. Kaigtti-Fabian, K. H. H.; Lindner, H.-J.; Nimmerfroh, N.; Hafner, K. Angew. Chem., Int. Ed. 2001, 40, 3402. 11. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632. (Review). 12. Inouchi, K.; Kabashi, S.; Takimiya, K.; Aso, Y.; Otsubo, T. Org. Lett. 2002, 4, 2533. 13. Xu, G.-L.; Zou, G.; Ni, Y.-H.; DeRosa, M. C.; Crutchley, R. J.; Ren, T. J. Am. Chem. Soc. 2003, 125, 10057. 267

Gomberg–Bachmann reaction Base-promoted radical coupling between an aryl diazonium salt and an arene to form a diaryl compound.

O N 2 OH

O

NN Ph Ph NN : N N NN OH O OH NN Ph

Ph

N2n N N O O

Ph N N O Ph N N OH H O

O

Example 14

O N BF KOAc, 18-C-6 O 2 4 O rt, 55% O O O 268

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. Moses Gomberg (18661947) was born in Elizabetgrad, Russia. He discovered the triphenylmethyl 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 (19011951), 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. DeTar, D. F.; Kazimi, A. A. J. Am. Chem. Soc. 1955, 77, 3842. 3. Eliel, E. L.; Saha, J. G.; Meyerson, S. J. Org. Chem. 1965, 30, 2451. 4. Beadle, J. R.; Korzeniowski, S. H.; Rosenberg, D. E.; Garcia-Slanga, B. J.; Gokel, G. W. J. Org. Chem. 1984, 49, 1594. 5. McKenzie, T. C.; Rolfes, S. M. J. Heterocycl. Chem. 1987, 24, 859. 6. Gurczynski, M.; Tomasik, P. Org. Prep. Proced. Int. 1991, 23, 438. 7. Hales, N. J.; Heaney, H.; Hollinshead, J. H.; Sharma, R. P. Tetrahedron 1995, 51, 7403. 8. Lai, Y.-H.; Jiang, J. J. Org. Chem. 1997, 62, 4412. 269

Gould–Jacobs reaction The Gould–Jacobs reaction is a sequence of the following reactions: a. condensation of an aniline 1 with either alkoxy methylenemalonic ester or acyl malonic ester 2 providing the anilidomethylenemalonic ester 3; b. cyclization of 3 to the 4- hydroxy-3-carboalkoxyquinoline 4; c. saponification to form acid 5, and d. decarboxylation to give the 4-hydroxyquinoline 6.

RO C 2 CO2R ' RO2C CO2R heat + R''OH N R' NH2 R' OR'' H 12 3 R = alkyl R' = alkyl, aryl, or H R'' = alkyl or H OH OH OH ' CO2R HO CO2H

N R' N R' N R' 456

H O O EtO2C EtO2C OEt heat OEt

NH2 OEt N OEt H2

O O H EtO EtO CO2Et CO2Et EtOH '

N N H H

O O H CO2Et electrocylization EtOH CO2Et 6S N N 270

OH tautomerization CO2Et

N Example 113 EtO2CCO2Et O Ph2O, reflux

N 75%, 10:1 H

OH OH O CO2Et O CO2Et

N N References

1. Gould, R. G.; Jacobs, W. A. J. Am. Chem. Soc. 1939, 61, 2890. 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 Rockefeller Institute for Medical Research where he discovered the Gould–Jacobs reaction with his colleague Walter A. Jacobs. 2. Baker, R. H., Lappin, G. R., Albisetti, C. J., Riegel, B. J. Am. Chem. Soc. 1946, 68, 1267. 3. Jones, G. In Heterocyclic Compounds, Quinolines Vol. 32, chapter 2, pp 146150, 158, 159. (Review). 4. Reitsema, R. H. Chem. Rev. 1948, 53, 43. (Review). 5. Elderfield, R. C. In Heterocyclic Compounds, Elderfield, R. C., Wiley & Sons, New York, 1952, vol. 4, pps. 3841. (Review). 6. Price, C. C., Snyder, H. R., Bullitt, O. H., Kovacic, P. J. Am. Chem. Soc. 1947, 69, 374. 7. Briehl, H., Lukosch, A., Wentrup, C. J. Org. Chem. 1984, 49, 2772. 8. Ouali, M. S., Vaultier, M., Carrie, R. Tetrahedron 1980, 36, 1821. 9. Horvath, G., Hermecz, I., Gorvath, A., Pongor-Csakvari, M., Pusztay, L. J. Hetero- cycl. Chem. 1985, 22, 481. 10. Agui, H., Komatsu, T., Nakagome, T. J. Heterocycl. Chem. 1975, 12, 557. 11. Sabnis, R. W., Rangnekar, D. W. J. Heterocycl. Chem. 1991, 28, 1105. 12. Suzuki, N., Tanaka, Y., Dohmori, R. Chem. Pharm. Bull. 1979, 27, 1. 13. Cruickshank, P. A., Lee, F. T., Lupichuk, A. J. Med. Chem. 1970, 13, 1110. 14. Hayakawa, I., Suzuki, N., Suzuki, K., Tanaka, Y. Chem. Pharm. Bull. 1984, 32, 4914. 15. Wang, C. G., Langer, T., Kiamath, P. G., Gu, Z. Q., Skolnick, P., Fryer, R. I. J. Med. Chem. 1995, 38, 950. 16. Leyva, E., Monreal, E., Hernandez, A. J. Fluorine Chem. 1999, 94, 7. 17. Dave, C. G.; Joshipura, H. M. Indian J. Chem., Sect. B 2002, 41B, 650. 18. Curran, T. T. Gould–Jacobs REaction in Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 423436. (Review). 271

Grignard reaction Addition of organomagnesium compounds (Grignard reagents), generated from organohalides and magnesium metal, to electrophiles.

O 1 2 Mg(0) R1 R2 R R RX R MgX ROH

Formation of the Grignard reagent:

Mg Mg Mg Mg

RX R X

Mg Mg single electron RMgX transfer R MgBr

Grignard reaction, ionic mechanism:

R2 G G R2 1 2 O O R R R1 R1 R MgX RMgX ROMgX G G

Radical mechanism,

R2 R O R1 R2 O RMgX R1 MgX

R1 R2 H R1 R2 R OMgX ROH 272

Example 16

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 24

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.

References

1. Grignard, V. C. R. Acad. Sci. 1900, 130, 1322. Victor Grignard (France, 18711935) won the Nobel Prize in Chemistry in 1912 for his discovery of the Grignard reagent. 2. Ashby, E. C.; Laemmle, J. T.; Neumann, H. M. Acc. Chem. Res. 1974, 7, 272. (Re- view). 3. Ashby, E. C.; Laemmle, J. T. Chem. Rev. 1975, 75, 521. (Review). 4. Sasaki, T.; Eguchi, S.; Hattori, S. Heterocycles 1978, 11, 235. 5. Lasperas, M.; Perez-Rubalcaba, A.; Quiroga-Feijoo, M. L. Tetrahedron 1980, 36, 3403. 6. Meyers, A. I.; Flisak, J. R.; Aitken, R. A. J. Am. Chem. Soc. 1987, 109, 5446. 7. Grignard Reagents Richey, H. G., Jr., Ed.; Wiley: New York, 2000. (Book). 8. Holm, T.; Crossland, I. In Grignard Reagents Richey, H. G., Jr., Ed.; Wiley: New York, 2000, Chapter 1, pp 126. (Review). 9. Toda, N.; Ori, M.; Takami, K.; Tago, K.; Kogen, H. Org. Lett. 2003, 5, 269. 10. Shinokubo, H.; Oshima, K. Eur. J. Org. Chem. 2004, 20812091. (Review). 11. Graden, H.; Kann, N. Cur. Org. Chem. 2005, 9, 733763. (Review). 273

Grob fragmentation CC bond cleavage primarily via a concerted process involving a five atom system. General scheme:

: X Y X Y

+ X = OH2 , OTs, I, Br, Cl; Y = O , NR2

Example 1

OMOM OMOM MsO MsO NaH

15-crown-5 O OH

OMOM

O

Example 2, aza-Grob fragmentation7

15 eq. NaBH4, THF OH NO SH N o S 70 C, 31 h, 53% H 274

Example 312

OTs NaH, DMSO, 40 oC, 1 h;

OH then tosylate, 40 oC, 1 h MeO 52%

O MeO

References

1. Grob, C. A.; Baumann, W. Helv. Chim. Acta 1955, 38, 594. 2. Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl. 1967, 6, 1. 3. French, L. G.; Charlton, T. P. Heterocycles 1993, 35, 305. 4. Harmata, M.; Elahmad, S. Tetrahedron Lett. 1993, 34, 789. 5. Armesto, X. L.; Canle L., M.; Losada, M.; Santaballa, J. A. J. Org. Chem. 1994, 59, 4659. 6. Yoshimitsu, T.; Yanagiya, M.; Nagaoka, H. Tetrahedron Lett. 1999, 40, 5215. 7. Hu, W.-P.; Wang, J.-J.; Tsai, P.-C. J. Org. Chem. 2000, 65, 4208. 8. Molander, G. A.; Le Huerou, Y.; Brown, G. A. J. Org. Chem. 2001, 66, 4511. 9. Paquette, L. A.; Yang, J.; Long, Y. O. J. Am. Chem. Soc. 2002, 124, 6542. 10. Barluenga, J.; Alvarez-Perez, M.; Wuerth, K.; Rodriguez, F.; Fananas, F. J. Org. Lett. 2003, 5, 905. 11. Tada, N.; Miyamoto, K.; Ochiai, M. Chem. Pharm. Bull. 2004, 52, 1143. 12. Khripach, V. A.; Zhabinskii, V. N.; Fando, G. P.; et al. Steroids 2004, 69, 495. 275

Guareschi–Thorpe condensation 2-Pyridone formation from the condensation of cyanoacetic ester with diketone in the presence of ammonia.

R R CN CN NH O 3 1 R O O RON R O H

H3N: CN H CN H3N: CN 1 H2N R OH 1 1 R O O R O O H2N O H

H3NH O R OH CN HO R :NH CN H 3 R O RO O NH2 H2N O

R H3N: R R CN H CN CN H2O RON RO O O :NH2 H RON H3NH H H

Example7

NC CN CN NH3 + 75% O CO2Et OON H Guareschi imide 276

References

1. Guareschi, I. Mem. Reale Accad. Sci. Torino 1896, II, 7, 11, 25. 2. Baron, H.; Renfry, F. G. P.; Thorpe, J. F. J. Chem. Soc. 1904, 85, 1726. 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 Col- lege. 3. Vogel, A. I. J. Chem. Soc. 1934, 1758. 4. McElvain, S. M.; Lyle, R. E. Jr. J. Am. Chem. Soc. 1950, 72, 384. 5. Brunskill, J. S. A. J. Chem. Soc. (C) 1968, 960. 6. Brunskill, J. S. A. J. Chem. Soc., Perkin Trans. 1 1972, 2946. 7. Holder, R. W.; Daub, J. P.; Baker, W. E.; Gilbert, R. H. III; Graf, N. A. J. Org. Chem. 1982, 47, 1445. 8. Collins, D. J.; Jones, A. M. Aust. J. Chem. 1989, 42, 215. 9. Krstic, V.; Misic-Vukovic, M.; Radojkovic-Velickovic, M. J. Chem. Res. (S) 1991, 82. 10. Narsaiah, B.; Sivaprasad, A.; Venkataratnam, R. V. Org. Prep. Proced. Int. 1993, 25, 116. 11. Mijin, D. Z.; Misic-Vukovic, M. M. Indian J. Chem., Sect. B 1995, 34B, 348. 12. Mijin, D. Z.; Misic-Vukovic, M. M. Indian J. Chem., Sect. B 1998, 37B, 988. 13. Al-Omran, F.; El-Khair, A. A. Mijin, D. Z.; Misic-Vukovic, M. M. Indian J. Chem., Sect. B 2001, 40B, 608. 14. Galatsis, P. GuareschiThorpe Pyridine Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 307308. (Review). 277

Hajos–Wiechert reaction Asymmetric Robinson annulation catalyzed by (S)-()-proline.

O HO C 2 O cat. H N H

CH3CN O O O

H O O HO2C Michael H N H O addition enamine formation O O O

O O

catalytic asymmetric : N O N H O enamine aldol H CO2 N CO CO H 2 2

O O

H2O: hydrolysis : HO N N OH of iminium salt OH

CO2 CO2

O O O E1cB O OH O H OH O B: 278

Example 11

O O 3 mol% (S)-proline

CH3CN, 100%, 93.4% ee O O O

Example 29

O O L-phenylalanine, PPTS

DMSO, 50 oC, 24 h O O O sonication, 97%, 93% ee OBz OBz

References

1. Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. Hajos and Parrish were chemists at Hoffmann-La Roche. 2. Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496. 3. Brown, K. L.; Dann, L.; Duntz, J. D.; Eschenmoser, A.; Hobi, R.; Kratky, C. Helv. Chim. Acta 1978, 61, 3108. 4. Agami, C. Bull. Soc. Chim. Fr. 1988, 499. 5. Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357. 6. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395. 7. List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573. 8. Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16. 9. Shigehisa, H.; Mizutani, T.; Tosaki, S.-y.; Ohshima, T.; Shibasaki, M. Tetrahedron 2005, 61, 5057. 279

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 HR5 RR5 2 R NH 4 1 4 R1 2 3 R R 2 3 R PhH, reflux 2 R R R R non-enolizable ketone

O O NH RR5 2 RR5 R1 R4 R2 R3 R1 R4 R2 R3 NH2

O R5 HR5 R 4 4 NH2 R R R1 R3 R3 R2

Example 14

CO2H t-BuOK, t-BuOH

43% O

Example 212

HN C6H13 10 mol% LDA, THF O O LiHNC6H13 Ph 0 oC to rt., 5 h, 86% Ph 280

References

1. Haller, A.; Bauer, E. Compt. Rend. 1908, 147, 824. 2. Gilday, J. P.; Gallucci, J. C.; Paquette, L. A. J. Org. Chem. 1989, 54, 1399. 3. Paquette, L. A.; Gilday, J. P.; Maynard, G. D. J. Org. Chem. 1989, 54, 5044. 4. Paquette, L. A.; Gilday, J. P. Org. Prep. Proc. Int. 1990, 22, 167. 5. Muir, D. J.; Stothers, J. B. Can. J. Chem. 1993, 71, 1290. 6. Mehta, G.; Praveen, M. J. Org. Chem. 1995, 60, 279. 7. Mehta, G.; Reddy, K. S.; Kunwar, A. C. Tetrahedron Lett. 1996, 37, 2289. 8. Mehta, G.; Reddy, K. S. Synlett 1996, 229. 9. Mittra, A.; Bhowmik, D. R.; Venkateswaran, R. V. J. Org. Chem. 1998, 63, 9555. 10. Mehta, G.; Venkateswaran, R. V. Tetrahedron 2000, 56, 13991422. (Review). 11. Arjona, O.; Medel, R.; Plumet, J. Tetrahedron Lett. 2001, 42, 1287. 12. Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983. 281

Hantzsch dihydropyridine synthesis Dihydropyridine from the condensation of aldehyde, E-ketoester and ammonia.

R CO2Et O NH3 EtO2C CO2Et

RH O R1 R1 N R1 H

O H3N: H CO2Et enolate RH CO2Et 1 formation O R H 1 H3N: O R

OH :NH3 OH R aldol H CO2Et R CO2Et R CO2Et condensation 1 O R1 O R1 O R

CO2Et CO2Et enamine H O :NH3 2 1 HO 1 O R formation R H2N:

R H CO Et H N: 2 EtO2C Michael 3 CO2Et

H N R1 1 : addition 2 R O 1 H2N R

:NH3 H NH R R 2 H EtO C CO Et EtO2C CO2Et 2 2 tautomerization 1 1 R1 O 1 R R R NH2 O N H2NH H 282

H3N: R R H EtO2C CO2Et EtO2C CO2Et

1 1 HO 1 R N R 1 N R R H H

Example 16

O NO2 CO2Et NH3 H EtO2C CO2Et O NO2 N H nifedipine

References

1. Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 183. 2. Bottorff, E. M.; Jones, R. G.; Kornfeld, E. C.; Mann, M. J. J. Am. Chem. Soc. 1951, 73, 4380. 3. Berson, J. A.; Brown, E. J. Am. Chem. Soc. 1955, 77, 444 4. Marsi, K. L.; Torre, K. J. Org. Chem. 1964, 29, 3102. 5. Meyers, A. I.; Sircar, J. C.; Singh, S. J. Heterocycl. Chem. 1967, 4, 461 6. Bossert, F.; Vater, W. Naturwissinschaften 1971, 58, 578 7. Balogh, M.; Hermecz, I.; Naray-Szabo, G.; Simon, K.; Meszaros, Z. J. Chem. Soc., Perkin Trans. 1 1986, 753. 8. Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1986, 42, 5729. 9. Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43, 5171. 10. Sainai, J. B.; Shah, A. C.; Arya, V. P. Indian J. Chem. B. 1995, 34B(1), 17. 11. Menconi, I.; Angeles, E.; Martinez, L.; Posada, M. E.; Toscano, R. A.; Martinez, R. J. Heterocycl. Chem. 1995, 32, 831. 12. Goerlitzer, K.; Heinrici, C.; Ernst, L. Pharmazie 1999, 54, 35. 13. Raboin, J.-C.; Kirsch, G.; Beley, M. J. Heterocycl. Chem. 2000, 37, 1077. 14. Sambongi, Y.; Nitta, H.; Ichihashi, K.; Futai, M.; Ueda, I. J. Org. Chem. 2002, 67, 3499. 15. Galatsis, P. Hantzsch Dihydro-Pyridine Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 304307. (Review). 283

Hantzsch pyrrole synthesis Reaction of D-chloromethyl ketones with E-ketoesters and ammonia to assemble pyrroles.

CO2Et O CO2Et NH3

Cl O N H

CO Et CO Et 2 enamine 2 :NH3 O formation HO H2N:

H CO Et 2 CO2Et H2O H3N: H N 2 H2N

H NH 3 OH O H2O CO2Et Cl CO2Et Cl H H N 2 : HN :NH3

CO2Et CO2Et Cl CO2Et

: H H3N: N N HN H H

Example 15

DME, 87140 oC F3C O F C 3 N CO2Me Br H2N CO2Me 2.5 h, 60% H 284

Example 28

CO Et 2 NH3, EtOH CO Et O 2 Cl O 48 h, 48% N H

References

1. Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474. 2. Hort, E. V.; Anderson, L. R. Kirk-Othmer Encycl. Chem. Technol.; 3rd Ed.; 1982, 19, 499. (Review). 3. Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43, 5171. 4. Kirschke, K.; Costisella, B.; Ramm, M.; Schulz, B. J. Prakt. Chem. 1990, 332, 143. 5. Kameswaran, V.; Jiang, B. Synthesis 1997, 530. 6. Trautwein, A. W.; Süȕmuth, R. D.; Jung, G. Bioorg. Med. Chem. Lett. 1998, 8, 2381. 7. 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, 411454. (Review). 8. Matiychuk, V. S.; Martyak, R. L.; Obushak, N. D.; Ostapiuk, Yu. V.; Pidlypnyi, N. I. Chem. Heterocyclic Compounds 2004, 40, 1218. 285

Heck reaction Palladium-catalyzed coupling between organohalides or triflates with olefins.

Pd(0) R RX Z Z

X = I, Br, OTf, Cl, etc. Z = H, R, Ar, CN, CO2R, OR, OAc, NHAc, etc.

RX Pd(0) oxidative addition R HXPd Z cis-E- elimination RPd(II)X R Pd X H Z H Z coordination

RPd(II)X insertion (cis) Z

Example 17

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% 286

Example 26

OTBS N N

I 0.3 eq. Pd(OAc)2

N N Bu4NCl, DMF, K2CO3 H H H o 70 C, 3 h, 74% O OTBS O

References

1. Heck, R. F.; Nolley, J. P., Jr. J. Am. Chem. Soc. 1968, 90, 5518. 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. (Review). 3. Heck, R. F. Org. React. 1982, 27, 345. (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 103113. (Book). 6. Rawal V. H.; Iwasa, H. J. Org. Chem. 1994, 59, 2685. 7. Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10. 8. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 30093066. (Review). 9. Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314. (Review). 10. Link, J. T. Org. React. 2002, 60, 157534. (Review). 11. Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 29452963. (Review). 12. Beller, M.; Zapf, A.; Riermeier, T. H. Transition Metals for Organic Synthesis (2nd edn.) 2004, 1, 271305. (Review). 13. Oestreich, M. Eur. J. Org. Chem. 2005, 783792. (Review). 287

Heteroaryl Heck reaction Intermolecular or intramolecular Heck reaction that occurs onto a heteroaryl re- cipient.

N Pd(Ph3P)4, Ph3P, CuI S I N S o Cs2CO3, DMF, 140 C

N

Pd(0) S I Pd(II)I insertion oxidative addition

S N Cs CO S H 2 3 Pd(II) N B: I

Pd(0) CsI CsHCO3

Example 13

O N N N O N Pd(Ph3P)4, KOAc N NClDMA, reflux, 65%

Example 22

N N Br Pd(OAc)2, NaHCO3 N N N n-Bu4NCl, DMA N O Bu O 150 oC, 24 h, 83% Bu 288

References

1. Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaka, R.; Miyafuji, A.; Nakata, T.; Tani, N. Aoyagi, Y. Heterocycles 1990, 31, 1951. 2. Kuroda, T.; Suzuki, F. Tetrahedron Lett. 1991, 32, 6915 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. 4. Proudfoot, J. R. et al. J. Med. Chem. 1995, 38, 1406. 5. Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467. 6. Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic Chemistry; 2000, Pergamon: Oxford, p16. (Review). 289

Hegedus indole synthesis Stoichiometric Pd(II)-mediated oxidative cyclization of alkenyl anilines to indoles. Cf. Wacker oxidation.

PdCl2(CH3CN)2, THF CH3 N MeO C NH then, Et3N, 84% MeO2C 2 2 H

PdCl2(CH3CN)2 Cl Pd MeO C NH palladation MeO C NH 2 2 2 2 Cl precipitate

Cl Cl Et3N Pd Et3N :

MeO2C NH2

Et N 3 Cl H Pd – HCl "PdH" Cl N N – "PdH" MeO2C MeO2C H H2

H -elimination PdLn E CH3 N CH MeO2C MeO C N 3 H 2 H

Example 11

10 mol% (CH3CN)2PdCl2 100 mol% benzoquinone CH3 NH N 2 10 eq. Et3N, THF, reflux, 85% H 290

Example 24

Br Br 10 mol % (CH3CN)2PdCl2 100 mol% benzoquinone

NHTs 10 eq. LiCl, THF, reflux, 79% N Ts

References

1. Hegedus, L. S.; Allen, G. F.; Waterman, E. L. J. Am. Chem. Soc. 1976, 98, 2674. Lou Hegedus is a professor at Colorado State University. 2. Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100, 5800. 3. Hegedus, L. S.; Winton, P. M.; Varaprath, S. J. Org. Chem. 1981, 46, 2215. 4. Harrington, P. J.; Hegedus, L. S. J. Org. Chem. 1984, 49, 2657. 5. Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113. (Review). 6. Brenner, M.; Mayer, G.; Terpin, A.; Steglich, W. Chem. Eur. J. 1997, 3, 70. 7. Osanai, Y. Y.; Kondo, K.; Murakami, Y. Chem. Pharm. Bull. 1999, 47, 1587. 8. A ruthenium variant: Kondo, T.; Okada, T.; Mitsudo, T. J. Am. Chem. Soc. 2002, 124, 186. 9. 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, 135139. (Re- view). 291

Hell–Volhard–Zelinsky reaction

D-Bromination of carboxylic acids using Br2/PBr3.

O O O PBr H O 3 R 2 R R Br OH OH Br 2 Br Br D-bromoacid

Br O Br PBr O Br R P Br R P O O Br O Br Br R H O Br

O H O R Br enolization R Br OPBr H Br Br Br

H+ B: H O O hydrolysis O R R R OH Br Br OH Br Br :OH2 Br

Example 17

Cl CO2H Cl2, cat. PCl3 CO2H

97 oC, 6 h, 77% 292

Example 28

Br CO2H PBr3 Br H Br2, 57% CO2H CO2H

References

1. Hell, C. Ber. Dtsch. Chem. Ges. 1881, 14, 891. Carl M. von Hell (18491926) was born in Stuttgart, 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. 2. Volhard, J. Justus Liebigs Ann. Chem. 1887, 242, 141. Jacob Volhard (18491909) was born in Darmstadt, Germany. He apprenticed under Liebig, Will, Bunsen, Hof- mann, Kolbe, and von Baeyer. He improved Hell’s original procedure in preparing D- bromo-acid during his research in thiophenes. 3. Zelinsky, N. A. Ber. Dtsch. Chem. Ges. 1887, 20, 2026. Nikolai D. Zelinsky (18611953) was born in 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 Moscow. On his ninetieth birthday in 1951, he was awarded the Order of Lenin. 4. Watson, H. B. Chem. Rev. 1930, 7, 173201. (Review). 5. Sonntag, N. O. V. Chem. Rev. 1953, 52, 237246. (Review). 6. Harwood, H. J. Chem. Rev. 1962, 62, 99154. (Review). 7. Jason, E. F.; Fields, E. K. US Patent 3,148,209 (1964). 8. Chow, A. W.; Jakas, D. R.; Hoover, J. R. E. Tetrahedron Lett. 1966, 5427. 9. Little, J. C.; Sexton, A. R.; Tong, Y.-L. C.; Zurawic, T. E. J. Am. Chem. Soc. 1969, 91, 7098. 10. Chatterjee, N. R. Indian J. Chem., Sect. B 1978, 16B, 730. 11. Kortylewicz, Z. P.; Galardy, R. E. J. Med. Chem. 1990, 33, 263. 12. Kolasa, T.; Miller, M. J. J. Org. Chem. 1990, 55, 4246. 13. Liu, H.-J.; Luo, W. Synth. Commun. 1991, 21, 2097. 14. Krasnov, V. P.; Bukrina, I. M.; Zhdanova, E. A.; Kodess, M. I.; Korolyova, M. A. Synthesis 1994, 961. 15. Zhang, L. H.; Duan, J.; Xu, Y.; Dolbier, W. R., Jr. Tetrahedron Lett. 1998, 39, 9621. 16. Sharma, A.; Chattopadhyay, S. J. Org. Chem. 1999, 64, 8059. 17. Stack, D. E.; Hill, A. L.; Diffendaffer, C. B.; Burns, N. M. Org. Lett. 2002, 4, 4487. 293

Henry nitroaldol reaction The nitroaldol condensation reaction involving aldehydes and nitronates, derived from deprotonation of nitroalkanes by bases.

OH O N H R NO2 R2 NO2 R1 RR1 R2

N HH N: O H deprotonation H RR1 O O R2 N R2 N O O nitronate

OH nucleophilic R NO2 addition R1 N R2 H

Example 16

CHO HO NO2 Amberlyst A-21 (basic) NO2 rt, 62% 294

Example 2, aza-Henry reaction14

O O 5 mol% TMG, 100 oC P Ph P Ph HN N Ph Ph Ph NO2 0.1 mBar, 26 h Ph Ph Ph 95%, anti:syn = 98:2 NO2

References

1. Henry, L. Compt. Rend. 1895, 120, 1265. 2. Matsumoto, K. Angew. Chem. 1984, 96, 599. 3. Sakanaka, O.; Ohmori, T.; Kozaki, S.; Suami, T.; Ishii, T.; Ohba, S.; Saito, Y. Bull. Chem. Soc. Jpn. 1986, 59, 1753. 4. Barrett, A. G. M.; Robyr, C.; Spilling, C. D. J. Org. Chem. 1989, 54, 1233. 5. Rosini, G. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Per- gamon, 1991, 2, 321340. (Review). 6. Chen, Y.-J.; Lin, W.-Y. Tetrahedron Lett. 1992, 33, 1749. 7. Bandgar, B. P.; Uppalla, L. S. Synth. Commun. 2000, 30, 2071. 8. Luzzio, F. A. Tetrahedron 2001, 57, 915. (Review). 9. Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861. 10. Ma, D.; Pan, Q.; Han, F. Tetrahedron Lett. 2002, 43, 9401. 11. Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151. (Review on aza-Henry reaction). 12. Risgaard, T.; Gothelf, K. V.; Jøgensen, K. A. Org. Biomol. Chem. 2003, 1, 153. 13. Ballini, R.; Bosica, G.; Livi, D.; Palmieri, A.; Maggi, R.; Sartori, G. Tetrahedron Lett. 2003, 44, 2271. 14. Bernardi, L.; Bonini, B. F.; Capito, E.; Dessole, G.; Comes-Franchini, M.; Fochi, M.; Ricci, A. J. Org. Chem. 2004, 69, 8168. 15. Chung, W. K.; Chiu, P. Synlett 2005, 55. 16. Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem. Int. Ed. Engl. 2005, 44, 3881. 295

Hinsberg synthesis of thiophene derivatives Condensation of diethyl thiodiglycolate and D-diketones under basic conditions, which provides 3,4-disubstituted thiophene-2,5-dicarboxylic acids upon hydrolysis of the crude ester product with aqueous acid.

O O O O 1. S EtO OEt HO S O

NaOEt, EtOH OH O + Ph 2. H3O Ph

O O

Ph Ph EtO O PhO CO2Et O S Ph S CO2Et

CO2Et

O Ph O O Ph O Ph S CO Et O2C Ph H 2 SCO2Et

EtO

Ph Ph + Ph Ph H , H2O CO Et reflux CO H HO2C S 2 HO2C S 2 296

Example 111

O O

(CHO)3, NaOMe S S MeOH, 59%

O O

Example 215

H3C CH3 H3C CH3 NaOH, MeOH NC SCN NH2 NC O O 94% S O

References

1. Hinsberg, O. Ber. Dtsch. Chem. Ges. 1910, 43, 901. 2. Gronowitz, S. In Thiophene and Its Derivatives, Part 1, Gronowitz, S., ed.; Wiley- Interscience: New York, 1985, 3441. (Review). 3. Wynberg, H.; Zwanenburg, D. J. J. Org. Chem. 1964, 29, 1919. 4. Wynberg, H.; Kooreman, H. J. J. Am. Chem. Soc. 1965, 87, 1739. 5. Chadwick, D. J.; Chambers, J.; Meakins, G. D.; Snowden, R. L. J. Chem. Soc., Perkin I, 1972, 2079. 6. Kumar, A.; Tilak, B. D. Indian J. Chem.1986, 25B, 880. 7. Miyahara, Y.; Inazu, T.; Yoshino, T. Chem. Lett. 1980, 397. 8. Miyahara, Y.; Inazu, T.; Yoshino, T. Bull. Chem. Soc. Jpn. 1980, 53, 1187. 9. Huybrechts, L.; Buffel, D.; Freyne, E.; Hoornaert, G. Tetrahedron 1984, 40, 2479. 10. Miyahara, Y.; Inazu, T.; Yoshino, T. Tetrahedron Lett. 1984, 25, 415. 11. Miyahara, Y.; Inazu, T.; Yoshino, T. J. Org. Chem. 1984, 49, 1177. 12. Vogel, E. Pure Appl. Chem. 1990, 62, 557. 13. Christl, M.; Krimm, S.; Kraft, A. Angew. Chem. Int. Ed. Engl. 1990, 29, 675. 14. Rangnekar, D. W.; Mavlankar, S. V. J. Heterocycl. Chem. 1991, 28, 1455. 15. Beye, N.; Cava, M. P. J. Org. Chem. 1994, 59, 2223. 16. Vogel, E.; Pohl, M.; Herrmann, A.; Wiss, T.; König, C.; Lex, J.; Gross, M.; Gissel- brecht, J. P. Angew. Chem. Int. Ed. Engl. 1996, 35, 1520. 17. 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, 199206. (Review). 297

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 (transmetalation is reluctant to occur without the effect of an activating agent). For the catalytic cycle, see the Kumada coupling on page 345.

O

MeO C F Si O 2 O Br 3

Pd(Ph3P)4, TBAF MeO C O 2 O THF O

O nucleophilic F3Si O attack Bu4N F

O O F4Si O Bu4N F4Si O Bu4N

oxidative Pd(Ph P) MeO2C Br 3 4 MeO C Pd Br O addition 2 O

O CO Me F Si O 2 4 MeO C 2 O Pd trans"metal"lation

reductive MeO C O 2 O Pd(Ph3P)4 elimination O 298

Example 11

I

MeO C 2 S S

Si(Et)F2 3 S (K -C3H5PdCl)2 MeO C DMF, KF, 100 oC 2 S 82%

Example 25

Br N C5H11 Si(OMe)3 Bu4NF, Pd(OAc)2, Ph3P DMF, reflux, 72%

C5H11 N

References

1. Hatanaka, Y.; Fukushima, S.; Hiyama, T. Heterocycles 1990, 30, 303. 2. Hiyama, T.; Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471. 3. Matsuhashi, H.; Kuroboshi, M.; Hatanaka, Y.; Hiyama, T. Tetrahedron Lett. 1994, 35, 6507. 4. Mateo, C.; Fernandez-Rivas, C.; Echavarren, A. M.; Cardenas, D. J. Organometallics 1997, 16, 1997. 5. Shibata, K.; Miyazawa, K.; Goto, Y. Chem. Commun. 1997, 1309. 6. Hiyama, T. In Metal-Catalyzed Cross-Coupling Reactions; 1998, Diederich, F.; Stang, P. J., Eds.; Wiley–VCH: Weinheim, Germany, 421–53. (Review). 7. Denmark, S. E.; Wang, Z. J. Organomet. Chem. 2001, 624, 372. 8. Hiyama, T. J. Organomet. Chem. 2002, 653, 58. 9. Pierrat, P.; Gros, P.; Fort, Y. Org. Lett. 2005, 7, 697. 10. Clarke, M. L. Adv. Synth. Cat. 2005, 347, 303. 11. Domin, D.; Benito-Garagorri, D.; Mereiter, K.; Froehlich, J.; Kirchner, K. Or- ganometallics 2005, 24, 3957. 299

Hiyama–Denmark cross-coupling reaction A synthetically important and mechanistically distinct cross-coupling process of organosilanols has been developed. Unlike the Hiyama cross-coupling reaction of polychloro- and fluorosilanes that requires activation by fluoride ion, the Denmark process involves the simple deprotonation of an organosilanol to initiate the coupling. This variant has obvious advantages of avoiding incompatibility with fluoride (silicon protective groups and large-scale reactors).

Mechanistic study5

Me Me Me Me MH ArylPdL2X Si Si - + n-C5H11 OH n-C5H11 O M MX

Me Me transmetalation L Si n-C H OPdAryl 5 11 Me Me L C H Me Si Si 7 13 2 O OK

L Aryl Pd Aryl n-C H n-C H 5 11 5 11 L

Many organosilanol substrates and different bases have been demonstrated.

6 1. Alkenylsilanol (KOSiMe3)

CH2OTBS OH KOSiMe3 (2.0 eq.) n-C H I 5 11 Si Me + Me Pd(dba)2 (5 mol %) DME, 9 h, r.t.

CH2OTBS n-C H 5 11 80% (E: Z = 99.5/0.5) 300

7 2. Arylsilanol (Cs2CO3)

Me Me Si CO2Et OH + MeO Br

CO2Et Cs2CO3 + 3 H2O (2 equiv)

[(allyl)PdCl]2 (5 mol %)

dppb (10 mol %) MeO toluene, 90 oC 24 h, 90%

8 3. Arylsilanol (Ag2O) Me Ag O (1 equiv) Me 2 Si OH + Aryl-I Pd(PPh3)4 (5 mol %) Me MeO o MeO THF, 60 C, 36 h 69%

9 4. Alkynylsilanol (KOSiMe3)

SiMe2OH

C5H11 I CH2OH

TMSOK (2 equiv), PdCl2(PPh3)2 (2.5 mol %) CH2OH DME, rt, 3 h, 84% C5H11

5. 2-Indolylsilanol (KOt-Bu)10

Me Me Si + I CO2t-Bu N OH Boc 301

NaOt-Bu (2.0 equiv) CO2t-Bu Pd2(dba)3•CHCl3 (5 mol%) N CuI (1.0 equiv) Boc toluene, rt, 84%

6. 4-Isoxazolylsilanol (NaOt-Bu)11 Et N Pd2dba3•CHCl3(5 mol %) O N Et O I NaOtB-u (2.5 equiv) + Ph Me Si Ph NO2 Cu(OAc)2 (1.0 equiv) HO Me toluene, 40 ºC, 78% O2N

12 7. 1,4-Bis-silyl-1,3-butadienes (KOSiMe3)

SiMe2Bn + I CO Et MeO 2

+ - n-Bu4N F (2.0 equiv) CO2Et Pd(dba)2 (2.5 mol%) THF, rt, 1 h MeO 90%

References

1. Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835. Scott Denmark is a professor at the University of Illinois at Urbana-Champaign. 2. Denmark, S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002, 50, 1531. 3. Denmark, S. E.; Ober, M. H. Aldrichimica Acta 2003, 36, 75. 4. Denmark, S. E.; Sweis, R. F. Organosilicon Compounds in Cross-Coupling Reactions In Metal-Catalyzed C-C and C-N Cross-Coupling Reactions; F. Diederich, A. deMei- jere, Eds. Wiley-VCH, 2004; Vol. 1; Chapt. 4. 5. Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2004, 126, 4876. 6. Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2001, 123, 6439. 7. Denmark, S. E.; Ober, M. H. Adv. Synth. Catal., 2004, 346, 1703. 8. Hirabayashi K.; Mori A.; Kawashima J.; Suguro M.; Nishihara Y.; Hiyama T. J. Org. Chem. 2000, 65, 5342. 9. Denmark, S. E.; Tymonko, S. A. J. Org. Chem. 2003. 68, 9151. 10. Denmark, S. E.; Baird, J. D. Org. Lett. 2004, 6(20), 3649. 11. Denmark, S. E.; Kallemeyn, J. J. Org. Chem. 2005, 70, 2839. 12. Denmark, S. E.; Tymonko, S. A. J. Am. Chem. Soc. 2005, 127, 8004. 302

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.

Br O 2 H2O RNCO RNH2 CO2n NaOH RNH2

O O Br RN O RNH O Br Br H H Br RNH RN OH OH

H R NCO NO R H RNH2 CO2n O OH OH isocyanate intermediate

Example 14

O H NBS, DBU, MeOH N O NH2 reflux, 25 min., 70% O O2N O2N 303

Example 29

OCOCF O 3 O Ph O I : I OCOCF3 NH2 N OCF3 H CH CN/H O, 4.5 h, 100% OH 3 2 OH

H O H C N N O

: O OH

References

1. Hofmann, A. W. Ber. Dtsch. Chem. Ges. 1881, 14, 2725. 2. Grillot, G. F. Mech. Mol. Migr. 1971, 237. (Review). 3. Jew, S. S.; Park, H. G.; Park, H. J.; Park, M. S.; Cho, Y. S. Ind. Chem. Library 1991, 3, 14753. (Review). 4. Jew, S.-s.; Kang, M.-h. Arch. Pharmacal Res. 1994, 17, 490. 5. Huang, X.; Seid, M.; Keillor, J. W. J. Org. Chem. 1997, 62, 7495. 6. Spanggord, R. J.; Clizbe, L. A. J. Labelled Compd. Radiopharm. 1998, 41, 615. 7. Monk, K. A.; Mohan, R. S. J. Chem. Educ. 1999, 76, 1717. (Review). 8. Togo, H.; Nabana, T.; Yamaguchi, K. J. Org. Chem. 2000, 65, 8391. 9. Yu, C.; Jiang, Y.; Liu, B.; Hu, L. Tetrahedron Lett. 2001, 42, 1449. 10. Keillor, J. W.; Huang, X. Org. Synth. 2002, 78, 234. 11. Lopez-Garcia, M.; Alfonso, I.; Gotor, V. J. Org. Chem. 2003, 68, 648. 12. Moriarty, R. M. J. Org. Chem. 2005, 70, 28932903. (Review). 304

Hofmann–Löffler–Freytag reaction Formation of pyrrolidines or piperidines by thermal or photochemical decomposi- tion of protonated N-haloamines.

+ Cl 1. H , ' R1 N N R1 R2 2. OH R2

+ Cl H Cl ' H 1 N 1 N 2 R R2 R R homolytic cleavage chloroammonium salt

H 1,5-hydrogen Cl H 1 N 1 N H R R R H 2 2 R atom transfer nitrogen radical cation

NH R 2 1 2 H R N 2 R R 1 NH2 Cl 1 R Cl H 2 N R R1 R2

OH SN2 R1 OH R1 : NH N H N Cl 2 2 2 R1 R R R

Example 16

NCS, ether, Et3N then hv, (Hg0 lamp) NH N NN o 0 C, 3.5 h in N2 100% 305

Example 23

NH 1. NaOCl, 95% H 2. TFA, hv, 87% HH 3. NaOH, MeOH, 76% O

N

H

HH O

References

1. Hofmann, A. W. Ber. Dtsch. Chem. Ges. 1879, 12, 984. 2. Löffler, K.; Freytag, C. Ber. Dtsch. Chem. Ges. 1909, 42, 3727. 3. Kerwin, J. F.; Wolff, M. E.; Owings, F. F.; Lewis, B. B.; Blank, B.; Magnani, A.; Karash, C.; Georgian, V. J. Am. Chem. Soc. 1960, 82, 4117. 4. Wolff, M. E. Chem. Rev. 1963, 63, 55. (Review). 5. Furstoss, R.; Teissier, P.; Waegell, B. Tetrahedron Lett. 1970, 11, 1263. 6. Kimura, M.; Ban, Y. Synthesis 1976, 201. 7. Deshpande, R. P.; Nayak, U. R. Indian J. Chem., Sect. B 1979, 17B, 310. 8. Hammerum, S. Tetrahedron Lett. 1981, 22, 157. 9. Uskokovic, M. R.; Henderson, T.; Reese, C.; Lee, H. L.; Grethe, G.; Gutzwiller, J. J. Am. Chem. Soc. 1978, 100, 571. 10. Stella, L. Angew. Chem., Int. Ed. Engl. 1983, 22, 337422. (Review). 11. Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095. (Review). 12. Madsen, J.; Viuf, C.; Bols, M. Chem. Eur. J. 2000, 6, 1140. 13. Togo, H.; Katohgi, M. Synlett 2001, 565. (Review). 14. Pellissier, H.; Santelli, M. Org. Prep. Proced. Int. 2001, 33, 455. (Review). 15. Li, J. J. Hofmann–Löffler–Freytag Reaction In Name Reactions in Heterocyclic Chem- istry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 8097. (Review). 306

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.

O O NaH, then CO2Et O EtO EtO P P EtO OEt RCHO R EtO ONa

O O O O EtO P EtO P EtO OEt EtO OEt H H OR H

O O EtO P EtO OEt

OR

erythro (kinetic) or threo (thermodynamic)

O O OEt OEt O P O P OEt OEt RCO2Et H H H H R CO2Et R CO2Et erythro, kinetic adduct

O O OEt OEt CO2Et O P OEt O P OEt CO Et H 2 H CO2Et R R H R H threo, thermodynamic adduct 307

Example 15

O O O O EtO P CO2Et CHO EtO OEt

NaH, THF, 91% OMe OMe

Example 28

O O CHO EtO P CO2Et EtO OEt

BnO KOH, THF, 95% BnO

References

1. Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G. Chem. Ber. 1959, 92, 2499. 2. Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733. 3. Wadsworth, D. H.; Schupp, O. E.; Seus, E. J.; Ford, J. A., Jr. J. Org. Chem. 1965, 30, 680. 4. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863927. (Review). 5. Shair, M. D.; Yoon, T. Y.; Mosny, K. K.; Chou, T. C.; Danishefsky, S. J. J. Am. Chem. Soc. 1996, 118, 9509. 6. Ando, K. J. Org. Chem. 1997, 62, 1934. 7. Ando, K. J. Org. Chem. 1999, 64, 6815. 8. Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.; Hughes, R. J.; Natarajan, S.; Jain, N. F.; Ramajulu, J. M.; Bräse, S.; Solomon, M. E. Chem. Eur. J. 1999, 5, 2602. 9. Reiser, U.; Jauch, J. Synlett 2001, 90. 10. Comins, D. L.; Ollinger, C. G. Tetrahedron Lett. 2001, 42, 4115. 11. Harusawa, S.; Koyabu, S.; Inoue, Y.; Sakamoto, Y.; Araki, L.; Kurihara, T. Synthesis 2002, 1072. 12. Lattanzi, A.; Orelli, L. R.; Barone, P.; Massa, A.; Iannece, P.; Scettri, A. Tetrahedron Lett. 2003, 44, 1333. 13. Blasdel, L. K.; Myers, A. G. Org. Lett. 2005, 7, 4281. 308

HoubenHoesch reaction Acid-catalyzed acylation of phenols as well as phenolic ethers using nitriles.

OH OH OH RCN

HCl, AlCl3 OH OH OH R NH•HCl RO

:OH

complexation electrophilic AlCl3 RN: OH substitution

RNAlCl3

H+ OH O

H2O: OH OH H R NH•HCl Cl RNH

OH OH

hydrolysis OH + NH H R 2 OH O H RO Cl

Example 1, intramolecular HoubenHoesch reaction5

O OMe OOMe

1. ZnCl2, HCl(g), Et2O CN 2. H O, reflux, 89% OMe 2 O OMe 309

Example 28

F OH PivO CN CO2Me

OMe MeO OH

OPiv

MeO F OMe SbCl5, 2-chloropropane N CH2Cl2, rt, 2 h, 95% H O OH

CO2Me

References

1. Hoesch, K. Ber. Dtsch. Chem. Ges. 1915, 48, 1122. Kurt Hoesch (18821932) 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. 2. Houben, J. Ber. Dtsch. Chem. Ges. 1926, 59, 2878. 3. Amer, M. I.; Booth, B. L.; Noori, G. F. M.; Proenca, M. F. J. R. P. J. Chem. Soc., Perkin Trans. 1 1983, 1075. 4. Yato, M.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 691. 5. Rao, A. V. R.; Gaitonde, A. S.; Prakash, K. R. C.; Rao, S. P. Tetrahedron Lett. 1994, 35, 6347. 6. Sato, Y.; Yato, M.; Ohwada, T.; Saito, S.; Shudo, K. J. Am. Chem. Soc. 1995, 117, 3037. 7. Kawecki, R.; Mazurek, A. P.; Kozerski, L.; Maurin, J. K. Synthesis 1999, 751. 8. Udwary, D. W.; Casillas, L. K.; Townsend, C. A. J. Am. Chem. Soc. 2002, 124, 5294. 9. Sanchez-Viesca, F.; Gomez, M. R.; Berros, M. Org. Prep. Proc. Int. 2004, 36, 135. 310

HunsdieckerBorodin reaction Conversion of silver carboxylate to halide by treatment with halogen.

O X2 Ag RX CO2n AgX RO

XX O homolytic O AgX X RO Ag cleavage RO

O X O RO O X CO2n R RX RO RO

Example 16

Br CO2H + NBS, n-Bu4N CF3CO2

ClCH2CH2Cl, 96% MeO MeO

Example 210

Cl

CO2H N Br 2 BF4

N "Select fluor" F HO HO KBr, CH3CN, 82%

References

1. Borodin, A. Justus Liebigs Ann. Chem. 1861, 119, 121. Aleksandr Porfireviþ Borodin (18331887) 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 311

Heinz and Cläre Hunsdiecker converted Borodin's synthesis into a general method, the Hunsdiecker or HunsdieckerBorodin reaction. Borodin was also an accomplished composer and is now best known for his musical masterpiece, opera Prince Egor. He kept a piano outside his laboratory. 2. Hunsdiecker, H.; Hunsdiecker, C. Ber. Dtsch. Chem. Ges. 1942, 75, 291. Cläre Huns- diecker was the only woman to give a name reaction in this book. I hope there will be many more in future editions. Cläre Hunsdiecker was born in 1903 and educated in Cologne. She developed the bromination of silver carboxylate alongside her husband, Heinz. 3. Sheldon, R. A.; Kochi, J. K. Org. React. 1972, 19, 326. (Review). 4. Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron Lett. 1983, 24, 4979. 5. Crich, D. In Comprehensive Organic Synthesis; Trost, B. M.; Steven, V. L., Eds.; Per- gamon, 1991, Vol. 7, 723734. (Review). 6. Naskar, D.; Chowdhury, S.; Roy, S. Tetrahedron Lett. 1998, 39, 699. 7. Camps, P.; Lukach, A. E.; Pujol, X.; Vazquez, S. Tetrahedron 2000, 56, 2703. 8. De Luca, L.; Giacomelli, G.; Porcu, G.; Taddei, M. Org. Lett. 2001, 3, 855. 9. Das, J. P.; Roy, S. J. Org. Chem. 2002, 67, 7861. 10. Ye, C.; Shreeve, J. M. J. Org. Chem. 2004, 69, 8561. 312

Hurd–Mori 1,2,3-thiadiazole synthesis Reaction of thionyl chloride with the N-acylated or tosyl hydrazone derivatives to provide the 1,2,3-thiadiazole in one step.

O N N S 1 SOCl2 HN R R1 N 3 R1 = OR, NH R 2 R2 R2

Tos HN SOCl2 N S R3 N 3 N R R1 = OR, NH 2 2 R R2

O X X X S NH Cl Cl N N HN N N + S O S O 1 1 R R1 R S O HCl 2 2 R R2 R

X = Tos, COR1

Cl- X N N SO N S 2 N + S R1 HCl R1 R2 R2

Example17 N S N O H2N HN N SOCl2, CH2Cl2 rt, 6 h, 56%

CN CN 313

References

1. Hurd, C. D.; Mori, R. I. J. Am. Chem. Soc. 1955, 77, 5359. 2. Meier, H.; Hanold, N. In Methoden der Organischen Chemie: HoubenWeyl, Georg Thieme: Stuttgart – New York, 1994; Vol. E8d, p.60. (Review). 3. Thomas, E. W. In Comprehensive Heterocyclic Chemistry; Potts, K. T., Vol. Ed.; Katrizky, A. R.; Rees, C. W.; Series Eds.; Pergamon Press: London, 1984; Vol. 6, Part 4B, p. 447. (Review). 4. Thomas, E. W. In Comprehensive Heterocyclic Chemistry II; Storr, R. C., Vol. Ed.; Katrizky, A. R.; Rees, C. W.; Scriven, E. F.; Series Eds.; Pergamon Press: London, 1996; Vol. 4, p. 289. (Review). 5. Stanetty, P.; Turner, M.; Mihovilovic, M. D. In Targets in Heterocyclic Systems 1999, 3, 265–299. (Review). 6. Thomas, E. W.; Nishizawa, E. E.; Zimmermann, D. C.; Williams, D. J. J. Med. Chem. 1985, 28, 442. 7. Lewis, G. S.; Nelson, P. H. J. Med. Chem. 1979, 22, 1214. 8. Fujita, M.; Nimura, K.; Kobori, T.; Hiyama, T.; Kondo, K. Heterocycles 1995, 41, 2413. 9. Peet, N. P.; Sunder, S. J. Heterocycl. Chem. 1975, 12, 1191. 10. Zimmer, O.; Meier, H. Chem. Ber. 1981, 114, 2938. 11. Britton, T. C.; Lobl, T. J.; Chidester, C. G. J. Org. Chem. 1984, 49, 4773. 12. Fujita, M.; Kobori, T.; Hiyama, T.; Kondo, K. Heterocycles 1993, 36, 33. 13. D'Hooge, B.; Smeets, S.; Toppet, S.; Dehaen, W. Chem. Commun. 1997, 1753. 14. Stanetty, P.; Kremslehner, M.; Vollenkle, H. J. Chem. Soc., Perkin Trans. 1 1998, 853; Stanetty, P.; Kremslehner, M.; Jaksits, M. Pest. Sci. 1998, 54, 316. 15. Hu, Y.; Baudart, S.; Porco, J. A., Jr. J. Org. Chem. 1999, 64, 1049. 16. Abramov, M. A.; Dehaen, W. Synthesis 2000, 1529. 17. Morzherin, Y. Y.; Glukhareva, T. V.; Mokrushin, V. S.; Tkachev, A. V.; Bakulev, V. A. Heterocyclic Commun. 2001, 7, 173. 18. Hameurlaine, A.; Abramov, M. A.; Dehaen, W. Tetrahedron Lett. 2002, 43, 1015. 19. Sakya, S. M. Hurd–Mori 1,2,3-Thiadiazole Synthesis In Name Reactions in Heterocyc- lic Chemistry, Eds, Li, J. J.; Corey, E. J. Wiley & Sons: Hoboken, NJ, 2005, 199206. (Review). 314

Jacobsen–Katsuki epoxidation Manganese-catalyzed asymmetric epoxidation of (Z)-olefins.

HH NN Mn t-Bu O Cl O t-Bu O

t-Bu t-Bu Ph CO2Me Ph CO2Me NaOCl, aq. buffer, CH2Cl2

1. Concerted oxygen transfer (cis-epoxide):

R R1 R R1 R R1 R R1 O O Mn(V) O O Mn(V) Mn(V)

2. Oxygen transfer via radical intermediate (trans-epoxide):

R R1 R R1 R R1 R R O 1 O Mn(V) O Mn(V) O Mn(V)

3. Oxygen transfer via manganaoxetane intermediate (cis-epoxide):

O R1 R R1 O Mn(V) Mn(V) R

[2 + 2] R R R 1 O 1 Mn(V) cycloaddition R O 315

Example5

cat, 4-phenylpyridine-N-oxide CO2Et CO2Et o NaOCl, CH2Cl2, 4 C, 12 h O 56%, 9597% ee

HH N N Mn cat. = t-Bu O O t-Bu Cl t-Bu t-Bu

References

1. Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1990, 112, 2801. 2. Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.; Katsuki, T. Tetrahedron Lett. 1990, 31, 7345. 2. Irie, R.; Noda, K.; Ito, Y.; Katsuki, T. Tetrahedron Lett. 1991, 32, 1055. 3. Zhang, W.; Jacobsen, E. N. J. Org. Chem. 1991, 56, 2296. 4. Schurig, V.; Betschinger, F. Chem. Rev. 1992, 92, 873. (Review). 5. Deng, Li; Jacobsen, E. N. J. Org. Chem. 1992, 57, 4320. 6. Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: Weinheim, New York, 1993, Ch. 4.2. (Review). 7. Katsuki, T. Coord. Chem. Rev. 1995, 140, 189214. (Review). 8. E. N. Jacobsen, 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). 9. Palucki, M.; McCormick, G. J.; Jacobsen, E. N. Tetrahedron Lett. 1995, 36, 5457. 10. Senananyake, C. H. Aldrichimica Acta 1998, 31, 3. (Review). 11. 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). 12. Katsuki, T. In Catalytic Asymmetric Synthesis; 2nd edn.; Ojima, I., Ed.; Wiley-VCH: New York, 2000, 287. (Review). 13. Katsuki, T. Synlett 2003, 281. (Review). 14. Palucki, M. Jacobsen–Katsuki epoxidation In Name Reactions in Heterocyclic Chem- istry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 2943. (Review). 316

Japp–Klingemann hydrazone synthesis Hydrazones from D-ketoesters and diazonium salts with the acid of base.

KOH H O ArN2 Cl CO2R N O Ar NCO2R OH Diazonium salt E-keto-ester hydrazone

OH NNAr H deprotonation coupling

CO2R CO2R O O

Ar Ar N N HO N N CO2R CO2R OOH O

H O H N N Ar NCO2R OH Ar NCO2R

Example 16

CO2Et CO2Et N NaNO N Me S 2 Me S Cl O O conc. HCl, H2O O O o N NH2 0 C N 317

O CO2Et NMe2 Me NMe2 N Me S CO2Et O O N NaOAc (pH 34) N o H 0 to 50 C CO2Et 72% Example 29

0.5 N KOH, THF, rt, 1 h H NH then N NH HO2C N O O + OBn N2 Cl OBn 62% yield

References

1. Japp, F. R.; Klingemann, F. Justus Liebigs Ann. Chem. 1888, 247, 190. 2. Laduree, D.; Florentin, D.; Robba, M. J. Heterocycl. Chem. 1980, 17, 1189. 3. Strandtmann, M. v.; Cohen, Marvin P.; Shavel, J. Jr. J. Med. Chem. 1963, 6, 719. 4. Loubinoux, B.; Sinnes, J.-L.; O'Sullivan, A. C.; Winkler, T. J. Org. Chem. 1995, 60, 953. 5. Saha, C., Miss; Chakraborty, A.; Chowdhury, B. K. Indian J. Chem. 1996, 35B, 677. 6. Pete, B.; Bitter, I.; Harsanyi, K.; Toke, L. Heterocycles 2000, 53, 665. 7. Atlan, V.; Kaim, L. E.; Supiot, C. Chem. Commun. 2000, 1385. 8. Shawali, A. S.; Abdallah, M. A.; Mosselhi, M. A. N.; Farghaly, T. A. Heteroatom Chem. 2002, 13, 136. 9. Dubash, N. P.; Mangu, N. K.; Satyam, A. Synth. Commun. 2004, 34, 1791. 318

Jones oxidation The Collins/Sarett oxidation (chromium trioxide-pyridine complex), and Co- rey´s PCC (pyridinium chlorochromate) and PDC (pyridinium dichromate) oxidations follow a similar pathway as the Jones oxidation. All these oxidants have a chromium (VI), normally yellow, which is reduced to Cr(IV), often green.

Cr2O7 CrO3Cl CrO3 N N 2 N 2 H H

Collins/Sarett PCC PDC

Jones oxidation

O OH CrO3

R1 R2 R1 R2 H2SO4, acetone

O O O H Cr OO Cr H O OH O: H R H 1 R R1 R2 2 :OH2

O OH Cr R1 R2 OOH

The intramolecular mechanism is also operative:

O OH Cr O OH O O Cr OOH H R1 R2 R1 R2 319

Example 114

OH H O O O 1. Jones reagent O O acetone, 20 min. O 2. HCO2H, rt, 1 h 96% 2 steps CO2t-Bu

O H O O O O O O

CO2H ()-CP-263114

Example 215

O O CO Me CO2Me 2 HO CrO3, H2SO4 O acetone/H O H 2 H rt, 74%

H H

Collins/Sarett oxidation5

O O CHO OH 8 eq CrO •2Pyr 3 O Ph O O Ph O CH2Cl2, 15 min. 86% O O

PCC oxidation6

O OH 1.5 eq PCC, CH2Cl2 EtO C EtO2C 2 N N rt, 3 h, 75% 320

PDC oxidation7

PDC, CH2Cl2 S S O 24 h, 68% O S CHO OH S

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. Poos, G. I.; Arth, G. E.; Beyler, R. E.; Sarett, L. H. J. Am. Chem. Soc. 1953, 75, 422. 3. Ratcliffe, R. W. Org. Syn. 1973, 53, 1852. 4. Andrieux, J.; Bodo, B.; Cunha, H.; Deschamps-Vallet, C.; Meyer-Dayan, M.; Molho, D. Bull. Soc. Chim. Fr. 1976, 1975. 5. Vanmaele, L.; De Clerq, P.; Vandewalle, M. Tetrahedron Lett. 1982, 23, 995. 6. Krow, G. R.; Shaw, D. A.; Szczepanski, S.; Ramjit, H. Synth. Commun. 1984, 14, 429. 7. Terpstra, J. W.; Van Leusen, A. M. J. Org. Chem. 1986, 51, 230. 8. Gomez-Garibay, F.; Quijano, L.; Pardo, J. S. C.; Aguirre, G.; Rios, T. Chem. Ind. 1986, 827. 9. Glinski, J. A.; Joshi, B. S.; Jiang, Q. P.; Pelletier, S. W. Heterocycles 1988, 27, 185. 10. Turjak-Zebic, V.; Makarevic, J.; Skaric, V. J. Chem. Soc. (S) 1991, 132. 11. Luzzio, F. A. Org. React. 1998, 53, 1222. (Review). 12. 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. (Catalytic CrO3 oxidation). 13. Caamano, O.; Fernandez, F.; Garcia-Mera, X.; Rodriguez-Borges, J. E. Tetrahedron Lett. 2000, 41, 4123. 14. Waizumi, N.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 2000, 122, 7825. 15. Hagiwara, H.; Kobayashi, K.; Miya, S.; Hoshi, T.; Suzuki, T.; Ando, M. Org. Lett. 2001, 3, 251. 16. Arumugam, N.; Srinivasan, P. C. Synth. Commun. 2003, 33, 2313. 17. Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2005, 44, 1275. 18. Xu, L.; Cheng, J.; Trudell, M. L. J. Org. Chem. 2005, 68, 5388. 321

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 R SO N SO2 R 2 N OH 2 N 1 N 2. R CHO Ph 2 Ph

O N(TMS)2 R2 R H O H 2 N N R N N R N 1 1 N R1 N SO2 N SO2 SO N N N 2 N Ph Ph Ph

K N N R2 N O N O R2 N N N Ph O N S R1 R S O 1 Ph 2 O

N N R2 N OH SO2 R1 N Ph

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 OK SO2PT 322

Example 1, (BT = benzotriazole)4

OHC OTIPS SO2BT

NaHMDS, DMF OTIPS

78 oC to rt, 90% E:Z (78:22) Example 26 OTBS OPiv

O O N OMe

O SS KHMDS, THF, 78 oC, 85% O O

OPiv OTBS

O

O OMe

References

1. Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32, 1175. 2. Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 336. 3. Baudin, J. B.; Hareau, G.; Julia, S. A.; Loene, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856. 4. Charette, A. B.; Lebel, H. J. Am. Chem. Soc. 1996, 118, 10327. 5. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morely, A. Synlett 1998, 26. 6. Blakemore, P. R.; Kocienski, P. J.; Morley, A.; Muir, K. J. Chem. Soc., Perkin Trans. 1 1999, 955. 7. Williams, D. R.; Brooks, D. A.; Berliner, M. P. J. Am. Chem. Soc. 1999, 121, 4924. 8. Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365. 9. Smith, A. B., III; Wan, Z. J. Org. Chem. 2000, 65, 3738. 10. Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772. 11. Compostella, F.; Franchin, L.; Panza, L.; Prosperi, D.; Ronchetti, F. Tetrahedron 2002, 58, 4425. 12. Meyers, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42, 694. 13. Furuichi, N.; Hara, H.; Osaki, T.; Nakano, M.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 7949. 14. Bedel, O.; Haudrechy, A.; Langlois, Y. Eur. J. Org. Chem. 2004, 3813. 15. Alonso, D. A.; Najera, C.; Varea, M. Tetrahedron Lett. 2004, 45, 573. 16. Alonso, D. A.; Fuensanta, M.; Najera, C.; Varea, M. J. Org. Chem. 2005, 70, 6404. 323

Julia–Lythgoe olefination (E)-Olefins from sulfones and aldehydes.

1. n-BuLi SO Ar 1 2 Na(Hg) Ar 2. R CHO R1 R1 RS R R O O 3. Ac O CH OH 2 OAc 3

SO2Ar R1 n-Bu R SO2Ar D-deprotonation 1 coupling O H R R O Ar RS HO O O OO

SO2Ar 1 R SO2Ar acetylation Na(Hg) R R1 R O O single electron OAc transfer (SET) O O 4 possible diastereomers

Na(Hg) R1 SO2Ar R OAc single electron transfer (SET)

R1 R R1 OAc R OAc 324

Example 13

1. n-BuLi, THF, 78 oC 3. Ac2O

SO2Ph 2. 4. Na(Hg) E:Z (99:1) OHC

Example 24 OTBS O

OTBS SO2Ph O Li N TEOC H N TEOC H 1. THF, 78 oC

2. Ac2O CHO 3. 5% Na(Hg), 77%

References

1. Julia, M.; Paris, J. M. Tetrahedron. Lett. 1973, 4833. 2. Lythgoe, B. J. Chem. Soc., Perkin Trans. 1 1978, 834. 3. Kocienski, P. J.; Lythgoe, B. J. Chem. Soc., Perkin Trans. 1 1980, 1045. 4. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. 5. Keck, G. E.; Savin, K. A.; Weglarz, M. A. J. Org. Chem. 1995, 60, 3194. 6. Marko, I. E.; Murphy, F.; Dolan, S. Tetrahedron Lett. 1996, 37, 2089. 7. Satoh, T.; Hanaki, N.; Yamada, N.; Asano, T. Tetrahedron 2000, 56, 6223. 8. Charette, A. B.; Berthelette, C.; St-Martin, D. Tetrahedron Lett. 2001, 42, 5149. 9. Marko, I. E.; Murphy, F.; Kumps, L.; Ates, A.; Touillaux, R.; Craig, D.; Carballares, S.; Dolan, S. Tetrahedron 2001, 57, 2609. 10. Breit, B. Angew. Chem., Int. Ed. 1998, 37, 453. 11. Zanoni, G.; Porta, A.; Vidari, G. J. Org. Chem. 2002, 67, 4346. 12. Marino, J. P.; McClure, M. S.; Holub, D. P.; Comasseto, J. V.; Tucci, F. C. J. Am. Chem. Soc. 2002, 124, 1664. 13. D’herde, J. N. P.; De Clercq, P. J. Tetrahedron Lett. 2003, 44, 6657. 14. Bernard, A. M.; Frongia, A.; Piras, P. P.; Secci, F. Synlett 2004, 1064. 15. Pospisil, J.; Pospisil, T.; Marko, I. E. Org. Lett. 2005, 7, 2373. 325

Kahne–Crich 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 Ph O t-Bu N t-Bu O O O o PivO O Tf2O, CH2Cl2,78 to 30 C PivO N3 SPh

F O O F F SOS F OPiv FF PivO O O O O PivO S PivO Ph

OPiv PivO S 1 N S TfO O: OTf Ph OTf PivO S PivO Ph

OPiv PivO Ph O O O O PivO HO PivO N3 SPh oxonium ion 326

OPiv PivO Ph O O O O PivO O PivO N3 SPh Example 12 S(O)Ph O OMOM O OMOM OBn OBn BzO OMe OH OBn

O OMOM Tf O, DTBMP, CH Cl OMOM 2 2 2 BzO OMe O

o O 70 to 50 C, 38% OBn OBn OBn Example 26 O O OTIPS O SPh O MeO OTBS Ph OOTBS OH OPMB

Ph O MeO Tf2O, DTBMP, CH2Cl2 O O O

o 78 to 0 C, 67% PMBO O OTIPS OTBS OTBS References

1. Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc. 1989, 111, 6881. 2. Yan, L.; Taylor, C. M.; Goodnow, R., Jr.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 6953. 3. Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239. 4. Gildersleeve, J.; Pascal, R. A.; Kahne, D. J. Am. Chem. Soc. 1998, 120, 5961. 5. Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435. 6. Crich, D.; Li, H. J. Org. Chem. 2000, 65, 3095. 7. 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, 801. 8. Crich, D.; Li, H.; Yao, Q.; Wink, D. J.; Sommer, R. D.; Rheingold, A. L. J. Am. Chem. Soc. 2001, 123, 5826. 9. Berkowitz, D. B.; Choi, S.; Bhuniya, D.; Shoemaker, R. K. Org. Lett. 2000, 2, 1149. 10. Crich, D.; Lim, L. B. L. Org. React. . 2004, 64, 115251. (Review). 327

Keck macrolactonization Macrolactonization of Ȧ-hydroxyl acids using a combination of DCC, DMAP and DMAPxHCl.

O O DCC, DMAP O HOn OH DMAP•HCl, CHCl3 n

H Cy H+ NCN NCN Cy O H OOHn 1,3-dicyclohexylcarbodiimide (DCC)

HN Cy OH N O HN Cy + Cy O H N n Cy OOH

: n N N OH

N N dimethylaminopyridine (DMAP)

H+ O O

NOH: N N n H H N

1,3-dicyclohexylurea 328

N O

N O H O DMAP

O n

n

Example 17

H

N N-(3-methylaminopropyl)- HO2C N'-ethylcarbodiimide hydrochloride

H DMAP, DMAP•HCl, CHCl3, THF OH Cl reflux, 10 h, > 32% OH

H

O N

O H Cl halichlorine OH

References

1. Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394. 2. Paterson, I.; Yeung, K.-S.; Ward, R. A.; Cumming, J. G.; Smith, J. D. J. Am. Chem. Soc. 1994, 116, 9391. 3. Keck, G. E.; Sanchez, C.; Wager, C. A. Tetrahedron Lett. 2000, 41, 8673. 4. Tsai, C.-Y.; Huang, X.; Wong, C.-H. Tetrahedron Lett. 2000, 41, 9499. 5. Hanessian, S.; Ma, J.; Wang, W. J. Am. Chem. Soc. 2001, 123, 10200. 6. Lewis, A.; Stefanuti, I.; Swain, S. A.; Smith, S. A.; Taylor, R. J. K. Org. Biomol. Chem. 2003, 1, 104. 7. Christie, H. S.; Heathcock, C. H. PNAS 2004, 101, 12079. 329

Knoevenagel condensation Condensation between carbonyl compounds and activated methylene compounds catalyzed by amines.

N 1 H R CHO CH2(CO2R )2

1 CO2R OH R CO2H 1 R CO2R

1 H CH(CO2R )2 deprotonation 1

: NH CH(CO2R )2 NH 2

1 H (CO2R )2CH H iminium ion

: OH H NH R : N RO formation RN

NH O OH : R1 NH2 R O hydrolysis R H 1 1 R H CO2R OO 1 N CO2R OH

HO O O OH 1 R + R O R O H R O 1 O R workup H O OO HO OO

H+ decarboxylation R x O CO2H CO2n H R OH 330

Example 17 OO NCbz N OO H Boc NCbz Meldrum's acid N OO H o Boc EDDA, PhH, 60 C CHO OO 12 h, 84%

Example 2, using ionic liquid ethylammonium nitrate (EAN) as solvent13

CHO CN ethylammonium nitrate

CO2Et rt, 10 h, 87%

CN

CO2Et

References

1. Knoevenagel, E. Ber. Dtsch. Chem. Ges. 1898, 31, 2596. Emil Knoevenagel (1865- 1921) was born in Hannover, Germany. He studied at Göttingen under Victor Meyer and Gattermann, 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. (Review). 3. Van der Baan, J. L.; Bickelhaupt, F. Tetrahedron 1974, 30, 2447. 4. Green, B.; Khaidem, I. S.; Crane, R. I.; Newaz, S. S. Tetrahedron 1976, 31, 2997. 5. Angeletti, E.; Canepa, C.; Martinetti, G.; Venturello, P. J. Chem. Soc., Perkin Trans. 1 1989, 105. 6. Paquette, L. A.; Kern, B. E.; Mendez-Andino, J. Tetrahedron Lett. 1999, 40, 4129. 7. Tietze, L. F.; Zhou, Y. Angew. Chem., Int. Ed. 1999, 38, 2045. 8. Balalaie, S.; Nemati, N. Synth. Commun. 2000, 30, 869. 9. Pearson, A. J.; Mesaros, E. F. Org. Lett. 2002, 4, 2001. 10. Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.; Tsadjout, A. Synth. Commun. 2002, 32, 355. 11. Kourouli, T.; Kefalas, P.; Ragoussis, N.; Ragoussis, V. J. Org. Chem. 2002, 67, 4615. 12. Wada, S.; Suzuki, H. Tetrahedron Lett. 2003, 44, 399. 13. Hu, Yi; Chen, J.; Le, Z.-G.; Zheng, Q.-G. Synth. Comm. 2005, 35, 739. 331

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 333).

R R R3 N N R2 R N R2 NH O O N

NH2 R1 R2 R1 R3 R1 R3

R = H, Alkyl, Aryl, Het-aryl, Acyl, etc.

R R R R 3 N OH N O NH O O N N NH 2 R1 OR2 R R 1 3 R1 R3

R R OH O NH2NH2 NH NH O R R OH

R R N N NH NH R OH R Alternatively,

R R O N NH2NH2 NH2 O O R R

R R N N NH NH R OH R 332

Example 15 Me OMe O MeNHNH2 HCl, H2O N N MeO Me 84% Me Example 213 O O O EtO CCF , NaOMe, MeOH CF Me 2 3 3 reflux, 24 h, 94% Me Me

Me

O CF H2N S N NH2xHCl 3 N N O H

EtOH, reflux, 46% O S Celebrex H2NO References

1 Knorr, L. Ber Dtsch. Chem. Ges. 1883, 16, 2597. Ludwig Knorr (18591921) was born near Munich, Germany. After studying under Volhard, Emil Fischer, and Bun- sen, 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. 2 Knorr, L. Ber Dtsch. Chem. Ges. 1884, 17, 546, 2032. 3 Knorr, L. Ber Dtsch. Chem. Ges. 1885, 18, 311. 4 Knorr, L., Justus Liebigs Ann. Chem. 1887, 238, 137. 5 Burness, D. M. J. Org. Chem. 1956, 21, 97. 6 Jacobs, T. L., in Heterocyclic Compounds, Elderfield, R. C., Ed.; Wiley: New York, 1957, 5, 45. (Review). 7 Houben-Weyl, 1967, 10/2, 539, 587, 589, 590. (Review). 8 Marzinzik, A. L.; Felder, E. R. Tetrahedron Lett. 1996, 37, 1003. 9 Elguero, J., In Comprehensive Heterocyclic Chemistry II, Katrizky, A. R.; Rees, C. W.: Scriven, E. F. V., Eds; Elsevier: Oxford, 1996, 3, 1. (Review). 10 Penning, T. D.; Talley, J. J.; et al. J. Med. Chem. 1997, 40, 1347. 11 Shen, D-M.; Shu, M.; Chapman, K. T. Org. Lett. 2000, 2, 2789. 12 Stanovnik, E.; Svete, J. in Science Of Synthesis, 2002, 12, 15; Ed. by Neier, R.; Thieme. (Review). 13 Carpino, P. A.; Lefker, B. A.; Toler, S. M.; et al. Bioorg. Med. Chem. 2003,11, 581. 14 Sakya, S. M. Knorr Pyrazole Synthesis In Name Reactions in Heterocyclic Chemistry, Eds, Li, J. J.; Corey, E. J. Wiley & Sons: Hoboken, NJ, 2005, 292300. (Review). 333

Paal–Knorr pyrrole synthesis Reaction between 1,4-ketones and primary amines (or ammonia) to give pyrroles. A variation of the Knorr pyrazole synthesis (page 331).

O 1 2 R R NH2 1 R RRN O R2

H N R2 2 : O O R1 R1 R R HN OH 2 O R

HH slow HO OH : HO 1 R N R1 R N R R2 R2

H HH

1 HO : RR 1 R 1 N R N R N R 2 2 R R2 R

Example 15

EtO OEt

OEt F F O H2N OEt N

1 eq. pivalic acid O THF, reflux, 43% CONHPh CONHPh 334

Ca2+ HO CO2 HO

F N

H N O

Lipitor 2 Example 27 Cl N O NH4OAc

O HOAc F 110 °C N 90% F H Cl N

References

1. Paal, C. Ber. Dtsch. Chem. Ges. 1885, 18, 367. 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 5157, 7479. (Review). 4. Chiu, P. K.; Sammes, M. P. Tetrahedron 1990, 46, 3439. 5. Browner, P. L.; Butler, D. E.; Deering, C. F.; Le, T. V.; Millar, A.; Nanninga, T. N.; Roth, B. D. Tetrahedron Lett. 1992, 33, 2279, 2283. 6. Yu, S.-X.; Le Quesne, P. W. Tetrahedron Lett. 1995, 36, 6205. 7. de Laszlo, S. E.; Visco, D.; Agarwal, L.; et al. Bioorg. Med. Chem. Lett. 1998, 8, 2689. 8. Robertson, J.; Hatley, R. J. D.; Watkin, D. J. J. Chem. Soc., Perkin 1 2000, 3389. 9. Braun, R. U.; Zeitler, K.; Mueller, T. J. J. Org. Lett. 2001, 3, 3297. 10. Gorlitzer, K.; Fabian, J.; Frohberg, P.; Drutkowski, G. Pharmazie 2002, 57, 243. 11. Quiclet-Sire, B.; Quintero, L.; Sanchez-Jimenez, G.; Zard, Z. Synlett 2003, 75. 12. Gribble, G. W. Knorr and PaalKnorr Pyrrole Syntheses In Name Reactions in Het- erocyclic Chemistry, Eds, Li, J. J.; Corey, E. J. Wiley & Sons: Hoboken, NJ, 2005, 7988. (Review). 335

Koch–Haaf carbonylation

Strong acid-catalyzed tertiary carboxylic acid formation from alcohols or olefins and CO.

ROH R CO2H CO, H2O

H+

H H RO: protonation RO H H+

O R R :CO: R alkyl

migration

the tertiary carbocation is thermodynamically favored

O O R R OH2 :OH2

acylium ion

O R H+ OH

Example 15

OH CO2H HCO2H, H2SO4

rt, 66% 336

Example 27

HCO H, H SO OH 2 2 4

o CCl4, 5 C, 95%

CO2H

References

1. Koch, H.; Haaf, W. Justus Liebigs Ann. Chem. 1958, 618, 251. 2. Kell, D. R.; McQuillin, F. J. J. Chem. Soc., Perkin Trans. 1 1972, 2096. 3. Norell, J. R. J. Org. Chem. 1972, 37, 1971. 4. Booth, B. L.; El-Fekky, T. A. J. Chem. Soc., Perkin Trans. 1 1979, 2441. 5. Langhals, H.; Mergelsberg, I.; Rüchardt, C. Tetrahedron Lett. 1981, 22, 2365. 6. Farooq, O.; Marcelli, M.; Prakash, G. K. S.; Olah, G. A. J. Am. Chem. Soc. 1988, 110, 864. 7. Takahashi, Y. Synth. Commun. 1989, 19, 1945. 8. Stepanov, A. G.; Luzgin, M. V.; Romannikov, V. N.; Zamaraev, K. I. J. Am. Chem. Soc. 1995, 117, 3615. 9. Olah, G. A.; Prakash, G. K. S.; Mathew, T.; Marinez, E. R. Angew. Chem., Int. Ed. 2000, 39, 2547. 10. Xu, Q.; Inoue, S.; Tsumori, N.; Mori, H.; Kameda, M.; Tanaka, M.; Fujiwara, M.; Souma, Y. J. Mol. Catal. A: Chem. 2001, 170, 147. 11. Tsumori, N.; Xu, Q.; Souma, Y.; Mori, H. J. Mol. Catalysis A: Chem. 2002, 179, 271. 12. Mori, H.; Mori, A.; Xu, Q.; Souma, Y. Tetrahedron Lett. 2002, 43, 7871. 13. Li, T.; Tsumori, N.; Souma, Y.; Xu, Q. Chem. Commun. 2003, 2070. 14. Haubein, N. C.; Broadbelt, L. J.; Schlosberg, R. H. Ind. Eng. Chem. Res. 2004, 43, 18. 337

Koenig–Knorr glycosidation Formation of the E-glycoside from D-halocarbohydrate under the influence of silver salt.

AcO AcO O ROH O H OR AcO AcO AcO H O O Br Ag2CO3 AcO H H H Ac H Ac

AgBr CO2n H2O

AcO O: AcO H O AcO O AcO AcO H Br O + AcO H O: H Ac Ag H oxonium ion

H AcO : AcO O O O R E-anomer is OR AcO AcO O AcO H AcO H O O favored H H H Ac E-anomer

Example 113

NO2 MeO2C O Br HO N PivO OPiv NCF3 OPiv

Ag2O, 10 eq. HMTTA

CH3CN, rt, 6 h, 41% 338

NO2 MeO C O O 2 N NCF PivO OPiv 3 OPiv

Example 215 AcO OMe O H AcO O AcO H Br H Ac OH

OMe

Cd CO , Tol. AcO 2 3 O O reflux, 6 h, 84% AcO AcO H O H Ac

References

1. Koenig, W.; Knorr, E. Ber. Dtsch. Chem. Ges. 1901, 34, 957. 2. Igarashi, K. Adv. Carbohydr. Chem. Biochem. 1977, 34, 24383. (Review). 3. Schmidt, R. R. Angew. Chem. 1986, 98, 213. 4. Greiner, J.; Milius, A.; Riess, J. G. Tetrahedron Lett. 1988, 29, 2193. 5. Smith, A. B., III; Rivero, R. A.; Hale, K. J.; Vaccaro, H. A. J. Am. Chem. Soc. 1991, 113, 2092. 6. Li, H.; Li, Q.; Cai, M.-S.; Li, Z.-J. Carbohydr. Res. 2000, 328, 611. 7. Fürstner, A.; Radkowski, K.; Grabowski, J.; Wirtz, C.; Mynott, R. J. Org. Chem. 2000, 65, 8758. 8. Josien-Lefebvre, D.; Desmares, G.; Le Drian, C. Helv. Chim. Acta 2001, 84, 890. 9. Seebacher, W.; Haslinger, E.; Weis, R. Monatsh. Chem. 2001, 132, 8397. 10. Yashunsky, D. V.; Tsvetkov, Y. E.; Ferguson, M. A. J.; Nikolaev, A. V. J. Chem. Soc., Perkin Trans. 1 2002, 242. 11. Kroger, L.; Thiem, J. J. Carbohydrate Chem. 2003, 22, 9. 12. Somsak, L.; Kovacs, L.; Gyollai, V.; Osz, E. Chem. Commun. 1999, 591. 13. Stazi, F.; Palmisano, G.; Turconi, M.; Clini, S.; Santagostino, M. J. Org. Chem. 2004, 69, 1097. 14. Claffey, D. J.; Casey, M. F.; Finan, P. A. Carbohydrate Res. 2004, 339, 2433. 15. Wimmer, Z.; Pechova, L.; Saman, D. Molecules 2004, 9, 902. 339

Kolbe–Schmitt reaction Carboxylation of sodium phenoxides with carbon dioxide, to give salicylic acid, the precursor to the synthesis of aspirin.

O Na OH OH CO2 H CO2 Na CO2H pressure

Na O Na O Na O O nucleophilic O CO2 O H complexation O addition

OH OH aromatization H CO2 Na CO2H workup

Example 13

OH OH CO2, KHCO3 HO2C

o 8590 C, 60% NH2 NH2

Example 2, the Marasse modification of the Kolbe–Schmitt reaction uses excess of anhydrous potassium carbonate in place of carbon dioxide4

OH o OH K2CO3, 175 C CO2 K

1200200 psi CO2 340

Example 3, the Jones modification of the Kolbe–Schmitt reaction employs sodium ethyl carbonate5

OH OH NaOCO2C2H5 CO2 Na C2H5OH

Salicylic acid is the precursor to the synthesis of aspirin:

O OH O OH

HO (CH3CO2)2O O CH CO H 90% 3 2 O salicylic acid aspirin

References

1. Kolbe, H. Justus Liebigs Ann. Chem. 1860, 113, 1125. Hermann Kolbe (18181884) was born in Elliehausen, Germany. In 1860, at Marburg University, he developed a reaction to synthesize salicylic acid by simply treating phenol with carbon dioxide under high pressure at 180200 oC. Like Wöhler’s urea synthesis, Kolbe’s synthesis of acetic acid by treating trichloroacetic acid with potassium amalgam is considered one of the first total syntheses in organic chemistry. One of his students, Friedrich von Heyden, founded a company to profit from the Kolbe reaction with much financial success. 2. Schmitt, R. J. Prakt. Chem. 1885, 31, 397. 3. Erlenmeyer, H.; Prijs, B.; Sorkin, E.; Suter, E. Helv. Chim. Acta 1948, 31, 988. 4. Marasse, S. German Patent 73,279, 1893. 5. Jones, J. I. Chem. Ind. 1957, 889. 6. Lindsey, A. S.; Jeskey, H. Chem. Rev. 1957, 57, 583. (Review). 7. Kunert, M.; Dinjus, E.; Nauck, M.; Sieler, J. Ber. 1997, 130, 1461. 8. Kosugi, Y.; Takahashi, K. Stud. Surf. Sci. Catal. 1998, 114, 487. 9. Kosugi, Y.; Rahim, M. A.; Takahashi, K.; Imaoka, Y.; Kitayama, M. Appl. Or- ganomet. Chem. 2000, 14, 841. 10. Rahim, M. A.; Matsui, Y.; Kosugi, Y. Bull. Chem. Soc. Jpn. 2002, 75, 619. 341

Kostanecki reaction Also known as KostaneckiRobinson reaction. Transformation 1o2 represents an AllanRobinson reaction (see page 8), whereas 1o3 is a Kostanecki (acylation) reaction:

OO OH O OO RR R O R O O 1 2 3

R RH

: O O O O O acyl H O O O O R transfer R O

H O O O 6-exo-trig enolization O R R ring closure

O O

OO OO OO R H2O H R OH :B R OH

Example 15

OO O OH HO OEt OEt HCO Na, rt, 15 h, 76% 2 OO OO 342

Example 213

O O NaOAc, Ac2O, reflux

HO OO 62 % O OO

O O

References

1. von Kostanecki, S.; Rozycki, A. Ber. Dtsch. Chem. Ges. 1901, 34, 102. 2. Hauser, C. R.; Swamer, F. W.; Adams, J. T. Org. React. 1954, 8, 59. (Review). 3. Cook, D.; McIntyre, J. S. J. Org. Chem. 1968, 33, 1746. 4. Széll, T.; Dózsai, L.; Zarándy, M.; Menyhárth, K. Tetrahedron 1969, 25, 715. 5. Pardanani, N. H.; Trivedi, K. N. J. Indian Chem. Soc. 1972, 49, 599. 6. Okumura, K.; Kondo, K.; Oine, T.; Inoue, I. Chem. Pharm. Bull. 1974, 22, 331. 7. Wagner, H.; Farkas, L. In The Flavanoids; Harborne, J. B.; Mabry, T. J.; Mabry H., eds.; Academic Press: New York, 1975; p 127. (Review). 8. Ahluwalia, V. K. Indian J. Chem., Sect. B 1976, 14B, 682. 9. Ellis, G. P., Chromenes, Chromanones, and Chromones from The Chemistry of Het- erocyclic Compounds, Weissberger, A. and Taylor, E. C., eds.; Wiley & Sons: New York, 1977, vol. 31, p.495. (Review). 10. Looker, J. H.; McMechan, J. H.; Mader, J. W. J. Org. Chem. 1978, 43, 2344. 11. Stanton, J. In Comprehensive Organic Chemistry-The Synthesis and Reactions of Or- ganic Compounds; Sammes, P. G., ed.; Pergamon Press: New York, 1979, vol.4; p. 659. (Review). 12. Iyer, P. R.; Iyer, C. S. R.; Prasad, K. J. R. Indian J. Chem., Sect. B 1983, 22B, 1055. 13. Flavin, M. T.; Rizzo, J. D.; Khilevich, A.; et al. J. Med. Chem. 1996, 39, 1303. 14. Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Litvinov, I. A.; Levin, Ya. A. Chemistry of Heterocyclic Compounds 2003, 39, 96. 15. Limberakis, C. KostaneckiRobinson Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 521535. (Review). 343

Kröhnke pyridine synthesis Pyridines from D-pyridinium methyl ketone salts and DE-unsaturated ketones.

O R1 O R1 R2 N R NH4OAc, HOAc Br RRN 2

H+ H Br O O Michael N enolization N R R addition H Br O AcO R1 R2

Br Br R R N N O O 1 R1 R O H O H + 2 H R R2

R R R

O O O 1 1 R HO R R1 O HN H2N: OAc 2 :NH3 2 H R R R2 The ketone is more reactive than the enone

R1 R1 R 2 R N OH 2 H H+ R N R AcO 344

Example 12

Ph Ph NH4OAc N AcOH + 90% Ph O O Ph PhN Ph

Example 210

N N N N N NH4OAc AcOH N N 81% O N N N O N N O

References

1. Zecher, W.; Kröhnke, F. Ber. 1961, 94, 690. 2. Kröhnke, F.; Zecher, W. Angew. Chem. Intl. Ed. 1962, 1, 626. 3. Kröhnke, F. Synthesis 1976, 124. (Review). 4. Chatterjea, J. N.; Shaw, S. C.; Singh, J. N.; Singh, S. N. Indian J. Chem., Sect. B 1977, 15B, 430. 5. Potts, K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G. J. Am. Chem. Soc. 1981, 103, 3584, 3585. 6. Newkome, G. R.; Hager, D. C.; Kiefer, G. E. J. Org. Chem. 1986, 51, 850. 7. Constable, E. C.; Ward, M. D.; Tocher, D. A. J. Chem. Soc., Dalton Trans. 1991, 1675. 8. Constable, E. C.; Chotalia, R. J. Chem. Soc., Chem. Commun. 1992, 65. 9. Markovac, A.; Ash, A. B.; Stevens, C. L.; Hackley, B. E., Jr.; Steinberg, G. M. J. Het- erocycl. Chem. 1977, 14, 19. 10. Kelly, T. R.; Lee, Y.-J.; Mears, R. J. J. Org. Chem. 1997, 62, 2774. 11. Bark, T.; Von Zelewsky, A. Chimia 2000, 54, 589. 12. Malkov, A. V.; Bella, M.; Stara, I. G.; Kocovsky, P. Tetrahedron Lett. 2001, 42, 3045. 13. Cave, G. W. V.; Raston, C. L. J. Chem. Soc. Perkin Trans. 1 2001, 3258. 14. Galatsis, P. Kröhnke Pyridine Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 311313. (Review). 345

Kumada cross-coupling reaction

The Kumada cross-coupling reaction (also occasionally known as the Kharasch cross-coupling reaction) is a nickel- or palladium-catalyzed cross-coupling reaction of a Grignard reagent with an organic halide, triflate, etc.

1 Pd(0) 1 RX R MgXRR MgX2

oxidative R L R1 MgX RX L Pd(0) Pd 2 X transmetallation addition L isomerization

L L reductive 1 MgX2 Pd R R L Pd(0) R1 2 R elimination

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 cycle as shown on the next page. There are slight variations for the Hiyama and Suzuki reactions, for which an additional activation step is required for the transmetalation to occur.

The catalytic cycle:

R1 1 transmetallation LnPd(II) R M LnPd(II) R1

reductive 1 1 R R LnPd(0) elimination 346

R X

L2Pd(0) R R1

oxidative addition

R L Pd X L R1M reductive elimination transmetallation and isomerization

L L Pd R1 R MX

Example 12

Pd(dppf)Cl2, Et2O O Br MgBr O S –30 oC to rt, 5 h, 98% S

Example 24

Br NMgBr N NBr PdCl •(dppb) N 2 Br THF, rt, 87%

MgBr S N N PdCl2•(dppb) THF, reflux, 98% S 347

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. 2. Carpita, A.; Rossi, R.; Veracini, C. A. Tetrahedron 1985, 41, 1919. 3. Kalinin, V. N. Synthesis 1992, 413. 4. Meth-Cohn, O.; Jiang, H. J. Chem. Soc., Perkin Trans. 1 1998, 3737. 5. Stanforth, S. P. Tetrahedron 1998, 54, 263. (Review). 6. Park, M.; Buck, J. R.; Rizzo, C. J. Tetrahedron 1998, 54, 12707. 7. Huang, J.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 9889. 8. Uenishi, J.; Matsui, K. Tetrahedron Lett. 2001, 42, 4353. 9. Li, G. Y. J. Organomet. Chem. 2002, 653, 63. 10. Anctil, E. J.-G.; Snieckus, V. J. Organomet. Chem. 2002, 653, 150. 11. Banno, T.; Hayakawa, Y.; Umeno, M. J. Organomet. Chem. 2002, 653, 288. 12. Tasler, S.; Lipshutz, B. H. J. Org. Chem. 2003, 68, 1190. 13. Phan, N. T. S.; Brown, D. H.; Styring, P. Green Chem. 2004, 6, 526. 14. Mans, D. M.; Pearson, W. H. J. Org. Chem. 2004, 69, 6419. 15. Shao, L.-X.; Shi, M. Org. Biomol. Chem. 2005, 3, 1828. 16. Semeril, D.; Lejeune, M.; Jeunesse, C.; Matt, D. J. Mol. Cat. A: Chem. 2005, 239, 257. 348

Lawesson’s reagent 2,4-Bis-(4-methoxyphenyl)-[1,3,2,4]dithiadiphosphetane 2,4-disulfide, trans- forms the carbonyl groups of ketones, amides and esters into the corresponding thiocarbonyl compounds. Cf. Knorr thiophene synthesis.

S O P S SP O S O S N Lawesson's reagent N H H

S S 2 OP S O P S O : SP O NH S

S OPS O NH

S H O S NOP OP N S S O H

Example 14

H H O O Lawesson's reagent

O (Me2N)2C=S S H H O S xylene, 160 oC, 47% OMe OMe 349

Example 24

O S Lawesson's MeO C N H MeO2C N H 2 reagent, 95%

References

1. Lawesson, S. O.; Perregaad, J.; Scheibye, S.; Meyer, H. J.; Thomsen, I. Bull. Soc. Chim. Belg. 1977, 86, 679. 2. Navech, J.; Majoral, J. P.; Kraemer, R. Tetrahedron Lett. 1983, 24, 5885. 3. Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061. (Review). 4. Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. Angew. Chem., Int. Ed. Engl. 1989, 27, 1362. 5. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. 6. Luheshi, A. B. N.; Smalley, R. K.; Kennewell, P. D.; Westwood, R. Tetrahedron Lett. 1990, 31, 123. 7. Luo, Y.; He, L.; Ding, M.; Yang, G.; Luo, A.; Liu, X.; Wu, T. Heterocycl. Commun. 2001, 7, 37. 8. He, L.; Luo, Y.; Li, K.; Ding, M.; Luo, A.; Liu, X.; Wu, T.; Cai, F. Synth. Commun. 2002, 32, 1415. 9. Ishii, A.; Yamashita, R.; Saito, M.; Nakayama, J. J. Org. Chem. 2003, 68, 1555. 350

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 Eschweiler– Clarke reductive alkylation of amines.

1 3 R R R1 R3 HCO2H O HN N CO n H2O 2 4 2 R R R2 R4

H R1

4 HO H HO

R : N : O 1 3 R N R 1 3 H R2 H R N R 2 4 2 4 R3 R R R R D-aminoalcohol

R1 R3 1 3 R R 2 N 4 H2O HCO2H R R N 2 4 H H R R O O iminium ion intermediate reduction

1 3 1 3 + R R CO R R H 2 2 4 N R N R 2 4 H H R R

Example 15

H HCO H N 2 O N CHO o O 60 C, 57%

Example 27

O HCO2H, H2O N 190 oC, autoclave N OHC 16 h, 75% 351

References

1. Leuckart, R. Ber. Dtsch. Chem. Ges. 1885, 18, 2341. Carl L. R. A. Leuckart (18541889) 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 contributor by his sudden death at age 35 as a result of a fall in his parent’s house. 2. Wallach, O. Justus Liebigs Ann. Chem. 1892, 272, 99. Otto Wallach (18471931), born in Königsberg, Prussia, studied under Wöhler and Hofmann. He was the director of the Chemical Institute 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. 1948, 5, 301. (Review). 4. Staple, Ezra; Wagner, E. C. J. Org. Chem. 1949, 14, 559. 5. DeBenneville, P. L.; Macartney, J. H. J. Am. Chem. Soc. 1950, 72, 3073. 6. Lukasiewiecz, A. Tetrahedron 1963, 19, 1789. (Mechanism). 7. Bach, R. D. J. Org. Chem. 1968, 33, 1647. 8. Doorenbos, N. J.; Solomons, W. E. Chem. Ind. 1970, 1322. 9. Ito, K.; Oba, H.; Sekiya, M. Bull. Chem. Soc. Jpn. 1976, 49, 2485. 10. Musumarra, G.; Sergi, C. Heterocycles 1994, 37, 1033. 11. Kitamura, M.; Lee, D.; Hayashi, S.; Tanaka, S.; Yoshimura, M. J. Org. Chem. 2002, 67, 8685. 352

Lossen rearrangement Treatment of O-acylated hydroxamic acids with base provides isocyanates.

O 2 OH H2O 1 OR 1 1 R N R NCO R NH2 CO2n H O

O OR2 O R1 N OR2 H O R1 N O OH

HO H 2 1 R CO2 R NCO

:OH2 isocyanate intermediate

H NO decarboxylation R1 H 1 R NH2 CO2n O :B

Example 16

O H O N CO Et C EtO C O 2 N Cl 2 Et N, H O Br 3 2 Br

NH EtOH, H2O 2

50% Br 353

Example 28

N N H DBU, THF, H2O N N N AcO N reflux, 1 h C O O O O OMe OMe MeO MeO

N

N H2N O OMe MeO

References

1. Lossen, W. Ann. 1872, 161, 347. Wilhelm C. Lossen (18381906) 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. 1974, 86, 419. 3. Lipczynska-Kochany, E. Wiad. Chem. 1982, 36, 735. 4. Casteel, D. A.; Gephart, R. S.; Morgan, T. Heterocycles 1993, 36, 485. 5. Zalipsky, S. Chem. Commun. 1998, 69. 6. Anilkumar, R.; Chandrasekhar, S.; Sridhar, M. Tetrahedron Lett. 2000, 41, 5291. 7. Needs, P. W.; Rigby, N. M.; Ring, S. G.; MacDougall, A. J. Carbohydr. Res. 2001, 333, 47. 8. Ohmoto, K.; Yamamoto, T.; Horiuchi, T.; Kojima, T.; Hachiya, K.; Hashimoto, S.; Kawamura, M.; Nakai, H.; Toda, M. Synlett 2001, 299. 354

McFadyen–Stevens reduction Treatment of acylbenzenesulfonylhydrazines with base delivers the corresponding aldehydes.

O H Base O N RNSO Ar 2 RH H

O H O N RNSO Ar N 2 RNH H B:

homolytic O O N2n cleavage R H RH

Example 19

O O N 2 NH HN O SO2 K2CO3, MeOH O N 2 H reflux, 1 h, 75%

Example 211

O NaCO3, glass powder N O ethylene glycol

N NHNHTs microwave (450 W) H 90%

O N O

N H H 355

References

1. McFadyen, J. S.; Stevens, T. S. J. Chem. Soc. 1936, 584. Thomas S. Stevens (1900) 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 Glas- gow, 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. 3. Sprecher, M.; Feldkimel, M.; Wilchek, M. J. Org. Chem. 1961, 26, 3664. 4. Jensen, K. A.; Holm, A. Acta. Chem. Scand. 1961, 15, 1787. 5. Babad, H.; Herbert, W.; Stiles, A. W. Tetrahedron Lett. 1966, 2927. 6. Graboyes, H.; Anderson, E. L.; Levinson, S. H.; Resnick, T. M. J. Heterocycl. Chem. 1975, 12, 1225. 7. Eichler, E.; Rooney, C. S.; Williams, H. W. R. J. Heterocycl. Chem. 1976, 13, 841. 8. Nair, M.; Shechter, H. J. Chem. Soc., Chem. Commun. 1978, 793. 9. Dudman, C. C.; Grice, P.; Reese, C. B. Tetrahedron Lett. 1980, 21, 4645. 10. Manna, R. K.; Jaisankar, P.; Giri, V. S. Synth. Commun. 1998, 28, 9. 11. Jaisankar, P.; Pal, B.; Giri, V. S. Synth. Commun. 2002, 32, 2569. 356

McMurry coupling Olefination of carbonyls with low-valent titanium such as Ti(0) derived from TiCl3/LiAlH4. Single-electron process.

R1 R1 R1 1. TiCl3, LiAlH4 O TiO 2 2 2 R 2. H2O R R

Ti(III)Cl3 LiAlH4 Ti(0)

Ti Ti R1 single electron OO homocoupling O :Ti(0) 1 1 2 R R R transfer R2 R2 radical anion intermediate

Ti Ti Ti Ti OO OO 1 1 R R R1 R1 2 2 R R R2 R2

R1 R1 Ti Ti R2 R2 OO oxide-coated titanium surface

Example 112

OH

MeO2S

Zn, TiCl4, reflux O 4.5 h, 75%, >99% Z O 357

MeO2S OH

Example 213

o Zn, TiCl4, THF,110 C S CHO microwave (10 W), 10 min. 87%

S S

References

1. McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc. 1974, 96, 4708. 2. McMurry, J. E. Chem. Rev. 1989, 89, 15131524. (Review). 3. Ephritikhine, M. Chem. Commun. 1998, 2549. 4. Hirao, T. Synlett 1999, 175. 5. Yamato, T.; Fujita, K.; Tsuzuki, H. J. Chem. Soc., Perkin Trans. 1 2001, 2089. 6. Sabelle, S.; Hydrio, J.; Leclerc, E.; Mioskowski, C.; Renard, P.-Y. Tetrahedron Lett. 2002, 43, 3645. 7. Williams, D. R.; Heidebrecht, R. W., Jr. J. Am. Chem. Soc. 2003, 125, 1843. 8. Kowalski, K.; Vessieres, A.; Top, S.; Jaouen, G.; Zakrzewski, J. Tetrahedron Lett. 2003, 44, 2749. 9. Honda, T.; Namiki, H.; Nagase, H.; Mizutani, H. Tetrahedron Lett. 2003, 44, 3035. 10. Ephritikhine, M.; Villiers, C. in Modern Carbonyl Olefination Takeda, T. ed., Wiley- VCH: Weinheim, Germany, 2004, 223285. (Review). 11. Rajakumar, P.; Gayatri Swaroop, M. Tetrahedron Lett. 2004, 45, 6165. 12. Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Synlett 2004, 1513. 13. Stuhr-Hansen, N. Tetrahedron Lett. 2005, 46, 5491. 358

MacMillan catalyst Highly enantioselective and general asymmetric organocatalytic Diels-Alder reaction using D-amino acid-derived imidazolidinones (of type 1) as catalysts. The first generation of MacMillan catalyst (1) has been employed in a variety of organocatalytic enantioselective reactions. Typical examples are: Diels-Alder reaction;1 nitrone cycloaddition,2 pyrrole FriedelCrafts reaction,3 indole addition,4 vinylogous Michael addition;5 D-chlorination;6 hydride addition;7 cyclopropanation;8 D-fluorination.9 The second generation of MacMillan catalyst (2) was used to catalyze 1,4-addition of C-nucleophiles employing various indoles.

O Me N Me Ph N Me HX H imidazolidinone 1

O 5 mol% (1) + o 23 C CHO 82%, 94% ee (endo/exo 14:1)

O Me O N Me Ph dienophile CHO N Me HX H

OMe N Me Me Me + + N Me N H N Me Ph

O Ph

diene 359

O N

R2 N H

R3 imidazolidinone 2 R4 O N 20 mol% 2, CH2Cl2-i-PrOH o R1 87 to 50 C

R2 R4 H 7094% yield R3 O 8997% ee N

R1

Example 111

O O 20 mol% 2 O O Bn 90%, 90% ee Bn N N Bn Bn

Example 210

BocHN

Br 1. 20 mol% 2 N O 2. NaBH4, MeOH 360

OH

Br N N Br N N H H Boc Me

78% yield ()-flustramine B 90% ee

References

1. Ahrendt, K.; Borths, C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243. 2. Jen, W.; Wiener, J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874. 3. Paras, N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370. 4. Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172. 5. Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 1192. 6. Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108. 7. Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32. 8. Kunz, R. K; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240. 9. Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826. 10. Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Nat. Acad. Sci. USA, 2004, 101, 5482. 11. Kim, S.-G.; Kim, J.; Jung, H. Tetrahedron Lett. 2005, 46, 2437. 361

Mannich reaction Three-component aminomethylation from amine, formaldehyde and a compound with an acidic methylene moiety.

O R O O + H R 2 1 NR NH R 2 R HH R RR1

H O OH OH + 2 H : R R R N HHH NH NH N: R R R R R

+ When R = H, the Me2N=CH2 salt is known as Eschenmoser’s salt

H O 1 O + R O H R 1 2 R 2 R 2 NR R enolization R 1 N RR R

The Mannich reaction can also operate under basic conditions:

O O 1 1 R 2 O R 2 enolate R R R 2 NR H R 1 formation N RR B: R Mannich Base

Example 1, asymmetric Mannich reaction4

NH 2 OHC O

NO2 O 362

O

35 mol% (L)-proline O HN

DMSO, rt, 50%, 94% ee

NO2

Example 2, asymmetric aza-Mannich reaction13

o-Ts O N N OH O

o-Ts NH O In(Oi-Pr)3, ligand N MS 5 Å, THF, rt, 80% O OH

References

1. Mannich, C.; Krosche, W. Arch. Pharm. 1912, 250, 647. Carl U. F. Mannich (18771947) 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. Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1045. 3. Padwa, A.; Waterson, A. G. J. Org. Chem. 2000, 65, 235. 4. List, B. J. Am. Chem. Soc. 2000, 122, 9336. 5. Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron 2000, 56, 10023. 6. Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221. (Review). 7. Vicario, J. L.; Badía, D.; Carrillo, L. Org. Lett. 2001, 3, 773. 8. Martin, S. F. Acc. Chem. Res. 2002, 35, 895904. (Review). 9. Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851862. (Review). 10. Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851862. (Review). 11. Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580591. (Re- view). 12. Córdova, A. Acc. Chem. Res. 2004, 37, 102112. (Review). 13. Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 4365. 363

Marshall boronate fragmentation Marshall boronate fragmentation is a variation of the Grob fragmentation (page 273) category.

OMs

BH3xSMe2

NaOMe

OMs OMs

BH3xSMe2 H H2B

OMe

OMs

H2B H OMe

Example 15

OMs o 1. BH3xSMe2, THF, 0 C to rt, 3 h

2. NaOMe, MeOH, rt, overnight OH 68%

OH 364

Example 26

OMs o 1. BH3xSMe2, THF, 0 C to rt, 3 h

2. NaOMe, MeOH, rt, overnight OAc 11%

OH

References

1. Marshall, J. A.; Huffman, W. F. J. Am. Chem. Soc. 1970, 92, 6358. 2. Marshall, J. A. Synthesis 1971, 229. (Review). 3. Wharton, P. S.; Sundin, C. E.; Johnson, D. W.; Kluender, H. C. J. Org. Chem. 1972, 37, 34. 4. Minnaard, A. J.; Wijnberg, J. B. P. A.; de Groot, A. Tetrahedron 1994, 50, 4755. 5. Zhabinskii, V. N.; Minnard, A. J.; Wijnberg, J. B. P. A.; de Groot, A. J. Org. Chem. 1996, 61, 4022. 6. Minnard, A. J.; Stork, G. A.; Wijnberg, J. B. P. A.; de Groot, A. J. Org. Chem. 1997, 62, 2344. 365

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 Ph2SO HOC(CF3)2Ph

OC(CF3)2Ph HOtBu Ph2S OC(CF ) Ph 3 2 HOC(CF3)2Ph O Ph2S :OC(CF3)2Ph The alcohol is acidic

H OC(CF3)2Ph :

OC(CF3)2Ph protonation Ph S 2 OC(CF3)2Ph O

H OC(CF3)2Ph Ph2S Ph2S O OC(CF3)2Ph O H

E-elimination Ph2SO HOC(CF3)2Ph E1cB

Example 19

OMe OBn OH Martin's sulfurane O O O OPMB O Et N, CHCl , 50 oC BzO OMe O O 3 3 85% OBn 366

OMe OBn O O O OPMB O BzO OMe O O OBn

Example 210

CO2Me HO CO2Me

1.5 eq. Martin's sulfurane TBSO O TBS O OMe OMe CH2Cl2, rt, 24 h, 84% O O O MeO MeO

References

1. Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 2339, 2341. J. C. Martin was a professor at the University of Illinois at Urbana, where he discovered the Martin’s sulfurane dehydrating reagent. Martin also developed the DessMartin periodinane oxidation (page 195) with his student Daniele Dess. 2. Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327. 3. Martin, J. C.; Arhart, R. J.; Franz, J. A.; Perozzi, E. F.; Kaplan, L. J. Org. Synth. 1977, 57, 22. 4. Bartlett, P. D.; Aida, T.; Chu, H.-K.; Fang, T.-S. J. Am. Chem. Soc. 1980, 102, 3515. 5. Gallagher, T. F.; Adams, J. L. J. Org. Chem. 1992, 57, 3347. 6. Tse, B.; Kishi, Y. J. Org. Chem. 1994, 59, 7807. 7. Winkler, J. D.; Stelmach, J. E.; Axten, J. Tetrahedron Lett. 1996, 37, 4317. 8. Rao, P. N.; Wang, Z. Steroids 1997, 62, 487. 9. Nicolaou, K. C.; Rodríguez, R. M.; Fylaktakidou, K. C.; Suzuki, H.; Mitchell, H. J. Angew. Chem., Int. Ed. Engl. 1999, 38, 3340. 10. Box, J. M.; Harwood, L. M.; Humphreys, J. L.; Morris, G. A.; Redon, P. M.; White- head, R. C. Synlett 2002, 358. 11. Yokokawa, F.; Shioiri, T. Tetrahedron Lett. 2002, 43, 8679. 12. 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. 13. Begum, L.; Box, J. M.; Drew, M. G. B.; Harwood, L. M.; Humphreys, J. L.; Lowes, D. J.; Morris, G. A.; Redon, P. M.; Walker, F. M.; Whitehead, R. C. Tetrahedron 2003, 59, 4827. 367

Masamune–Roush conditions Applicable to base-sensitive aldehydes and phosphonates for the Horner– Wadsworth–Emmons reaction

OO CHO (EtO) P AcO 2 OEt D-keto or D-alkoxycarbonyl phosphonate required

N

N CO Et AcO 2 LiCl, CH3CN 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)

OO (EtO) P 2 OEt H deprotonation OO LiCl (EtO)2P

: OEt chelation N N

Li OO O (EtO)2P OEt EtO2CPOEt OEt H AcO O AcO O

O EtO2C CO Et P(OEt)2 AcO 2 O AcO 368

Example 16 H O O O MOMO OMe 7 OO (EtO)2(O)P MeO

O O 7

LiCl, Hunig base MOMO OMe OO MeCN, rt, 14 h, 58% MeO

Example 27

Ph Ph N O (EtO) (O)P CHO 2 BocN O O O Li, DBU, CH3CN, rt, 67%

Ph Ph N O BocN O O O

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. 2. Marshall, J. A.; DuBay, W. J. J. Org. Chem. 1994, 59, 1703. 3. Tius, M. A.; Fauq, A. H. J. Am. Chem. Soc. 1986, 108, 1035. 4. Tius, M. A.; Fauq, A. H. J. Am. Chem. Soc. 1986, 108, 6389. 5. Rychnovsky, S. D.; Khire, U. R.; Yang, G. J. Am. Chem. Soc. 1997, 119, 2058. 6. Dixon, D. J.; Foster, A. C.; Ley, S. V. Org. Lett. 2000, 2, 123. 7. Crackett, P.; Demont, E.; Eatherton, A.; Frampton, C. S.; Gilbert, J.; Kahn, I.; Red- shaw, S.; Watson, W. Synlett 2004, 679. 369

Meerwein–Ponndorf–Verley reduction

Reduction of ketones to the corresponding alcohols using Al(Oi-Pr)3 in isopropanol.

O O Al(Oi-Pr)3 OH 1 2 1 2 R R HOi-Pr R R

Al(Oi-Pr)3 R1 Oi-Pr : coordination O R2 O Al Oi-Pr HO R1 R2

cyclic transition state

i-PrO Oi-Pr Al O O hydride

R1 H transfer R2

Al(Oi-Pr) + O O 2 H OH 1 2 R1 R2 R R

Example 12

O OH H H H Al(Oi-Pr)3 O O H H HOi-Pr, 90% MeO C 2 H O H 370

Example 212

O OH Br3CHPh

O Al O O O Br3C

CH2Cl2, rt, 2.5 h, 58% Ph

References

1. Meerwein, H.; Schmidt, R. Justus Liebigs Ann. Chem. 1925, 444, 221. Hans L. Meerwein, born in Hamburg Germany in 1879, received his Ph.D. at Bonn in 1903. In his long and productive 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. 3. Ashby, E. C. Acc. Chem. Res. 1988, 21, 414. (Review). 4. de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J. Synthesis 1994, 1007. (Review). 5. Aremo, N.; Hase, T. Tetrahedron Lett. 2001, 42, 3637. 6. Campbell, E. J.; Zhou, H.; Nguyen, S. T. Angew. Chem., Int. Ed. Engl. 2002, 41, 1020. 7. Faller, J. W.; Lavoie, A. R. Organometallics 2002, 21, 2010. 8. Nishide, K.; Node, M. Chirality 2002, 14, 759. 9. Jerome, J. E.; Sergent, R. H. Chem. Ind. 2003, 89, 97. (Review). 10. Sominsky, L.; Rozental, E.; Gottlieb, H.; Gedanken, A.; Hoz, S. J. Org. Chem. 2004, 69, 1492. 11. Fukuzawa, S.-i.; Nakano, N.; Saitoh, T. Eur. J. Org. Chem. 2004, 2863. 12. Ooi, T.; Miura, T.; Ohmatsu, K.; Saito, A.; Maruoka, K. Org. Biomol. Chem. 2004, 2, 3312. 371

Meisenheimer complex Also known as MeisenheimerJackson salt, the stable intermediate for certain SNAr reactions.

R F NH

NO2 NO2 RNH2

SNAr NO2 NO2 Sanger’s reagent

RNH: 2 R F HN F SNAr, slow, NO2 NO2 rate-determining step

NO2 NO2 ipso attack ipso substitution

R R NH F NH NO2 fast NO2 F

NO2 NO2

Meisenheimer complex (MeisenheimerJackson salt)

Example 110

OO N NO CO Et 2 t-BuOK, DMF/THF 2 CO2Et Ph CN o 70 C, argon H NC Ph 372

Example 213

OH CH Cl O2N NO2 2 2 2 NCN argon, rt, 3 h

NO2

H O ONN N N i-Pr i-Pr H N N O2N O2NNO2 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 iodo-dinitrobenzene—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.

References

1. Meisenheimer, J. Justus Liebigs Ann. Chem. 1902, 323, 205. 2. Strauss, M. J. Acc. Chem. Res. 1974, 7, 181. (Review). 3. Bernasconi, C. F. Acc. Chem. Res. 1978, 11, 147. (Review). 4. Terrier, F. Chem. Rev. 1982, 82, 77. (Review). 5. Buncel, E.; Dust, J. M.; Manderville, R. A. J. Am. Chem. Soc. 1996, 118, 6072. 6. Sepulcri, P.; Goumont, R.; Hallé, J.-C.; Buncel, E.; Terrier, F. Chem. Commun. 1997, 789. 7. Manderville, R. A.; Buncel, E. J. Org. Chem. 1997, 62, 7614. 8. Weiss, R.; Schwab, O.; Hampel, F. Chem. Eur. J. 1999, 5, 968. 9. Hoshino, K.; Ozawa, N.; Kokado, H.; Seki, H.; Tokunaga, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 4572. 10. Adam, W.; Makosza, M.; Zhao, C.-G.; Surowiec, M. J. Org. Chem. 2000, 65, 1099. 11. Gallardo, I.; Guirado, G.; Marquet, J. J. Org. Chem. 2002, 67, 2548. 12. Kim, H.-Y.; Song, H.-G. Appl. Microbiol. Biotech. 2003, 61, 150. 13. Al-Kaysi, R. O.; Guirado, G.; Valente, E. J. Eur. J. Org. Chem. 2004, 3408. 373

[1,2]-Meisenheimer rearrangement [1,2]-Sigmatropic rearrangement of tertiary amine N-oxides to hydroxylamines:

R R1 R ' 1 N N R R2 O R2 O

Example 15 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 N O 64%, 2 steps O

Example 26 O O O O m-CPBA O N N O N N O CH2Cl2, 50% N N

Cl O O POCl3 N N O 100 oC, 66% N

References

1. Meisenheimer, J. Ber. Dtsch. Chem. Ges. 1919, 52, 1667. 2. [1,2]-Sigmatropic rearrangement, Castagnoli, N., Jr.; Craig, J. C.; Melikian, A. P.; Roy, S. K. Tetrahedron 1970, 26, 4319. 3. Johnstone, R. A. W. Mech. Mol. Migr. 1969, 2, 249. (Review). 4. Molina, J. M.; El-Bergmi, R.; Dobado, J. A.; Portal, D. J. Org. Chem. 2000, 65, 8574. 5. Yoneda, R.; Sakamoto, Y.; Oketo, Y.; Harusawa, S.; Kurihara, T. Tetrahedron 1996, 52, 14563. 6. Williams, E. J.; Kenny, P. W.; Kettle, J. G.; Mwashimba, P. G. Tetrahedron Lett. 2004, 45, 3737. 374

[2,3]-Meisenheimer rearrangement [2,3]-Sigmatropic rearrangement of allylic tertiary amine-N-oxides to give O-allyl hydroxylamines:

3 2 3 2 2 O 1 O ' N 2 1 N 1 R 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 m-CPBA O O N O N OH OH CH2Cl2, 100%

Bn O O O Al2O3 (alumina) N OH MeOH

Bn

CDCl3, rt O O N O OH 67%, 65% de 375

References

1. Meisenheimer, J. Ber. Dtsch. Chem. Ges. 1919, 52, 1667. 2. [2,3]-Sigmatropic rearrangement, Yamamoto, Y.; Oda, J.; Inouye, Y. J. Org. Chem. 1976, 41, 303. 3. Johnstone, R. A. W. Mech. Mol. Migr. 1969, 2, 249. (Review). 4. Kurihara, T.; Sakamoto, Y.; Matsumoto, H.; Kawabata, N.; Harusawa, S.; Yoneda, R. Chem. Pharm. Bull. 1994, 42, 475. 5. Blanchet, J.; Bonin, M.; Micouin, L.; Husson, H.-P. Tetrahedron Lett. 2000, 41, 8279. 6. Enders, D.; Kempen, H. Synlett 1994, 969. 7. Buston, J. E. H.; Coldham, I.; Mulholland, K. R. Synlett 1997, 322. 8. Guarna, A.; Occhiato, E. G.; Pizzetti, M.; Scarpi, D.; Sisi, S.; van Sterkenburg, M. Tet- rahedron: Asymmetry 2000, 11, 4227. 9. Mucsi, Z.; Szabó, A.; Hermecz, I.; Kucsman, Á.; Csizmadia, I. G. J. Am. Chem. Soc. 2005, 127, 7615. 376

Meth–Cohn quinoline synthesis Conversion of acylanilides into 2-chloro-3-substituted quinolines by the action of Vilsmeier’s reagent in warmed phosphorus oxychloride (POCl3) as solvent.

2 2 R DMF, POCl3 R R1 R1 N O ' N Cl H

O O Cl P Cl SN2 NOPCl2 Cl NO: H Cl H

O

NO: PCl 2 NH O H Cl Cl OPCl2 Vilsmeier–Haack reagent

R2 R2 POCl3 R1 R1 N O N Cl H

2 (Me) N R Cl Me 2 R2 R1 N R1 N Cl H Me N Cl H OPOCl2 Cl

2 R2 = H R R1 N Cl 377

Example 15

Me CHO DMF, POCl3 N O 75 oC, 16.5 h, 68% N Cl H

Example 25

DMF (1 equiv.), POCl3 Me (3 equiv.), (CH2Cl)2

S N O ', 4 h, 79% S H N Cl

References

1. Meth-Cohn, O.; Narine, B. Tetrahedron Lett. 1978, 2045; 2. Meth-Cohn, O.; Narine, B.; Tarnowski, B. Tetrahedron Lett. 1979, 3111. 3. Meth-Cohn, O.; Tarnowski, B. Tetrahedron Lett. 1980, 21, 3721. 4. Meth-Cohn, O; Rhouati, S.; Tarnowski, B.; Robinson, A. J. Chem. Soc., Perkin Trans. 1 1981, 1537. 5. Meth-Cohn, O; Narine, B.; Tarnowski, B. J. Chem. Soc., Perkin Trans. 1 1981, 1520. 6. Meth-Cohn, O.; Tarnowski, B. Adv. Heterocycl. Chem. 1982, 31, 207. (Review). 7. Marson, C. M. Tetrahedron 1992, 48, 3659. (Review). 8. Meth-Cohn, O. Heterocycles 1993, 35, 539. (Review). 9. Swahn, B.-M.; Claesson, A.; Pelcman, B.; Besidski, Y.; Molin, H.; Sandberg, M. P.; Berge, O.-G. Bioorg. Med. Chem. Lett. 1996, 6, 1635. 10. Swahn, B.-M.; Andersson, F.; Pelcman, B.; Söderberg, J.; Claesson, A. J. Labelled. Compd. Radiopharm. 1997, 39, 259. 11. Ali, M. M.; Sana, S.; Tasneem; Rajanna, K. C.; Saiprakash, P. K. Synth. Comm. 2002, 32, 1351. 12. Moore, A. J. Meth–Cohn quinoline synthesis In Name Reactions in Heterocycl. Chem- istry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 443450. (Re- view). 378

Meyers oxazoline method Chiral oxazolines employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construc- tion of carbon-carbon bonds.

Ph O Ph 1) LDA O

N OMe 2) R-X R N OMe

N(i-Pr)2 Ph H O Ph N H O H C 3 Li O N OMe Me

Ph Ph H C 3 O H3C O N N H H Li R R X O O Me Me

Example 18

1) LDA O Ph 2) TMSO Br N 3) LDA OMe 4) Me2SO4

TMSO O O Ph H O+ 3 O 66% yield H N 70% ee OMe 379

Example 212

OMe Ph Ph O O OMe 1) O N Li O N

2) O O I 99% yield

References

1. Meyers, A. I.; Knaus, G.; Kamata, K. J. Am. Chem. Soc. 1974, 96, 268. 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. Meyers is currently Professor Emeritus at Colorado State University. 2. Meyers, A. I.; Knaus, G. J. Am. Chem. Soc. 1974, 96, 6508. 3. Meyers, A. I.; Knaus, G. Tetrahedron Lett. 1974, 1333. 4. Meyers, A. I.; Whitten, C. E. J. Am. Chem. Soc. 1975, 97, 6266. 5. Meyers, A. I.; Mihelich, E. D. J. Org. Chem. 1975, 40, 1186. 6. Meyers, A. I.; Mihelich, E. D. Angew. Chem. Int. Ed. 1976, 15, 270. (Review). 7. Meyers, A, I. Acc. Chem. Res. 1978, 11, 375–381. (Review). 8. Meyers, A. I.; Yamamoto, Y.; Mihelich, E. D.; Bell, R. A. J. Org. Chem. 1980, 45, 2792. 9. Meyers, A. I., Lutomski, K. A. in Asymmetric Synthesis, Morrison, J. D. ed. Vol III, part B, Chapter 3, Academic Press, 1983. (Review). 10. Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837–860. (Review). 11. Meyers, A. I.; Barner, B. A. J. Org. Chem. 1986, 51, 120. 12. Robichaud, A. J.; Meyers, A. I. J. Org. Chem. 1991, 56, 2607. 13. Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297–2360. (Review). 14. Meyers, A. I. J. Heterocycl. Chem. 1998, 35, 991–1002. (Review). 15. Wolfe, J. P. Meyers Oxazoline Method In Name Reactions in Heterocycl. Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 237248. (Review). 380

Meyer–Schuster rearrangement The isomerization of secondary and tertiary D-acetylenic alcohols to DE- 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 + RO H , H2O R RR1 R1

OH OH2 R R H+ E1 R R R R1 1

R R

R R•R1

R1 :OH2

R + H tautomerization RO R•R1 RR1 OH

Example 18

O P O O O OO P P O PhS O TMSO OPOTMS 54% OH OTMS PhS PhS o ClCH2CH2Cl, 83 C, 30 min. 6% 381

Example 210

O O O

O O O O O O 10% H2SO4

THF, rt, 1.5 h HO HO 70% OEt CO2Et 21% CO2Et

References

1. Meyer, K. H.; Schuster, K. Ber. Dtsch. Chem. Ges. 1922, 55, 819. 2. Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429. (Review). 3. Edens, M.; Boerner, D.; Chase, C. R.; Nass, D.; Schiavelli, M. D. J. Org. Chem. 1977, 42, 3403. 4. Cachia, P.; Darby, N.; Mak, T. C. W.; Money, T.; Trotter, J. Can. J. Chem. 1980, 58, 1172. 5. Andres, J.; Cardenas, R.; Silla, E.; Tapia, O. J. Am. Chem. Soc. 1988, 110, 666. 6. Tapia, O.; Lluch, J. M.; Cardenas, R.; Andres, J. J. Am. Chem. Soc. 1989, 111, 829. 7. Omar, E. A.; Tu, C.; Wigal, C. T.; Braun, L. L. J. Heterocycl. Chem. 1992, 29, 947. 8. Yoshimatsu, M.; Naito, M.; Kawahigashi, M.; Shimizu, H.; Kataoka, T. J. Org. Chem. 1995, 60, 4798. 9. Lorber, C. Y.; Osborn, J. A. Tetrahedron Lett. 1996, 37, 853. 10. Crich, D.; Natarajan, S.; Crich, J. Z. Tetrahedron 1997, 53, 7139. 11. Chihab-Eddine, A.; Daich, A.; Jilale, A.; Decroix, B. J. Heterocycl. Chem. 2000, 37, 1543. 382

Michael addition Conjugate addition of a carbon-nucleophile to an DE-unsaturated system.

Example 1

ONa O

CO2Et NaCH(CO2Et)2 CO2Et

O

acidic

CO2Et workup CO2Et

Example 2

O O R2CuX

R

O O O + conjugate H workup R Cu addition R R R

Example 34

O O

H2S, NaOMe HS O O N MeOH, 75% N 383

Example 43

OPh O O O PhMgBr, CuBr•DMS NSi(Me)2Ph NSi(Me)2Ph

ether, THF, 55 oC O 92%, 92% de O CPh3 CPh3

References

1. Michael, A. J. Prakt. Chem. 1887, 35, 349. Arthur Michael (18531942) 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 women 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. Fleming, I.; Kindon, N. D. J. Chem. Soc., Chem. Commun. 1987, 1177. 3. Hunt, D. A. Org. Prep. Proced. Int. 1989, 21, 705. 4. D’Angelo, J.; Desmaële, D.; Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459. 5. Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135631. (Review). 6. Hoz, S. Acc. Chem. Res. 1993, 26, 69. (Review). 7. Ihara, M.; Fukumoto, K. Angew. Chem., Int. Ed. Engl. 1993, 32, 1010. (Review). 8. Itoh, T.; Shirakami, S. Heterocycles 2001, 55, 37. 9. Cai, C.; Soloshonok, V. A.; Hruby, V. J. J. Org. Chem. 2001, 66, 1339. 10. Sundararajan, G.; Prabagaran, N. Org. Lett. 2001, 3, 389. 11. Eilitz, U.; Leȕmann, F.; Seidelmann, O.; Wendisch, V. Tetrahedron: Asymmetry 2003, 14, 189. 384

MichaelisArbuzov phosphonate synthesis Phosphonate synthesis from the reaction of alkyl halides with phosphites.

General scheme:

O ' 1 1 R1 X (R O)3P R2 X R2 P OR OR1

1 R = alkyl, etc.; R2 = alkyl, acyl, etc.; X = Cl, Br, I

For instance:

O O O ' CH O (CH O) P 3 P CH3Brn 3 3 Br O O CH3O

Br O CH Br CH SN2 3 O O O 3 CH3O P CH3 (CH O) P: O 3 3 CH3O

S 2 O O N CH O 3 P CH3Brn O CH3O

Example 13

Br (EtO)3P, Tol.

o Br 145 C, 4 h, 70%

P(OEt)2 O 385

Example 213

o O 140 C O O OBn BnO BnO P Cl (BnO)3P P P OBn BnO 8 h, 92% BnO

Example 314

O (EtO) P, NiCl FBrO 3 2 FPO OEt OEt F F 100 oC, 72 h, 10% F F

References

1. Michaelis, A.; Kaehne, R. Ber. 31, 1048 (1898). 2. Arbuzov, A. E. J. Russ. Phys. Chem. Soc. 1906, 38, 687. 3. Surmatis, J. D.; Thommen, R. J. Org. Chem. 1969, 34, 559. 4. Gillespie, P.; Ramirez, F.; Ugi, I.; Marquarding, D. Angew. Chem., Int. Ed. Engl. 1973, 12, 91. (Review). 5. Saady, M.; Lebeau, L.; Mioskowski, C. Tetrahedron Lett. 1995, 36, 5183. 6. Kato, T.; Tejima, M.; Ebiike, H.; Achiwa, K. Chem. Pharm. Bull. 1996, 44, 1132. 7. WaschbĦsch, R.; Carran, J.; Marinetti, A.; Savignac, P. Synthesis 1997, 727. 8. Griffith, J. A.; McCauley, D. J.; Barrans, R. E., Jr.; Herlinger, A. W. Synth. Commun. 1998, 28, 4317. 9. Kiddle, J. J.; Gurley, A. F. Phosphorus, Sulfur Silicon Relat. Elem. 2000, 160, 195. 10. Bhattacharya, A. K.; Stolz, F.; Schmidt, R. R. Tetrahedron Lett. 2001, 42, 5393. 11. Nifantiev, E. E.; Khrebtova, S. B.; Kulikova, Y. V.; Predvoditelv, D. A.; Kukhareva, T. S.; Petrovskii, P. V.; Rose, M.; Meier, C. Phosphorus, Sulfur Silicon Relat. Elem. 2002, 177, 251. 12. Battaggia, S.; Vyle, J. S. Tetrahedron Lett. 2003, 44, 861. 13. Erker, T.; Handler, N. Synthesis 2004, 668. 14. Souzy, R.; Ameduri, B.; Boutevin, B.; Virieux, D. J. Fluorine Chem. 2004, 125, 1317. 15. Kadyrov, A. A.; Silaev, D. V.; Makarov, K. N.; Gervits, L. L.; Röschenthaler, G.-V. J. Fluorine Chem. 2004, 125, 1407. 386

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)-(+)-D-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 (R)-Alpine-borane, THF BnO

H 10 oC to rt, 95%, 88% ee 387

OH BnO

H

Example 27

O (R)-Alpine-borane OPMB TBSO 22 oC, 6 kbar, 82% 80% de

OH

OPMB TBSO

References

1. Midland, M. M.; Greer, S.; Tramontano, A.; Zderic, S. A. J. Am. Chem. Soc. 1979, 101, 2352. M. Mark Midland was a professor at the University of California, River- side. 2. Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano, A. J. Am. Chem. Soc. 1980, 102, 867. 3. Brown, H. C.; Pai, G. G.; Jadhav, P. K. J. Am. Chem. Soc. 1984, 106, 1531. 4. Brown, H. C.; Pai, G. G. J. Org. Chem. 1982, 47, 1606. 5. Singh, V. K. Synthesis 1992, 605. (Review). 6. Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3, 2721. 7. Mulzer, J.; Berger, M. J. Org. Chem. 2004, 69, 891. 388

Mislow–Evans rearrangement [2,3]-Sigmatropic rearrangement of allylic sulfoxide to allylic alcohol.

HO O ' Ar O P(OCH3)3 S RS Ar R R

2 2 1 Ar O 1 R2 [2,3]-sigmatropic S 3 3 O 1 R S rearrangement 2 Ar 1 :P(OCH3)3

+ HO SN2 O H Ar P(OCH ) S 3 3 R R

Example 16

O O NaIO4 dioxane/H2O

TBSO 50% TBSO PhS OMe CHO

Example 211

OMe OMe MeO O O OTBS MeO O (EtO)3P, EtOH O OTBS reflux, 16 h, 98% O OH S Ph

References

1. Tang, R.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 2100. 2. Evans, D. A.; Andrews, G. C.; Sims, C. L. J. Am. Chem. Soc. 1971, 93, 4956. 3. Evans, D. A.; Andrews, G. C. J. Am. Chem. Soc. 1972, 94, 3672. 389

4. Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147. (Review). 5. Masaki, Y.; Sakuma, K.; Kaji, K. Chem. Pharm. Bull. 1985, 33, 2531. 6. Sato, T.; Shima, H.; Otera, J. J. Org. Chem. 1995, 60, 3936. 7. Jones-Hertzog, D. K.; Jorgensen, W. L. J. Am. Chem. Soc. 1995, 117, 9077. 8. Jones-Hertzog, D. K.; Jorgensen, W. L. J. Org. Chem. 1995, 60, 6682. 9. Mapp, A. K.; Heathcock, C. H. J. Org. Chem. 1999, 64, 23. 10. Zhou, Z. S.; Flohr, A.; Hilvert, D. J. Org. Chem. 1999, 64, 8334. 11. Shinada, T.; Fuji, T.; Ohtani, Y.; Yoshida, Y.; Ohfune, Y. Synlett 2002, 1341. 12. Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem. Int. Ed. 2005, 44, 3485. 390

Mitsunobu reaction

SN2 inversion of an alcohol by a nucleophile using diethyl azodicarboxylate (DEAD) and triphenylphosphine.

OH NuH Nu 1 2 R1 R2 R R DEAD, PPh3

HNu CO2Et adduct NN CO2Et EtO2C NN formation :PPh3 Ph3P EtO2C Diethyl azodicarboxylate (DEAD)

CO2Et H NN Ph P EtO C 3 2 alcohol EtO2C H O PPh 3 + NN :OH activation R1 R2 H CO2Et

R1 R2

OPPh3 SN2 Nu 1 2 + O PPh R R 1 2 3 reaction R R Nu

Example 14

OH O O2N CO2H O

DEAD, PPh3, Tol. 4-O2NPhCOO O O 30 to 0 oC, 1 h, 90% 391

Example 23

CH OAc CH2OAc 2 PhCO2H O O DIAD, PPh3, THF OAc OH OAc O2CPh OAc o OAc 50 C to rt, 2 h, 80% 2:1ED OAc OAc

References

1. Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380. 2. Mitsunobu, O. Synthesis 1981, 1. (Review). 3. Smith, A. B., III; Hale, K. J.; Rivero, R. A. Tetrahedron Lett. 1986, 27, 5813. 4. KocieĔski, P. J.; Yeates, C.; Street, D. A.; Campbell, S. F. J. Chem. Soc., Perkin Trans. 1, 1987, 2183. 5. Hughes, D. L. Org. React. 1992, 42, 335656. (Review). 6. Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127. (Review). 7. Barrett, A. G. M.; Roberts, R. S.; Schroeder, J. Org. Lett. 2000, 2, 2999. 8. Racero, J. C.; Macias-Sanchez, A. J.; Herandez-Galen, R.; Hitchcock, P. B.; Hanson, J./ R.; Collado, I. G. J. Org. Chem. 2000, 65, 7786. 9. Langlois, N.; Calvez, O. Tetrahedron Lett. 2000, 41, 8285. 10. Charette, A. B.; Janes, M. K.; Boezio, A. A. J. Org. Chem. 2001, 66, 2178. 11. Ahn, C.; Correia, R.; DeShong, P. J. Org. Chem. 2002, 67, 1751. 12. Dandapani, S.; Curran, D. P. Tetrahedron 2002, 58, 3855. 13. Bitter, I.; Csokai, V. Tetrahedron Lett. 2003, 44, 2261. 392

Miyaura borylation Palladium-catalyzed reaction of aryl halides with diboron reagent to produce aryl- boronates. Also known as HosomiMiyaura borylation.

O O Pd(0) O Ar I B B Ar B O O base O

oxidative Ar L Ar I L Pd(0) Pd 2 I addition L

base transmetallation O O base O O L B B Ar B B Pd O O I O O L

L L Pd O B O reductive O I B Ar L Pd(0) O Ar B 2 O elimination O

Example 111 O O O B OAc O B Ph O O O Ph B CuCl, LiCl, KOAc, DMF, 92% O

Example 212

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% 393

References

1. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508. 2. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 24572483. (Review). 3. Suzuki, A. J. Organomet. Chem. 1995, 576, 147. (Review). 4. Carbonnelle, A.-C.; Zhu, J. Org. Lett. 2000, 2, 3477. 5. Willis, D. M.; Strongin, R. M. Tetrahedron Lett. 2000, 41, 8683. 6. Takahashi, K.; Takagi, J.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 126. 7. Todd, M. H.; Abell, C. J. Comb. Chem. 2001, 3, 319. 8. Giroux, A. Tetrahedron Lett. 2003, 44, 233. 9. Arterburn, J. B.; Bryant, B. K.; Chen, D. Chem. Commun. 2003, 1890. 10. Kabalka, G. W.; Yao, M.-L. Tetrahedron Lett. 2003, 44, 7885. 11. Ramachandran, P. V.; Pratihar, D.; Biswas, D.; Srivastava, A.; Reddy, M. V. R. Org. Lett. 2004, 6, 481. 12. Occhiato, E. G.; Lo Galbo, F.; Guarna, A. J. Org. Chem. 2005, 70, 7324. 394

Moffatt oxidation Oxidation of alcohols using DCC and DMSO, also known as “PfitznerMoffatt oxidation”.

OH DCC O

1 2 1 2 R R DMSO, HX R R DCC, 1,3-dicyclohexylcarbodiimide

+ H H NCN NCN

O S

H

HN C N O O S H N N :O H H

R1 R2 1,3-dicyclohexylurea

H X S S H O O H H 1 2 R R R1 R2

O (CH3)2S R1 R2

Example 13

+ OH DCC, DMSO, PhNH CF3CO2 O

OH PhH, rt, 70% O 395

Example 210

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. 2. Harmon, R. E.; Zenarosa, C. V.; Gupta, S. K. J. Org. Chem. 1970, 35, 1936. 3. Schobert, R. Synthesis 1987, 741. 4. Liu, H. J.; Nyangulu, J. M. Tetrahedron Lett. 1988, 29, 3167. 5. Tidwell, T. T. Org. React. 1990, 39, 297. (Review). 6. Gordon, J. F.; Hanson, J. R.; Jarvis, A. G.; Ratcliffe, A. H. J. Chem. Soc., Perkin Trans. 1, 1992, 3019. 7. Krysan, D. J.; Haight, A. R.; Lallaman, J. E. Org. Prep. Proced. Int. 1993, 25, 437. 8. Wnuk, S. F.; Ro, B.-O.; Valdez, C. A.; Lewandowska, E.; Valdez, N. X.; Sacasa, P. R.; Yin, D.; Zhang, J.; Borchardt, R. T.; De Clercq, E. J. Med. Chem. 2002, 45, 2651. 9. Adak, A. K. Synlett 2004, 1651. 10. Wang, M.; Zhang, J.; Andrei, D.; Kuczera, K.; Borchardt, R. T.; Wnuk, S. F. J. Med. Chem. 2005, 48, 3649. 396

Montgomery coupling Oxidative nickel-catalyzed coupling of aldehydes and alkynes to generate allylic alcohols. Intermolecular and intramolecular examples are both effective, and the transmetalating agent (MR4) may be an organosilane, organoborane, organozinc, or alkenylzirconium.15

4 4 O R3 MR OH R + 1 1 3 R H R2 R R Ni(COD) , L 2 R2 R1, R3 = alkyl or aryl R2, R4 = alkyl, aryl, or H

The mechanism was proposed to involve the formation of a nickel metallacycle by the oxidative cyclization of Ni(0) with the aldehyde and alkyne, followed by conversion of the metallacycle to product by a transmetalation/reductive elimination sequence. If R4 possesses a E-hydrogen, then E-hydride elimination after the transmetalation step generates the product with R4 = H in some instances. The mechanism was shown to be ligand dependent, and the mechanism depicted below is undoubtedly oversimplified.4

3 L R Ln n 3 Ni Ni R 4 O O MR H 1 R2 R R1 R2 R4 4 LnNi 4 OM R MO R3 R lacks E-H R1 R3 1 2 R R R2 4 4 R = H R = Et H2CCH2 H OM H LnNi MO R3 R1 R3 2 R1 R2 R 397

Example 16

CH3 CH3

H3C O CH3 CH3 O H3C O Et3SiH O N N H Ni(COD)2 PBu3 OSiEt3 O H H H3C OBn 93 % H3COBn (single diast.)

Example 27

H H C H 6 13 Ni(COD)2 N N O +

ZnCl2 OH ZrCp2Cl CH3 H3C

69 % C6H13

Example 38

O Me O O H Me O Ph Ph Me Me Me Ph Me HO O Ni(COD)2, PBu3 Me O Et3B Ph O

Me 44 % (>10:1 dr) 398

Example 49

O R1

H Ni(COD)2, ligand

reducing agent O

O 1 OR2 R R2O R1 or O O O O

ligandreducing agent yield (ratio)

PMe3 Et3B 89 % (4.5:1)

Et3SiH 93 % (1:5) Ar NNAr : Ar = 2,6 di-isopropylphenyl

A number of related processes involving alternate S-systems including enones, dienes, and allenes have been reported.10

References

1. Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065. 2. Tang, X. Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098. 3. Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221. 4. Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698. 5. Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442. 6. Tang, X. Q.; Montgomery, J. J. Am. Chem. Soc. 2000, 122, 6950. 7. Ni, Y.; Amarasinghe, K. K. D.; Montgomery, J. Org. Lett. 2002, 4, 1743. 8. Colby, E. A.; O'Brien, K. C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 998. 9. Knapp-Reed, B.; Mahandru, G. M.; Montgomery, J. J. Am. Chem. Soc. 2005, 127, 13156. 10. Montgomery, J. Angew. Chem. Int. Ed. 2004, 43, 3890. (Review). 399

Morgan–Walls reaction Phenanthridine cyclization by dehydrative ring closure of acyl-o-aminobiphenyls with phosphorus oxychloride in boiling nitrobenzene.

R R NH O POCl3 N R1 R1

O ClP Cl POCl2 Cl O O : NH NH R R R1 R1

OPOCl2 R R N

NH: HOPOCl H 2 1 R1 R

Example 110

O2NNO2 O2NNO2

HN nitrobenzene, POCl3 N O

SnCl4, 98%

CN CN 400

Pictet–Hubert reaction Phenanthridine cyclization by dehydrative ring closure of acyl-o-aminobiphenyls on heating with zinc chloride at 250300 °C.

R R NH N OZnCl2 1 1 R 250300 oC R

Example 27

o ZnCl2, 250300 C

N N H 80% O

References

1. Pictet, A.; Hubert, A. Ber. Dtsch. Chem. Ges. 1896, 29, 1182. 2. Morgan, C. T.; Walls, L. P. J. Chem. Soc. 1931, 2447. 3. Morgan, C. T.; Walls, L. P. J. Chem. Soc. 1932, 2225. 4. Gilman, H.; Eisch, J. J. Am. Chem. Soc. 1957, 79, 4423. 5. Hollingsworth, B. L.; Petrow, V. J. Chem. Soc. 1961, 3664. 6. Nagarajan, K.; Shah, R. K. Indian J. Chem. 1972, 10, 450. 7. Fodor, G.; Nagubandi, S. Tetrahedron 1980, 1279. 8. Sivasubramanian, S.; Muthusubramanian, S.; Ramasamy, S.; Arumugam, N. Indian J. Chem., Sect. B 1981, 20B, 552. 9. Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1988, 31, 774. 10. 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. 11. Holsworth, D. D. Pictet–Hubert Reaction In Name Reactions in Heterocycl. Chemis- try, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 465468. (Re- view). 401

MoriBan indole synthesis Intramolecular Heck reaction of o-halo-aniline with pendant olefin to prepare indole.

CO2Me CO2Me Br Pd(OAc)2, Ph3P

N N NaHCO , DMF, 130 oC, 3 Ac Ac

Reduction of Pd(OAc)2 to Pd(0) using Ph3P:

AcO Pd OAc

AcO Ph3P Pd OAc :PPh3

O OO OPPh3 Pd(0) AcO OPPh3 O

MoriBan indole synthesis:

CO Me Br 2 CO2Me Br PdLn Pd(0) insertion oxidative N addition N Ac Ac

MeO2C CO2Me PdBrLn E-hydride H H PdBrLn N N elimination Ac Ac 402

CO Me addition CO2Me E-hydride 2 PdBrLn of PdH N H elimination N Ac Ac

Regeneration of Pd(0):

HPdBrLn NaHCO3 Pd(0) NaBr H2O CO2n

Example 11 I Me Pd(OAc)2 N N Et N, MeCN H 3 H sealed tube 110 °C, 87% Example 212

SO2NHMe Br Cbz N SO2NHMe COCF Pd(OAc)2, Bu4NCl N 3 Br Cbz Et3N, DMF N N heat, DME, 76% Br H

References

1. MoriBan indole synthesis, (a) Mori, M.; Chiba, K.; Ban, Y. Tetrahedron Lett. 1977, 12, 1037; (b) Ban, Y.; Wakamatsu, T.; Mori, M. Heterocycles 1977, 6, 1711. 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; (b) Amatore, C.; Carre, E.; M’Barki, M. A. Organometallics 1995, 14, 1818; (c) Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics 1992, 11, 3009; (d) Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc. 1991, 113, 8375. 3. Macor, J. E.; Ogilvie, R. J.; Wythes, M. J. Tetrahedron Lett. 1996, 37, 4289. 4. Li, J. J. J. Org. Chem. 1999, 64, 8425. 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. 6. Sparks, S. M.; Shea, K. J. Tetrahedron Lett. 2000, 41, 6721. 7. Bosch, J.; Roca, T.; Armengol, M.; Fernandez-Forner, D. Tetrahedron 2001, 57, 1041. 403

Mukaiyama aldol reaction Lewis acid-catalyzed aldol condensation of aldehyde and silyl enol ether.

2 OH O R Lewis R CHO R1 RR2 OSiMe3 acid R1

O LA OH O X 2 XSiMe RHR RR2 3 1 R SiMe R1 O 3

Example 114

O

O

OHC N OTBDMS Boc N Bn

O OH BF3•OEt2, DTBMP O N CH Cl , 78 to 50 oC, 93% Boc 2 2 N O Bn

Example 215

CHO OH O O O O 1. PhCO2H, rt O OSiMe3 2. TFA, 60% CN NC 404

References

1. Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011. 2. Mukaiyama, T.; Narasaka, K.; Banno, K. J. Am. Chem. Soc. 1974, 96, 7503. 3. Langer, P.; Koehler, V. Org. Lett. 2000, 2, 1597. 4. Matsukawa, S.; Okano, N.; Imamoto, T. Tetrahedron Lett. 2000, 41, 103. 5. Delas, C.; Blacque, O.; Moise, C. Tetrahedron Lett. 2000, 41, 8269. 6. Ishihara, K.; Kondo, S.; Yamamoto, H. J. Org. Chem. 2000, 65, 9125. 7. Kumareswaran, R.; Reddy, B. G.; Vankar, Y. D. Tetrahedron Lett. 2001, 42, 7493. 8. Armstrong, A.; Critchley, T. J.; Gourdel-Martin, M.-E.; Kelsey, R. D.; Mortlock, A. A. J. Chem. Soc., Perkin Trans. 1 2002, 1344. 9. Clézio, I. L.; Escudier, J.-M.; Vigroux, A. Org. Lett. 2003, 5, 161. 10. Muñoz-Muñiz, O.; Quintanar-Audelo, M.; Juaristi, E. J. Org. Chem. 2003, 68, 1622. 11. Ishihara, K.; Yamamoto, H. Boron and Silicon Lewis Acids for Mukaiyama Aldol Re- actions. In Modern Aldol Reactions Mahrwald, R. (ed.), 2004, 2568. (Review). 12. Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 55905614. (Review). 13. Li, H.-J.; Tian, H.-Y.; Wu, Y.-C.; Chen, Y.-J.; Liu, L.; Wang, D.; Li, C.-J. Adv. Synth. Cat. 2005, 347, 1247. 14. Adhikari, S.; Caille, S.; Hanbauer, M.; Ngo, V. X.; Overman, L. E. Org. Lett. 2005, 7, 2795. 15. Acocella, M. R.; Massa, A.; Palombi, L.; Villano, R.; Scettri, A. Tetrahedron Lett. 2005, 46, 6141. 405

Mukaiyama Michael addition Lewis acid-catalyzed Michael addition of silyl enol ether to DE-unsaturated system. 2 O O R Lewis R1 R1 R2 O R OSiMe3 acid R

Example 14

OSiMe O 3 OMe

1. 0.1 mol% TBABB, THF, 3 h O O

O 2. 1 N HCl, THF, 0 oC, 0.5 h 87%

TBABB = tetra-n-butylammonium bibenzoate

Example 27

O O OSiMe3 1. neat DBU, rt, 24 h OMe O 2. 1 N HCl, THF, 68% O

References

1. Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011. 2. Mukaiyama, T.; Narasaka, K.; Banno, K. J. Am. Chem. Soc. 1974, 96, 7503. 3. Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 55905614. (Review). 4. Gnaneshwar, R.; Wadgaonkar, P. P.; Sivaram, S. Tetrahedron Lett. 2003, 44, 6047. 5. Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku, A.; Harada, T. J. Org. Chem. 2003, 68, 10046. 6. Jaber, N.; Assie, M.; Fiaud, J.-C.; Collin, J. Tetrahedron 2004, 60, 3075. 7. Shen, Z.-L.; Ji, S.-J.; Loh, T.-P. Tetrahedron Lett. 2005, 46, 507. 8. Wang, W.; Li, H.; Wang, J. Org. Lett. 2005, 7, 1637. 406

Mukaiyama reagent Mukaiyama reagent such as 2-chloro-1-methyl-pyridinium iodide for esterification or amide formation.

General scheme:

X N base Y O R 3 R R1CO2H R2OH 2 O N R1 O R3 X = F, Cl, Br

Example 13

NBr F4B HO O CO H O 2 Bu N, CH Cl O 3 2 2 O

O SNAr

O : O O Br N BF O N 4 + Br O H H

NBu3

O O Br O O N O O O N BF4 BF : Bn 4

HO Bn : OBn HO N O O N + BF O H 4 407

Amide formation using the Mukaiyama reagent follows a similar mechanistic pathway.4

Example 2, polymer-supported Mukaiyama reagent8

TfO OH N O NCl O Cl

Tf2O, CH2Cl2, 16 h, rt 1.25 mmol/g

O NHBoc NHBoc O

CO2H NH2 NH O polymer-supported N O N Mukaiyama reagent H O H Et3N, CH2Cl2, rt 16 h, 88%

References

1. Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K. Chem. Lett. 1975, 1045. 2. Hojo, K.; Kobayashi, S.; Soai, K.; Ikeda, S.; Mukaiyama, T. Chem. Lett. 1977, 635. 3. Mukaiyama, T. Angew. Chem., Int. Ed. 1979, 18, 707. 4. For amide formation, see: Huang, H.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1984, 1465. 5. Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J. Am. Chem. Soc. 1994, 116, 8402. 6. Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem. 1997, 62, 1540. 7. Folmer, J. J.; Acero, C.; Thai, D. L.; Rapoport, H. J. Org. Chem. 1998, 63, 8170. 8. Crosignani, S.; Gonzalez, J.; Swinnen, D. Org. Lett. 2004, 6, 4579. 9. Mashraqui, S. H.; Vashi, D.; Mistry, H. D. Synth. Commun. 2004, 334, 3129. 10. Donati, D.; Morelli, C.; Taddei, M. Tetrahedron Lett. 2005, 46, 2817. 408

MyersSaito cyclization Cf. Bergman cyclization and Schmittel cyclization.

' or

• hydrogen hv atom donor

H reversible

•

allenyl enyne diradical

H

Example 16

Ph PhH, reflux

Ph 96 h, 40% Ph Ph H 409

Example 2, aza-MyersSaito reaction16

MeOH CDCl CHO N OMe N 3 N

o Ph 0 C, 14 h Ph 10 oC, 12 h Ph

References

1. Myers, A. G.; Proteau, P. J.; Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212. 2. Saito, K.; Watanabe, T.; Takahashi, K. Chem. Lett. 1989, 2099. 3. Saito, I.; Nagata, R.; Yamanaka, H.; Murahashi, E. Tetrahedron Lett. 1990, 31 2907. 4. Myers, A. G.; Dragovich, P. S.; Kuo, E. Y. J. Am. Chem. Soc. 1992, 114, 9369. 5. Schmittel, M.; Strittmatter, M.; Kiau, S. Tetrahedron Lett. 1995, 36, 4975. 6. Schmittel, M.; Steffen, J.-P.; Auer, D.; Maywald, M. Tetrahedron Lett. 1997, 38, 6177. 7. Engels, B.; Lennartz, C.; Hanrath, M.; Schmittel, M.; Strittmatter, M. Angew. Chem., Int. Ed. 1998, 37, 1960. 8. Ferri, F.; Bruckner, R.; Herges, R. New J. Chem. 1998, 22, 531. 9. Cramer, C. J.; Squires, R. R. Org. Lett. 1999, 1, 215. 10. Bruckner, R; Suffert, J. Synlett 1999, 657679. (Review). 11. Kim, C.-S.; Diez, C.; Russell, K. C. Chem. Eur. J. 2000, 6, 1555. 12. Cramer, C. J.; Kormos, B. L.; Seierstad, M.; Sherer, E. C.; Winget, P. Org. Lett. 2001, 3, 1881. 13. Stahl, F.; Moran, D.; Schleyer, P. von R.; Prall, M.; Schreiner, P. R. J. Org. Chem. 2002, 67, 1453. 14. Musch, P. W; Remenyi, C.; Helten, H.; Engels, B. J. Am. Chem. Soc. 2002, 124, 1823. 15. Bui, B. H.; Schreiner, P. R. Org. Lett. 2003, 5, 4871. 16. Feng, L.; Kumar, D.; Birney, D. M.; Kerwin, S. M. Org. Lett. 2004, 6, 2059. 17. Schmittel, M.; Mahajan, A. A.; Bucher, G. J. Am. Chem. Soc. 2005, 127, 5324. 410

Nazarov cyclization Acid-catalyzed electrocyclic formation of cyclopentenone from di-vinyl ketone.

O O H+

+ H H HO O O protonation

H

OH O tautomerization

Example 12

O H O ZrCl4, (CH2Cl)2

N N SiMe3 60 oC, 36 h, 76% H CO Me CO2Me 2

Example 2, cyclization of in situ generated di-vinyl ketone12

o O H3PO4, 6065 C

6 h, 65%

References

1. Nazarov, I. N.; Torgov, I. B.; Terekhova, L. N. Bull. Acad. Sci. (USSR) 1942, 200. I. N. Nazarov (19001957) discovered this reaction in 1942 in Russia. 2. Denmark, S. E.; Habermas, K. L.; Hite, G. A. Helv. Chim. Acta 1988, 71, 2821. 3. Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React. 1994, 45, 1158. (Review). 411

4. Kuroda, C.; Koshio, H.; Koito, A.; Sumiya, H.; Murase, A.; Hitono, Y. Tetrahedron 2000, 56, 6441. 5. Giese, S.; Kastrup, L.; Stiens, D.; West, F. G. Angew. Chem., Int. Ed. 2000, 39, 1970. 6. Kim, S.-H.; Cha, J. K. Synthesis 2000, 2113. 7. Giese, S.; West, F. G. Tetrahedron 2000, 56, 10221. 8. Fernández M., A.; Martin de la Nava, E. M.; González, R. R. Tetrahedron 2001, 57, 1049. 9. Harmata, M.; Lee, D. R. J. Am. Chem. Soc. 2002, 124, 14328. 10. Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 1171. 412

Neber rearrangement D-Aminoketone from tosyl ketoxime and base.

OTs NH2 N 1. KOEt 2 R TsOH 1 R1 R 2 R 2. H2O O ketoxime D-aminoketone

OTs N OTs deprotonation N cyclization H R 2 EtO 2 R R1 R1

+ H :OH2 hydrolysis N TsOH 1 R R2 azirine intermediate

H NH2 N O R2 H R1 1 R R2 O

Example 15

TsO N EtO OEt 1. EtOH, HCl (g) NH2

2. Na2CO3, 92% Br Br 413

Example 215

Ts TsON N . KOH, H O, EtOH, 0 oC, 3 h N Br 1 2

MeO o N OMe 2. 6 N HCl, 60 C, 10 h, 96% O N 3. K2CO3, THF, H2O, 10 min. SEM

Ts O N N H2N Br MeO N OMe O HN

References

1. Neber, P. W.; v. Friedolsheim, A. Justus Liebigs Ann. Chem. 1926, 449, 109. 2. O’Brien, C. Chem. Rev. 1964, 64, 81. (Review). 3. Kakehi, A.; Ito, S.; Manabe, T.; Maeda, T.; Imai, K. J. Org. Chem. 1977, 42, 2514. 4. Friis, P.; Larsen, P. O.; Olsen, C. E. J. Chem. Soc., Perkin Trans. 1 1977, 661. 5. LaMattina, J. L.; Suleske, R. T. Synthesis 1980, 329. 6. Corkins, H. G.; Storace, L.; Osgood, E. J. Org. Chem. 1980, 45, 3156. 7. Hyatt, J. A. J. Org. Chem. 1981, 46, 3953. 8. Parcell, R. F.; Sanchez, J. P. J. Org. Chem. 1981, 46, 5229. 9. Verstappen, M. M. H.; Ariaans, G. J. A.; Zwanenburg, B. J. Am. Chem. Soc. 1996, 118, 8491. 10. Oldfield, M. F.; Botting, N. P. J. Labelled Compounds Radio. 1998, 41, 29. 11. Mphahlele, M. J. Phosphorus, Sulfur Silicon Relat. Elem. 1999, 144146, 351. 12. Banert, K.; Hagedorn, M.; Liedtke, C.; Melzer, A.; Schoffler, C. Eur. J. Org. Chem. 2000, 257. 13. Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I. Tetrahedron Lett. 2002, 41, 5363. 14. Ooi, T.; Takahashi, M.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2002, 124, 7640. 15. Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5970. 414

Nef reaction Conversion of a primary or secondary nitroalkane into the corresponding carbonyl compound.

NO2 1. NaOH O 1/2N O 1/2H2O 1 2 1 2 2 R R 2. H2SO4 R R

OO OO + N H2O N H 1 2 R R R1 R2 H nitronate HO

HO OH + N H O + HO O H2O N + H 1 2 N H R R 1 2 R R R1 R2 OH :OH2 OH nitronic acid

HO N O O HNO 1/2N O1/2HO 1 2 2 2 R1 R2 R R 1 2 O R R H

Example 17

O O 1. NaOH, EtOH, 0 oC, 30 min.

NO O 2 2. 3 M HCl, 20 oC, 12 h, 68% 415

Example 211

NO O HO 2 HO 1. 2 M NaOH, MeOH

2. ice-cooled KMnO4 H 45% H

References

1. Nef, J. U. Justus Liebigs Ann. Chem. 1894, 280, 263. John Ulrich Nef (18621915) was born in Switzerland and emmigrated to the US at the age of four with his parents. He went to Munich, 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 Univer- sity, and the University of Chicago. The Nef reaction was discovered at Clark Univer- sity 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. (Review). 3. Hwu, J. R.; Gilbert, B. A. J. Am. Chem. Soc. 1991, 113, 5917. 4. Ceccherelli, P.; Curini, M.; Marcotullio, M. C.; Epifano, F.; Rosati, O. Synth. Com- mun. 1998, 28, 3057. 5. Adam, W.; Makosza, M.; Saha-Moeller, C. R.; Zhao, C.-G. Synlett 1998, 1335. 6. Shahi, S. P.; Vankar, Y. D. Synth. Commun. 1999, 29, 4321. 7. Thominiaux, C.; Rousse, S.; Desmaele, D.; d’Angelo, J.; Riche, C. Tetrahedron: Asymmetry 1999, 10, 2015. 8. Capecchi, T.; de Koning, C. B.; Michael, J. P. J. Chem. Soc., Perkin 1 2000, 2681. 9. Ballini, R.; Bosica, G.; Fiorini, D.; Petrini, M. Tetrahedron Lett. 2002, 43, 5233. 10. Petrus, L.; Petrusova, M.; Pham-Huu, D.-P.; Lattova, E.; Pribulova, B.; Turjan, J. Monatsh. Chem. 2002, 133, 383. 11. Chung, W. K.; Chiu, P. Synlett 2005, 55. 416

Negishi cross-coupling reaction Palladium-catalyzed cross-coupling reaction of organozinc reagents with organic halides, triflates, etc. It is compatible with many functional groups including ketones, esters, amines, and nitriles. For the catalytic cycle, see the Kumada coupling on page 345.

Pd(0) 1 1 RX R ZnX RR ZnX2

1 oxidative R L R ZnX RX L2Pd(0) Pd X transmetallation addition L isomerization

L L reductive 1 L Pd(0) ZnX2 Pd R R 2 R1 R elimination

Example 15 I CH2CO2Et

N N

BrZnCH2CO2Et, Pd(Ph3P)4 HO HO O O HMPA/(CH2OCH3)2 (1:1) O Ph 3.5 h, 40% O Ph O O Ph Ph O O

Example 26

O O activated I ZnI BnO BnO Zn/Cu couple NHTrt NHTrt 417

Boc N NHBoc Boc O N NHBoc I N CO2t-Bu BnO N CO2t-Bu PdCl2(Ph3P)2, DMA NHTrt 40 oC, 79%

References

1. Negishi, E.-I.; Baba, S. J. Chem. Soc., Chem. Commun. 1976, 596. 2. Negishi, E.-I. et al. J. Org. Chem. 1977, 42, 1821. 3. Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340. (Review). 4. Erdik, E. Tetrahedron 1992, 48, 9577. (Review). 5. De Vos, E.; Esmans, E. L.; Alderweireldt, F. C.; Balzarini, J.; De Clercq, E. J. Hetero- cycl. Chem. 1993, 30, 1245 6. Evans, D. A.; Bach, T. Angew. Chem., Int. Ed. Engl, 1993, 32, 1326. 7. Negishi, E.-I.; Liu, F. In Metal-Catalyzed Cross-Coupling Reactions; 1998, Diederich, F.; Stang, P. J. eds.; Wiley–VCH: Weinheim, Germany, pp 1–47. (Review). 8. Yus, M.; Gomis, J. Tetrahedron Lett. 2001, 42, 5721. 9. Lutzen, A.; Hapke, M. Eur. J. Org. Chem. 2002, 2292. 10. Fang, Y.-Q.; Polson, M. I. J.; Hanan, G. S. Inorg. Chem. 2003, 42, 5. 11. 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. 12. Ma, S.; Ren, H.; Wei, Q. J. Am. Chem. Soc. 2003, 125, 4817. 418

Nenitzescu indole synthesis 5-Hydroxylindole from condensation of p-benzoquinone and E-aminocrotonate.

3 H CO R3 CO2R 2 HO O ' 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 2 R H+

CO R3 3 H 2 CO2R HO HO

R1 N 1 N OH 2 R R R2 H+

Example 17

O O NH Bn 2 O HN HO O N 1. aetone, rt, 48 h N H 2. 20% TFA, CH Cl 2 2 Bn 86%

Example 28

H CO CH CO2CH3 2 3 HO

O CH3NO2, rt HN N 95% O 419

References

1. Nenitzescu, C. D. Bull. Soc. Chim. Romania 1929, 11, 37. 2. Allen, Jr. G. R. Org. React. 1973, 20, 337. (Review). 3. Patrick, J. B.; Saunders, E. K. Tetrahedron Lett. . 1979, 4009. 4. Bernier, J. L.; Henichart, J. P. J. Org. Chem. 1981, 46, 4197. 5. Kinugawa, M.; Arai, H.; Nishikawa, H.; Sakaguchi, A.; Ogasa, T.; Tomioka, S.; Kasai, M. J. Chem. Soc., Perkin Trans. 1 1995, 2677. 6. Mukhanova, T. I.; Panisheva, E. K.; Lyubchanskaya, V. M.; Alekseeva, L. M.; Sheinker, Y. N.; Granik, V. G. Tetrahedron 1997, 53, 177. 7. Ketcha, D. M.; Wilson, L. J.; Portlock, D. E. Tetrahedron Lett. 2000, 41, 6253. 8. Brase, S.; Gil, C.; Knepper, K. Bioorg. Med. Chem. Lett. 2002, 10, 2415. 9. Lyubchanskaya, V. M.; Savina, S. A.; Alekseeva, L. M.; Shashkov, A. S.; Granik, V. G. Mendeleev Commun. 2004, 73. 10. Schenck, L. W.; Sippel, A.; Kuna, K.; Frank, W.; Albert, A.; Kucklaender, U. Tetra- hedron 2005, 61, 9129. 420

Nicholas reaction Hexacarbonyldicobalt-stabilized propargyl cation is captured by a nucleophile. Subsequent oxidative demetallation then gives propargylated product.

2 OR 1. Co2(CO)8 1. NuH Nu R1 R3 R1 R3 4 4 R 2. H+ or Lewis acid 2. [O] R

CO CO (CO)4Co Co(CO)3 CO CO (CO)3Co Co(CO)3 OR2 R1 OR2 R1 R3 R4 R3 R4

(CO) Co Co(CO) (CO)3Co Co(CO)3 + H+ 3 3 SN1 1 2 1 H R OR R O 2 4 3 R R4 R3 R R

(CO) Co Co(CO) (CO) Co Co(CO) 3 3 NuH 3 3 [O] 1 1 R R Nu demetallation R4 R3 R4 R3 propargyl cation intermediate (stabilized by the hexacarbonyldicobalt complex).

(CO)3Co Co(CO)2 Nu 1 3 O COn 1 R R R Nu 4 4 3 R R R

Example 1, chromium variant of the Nicholas reaction5

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 421

Cl Cl

2HCl NN O NN O CO2n-Bu CO2H Zyrtec Cr(CO)3

Example 2, intramolecular Nicholas reaction using chromium11

Cr(CO)3 BF •OEt , CH Cl OAc 3 2 2 2

0 oC, 3.5 h, 49% Cr(CO)3

References

1. Nicholas, K. M. J. Organomet. Chem. 1972, C21, 44. 2. Lockwood, R. F.; Nicholas, K. M. Tetrahedron Lett. 1977, 4163. 3. Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207. (Review). 4. Roth, K. D. Synlett 1992, 435. 5. Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837. 6. Diaz, D.; Martin, V. S. Tetrahedron Lett. 2000, 41, 743. 7. Guo, R.; Green, J. R. Synlett 2000, 746. 8. Green, J. R. Curr. Org. Chem. 2001, 5, 809826. (Review). 9. Teobald, B. J. Tetrahedron 2002, 58, 41334170. (Review). 10. Takase, M.; Morikawa, T.; Abe, H.; Inouye, M. Org. Lett. 2003, 5, 625. 11. Ding, Y.; Green, J. R. Synlett 2005, 271. 12. Crisostomo, F. R. P.; Carrillo, R.; Martin, T.; Martin, V. S. Tetrahedron Lett. 2005, 46, 2829. 422

Nicolaou dehydrogenation D,E-Unsaturation of aldehydes and ketones mediated by stoichiometric amounts of IBX (o-iodoxybenzoic acid), alternative to Saegusa oxidation (page 515).1

O HO I O

2 O R O O R2

1 3 1 3 R R IBX = o-iodoxybenzoic acid R R

A SET mechanism has also been proposed.2 Additionally, silyl enol ethers are also viable substrates.3

O 2 2 I O R tautomerization HO R HO O 1 3 R1 R3 R R O

O R2 O OH I O O R2 R1 R3 HO R1 R3 H

Example 11

IBX fluorobenzene H DMSO H HH HH 65 °C, 24 h O 80% O H H 423

Example 24

O O H H IBX TBSO O TBSO DMSO–Tol. O H 80 °C, 3 h, 52% H MeO2C CO Me 2 MeO2C CO2Me e. g.310

H H IBX O N MeO N Tol., DMSO Me H H 70 °C O

H H O N MeO N Me H H O

References

1. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596. 2. Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem., Int. Ed. 2002, 41, 993. 3. Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T. Angew. Chem., Int. Ed. 2002, 41, 996. 4. Ohmori, N. J. Chem. Soc., Perkin Trans. 1 2002, 755. 5. Shimokawa, J.; Shirai, K.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Angew. Chem., Int. Ed. 2004, 43, 1559. 6. Zhang, D.-H.; Cai, F.; Zhou, X.-D.; Zhou, W.-S. Org. Lett. 2003, 5, 3257. 7. Hayashi, Y.; Yamaguchi, J.; Shoji, M. Tetrahedron 2002, 58, 9839. 8. Miyazawa, N.; Ogasawara, K. Synlett 2002, 1065. 9. Smith, N. D.; Hayashida. J.; Rawal, V. H. Org. Lett. 2005, 7, 4309. 10. Liu, X.; Deschamp, J. R.; Cook, J. M. Org. Lett. 2002, 4, 3339. 11. Nagata, H.; Miyazawa, N.; Ogasawara, K. Org. Lett. 2001, 3, 1737. 12. Herzon, S. B.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 5342. 424

Nicolaou hydroxy-dithioketal cyclization Two step synthesis of medium-ring ethers through the intermediacy of thionium ions followed by sulfide reduction.

EtS H 1. NCS, AgNO3, H EtS O SiO2, 2,6-lut. OH 2. Ph3SnH, AIBN

The mechanism is analogous to the hydroxy-ketone cyclization except that the mixed ketal is isolable. It can be reductively cleaved using Ph3SnH/AIBN:

O NO3 Ag Cl N Cl EtS O EtS EtS EtS HO OH

SnPh3

EtS EtS thionium H formation O OH

H H homolytic H O H O reduction 425 e. g. 11

EtS 1. AgNO3, NCS, SiO2 H H OH 2,6-lut., 3 Å MS H O EtS O 5 min, 95% O H 2. Ph3SnH, AIBN, H O toluene, 110 °C, O 95%

Example 2, carbocyclization is also possible3:

EtS

EtS N AgNO3, 3 Å MS EtS H N SiO2, 2,6-lut., NCS H H H CH3CN, 44% N H N H H OAc H H OAc

Example 3, the cyclizations tolerate ordinary acetals5:

1. AgClO4, NaHCO3 H SiO , 3 Å MS O 2 CH3NO2, 25 °C H EtS 4 h, 74% O EtS OH OPiv 2. Ph3SnH, AIBN Ph H O toluene, 110 °C 3 h, 95%

H O H O OPiv O H Ph H O References

1. Nicolaou, K. C.; Duggan, M. E.; Hwang, C.-K. J. Am. Chem. Soc. 1986, 108, 2468. 2. Inoue, M.; Sasaki, M.; Tachibana, K. J. Org. Chem. 1999, 64, 9416. 3. Shin, K.; Moriya, M.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 3765. 4. Trost, B. M.; Nübling, C. Carbohydrate Res. 1990, 202, 1. 5. Nicolaou, K. C.; Bunnage, M. E.; McGarry, D. G.; Shi, S.; Somers, P. K.; Wallace, P. A.; Chu, X.-J.; Agrios, K. A.; Gunzner, J. L.; Yang, Z. Chem. Eur. J. 1999, 5, 599. 6. Nicolaou, K. C.; Gunzner, J. L.; Shi, G.-Q.; Agrios, K. A.; Gärtner, P.; Yang, Z. Chem. Eur. J. 1999, 5, 646. 426

Nicolaou hydroxy-ketone reductive cyclic ether formation Acid-catalyzed conversion of a ketone with a pendant hydroxyl group into a cyclic ether with net reduction of the carbonyl.

Et3SiH, TMSOTf O CH Cl , 0 °C O Ph OH Ph 2 2 HH 15 min., 90%

The mechanism involves hemiketal formation followed by reduction of the oxocarbonium group:

silylation; O hemiketal OH Ph O Ph formation H OTMS TMS OTf

O Ph O Ph H HH TES H

Example 11

H H H O O O TMSOTf, MePh2SiH BnO O CH Cl , 0 °C, 2 h, 62% HO 2 2 BnO O H HHH

O H Me H H O O BnO O H BnO O H H HH Me 427

e. g. 22

H OMTM O TfOH, EtMe2SiH

CH2Cl2, CH3CN, O OBn OBz 50 to 20 °C, O 1 h, 81%

H

O OBz O O HHOBn

References

1. Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. J. Am. Chem. Soc. 1989, 111, 4136. 2. Smith, A. B.; Cui, H. Helv. Chim. Acta 2003, 86, 3908. 3. Watanabe, K.; Suzuki, M.; Murata, M.; Oishi, T. Tetrahedron Lett. 2005, 46, 3991. 4. Fujiwara, K.; Goto, A.; Sato, D.; Ohtaniuchi, Y.; Tanaka, H.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2004, 45, 7011. 5. González, I. C.; Forsyth, C. J. J. Am. Chem. Soc. 2000, 122, 9099. 6. Alvarez, E.; Pérez, R.; Rico, M.; Rodríguez, R. M.; Martín, J. D. J. Org. Chem. 1996, 61, 3003. 428

Nicolaou oxyselenation Activation of alkenes towards nucleophilic attack by a variety of nucleophiles employing N-phenylselenophthalimide or N-phenylselenosuccinimide as an electrophilic source of the phenylseleno group.

O O

N Se N Se

O O N-PSP = N-phenylselenophthalimide N-PSS = N-phenylselenosuccinimide

Se N-PSP CH Cl , 2 2 OH H2O, 89%

The reagent may require acid activation depending on the type of transformation being attempted. The mechanism parallels that of halohydrin formation using an electrophilic source of halide in an aqueous medium:

O selenonium formation Se N Ph O

Se Markovnikov O Nu M addition N

O

O Se + N M

Nu O 429

Example 13

BnO BnO

MeO O N-PSP, CSA MeO O O O CH2Cl2, rt O OH 2 h, 60% H PhSe

Example 2, in addition to oxyselenide formation, carbo- and heteroseleno cyclization, N-PSP can be used to generate selenides from alcohols and selenol esters from carboxylic acids, respectively, in the presence of a stoichiometric amount of 6 n-Bu3P.

O O O O

N-PSP, n-Bu3P

CH Cl , 25 to 20 °C OH 2 2 SePh 3 h, 73% OTBDPS OTBDPS

References

1. Nicolaou, K. C.; Claremon, D. A.; Barnette, W. E.; Seitz, S. P. J. Am. Chem. Soc. 1979, 101, 3704. 2. Chrétien, F.; Chapleur, Y. J. Org. Chem. 1988, 53, 3615. 3. Kühnert, S. M.; Maier, M. E. Org. Lett. 2002, 4, 643. 4. Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem. Soc. 2003, 125, 7822. 5. Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.; Bornmann, W. G.; Dan- ishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953. 6. Grieco, P. A.; Jaw, J. Y.; Claremon, D. A.; Nicolaou, K. C. J. Org. Chem. 1981, 46, 1215. 7. Nicolaou, K. C.; Petasis, N. A.; Claremon, D. A. Tetrahedron 1985, 41, 4835. 430

Noyori asymmetric hydrogenation Asymmetric reduction of carbonyl via hydrogenation catalyzed by ruthenium(II) BINAP complex.

OO H2 OH O 1 1 ROR(R)-BINAP-Ru ROR

(R)-BINAP-Ru =

PPh2 RuCl2L2 PPh2

H2 [RuCl2(binap)(solv)2] [RuHCl(binap)(solv)2] HCl

The catalytic cycle: OR1 O + (binap)ClHRu H solv O R

OO

ROR1

OR1 O [RuHCl(binap)(solv)2] (binap)ClRu O H H R

H+, solv solv

[RuCl(binap)(solv) ]+ OH O H2 2 ROR1 431

Example 12

Ru((S)-BINAP(CF3CO2)2 OH 30 atm H2, rt, 96% ee

OH

Example 23

Ru((R)-BINAP(Cl) O 2 OH 100 atm H , rt, 92% ee Br 2 Br

References

1. Noyori, R.; Ohta, M.; Hsiao, Y.; Kitamura, Ma.; Ohta, T.; Takaya, H. J. Am. Chem. Soc. 1986, 108, 7117. Ryoji Noyori (Japan, 1938) and Herbert 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. 2. Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Inoue, S.; Kasahara, I.; Noyori, R.; nnn J. Am. Chem. Soc. 1987, 109, 1596. 3. Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, Hi.Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. et al. J. Am. Chem. Soc. 1988, 110, 629. 4. Noyori, R.; Ohkuma, T.; Kitamura, H.; Takaya, H.; Sayo, H.; Kumobayashi, S.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856. 5. Case-Green, S. C.; Davies, S. G.; Hedgecock, C. J. R. Synlett 1991, 781. 6. King, S. A.; Thompson, A. S.; King, A. O.; Verhoeven, T. R. J. Org. Chem. 1992, 57, 6689. 7. Noyori, R. In Asymmetric Catalysis in Organic Synthesis; Ojima, I., ed.; Wiley: New York, 1994, chapter 2. (Review). 8. 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. 9. Bayston, D. J.; Travers, C. B.; Polywka, M. E. C. Tetrahedron: Asymmetry 1998, 9, 2015. 10. Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40, 40. 11. Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (Review, Nobel Prize Address). 12. Berkessel, A.; Schubert, T. J. S.; Mueller, T. N. J. Am. Chem. Soc. 2002, 124, 8693. 13. Fujii, K.; Maki, K.; Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 733. 432

Nozaki–Hiyama–Kishi reaction CrNi bimetallic catalyst-promoted redox addition of vinyl halides to aldehydes.

CrCl2, NiBr2 OH 1 Br R CHO 1 R RR DMSOSMe2

Br SMe2 R Ni(II) Br NiBr2 Ni(0) R reduction oxidative addition

CrCl CrCl2 3 R1 CHO Cr(III)Cl2 R nucleophilic addition Ni(II) Ni(0)

Transmetalation and then reduction by Me2S

OH OCrCl2 hydrolysis CrCl X 1 2 RR1 RR

The catalytic cycle:7

X CrX2 RCHO

OCrX 2 CrX 2 2 2 CrX3 R

MnX2 Mn OSiMe 3 Me3SiX R 433

Example 18

OTHP IOTBDPS AcO CHO

OTHP 10 eq CrCl2, cat. NiCl2 AcO OTBDPS o DMSO, 25 C, 12 h, 80% OH

Example 212

O OH O OTf OHC 4 eq CrCl O 2 0.008 eq NiCl2 O O DMF, rt, 15 h O 35%

References

1. Okude, C. T.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc. 1977, 99, 3179. Hitosi Nozaki and T. Hiyama are professors at the Japanese Academy. 2. Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281. Kazuhiko Takai was Prof. Nozaki’s student during the discovery of the reaction and is a professor at Okayama University. 3. Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644. Yo- shita Kishi at Harvard independently discovered the catalytic effect of nickel during his total synthesis of polytoxin. 4. Takai, K.; Tagahira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048. 5. Wessjohann, L. A.; Scheid, G. Synthesis 1991, 1. (Review). 6. Kress, M. H.; Ruel, R.; Miller, L. W. H.; Kishi, Y. Tetrahedron Lett. 1993, 34, 5999. 7. The catalytic cycle: Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349. 8. Chakraborty, T. K.; Suresh, V. R. Chem. Lett. 1997, 565. 9. Boeckman, R. K., Jr.; Hudack, R. A., Jr. J. Org. Chem. 1998, 63, 3524. 10. Fürstner, A. Chem. Rev. 1999, 99, 9911046. (Review). 11. Kuroboshi, M.; Tanaka, M.; Kishimoto, S. Goto, K.; Mochizuki, M.; Tanaka, H. Tet- rahedron Lett. 2000, 41, 81. 12. 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. 13. Berkessel, A.; Menche, D.; Sklorz, C. A.; Schroder, M.; Paterson, I. Angew. Chem. Int. Ed. 2003, 42, 1032. 14. Takai, K. Org. React. 2004, 64, 253612. (Review). 434

Oppenauer oxidation Alkoxide-catalyzed oxidation of secondary alcohols.

OH Al(Oi-Pr)3 O OH

R1 R2 O R1 R2

Oi-Pr O Al(Oi-Pr)2 Al(Oi-Pr) OH O 2 : OH R1 R2 coordination

R1 R2

i-PrO Oi-Pr Oi-Pr R1 Al O Al Oi-Pr O O HO R2 H R2 R1 cyclic transition state

hydride O OH

transfer R1 R2

Example 1, magnesium Oppenauer oxidation3

O OH 1. EtMgBr, i-Pr2O

2. PhCHO, 60%

Example 212

OH O (i-PrO)2AlO2CCF3 p-O2N-Ph-CHO

PhH, rt, 24 h, 70% OH OH 435

References

1. Oppenauer, R. V. Rec. Trav. Chim. 1937, 56, 137. Rupert V. Oppenauer (1910), born in Burgstall, Italy, studied at ETH in Zurich under Ruzicka and Reichstei, both Nobel laureates. After a string of academic appointments around Europe and a stint at HoffmanLa Roche, Oppenauer worked for the Ministry of Public Health in Buenos Aires, Argentina. 2. Djerassi, C. Org. React. 1951, 6, 207. (Review). 3. Byrne, B.; Karras, M. Tetrahedron Lett. 1987, 28, 769. 4. de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J. Synthesis 1994, 1007. 5. Almeida, M. L. S.; Kocovsky, P.; Bäckvall, J.-E. J. Org. Chem. 1996, 61, 6587. 6. Akamanchi, K. G.; Chaudhari, B. A. Tetrahedron Lett. 1997, 38, 6925. 7. Raja, T.; Jyothi, T. M.; Sreekumar, K.; Talawar, M. B.; Santhanalakshmi, J.; Rao, B. S. Bull. Chem. Soc. Jpn. 1999, 72, 2117. 8. Nait Ajjou, A. Tetrahedron Lett. 2001, 42, 13. 9. Schrekker, H. S.; de Bolster, M. W. G.; Orru, R. V. A.; Wessjohann, L. A. J. Org. Chem. 2002, 67, 1975. 10. Ooi, T.; Otsuka, H.; Miura, T.; Ichikawa, H.; Maruoka, K. Org. Lett. 2002, 4, 2669. 11. Suzuki, T.; Morita, K.; Tsuchida, M.; Hiroi, K. J. Org. Chem. 2003, 68, 1601. 12. Auge, J.; Lubin-Germain, N.; Seghrouchni, L. Tetrahedron Lett. 2003, 44, 819. 13. Hon, Y.-S.; Chang, C.-P.; Wong, Y.-C. Byrne, B.; Karras, M. Tetrahedron Lett. 2004, 45, 3313. 436

Overman rearrangement Stereoselective transformation of allylic alcohol to allylic trichloroacetamide via trichloroacetimidate intermediate.

CCl3 CCl3 OH cat. NaH ' HN O HN O RR1 Cl3CCN or Hg(II) or Pd(II) 1 RR1 RR trichloroacetimidate

N CCl3 H O H H2n O RR1 RR1

CCl3 H O N O

RR1 RR1

CCl3 CCl3 ', [3,3]-sigmatropic HN O HN O rearrangement 1 RR1 RR

Example 113

O H O O H O O O O O Cl3CCN, DBU O O o HN CH2Cl2, 78 C O HO Cl3C 437

O H O K2CO3, p-xylene O O HN reflux, 90%, 2 steps Cl3C O O

Example 214

TBDMSO TBDMSO

Cl3C O O O K2CO3, p-xylene NH O O reflux, 77% Cl3C NH O

References

1. Overman, L. E. Acc. Chem. Res. 1971, 4, 49. (Review). 2. Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597. 3. Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901. 4. Isobe, M.; Fukuda, Y.; Nishikawa, T.; Chabert, P.; Kawai, T.; Goto, T. Tetrahedron Lett. 1990, 31, 3327. 5. Eguchi, T.; Koudate, T.; Kakinuma, K. Tetrahedron 1993, 49, 4527. 6. Toshio, N.; Masanori, A.; Norio, O.; Minoru, I. J. Org. Chem. 1998, 63, 188. 7. Cho, C.-G.; Lim, Y.-K.; Lee, K.-S.; Jung, I.-H.; Yoon, M.-Y. Synth. Commun. 2000, 30, 1643. 8. Martin, C.; Prunck, W.; Bortolussi, M.; Bloch, R. Tetrahedron: Asymmetry 2000, 11, 1585. 9. Demay, S.; Kotschy, A.; Knochel, P. Synthesis 2001, 863. 10. Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.; Iida, M.; Chida, N. Org. Lett. 2002, 4, 151. 11. Reilly, M.; Anthony, D. R.; Gallagher, C. Tetrahedron Lett. 2003, 44, 2927. 12. O’Brien, P.; Pilgram, C. D. Org. Biomol. Chem. 2003, 1, 523. 13. Tsujimoto, T.; Nishikawa, T.; Urabe, D.; Isobe, M. Synlett 2004, 433. 14. Montero, A.; Mann, E.; Herradon, B. Tetrahedron Lett. 2005, 46, 401. 15. Ramachandran, P. V.; Burghardt, T. E.; Reddy, M. V. R. Tetrahedron Lett. 2005, 46, 2121. 438

Paal thiophene synthesis Thiophene synthesis from addition of a sulfur atom to 1,4-dicarbonyl compounds and subsequent dehydration.

OO H3C P2S5, tetralin, reflux S H3CCH3 CH3

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 348.

O S P2S5 CH3 CH3 X = O or S H3C H3C O X

tautomerization SH CH3 H3C X

H C 3 S XH H X 2 H3C S CH3 CH3 H

Example 14

O Lawesson's reagent S N Ph N Ph 110 ºC, 10 min, 82% O 439

Example 28

Lawesson's reagent O chlorobenzene, reflux, 36 h Ph O Ph Ph 69% S Ph S O Ph O Ph Ph Ph

References

1. Paal, C. Chem. Ber. 1885, 18, 251. 2. Paal, C. Chem. Ber. 1885, 18, 367. 3. Campaigne, E.; Foye, W. O. J. Org. Chem. 1952, 17, 1405. 4. Thomsen, I.; Pedersen, U.; Rasmussen, P. B.; Yde, B.; Andersen, T. P.; Lawesson, S.- O. Chem. Lett. 1983, 809. 5. Freeman, F.; Kim, D. S. H. L. J. Org. Chem. 1992, 57, 1722. 6. Johnson, M. R.; Miller, D. C.; Bush, K.; Becker, J. J.; Ibers, J. A. J. Org. Chem. 1992, 57, 4414. 7. Freeman, F.; Lee, M. Y.; Lu, H.; Rodriguez, E.; Wang, X. J. Org. Chem. 1994, 59, 3695. 8. Parakka, J. P.; Sadannandan, E. V.; Cava, M. P. J. Org. Chem. 1994, 59, 4208. 9. Hemperius, M. A.; Lengeveld, B. M. W.; van Haave, J. A. E. H.; Janssen, R. A. J. Sheiko, S. S.; Spatz, J. P.; Möller, M.; Meijer, E. W. J. Am. Chem. Soc. 1998, 120, 2798. 10. Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.; Tai, K.; Hida, T.; Yamauchi, T.; Nagai, M. J. Med. Chem. 2000, 43, 409. 11. Sonpatki, V. M.; Herbert, M. R.; Sandvoss, L. M.; Seed, A. J. J. Org. Chem. 2001, 66, 7283. 12. Kiryanov, A. A.; Sampson, P.; Seed, A. J. J. Org. Chem. 2001, 66, 7925. 13. 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, 207217. (Review). 440

Paal–Knorr furan synthesis Acid-catalyzed cyclization of 1,4-ketones to form furans.

1 2 O R2 R R cat. H+ R3 R or P O RR3 R1 O 2 5 O

H+ R1 R2 O R2 3 R R : 3 R O R 1 HO

R O: H+

1 R 2 R1 R2 H R + H3O 3 3 RRO RRO

Example 110

Cl F Cl O O TsOH O F toluene, reflux

N N

Example 214

OMe MeO OMe O n-Bu O p-TsOH O MeO toluene n-Bu

98% OMe MeO 441

References

1. Paal, C. Ber. Dtsch. Chem. Ges. 1884, 17, 2756. 2. Knorr, L. Ber. Dtsch. Chem. Ges. 1885, 18, 299 3. Paal, C. Ber. Dtsch. Chem. Ges. 1885, 18, 367. 4. Haley, J. F., Jr.; Keehn, P. M. Tetrahedron Lett. 1973, 4017. 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, 167238. (Review). 6. Amarnath, V.; Amarnath, K. J. Org. Chem. 1995, 60, 301. 7. Truel, I.; Mohamed-Hachi, A.; About-Jaudet, E.; Collignon, N. Synth. Commun. 1997, 27, 1165. 8. 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, 351393. (Review). 9. Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed.; Longman: Singapore, 1997; 211. (Re- view). 10. de Laszlo, S. E.; Visco, D.; Agarwal, L.; et al. Bioorg. Med. Chem. Lett. 1998, 8, 2689. 11. Gupta, R. R.; Kumar, M.; Gupta, V. Heterocyclic Chemistry, Springer: New York, 1999; Vol. 2, 8384. (Review). 12. Stauffer, F.; Neier, R. Org. Lett. 2000, 2, 3535. 13. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell Science: Cambridge, 2000; 308-309. (Review). 14. Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2001, 44, 3838. 15. 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, 183278. (Review). 16. 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, 168181. (Re- view). 442

Parham cyclization Annulation of aryl halides with ortho side chains bearing a pendant electrophilic moiety via treatment with an organolithium reagent, involving halogen-metal exchange and subsequent nucleophilic cyclization to form 4- to 7-membered rings.

CH3O I O 2.2 eq. t-BuLi CH3O N CH3O o N NEt2 THF, 78 Cort CH3O O

Et2NO CH O I 3 halogen-metal CH3O Li N CH O exchange I N 3 CH3O NEt2 O

O Et2N O CH O cyclization CH3O 3 N N CH O CH3O 3

The fate of the second equivalent of t-BuLi:

I H I

Example 19

O I MeO 2 eq. n-BuLi N N O MeO O THF, 78 oC MeO 2.5 h, 83% OMe 443

Example 216

OBr o O t-BuLi, THF, 100 C

NOMeAr, 30 min., 55% PMB

O O N PMB

References

1. Parham, W. E.; Jones, L. D.; Sayed, Y. J. Org. Chem. 1975, 40, 2394. William E. Par- ham was a professor at Duke University. 2. Parham, W. E.; Jones, L. D.; Sayed, Y. J. Org. Chem. 1976, 41, 1184. 3. Bradsher, C. K.; Hunt, D. A. Org. Prep. Proced. Int. 1978, 10, 267. 4. Bradsher, C. K.; Hunt, D. A. J. Org. Chem. 1981, 46, 4608. 5. Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300. (Review). 6. Quallich, G. J.; Fox, D. E.; Friedmann, R. C.; Murtiashaw, C. W. J. Org. Chem. 1992, 57, 761. 7. Couture, A.; Deniau, E.; Grandclaudon, P. J. Chem. Soc., Chem. Commun. 1994, 1329. 8. 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). 9. Collado, M. I.; Manteca, I.; Sotomayor, N.; Villa, M.-J.; Lete, E. J. Org. Chem. 1997, 62, 2080. 10. Ardeo, A.; Lete, E.; Sotomayor, N. Tetrahedron Lett. 2000, 41, 5211. 11. Osante, I.; Collado, M. I.; Lete, E.; Sotomayor, N. Eur. J. Org. Chem. 2001, 1267. 12. Ardeo, A.; Collado, M. I.; Osante, I.; Ruiz, J.; Sotomayor, N.; Lete, E. In Targets in Heterocyclic Systems Vol. 5; Atanassi, O., Spinelli, D., Eds.; Italian Society of Chem- istry: Rome, 2001; p 393. (Review). 13. Mealy, M. M.; Bailey, W. F. J. Organomet. Chem. 2002, 646, 59. (Review). 14. Sotomayor, N.; Lete, E. Current Org. Chem. 2003, 7, 275. (Review). 15. González-Temprano, I.; Osante, I.; Lete, E.; Sotomayor, N. J. Org. Chem. 2004, 69, 3875. 16. Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Org. Biomol. Chem. 2005, 3, 2305. 444

Passerini reaction Three-component condensation (3CC) of carboxylic acids, C-isocyanides, and carbonyl compounds to afford D-acyloxycarboxamides. Cf. Ugi reaction.

R2 R3 O O H 1 4 1 N R NC R CO2H R OR R2 R3 4 O isocyanide

H O O H 2 4 R O O 2 O R O 3 4 R 4 R R 3 R CO2H R R2 R3 C O N N R1 R1

H 2 O O R R2 R3 O acyl 3 H 4 R R 1 N 4 O R OR transfer N O R1 H+

Example 15

HOAc, THF CHO HN rt, 93% O CN AcO Et 445

Example 23 Ts

CN OMe TFA, PhH MeO OMe rt, 2 h, 93% MeO OMe OMe

OMe H MeO N Ts

O OMe MeO

OMe

References

1. Passerini, M. Gazz. Chim. Ital. 1921, 51, 126, 181. Mario Passerini (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. 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. 6. Ziegler, T.; Kaisers, H.-J.; Schlomer, R.; Koch, C. Tetrahedron 1999, 55, 8397. 7. Banfi, L.; Guanti, G.; Riva, R. Chem. Commun. 2000, 985. 8. Semple, J. E.; Owens, T. D.; Nguyen, K.; Levy, O. E. Org. Lett. 2000, 2, 2769. 9. Owens, T. D.; Semple, J. E. Org. Lett. 2001, 3, 3301. 10. Xia, Q.; Ganem, B. Org. Lett. 2002, 4, 1631. 11. Basso, A.; Banfi, L.; Riva, R.; Piaggio, P.; Guanti, G. Tetrahedron Lett. 2003, 44, 2367. 12. Banfi, L.; Riva, R. Org. React. 2005, 65, 1140. (Review). 446

Paternó–Büchi reaction Photoinduced electrocyclization of a carbonyl with an alkene to form polysubsti- tuted oxetane ring systems

O O hv 1 R RR R1 oxetane

O hv O RR1 RR1 n, S* triplet

O O O R R R 1 R1 R R1 triplet diradical singlet diradical

Example 14

O O H O O O O Ph Ph *ROOC Me O hQ, C6H6, 99% O Me Ph H

Example 26

i-Pr hQ, C H O i-Pr 6 6 O + Ph Ph Ph SMe SMe 73% Ph (E/Z = 6/1) 447

References

1. Paternó, E.; Chieffi, G. Gazz. Chim. Ital. 1909, 39, 341. Emaubuele Paternó (18471935) was born in Palermo, Sicily, Italy. 2. Büchi, G.; Inman, C. G.; Lipinsky, E. S. J. Am. Chem. Soc. 1954, 76, 4327. George H. Büchi (19211998) 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. Paterno in 1909. Büchi died of heart failure while hiking with his wife in his native Switzerland. 3. Jones, G. In Organic Photochemistry; Padwa, A., Ed.; Dekker: New York, 1981, pp 1. (Review). 4. Koch, H.; Runsink, J.; Scharf, H.-D. Tetrahedron Lett. 1983, 24, 3217. 5. Carless, H. A. J. In Synthetic Organic Photochemistry; Horspool, W. M., Ed.; Plenum Press: New York, 1984, pp 425. (Review). 6. Morris, T. H.; Smith, E. H.; Walsh, R. J. Chem. Soc., Chem. Commun. 1987, 964. 7. Porco, J. A., Jr.; Schreiber, S. L. In Comprehensive Organic Synthesis Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 5, 151192. (Review). 8. Griesbeck, A. G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res. 1994, 27, 70. (Re- view). 9. Fleming, S. A.; Gao, J. J. Tetrahedron Lett. 1997, 38, 5407. 10. Hubig, S. M.; Sun, D.; Kochi, J. K. J. Chem. Soc., Perkin Trans. 2 1999, 781. 11. D'Auria, M.; Racioppi, R.; Romaniello, G. Eur. J. Org. Chem. 2000, 3265. 12. Bach, T.; Brummerhop, H.; Harms, K. Chem. Eur. J. 2000, 6, 3838. 13. Bach, T. Synlett 2000, 1699. 14. Abe, M.; Tachibana, K.; Fujimoto, K.; Nojima, M. Synthesis 2001, 1243. 15. D'Auria, M.; Emanuele, L.; Poggi, G.; Racioppi, R.; Romaniello, G. Tetrahedron 2002, 58, 5045. 16. Griesbeck, A. G. Synlett 2003, 451. 17. Liu, C. M. Paternó–Büchi Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 4449. (Review). 448

PausonKhand cyclopentenone synthesis Formal [2 + 2 +1] cycloaddition of an alkene, alkyne, and carbon monoxide mediated by octacarbonyl dicobalt.

O

H O Co2(CO)8 Co(CO)3 o Co(CO)3 toluene, 60 80 C O 46 d, 60%

H CO H CO Co(CO) (CO) Co Co(CO) 3 CO Co(CO) 4 3 Co(CO) 3 3 Co(CO) OC 3 H hexacarbonyldicobalt complex

H H O Co(CO) (CO)3Co 3 CO O CO Co(CO)2 O insertion (CO)3Co H towards CH H exo complex sterically-favored isomer

H (CO)3Co (CO)3Co O (CO) Co H CO 3 O

insertion (CO)3Co O O

O reductive elimination

Co2(CO)6 O 449

Example 16

O Co2(CO)8 O O O o benzene, 65 C O 16 h, 23%

Example 2, a catalytic version9

5 mol% Co2(CO)8 20 mol% P(OPh)3 Ts N TsN O 3 atm CO, DME 120 oC, 48 h, 94%

References

1. Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E. J. Chem. Soc., Chem. Commun. 1971, 36. Ihsan U. Khand and Peter L. Pauson were at the University of Strathclyde, Glasgow in Scotland. 2. Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977. 3. Bladon, P.; Khand, I. U.; Pauson, P. L. J. Chem. Res. (M), 1977, 153. 4. Pauson, P. L. Tetrahedron 1985, 41, 5855. (Review). 5. Schore, N. E. Chem. Rev. 1988, 88, 1081. (Review). 6. Billington, D. C.; Kerr, W. J.; Pauson, P. L.; Farnocchi, C. F. J. Organometal. Chem. 1988, 356, 213. 7. Schore, N. E. In Comprehensive Organic Synthesis; Paquette, L. A.; Fleming, I.; Trost, B. M., Eds.; Pergamon: Oxford, 1991, Vol. 5, p.1037. (Review). 8. Schore, N. E. Org. React. 1991, Vol. 40, pp 190. (Review). 9. Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, J. J. Am. Chem. Soc. 1994, 116, 3159. 10. Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263. (Review). 11. Son, S. U.; Lee, S. I.; Chung, Y. K. Angew. Chem., Int. Ed. 2000, 39, 4158. 12. Kraft, M. E.; Fu, Z.; Boñaga, L. V. R. Tetrahedron Lett. 2001, 42, 1427. 13. Muto, R.; Ogasawara, K. Tetrahedron Lett. 2001, 42, 4143. 14. Areces, P.; Durán, M. Á.; Plumet, J.; Hursthouse, M. B.; Light, M. E. J. Org. Chem. 2002, 67, 3506. 15. Mukai, C.; Nomura, I.; Kitagaki, S. J. Org. Chem. 2003, 68, 1376. 16. Tsujimoto, T.; Nishikawa, T.; Urabe, D.; Isobe, M. Synlett 2005, 433. 450

Payne rearrangement Base-promoted isomerization of 2,3-epoxy alcohols. Also known as epoxide migration.

OH R aq. NaOH O R OH O

R R O OH O H O O

O + OH SN2 H R workup R 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 O CO Me rt, 2 h, 98% CO Me BzO 2 2

References

1. Payne, G. B. J. Org. Chem. 1962, 27, 3819. 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. 3. Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.; Mioskowski, C.; Samuelsson, B.; Hammerstrom, S. J. Am. Chem. Soc. 1980, 102, 1436, 3663. 4. Page, P. C. B.; Rayner, C. M.; Sutherland, I. O. J. Chem. Soc., Perkin Trans. 1, 1990, 1375. 5. Konosu, T.; Miyaoka, T.; Tajima, Y.; Oida, S. Chem. Pharm. Bull. 1992, 40, 562. 6. Dols, P. P. M. A.; Arnouts, E. G.; Rohaan, J.; Klunder, A. J. H.; Zwanenburg, B. Tet- rahedron 1994, 50, 3473. 451

7. Ibuka, T. Chem. Soc. Rev. 1998, 27, 145. (Review). 8. Bickley, J. F.; Gillmore, A. T.; Roberts, S. M.; Skidmore, J.; Steiner, A. J. Chem. Soc., Perkin Trans. 1 2001, 1109. 9. Tamamura, H.; Hori, T.; Otaka, A.; Fujii, N. J. Chem. Soc., Perkin Trans. 1 2002, 577. 10. Hanson, R. M. Org. React. 2002, 60, 1156. (Review). 11. Tamamura, H.; Kato, T.; Otaka, A.; Fujii, N. Org. Biomol. Chem. 2003, 1, 2468. 12. Yamazaki, T.; Ichige, T.; Kitazume, T. Org. Lett. 2004, 6, 4073. 13. Bilke, J. L.; Dzuganova, M.; Froehlich, R.; Wuerthwein, E.-U. Org. Lett. 2005, 7, 3267. 452

Pechmann coumarin synthesis Lewis acid-mediated condensation of phenol with E-ketoester to produce coumarin.

OH O O OO AlCl3 ROEt R

H O AlCl OEt EtO 3 O O O: O O

R R : OO OO H+ Michael O H addition R R OH

OO OO H O O H

H ROH ROH H+ R

Example 111

OO

OEt [bimim]Cl•2AlCl HO OH 3 HO OO 130 oC, 35 min., 90%

[bimim]Cl•2AlCl3 = 1-Butyl-3-methylimidazolium chloroaluminuminate (a Lewis acid ionic liquid) 453

Example 214

O OH OO O OH OEt o BiCl3, 75 C, 2 h, 66% OH OO

References

1. v. Pechmann, H.; Duisberg, C. Ber. Dtsch. Chem. Ges. 1883, 16, 2119. Hans von Pechmann (18501902) 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. Hirata, T.; Suga, T. Bull. Chem. Soc. Jpn. 1974, 47, 244. 3. Chaudhari, D. D. Chem. Ind. 1983, 568. 4. Holden, M. S.; Crouch, R. D. J. Chem. Educ. 1998, 75, 1631. 5. Corrie, J. E. T. J. Chem. Soc., Perkin Trans. 1 1990, 2151. 6. Hua, D. H.; Saha, S.; Roche, D.; Maeng, J. C.; Iguchi, S.; Baldwin, C. J. Org. Chem. 1992, 57, 399. 7. Biswas, G. K.; Basu, K.; Barua, A. K.; Bhattacharyya, P. Indian J. Chem., Sect. B 1992, 31B, 628. 8. Li, T.-S.; Zhang, Z.-H.; Yang, F.; Fu, C.-G. J. Chem. Res., (S) 1998, 38. 9. Sugino, T.; Tanaka, K. Chem. Lett. 2001, 110. 10. Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. Tetrahedron Lett. 2001, 42, 9285. 11. Khandekar, A. C.; Khandilkar, B. M. Synlett. 2002, 152. 12. Shockravi, A.; Heravi, M. M.; Valizadeh, H. Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 143. 13. Smitha, G.; Sanjeeva Reddy, C. Synth. Commun. 2004, 34, 3997. 14. De, S. K.; Gibbs, R. A. Synthesis 2005, 1231. 454

Perkin reaction Cinnamic acid synthesis from aryl aldehyde and acetic anhydride.

OAc O O AcONa OH O Ar CHO Ac O 2 Ar O H2O Ar OH cinnamic acid

OO enolate aldol OO O OAc H HAr O formation condensation O

O O intramolecular OO OO acyl transfer Ar O Ar O

O O OO OOO acyl OO O Ar O transfer Ar O H H OH

O O E2 Ac2O Ar O elimination OAc

O HO O O HOAc O Ar O Ar O Ar OH 455

Example 19

MeO

CHO MeO CO2H MeO

MeO H

o Ac2O, Et3N, 90 C CO2H MeO 5 h, 66% MeO

Example 210

ClF2C Ac2O, ' ClF2C O Ph AcONa, 46% Ph CO2H

References

1. Perkin, W. H. J. Chem. Soc. 1868, 21, 53. William Henry Perkin (18381907), born in London, England, studied under Hofmann at the Royal College of Chemistry. 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 catapulted the discipline into a higher level. In addition, Perkin was also an exceptionally talented pianist. 2. Pohjala, E. Heterocycles 1975, 3, 615. 3. Poonia, N. S.; Sen, S.; Porwal, P. K.; Jayakumar, A. Bull. Chem. Soc. Jpn. 1980, 53, 3338. 4. Gaset, A.; Gorrichon, J. P. Synth. Commun. 1982, 12, 71. 5. Kinastowski, S.; Nowacki, A. Tetrahedron Lett. 1982, 23, 3723. 6. Koepp, E.; Voegtle, F. Synthesis 1987, 177. 7. Brady, W. T.; Gu, Y.-Q. J. Heterocycl. Chem. 1988, 25, 969. 8. Pálinkó, I.; Kukovecz, A.; Török, B.; Körtvélyesi, T. Monatsh. Chem. 2001, 131, 1097. 9. Solladié, G.; Pasturel-Jacopé, Y.; Maignan, J. Tetrahedron 2003, 59, 3315. 10. Sevenard, D. V. Tetrahedron Lett. 2003, 44, 7119. 456

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.

R3 R O 2 R R (HO) B 4 2 N R NH HR 2 4 R1 3 R1

O R3 R2 HR3 N OH R R NH 1 R4 2 (HO)2B R1

R3 R R3 2 N O H R 2 N R R1 B(OH)2 4 R1

R4

Example 15

OH C5H11 O Ph N B Ph OH OH H

EtOH, rt Ph N C H Ph 5 11 84%, 99% de OH 457

Example 27

Me HO N Bn (HO)2B HO CHO MeNHBn, EtOH, rt HO 24 h, 72%, 99% de HO OMe OMe

References

1. Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583. 2. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445. 3. Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463. 4. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798. 5. Koolmeister, T.; Södergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5969. 6. Orru, R. V. A.; deGreef, M. Synthesis 2003, 1471. (Review). 7. Sugiyama, S.; Arai, S.; Ishii, K. Tetrahedron: Asymmetry 2004, 15, 3149. 8. Chang, Y. M.; Lee, S. H.; Nam, M. H.; Cho, M. Y.; Park, Y. S.; Yoon, C. M. Tetrahe- dron 2005, 46, 3053. 9. Follmann, M.; Graul, F.; Schaefer, T.; Kopec, S.; Hamley, P. Synlett 2005, 1009. 458

Peterson olefination Alkenes from D-silyl carbanion and carbonyl compounds. Also known as sila- Wittig reaction.

1 O H HO SiR3 acid or R H + 2 M SiR3 R H 1 2 3 R R R R1 R3 base R2 R3

Basic conditions:

O

1 2 R R O SiR3 R1 H H 2 3 + R R M SiR3 R3 E-silylalkoxide intermediate

R1 H O SiR3 syn- R1 H elimination R2 R3 R2 R3

Acidic conditions:

HO R3 + HO SiR3 H 1 rotation R1 H R H 2 R2 R3 R SiR3 E-hydroxysilane

H O R3 2 1 3 R1 H E2 anti- R R 2 R SiR3 elimination R2 H :OH2

Example 110

o F F 1. n-BuLi, Et2O, 78 C Ph PhO2S PhO2STBS 2. benzophenone, 63% Ph 459

Example 212

o 1. KHMDS, THF, 78 C CN (t-BuO)Ph2Si CN N 2. 88% yield N CHO 92:8 Z:E

References

1. Peterson, D. J. J. Org. Chem. 1968, 33, 780. 2. Ager, D. J. Synthesis 1984, 38498. (Review). 3. Ager, D. J. Org. React. 1990, 38, 1. (Review). 4. Barrett, A. G. M.; Hill, J. M.; Wallace, E. M.; Flygare, J. A. Synlett 1991, 764770. (Review). 5. Galano, J.-M.; Audran, G.; Monti, H. Tetrahedron Lett. 2001, 42, 6125. 6. van Staden, L. F.; Gravestock, D.; Ager, D. J. Chem. Soc. Rev. 2002, 31, 195. (Review). 7. Ager, D. J. Science of Synthesis 2002, 4, 789809. (Review). 8. Adam, W.; Ortega-Schulte, C. M. Synlett 2003, 414. 9. Murai, T.; Fujishima, A.; Iwamoto, C.; Kato, S. J. Org. Chem. 2003, 68, 7979. 10. Asakura, N.; Usuki, Y.; Iio, H. J. Fluorine Chem. 2003, 124, 81. 11. Suzuki, H.; Ohta, S.; Kuroda, C. Synth. Commun. 2004, 34, 1383. 12. Kojima, S.; Fukuzaki, T.; Yamakawa, A.; Murai, Y. Org. Lett. 2004, 6, 3917. 13. Kano, N.; Kawashima, T. The Peterson and Related Reactions in Modern Carbonyl Olefination Takeda, T. (ed.), Wiley-VCH: Weinheim, Germany, 2004, 18103. (Re- view). 14. Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44, 3485. 460

Pictet–Gams isoquinoline synthesis The isoquinoline framework is derived from the corresponding acyl derivatives of E-hydroxy-E-phenylethylamines. Upon exposure to a dehydrating agent such as phosphorus pentaoxide, or phosphorus oxychloride, under reflux conditions and in an inert solvent such as decalin, isoquinoline frameworks are formed.

4 OH H 3 N 1 R P2O5, decalin 4 1 N 3 reflux O R

P2O5 actually exists as P4O10, an adamantane-like structure.

OH O O OH POP OO HN: O HN O O P R R O

O O OH H O: POP OO :NH H N ROPO2 R

OPO2 H N N R R 461

Example 110

OH

P2O5 N NO H o-dichlorobenzene Cl Cl 80%

Example 27

POCl3, P4O10, decalin N HO ONH 180 oC, 6 h, 14% N OH H H OH N N N

O O

Reference

1. Pictet, A.; Gams, A. Ber. Dtsch. Chem. Ges. 1909, 42, 1973, 2943. Amé Pictet (18571937), born in Geneva, Switzerland, carried out a tremendous amount of work on alkaloids. 2. Kulkarni, S. N.; Nargund, K. S. Indian J. Chem., B 1967, 5, 294. 3. Ardabilchi, N.; Fitton, A. O.; Frost, J. R.; Oppong-Boachie, F. Tetrahedron Lett. 1977, 18, 4107. 4. 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. 5. Ardabilchi, N.; Fitton, A. O. J. Chem. Soc. (S) 1979, 310. 6. Cerri, A.; Mauri, P.; Mauro, M.; Melloni, P. J. Heterocycl. Chem. 1993, 30, 1581. 7. Dyker, G.; Gabler, M.; Nouroozian, M.; Schulz, P. Tetrahedron Lett. 1994, 35, 9697. 8. Poszávácz, L.; Simig, G. J. Heterocycl. Chem. 2000, 37, 343. 9. Poszávácz, L.; Simig, G. Tetrahedron 2001, 57, 8573. 10. Manning, H. C.; Goebel, T.; Marx, J. N.; Bornhop, D. J. Org. Lett. 2002, 4, 1075. 11. 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, 457465. (Review). 462

Pictet–Spengler tetrahydroisoquinoline synthesis Tetrahydroisoquinolines from condensation of E-arylethylamines and carbonyl compounds followed by cyclization.

R1O R1O O HCl NH NH R2 H R1O R1O 2 R2

1 R1O H R O O + H+ NH H 1 N OH 1 : 2 R OH R O R2 R2

R1O R1O H2O N: OH N R1OH 2 R1OH R2 R2

1 R1O R1O R O

NH NH 1 NH R1O R1O R O H H 2 R2 R2 R Example 112

Me N

MeO NHMe (CH2O)n MeO i-PrO i-PrO aq. HCl, EtOH

75% i-PrO i-PrO 463

Example 29

O

O HO AcO S O + NH Me MeO 2 N O O

HO

NH MeO silica gel O AcO S O dry EtOH Me 80% N O O

References

1. Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030. 2. Hudlicky, T.; Kutchan, T. M.; Shen, G.; Sutliff, V. E.; Coscia, C. J. J. Org. Chem. 1981, 46, 1738. 3. Miller, R. B.; Tsang, T. Tetrahedron Lett. 1988, 29, 6715. 4. Rozwadowska, M. D. Heterocycles 1994, 39, 903. 5. Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797. (Review). 6. Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 9202. 7. Yokoyama, A.; Ohwada, T.; Shudo, K. J. Org. Chem. 1999, 64, 611. 8. Kang, I.-J.; Wang, H.-M.; Su, C.-H.; Chen, L.-C. Heterocycles 2002, 57, 1. 9. Zhou, B.; Guo, J.; Danishefsky, S. J. Org. Lett. 2002, 4, 43. 10. Yu, J.; Wearing, X. Z.; Cook, J. M. Tetrahedron Lett. 2003, 44, 543. 11. Tsuji, R.; Nakagawa, M.; Nishida, A. Tetrahedron: Asymmetry 2003, 14, 177. 12. Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Tetrahedron: Asymmetry 2003, 14, 1309. 13. 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, 469479. (Review). 464

Pinacol rearrangement Acid-catalyzed rearrangement of vicinyl diols (pinacols) to carbonyl compounds.

O HO OH + 2 2 H R RR R 1 3 3 R R 1 R R

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

HO OH + HO OH H 2 H2O RR2 RR2 R1 R3 R1 R3

H O O HO 2 2 alkyl 2 R RR R H+ R 3 R 3 1 R 3 1 R R migration 1 R R R

Example 112

Ph O OH 1. MsCl, Et3N, CH2Cl2 Ph 0 oC, 10 min.

OH o 2. Et3Al, CH2Cl2, 78 C N N 10 min., 90% SO2Ph SO2Ph

Example 214

Ph OH O O Ph Ph Ph OH cat. TsOH Ph Ph

CDCl3 3:1 465

References

1. Fittig, R. Justus Liebigs Ann. Chem. 1860, 114, 54. 2. Toda, F.; Shigemasa, T. J. Chem. Soc., Perkin Trans. 1 1989, 209. 3. Nakamura, K.; Osamura, Y. J. Am. Chem. Soc. 1993, 115, 9112. 4. Paquette, L. A.; Lord, M. D.; Negri, J. T. Tetrahedron Lett. 1993, 34, 5693. 5. Jabur, F. A.; Penchev, V. J.; Bezoukhanova, C. P. J. Chem. Soc., Chem. Commun. 1994, 1591. 6. Patra, D.; Ghosh, S. J. Org. Chem. 1995, 60, 2526. 7. Magnus, P.; Diorazio, L.; Donohoe, T. J.; Giles, M.; Pye, P.; Tarrant, J.; Thom, S. Tet- rahedron 1996, 52, 14147. 8. Bach, T.; Eilers, F. J. Org. Chem. 1999, 64, 8041. 9. Razavi, H.; Polt, R. J. Org. Chem. 2000, 65, 5693. 10. Chen, X.; Esser, L.; Harran, P. G. Angew. Chem., Int. Ed. 2000, 39, 937. 11. Rashidi-Ranjbar, P.; Kianmehr, E. Molecules 2001, 6, 442. 12. Shinohara, T.; Suzuki, K. Tetrahedron Lett. 2002, 43, 6937. 13. Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 71437157. (Review). 14. Mladenova, G.; Singh, G.; Acton, A.; Chen, L.; Rinco, O.; Johnston, L. J.; Lee-Ruff, E. J. Org. Chem. 2004, 69, 2017. 15. Birsa, M. L.; Jones, P. G.; Hopf, H. Eur. J. Org. Chem. 2005, 3263. 466

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 ROR1 HCl (g) NH2 Cl RCN R1 OH NH ROR1 2 NH3, EtOH RNH2•HCl

RNH + nucleophilic H protonation NH2 Cl 1 : RN: R O addition ROR1 H common intermediate

NH2 Cl H+ hydrolysis O 1 ROR H2NHO ROR1 ROR1 H2O:

H+ NH2 Cl nucleophilic 1 NH2 HCl•H2N OR ROR1 RNH•HCl addition RNH2 2 H3N: H

Example 13

OPh EtSH, HCl, CH2Cl2 Ph N H N 0 oC, 10 min., 95%

Ph NH Ph NH2 pyr., H2S NO NO 4 h, 0 oC, 42% Ph Ph 467

Example 23

O EtSH, HCl, CH2Cl2 Ph N H N 0 oC, 1 h, 85%

O OPh pyr., H2S SEt SEt Ph N N o H H NH 2 h, 0 C, 40% S

References

1. Pinner, A.; Klein, F. Ber. Dtsch. Chem. Ges. 1877, 10, 1889. 2. Pinner, A.; Klein, F. Ber. Dtsch. Chem. Ges. 1878, 11, 1825. 3. Poupaert, J.; Bruylants, A.; Crooy, P. Synthesis 1972, 622. 4. Wagner, G.; Horn, H. Pharmazie 1975, 30, 353. 5. Lee, Y. B.; Goo, Y. M.; Lee, Y. Y.; Lee, J. K. Tetrahedron Lett. 1990, 31, 1169. 6. Cheng, C. C. Org. Prep. Proced. Int. 1990, 22, 643. 7. Neugebauer, W.; Pinet, E.; Kim, M.; Carey, P. R. Can. J. Chem. 1996, 74, 341. 8. Siskos, A. P.; Hill, A. M. Tetrahedron Lett. 2003, 44, 789. 9. Fringuelli, F.; Piermatti, O.; Pizzo, F. Synthesis 2003, 2331. 10. 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. 468

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.

R1 R1 (CH CO) O O 3 2 N R2 N R 2 O pyr., CH Cl R H R 2 2 O

R1 O OO R2 N O O acylation R R1 H R2 N O R CH3CO2

OO R1 2 1 O HOAc R N R R R2 N: R CH3CO2 OO

iminium ion

R1 O 2 1 R N R O R N O O R R2 H O OAc

The intramolecular pathway is also possible:

R1 2 1 1 R2 N R R R : R O R N N R 2 OO O O R H O 469

Example 11

(CH3CO)2O N N O o 100 C O

Example 22

O O

N (CH3CO)2O N

< 30 oC, 98%

References

1. Polonovski, M.; Polonovski, M. Bull. Soc. Chim. Fr. 1927, 41, 1190. 2. Michelot, R. Bull. Soc. Chim. Fr. 1969, 4377. 3. Volz, H.; Ruchti, L. Ann. 1972, 763, 184. 4. Hayashi, Y.; Nagano, Y.; Hongyo, S.; Teramura, K. Tetrahedron Lett. 1974, 15, 1299. 5. M’Pati, J.; Mangeney, P.; Langlois, Y. Tetrahedron Lett. 1981, 22, 4405. 6. Lounasmaa, M.; Koskinen, A. Tetrahedron Lett. 1982, 23, 349. 7. Lounasmaa, M.; Karvinen, E.; Koskinen, A.; Jokela, R. Tetrahedron 1987, 43, 2135. 8. Tamminen, T.; Jokela, R.; Tirkkonen, B.; Lounasmaa, M. Tetrahedron 1989, 45, 2683. 9. Grierson, D. Org. React. 1990, 39, 85. (Review). 10. Lounasmaa, M.; Jokela, R.; Halonen, M.; Miettinen, J. Heterocycles 1993, 36, 2523. 11. Morita, H.; Kobayashi, J. J. Org. Chem. 2002, 67, 5378. 12. McCamley, K.; Ripper, J. A.; Singer, R. D.; Scammells, P. J. J. Org. Chem. 2003, 68, 9847. 13. Nakahara, S.; Kubo, A. Heterocycles 2004, 63, 1849. 470

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 NO 3 2

pyr., CH2Cl2 OCF3 tertiary N-oxide

OO NO CF F3COCF3 acylation 3 H O NO

CF3CO2

N N:

H F3C O CF3

CF3CO2 O O iminium ion enamine

N N

CF CO 3 2 H

OCF3 OCF3 471

Example 12

O N (CF CO ) O, CH Cl , 0 oC N N 3 2 2 2 2 N H H H then, HCl, heat, 30% HO HO

Example 25

O O HHN O HN (CF CO ) O, pyr. H O 3 2 2 N N OH OH O CH Cl , 0 oC, 65% 2 2 H H F3C O

References

1. Ahond, A.; Cavé, A.; Kan-Fan, C.; Husson, H.-P.; cle Rostolan, J.; Potier, P. J. Am. Chem. Soc. 1968, 90, 5622. 2. Husson, H.-P.; Chevolot, L.; Langlois, Y.; Thal, C.; Potier, P. J. Chem. Soc., Chem. Commun. 1972, 930. 3. Grierson, D. Org. React. 1990, 39, 85. (Review). 4. Lewin, G.; Poisson, J.; Schaeffer, C.; Volland, J. P. Tetrahedron 1990, 46, 7775. 5. Kende, A. S.; Liu, K.; Jos Brands, K. M. J. Am. Chem. Soc. 1995, 117, 10597. 6. Sundberg, R. J.; Gadamasetti, K. G.; Hunt, P. J. Tetrahedron 1992, 48, 277. 7. Lewin, G.; Schaeffer, C.; Morgant, G.; Nguyen-Huy, D. J. Org. Chem. 1996, 61, 9614. 8. Renko, D.; Mary, A.; Guillou, C.; Potier, P.; Thal, C. Tetrahedron Lett. 1998, 39, 4251. 9. Suau, R.; Nájera, F.; Rico, R. Tetrahedron 2000, 56, 9713. 10. Thomas, O. P.; Zaparucha, A.; Husson, H.-P. Tetrahedron Lett. 2001, 42, 3291. 472

Pomeranz–Fritsch reaction Isoquinoline synthesis via acid-mediated cyclization of the appropriate aminoacetal intermediate.

OEt OEt + H H N OEt 2 OEt N CHO N

OEt OEt H N 2 : OEt condensation OEt :N H H O OH2

+ H H OEt imine : OEt OEt OEt : formation N N

OEt OEt HOEt

N N

H OEt H+ H N N 473

Example 15

EtO OEt MeO MeO BF3, (CF3CO)2O

N N MeO 6082 % MeO

Example 212

OMe MeO OMe H TiCl4, CH2Cl2 N 78 oC, 69 % N O Me O Me

Schlittler–Müller modification

OEt

NH2 OHC OEt R

OEt

OEt H+ N N R R

Example 37

OEt O i) EtO H ii) oleum H2N NH2 N N 30 % 474

References

1. Pomeranz, C. Monatsh. 1893, 14, 116. Cesar Pomeranz (18601926) received his Ph.D. degree at Vienna, where he was employed as an associate professor of chemistry. 2. Fritsch, P. Ber. Dtsch. Chem. Ges. 1893, 26, 419. Paul Fritsch (18591913) 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. 3. Schlittler, E.; Müller, J. Helv. Chim. Acta 1948, 31, 914, 1119. 4. Gensler, W. J. Org. React. 1951, 6, 191. (Review). 5. Bevis, M. J.; Forbes, E. J.; Naik, N. N.; Uff, B. C. Tetrahedron 1971, 27, 1253. 6. Birch, A. J.; Jackson, A. H.; Shannon, P. V. R. J. Chem. Soc., Perkin Trans. 1 1974, 2185, 2190. 7. Gill, E. W.; Bracher, A. W. J. Heterocycl. Chem. 1983, 20, 1107. 8. Ishii, H.; Ishida, T. Chem. Pharm. Bull. 1984, 32, 3248. 9. Bobbitt, J. M.; Bourque, A. J. Heterocycles 1987, 25, 601. (Review). 10. Katritzky, A. R.; Yang, Z.; Cundy, D. J. Heteroat. Chem. 1994, 5, 103. 11. Schlosser, M.; Simig, G.; Geneste, H. Tetrahedron 1998, 54, 9023. 12. Poli, G.; Baffoni, S. C.; Giambastiani, G.; Reginato, G. Tetrahedron 1998, 54, 10403. 13. GluszyĔska, A.; Rozwadowska, M. D. Tetrahedron: Asymmetry 2000, 11, 2359. 14. Capilla, A. S.; Romero, M.; Pujol, M. D.; Caignard, D. H.; Renard, P. Tetrahedron 2001, 57, 8297. 15. Hudson, A. Pomeranz–Fritsch Reaction In Name Reactions in Heterocyclic Chemis- try, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 480486. (Re- view). 475

Prévost trans-dihydroxylation Cf. Woodward cis-dihydroxylation.

OH I2 O2CPh hydrolysis

AgO2CPh OH O2CPh

II I SN2

O2CPh cyclic iodonium ion intermediate

O2CPh I SN2 SN2 OO O O

Ph Ph neighboring group assistance

OH O2CPh hydrolysis

OH O2CPh

Example 18

O AgOCOPh, I2 Ph O PhH, rt, 2 h, O O F reflux, 10 h, 46% F Ph 476

Example 212

O2C-C6H4-p-OMe AgOCOPh, I2

O CCl4, 74%

OH OAc 1. KOH, H O AcO OAc I O2C-C6H4-p-OMe 2

2. Ac2O, pyr. O O

Woodward cis-dihydroxylation13 Cf. Prévost trans-dihydroxylation.

1. I2, AgOAc

+ HO OH 2. H2O, H

II I SN2

OAc cyclic iodonium ion intermediate

I SN2 OO + H OO : O O H2O: H O neighboring group assistance

:OH2 protonation HO O HO O O O H 477

hydrolysis HO O HO OH HO O H

References

1. Prévost, C. Compt. Rend. 1933, 196 1129. 2. Campbell, M. M.; Sainsbury, M.; Yavarzadeh, R. Tetrahedron 1984, 40, 5063. 3. Campi, E. M.; Deacon, G. B.; Edwards, G. L.; Fitzroy, M. D.; Giunta, N.; Jackson, W. R.; Trainor, R. J. Chem. Soc., Chem. Commun. 1989, 407. 4. Prasad, K. J. R.; Subramaniam, M. Indian J. Chem., Sect. B 1994, 33B, 696. 5. Ciganek, E.; Calabrese, J. C. J. Org. Chem. 1995, 60, 4439. 6. Deota, P. T.; Singh, V. J. Chem. Res. (S), 1996, 258. 7. Brimble, M. A.; Nairn, M. R. J. Org. Chem. 1996, 61, 4801. 8. Zajc, B. J. Org. Chem. 1999, 64, 1902. 9. Hamm, S.; Hennig, L.; Findeisen, M.; Muller, D.; Welzel, P. Tetrahedron 2000, 56, 1345. 10. Ray, J. K.; Gupta, S.; Kar, G. K.; Roy, B. C.; Lin, J.-M.; Amin, S. J. Org. Chem. 2000, 65, 8134. 11. Sabat, M.; Johnson, C. R. Tetrahedron Lett. 2001, 42, 1209. 12. Hodgson, R.; Nelson, A. Org. Biomol. Chem. 2004, 2, 373. 13. Woodward, R. B.; Brutcher, F. V. J. Am. Chem. Soc. 1958, 80, 209. Robert Burns Woodward (USA, 19171979) won the Nobel Prize in Chemistry in 1953 for his synthesis of natural products. 478

Prins reaction Addition of alkene to formaldehyde.

O H+ OH R HHH2O ROH

OO or or ROH R

OH O + H H2O OH HH ROH HH ROH R the common intermediate

ROH H+ H ROH :B

H O H+ OO O H HHROH H R RO

Example 18

OAc SnBr4, CH2Cl2

O 78 oC, 84% TsO OBn

Br

O

TsO OBn 479

Example 210

O O

(CH2O)n, Bi(OTf)3

AcO CH3CN, rt, 10 h, 77% AcO

References

1. Prins, H. J. Chem. Weekblad 1919, 16, 64, 1072. Hendrik J. Prins (18891958), born in Zaandam, The Netherlands, 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 carcasses. But he had a small laboratory near his house where he carried out his experiments 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, 661672. (Review). 3. El Gharbi, R.; Delmas, M. Synthesis 1981, 361. 4. Hanaki, N.; Link, J. T.; MacMillan, D. W. C.; Overman, L. E.; Trankle, W. G.; Wurster, J. A. Org. Lett. 2000, 2, 223. 5. Yadav, J. S.; Reddy, B. V. S.; Kumar, G. M.; Murthy, C. V. S. R. Tetrahedron Lett. 2001, 42, 89. 6. Cho, Y. S.; Kim, H. Y.; Cha, J. H.; Pae, A. N.; Koh, H. Y.; Choi, J. H.; Chang, M. H. Org. Lett. 2002, 4, 2025. 7. Davis, C. E.; Coates, R. M. Angew. Chem., Int. Ed. 2002, 41, 491. 8. Marumoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S.D. Org. Lett. 2002, 4, 3919. 9. Braddock, D. C.; Badine, D. M.; Gottschalk, T.; Matsuno, A.; Rodrihuez-Lens, M. Synlett 2003, 345. 10. Sreedhar, B.; Swapna, V.; Sridhar, Ch.; Saileela, D.; Sunitha, A. Synth. Commun. 2005, 35, 1177. 11. Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44, 3485. 480

Pschorr cyclization The intramolecular version of the GombergBachmann reaction.

CO2H CO2H NaNO2, HCl

Cu NH2

H N + O O N H H2O O O O HO O N N N H2O O

CO2H CO2H + NO2 H NH : 2 NH N N N O O O O

CO2H CO2H

+ H H H2O N N: N O N OH + H 2

CO2H CO2H Cu(0) Cu(I) N2n

N2 H

CO2H 6-exo-trig

radical cyclization H 481

CO2H Cu(I) Cu(0) H+

Example 110

O O O

1. NaNO2, HCl-H2O-HOAc 0 to 5 oC, 2 h

NH2 S 2. CuSO4, HOAc, reflux 2 h, 86%

O O O O O O

S S 6:1

Example 211

O O

N NH N 2 NaNO , HCl N 2 N

5 to 20 oC, 64% 482

References

1. Pschorr, R. Ber. Dtsch. Chem. Ges. 1896, 29, 496. Robert Pschorr (18681930), 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. Kametani, T.; Fukumoto, K. J. Heterocycl. Chem. 1971, 8, 341. 3. Kupchan, S. M.; Kameswaran, V.; Findlay, J. W. A. J. Org. Chem. 1973, 38, 405. 4. Daidone, G.; Plesia, S.; Fabra, J. J. Heterocycl. Chem. 1980, 17, 1409. 5. Buck, K. T.; Edgren, D. L.; Blake, G. W.; Menachery, M. D. Heterocycles 1993, 36, 2489. 6. Wassmundt, F. W.; Kiesman, W. F. J. Org. Chem. 1995, 60, 196. 7. Qian, X.; Cui, J.; Zhang, R. Chem. Commun. 2001, 2656. 8. Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 13591469. (Review). 9. 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. 10. Xu, Y.; Qian, X.; Yao, W.; Mao, P.; Cui, J. Bioorg. Med. Chem. 2003, 11, 5427. 11. Tapolcsányi, P.; Maes, B. U. W.; Monsieurs, K.; et al. Tetrahedron 2003, 59, 5919. 12. 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). 483

Pummerer rearrangement The transformation of sulfoxides into D-acyloxythioethers using acetic anhydride.

O SR2 Ac2O R1 SR2 R1 OAc

O O O O O O O O SR2 acyl AcO R1 O O transfer 2 H 2 1 SR 1 SR R R AcO

2 1 SR 2 2 R SR HOAc SR R1 R1 OAc AcO

Example 12

OH o 1. m-CPBA, CH2Cl2, 78 C Ph HCO 2 SPh OH 2. Ac2O, NaOAc, ', 93%

OH OAc Ph HCO 2 SPh OH

Example 213

Bn OO Bn O Ac O, pyr., DMAP NS2 NS Bn Bn CH2Cl2, rt, 91% OAc Ph Ph 484

References

1. Pummerer, R. Ber. Dtsch. Chem. Ges. 1910, 43, 1401. 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 Laboratory, fulfilling his long-desired ambition. 2. Masamune, S.; Sharpless, K. B. et al. J. Org. Chem. 1982, 47, 1373. 3. De Lucchi, O.; Miotti, U.; Modena, G. Org. React. 1991, 40, 157406. (Review). 4. Padwa, A.; Gunn, D. E., Jr.; Osterhout, M. H. Synthesis 1997, 13531378. (Review). 5. Kita, Y. Phosphorus, Sulfur Silicon Relat. Elem. 1997, 120 & 121, 145164. (Re- view). 6. Padwa, A.; Waterson, A. G. Curr. Org. Chem. 2000, 4, 175203. (Review). 7. Marchand, P.; Gulea, M.; Masson, S.; Averbuch-Pouchot, M.-T. Synthesis 2001, 1623. 8. Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851862. (Review). 9. Padwa, A.; Danca, M. D.; Hardcastle, K. I.; McClure, M. S. J. Org. Chem. 2003, 68, 929. 10. Matsuda, H.; Fujita, J.; Morii, Y.; Hashimoto, M.; Okuno, T.; Hashimoto, K. Tetrahe- dron Lett. 2003, 44, 4089. 11. Fujita, J.; Matsuda, H.; Yamamoto, K.; Morii, Y.; Hashimoto, M.; Okuno, T.; Hashi- moto, K. Tetrahedron 2004, 60, 6829. 12. Ruano, J. L.; Alemán, J.; Aranda, M. T.; Arévalo, M. J.; Padwa, A. Org. Lett. 2005, 7, 19. 13. Suzuki, T.; Honda, Y.; Izawa, K.; Williams, R. M. J. Org. Chem. 2005, 70, 7317. 485

Ramberg–Bäcklund reaction Olefin synthesis via D-halosulfone extrusion.

X 1 Base R O SOn RRS 1 R OO

:B R XH backside XRS 1 1 displacement RRS OO OO

RR1 1 SO R 2 O SOn S extrusion R OO episulfone intermediate

Example 14

H H KOt-Bu, THF

S Br o H 15 C to rt, 71% O2

Example 25

Br KOt-Bu, THF/HOt-Bu

SO CH Br 0 oC to rt, 0.5 h, 65% H 2 2 486

References

1. Ramberg, L.; Bäcklund, B. Arkiv. Kemi, Mineral Geol. 1940, 13A, 50. 2. Paquette, L. A. Acc. Chem. Res. 1968, 1, 209216. (Review). 3. Paquette, L. A. Org. React. 1977, 25, 171. (Review). 4. Becker, K. B.; Labhart, M. P. Helv. Chim. Acta 1983, 66, 1090. 5. Block, E.; Aslam, M.; Eswarakishnan, V. et al. J. Am. Chem. Soc. 1986, 108, 4568. 6. Braverman, S.; Zafrani, Y. Tetrahedron 1998, 54, 1901. 7. Taylor, R. J. K. Chem. Commun. 1999, 217227. (Review). 8. MaGee, D. I.; Beck, E. J. Can. J. Chem. 2000, 78, 1060. 9. McAllister, G. D.; Taylor, R. J. K. Tetrahedron Lett. 2001, 42, 1197. 10. Murphy, P. V.; McDonnell, C.; Hämig, L.; Paterson, D. E.; Taylor, R. J. K. Tetrahe- dron: Asymmetry 2003, 14, 79. 11. Wei, C.; Mo, K.-F.; Chan, T.-L. J. Org. Chem. 2003, 68, 2948. 12. Taylor, R. J. K.; Casy, G. Org. React. 2003, 62, 357475. (Review). 487

Reformatsky reaction Nucleophilic addition of organozinc reagents generated from D-haloesters to carbonyls.

O OR2 HO OR2 Br Zn 1 R RR O R1 O

O

1 OR2 Zn(0) RR Br OR2 O oxidative addition or O electron transfer ZnBr

nucleophilic BrZnO OR2

R 1 addition R O

2 H2O, hydrolysis HO OR R during workup R1 O Example 15

OTBDMS OTBDMS

Ph BrCH2CO2Me Ph MeO2C S N N Zn, THF, reflux, 71% Boc Boc

Example 211 O O Zn, THF O 60 oC MeO Br

O HO O HCl O O THF, rt, 10 h 92% MeO MeO 488

References

1. Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210. Sergei Reformatsky (18601934) 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 Leipzig in Germany. After returning to Russia Reformatsky became the Chair of Organic Chemistry at the University of Kiev. 2. Gaudemar, M. Organometal. Chem. Rev., A 1972, 8, 183. (Review). 3. Rathke, M. W. Org. React. 1975, 22, 423460. (Review). 4. Fürstner, A. Synthesis 1989, 571590. (Review). 5. Lee, H. K.; Kim, J.; Pak, C. S. Tetrahedron Lett. 1999, 40, 2173. 6. Fürstner, A. In Organozinc Reagents Knochel, P.; Jones, P. eds.; Oxford University Press: New York, 1999, pp 287305. (Review). 7. Hirashita, T.; Kinoshita, K.; Yamamura, H.; Kawai, M.; Araki, S. J. Chem. Soc., Perkin Trans. 1 2000, 825. 8. Kurosawa, T.; Fujiwara, M.; Nakano, H.; Sato, M.; Yoshimura, T.; Murai, T. Steroids 2001, 66, 499. 9. Ocampo, R.; Dolbier, W. R., Jr.; Abboud, K. A.; Zuluga, F. J. Org. Chem. 2002, 67, 72. 10. Obringer, M.; Colobert, F.; Neugnot, B.; Solladié, G. Org. Lett. 2003, 5, 629. 11. Zhang, M.; Zhu, L. Tetrahedron: Asymmetry 2003, 14, 3447. 12. Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60, 93259374. (Review). 13. Scherkenbeck, T.; Siegel, K. Org. Proc. Res. Dev. 2005, 9, 216. 14. Orsini, F.; Sello, G.; Manzo, A. M.; Lucci, E. M. Tetrahedron: Asymmetry 2005, 16, 1913. 15. Cozzi, P. G.; Rivalta, E. Angew. Chem., Int. Ed. 2005, 44, 3600. 489

Regitz diazo synthesis Synthesis of 2-diazo-1,3-dicarbonyl or 2-diazo-3-ketoesters using sulfonyl azide.

N 1 2 RORTsN3, Et3N 1 RORTs NH2 OO MeCN OO

O :NEt3 N N N S H enolate O 1 ROR ROR1 formation OO OO

H N N SO Tol N 2 proton N SO2Tol N H N: 1 1 RORtransfer ROR

OO OO

N N O 1 RORH2N S O OO tosyl amide is the by-product

When only one carbonyl is present, ethylformate can be used as an activating auxiliary:69

O O O NaH, HCO Et MsN 2 3 N OH 2 Et2O Et2O 490

O :NEt3 N N N S Me O O H O O O

N N SO Me O 2 O N N N H N SO2Me O H O

O O O N HN S Me N N2 O O H

Alternatively, the triazole intermediate may be assembled via a 1,3-dipolar cycloaddition of the enol and mesyl azide:

O O O N N N S Me 1,3-dipolar N N N O SO2Me cycloaddition OH H OH

O O

HN S Me N2 O O H

Example 110

O H N Ot-Bu O O O SO2N3 491

O N Et3N, CH3CN 2 Ot-Bu o 0 C, 5 h, 45% O O

Example 26

OOOO OTIPS NN CH3SO2N3 H CH3CN, 84% N

OOOO OTIPS NN H N2 N

References

1. Regitz, M. Angew. Chem., Int. Ed. Engl. 1967, 6, 733. 2. Regitz, M.; Anschütz, W.; Bartz, W.; Liedhegener, A. Tetrahedron Lett. 1968, 3171. 3. Regitz, M. Synthesis 1972, 351–373. (Review). 4. Taber, D. F.; Ruckle, R. E., Jr.; Hennessy, M. J. J. Org. Chem. 1986, 51, 4077. 5. Taber, D. F.; Schuchardt, J. L. Tetrahedron 1987, 43, 5677. 6. Pudleiner, H.; Laatsch, H. Justus Liebigs Ann. Chem. 1990, 423. 7. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011. 8. Ihara, M.; Suzuki, T.; Katogi, M.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc., Chem. Commun. 1991, 646. 9. Charette, A. B.; Wurz, R. P.; Ollevier, T. J. Org. Chem. 2000, 65, 9252. 10. Hodgson, D. M.; Labande, A. H.; Pierard, F. Y. T. M.; Expésito Castro, M. A. J. Org. Chem. 2003, 68, 6153. 11. Sarpong, R.; Su, J. T.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 13624. 12. Mejía-Oneto, J. M.; Padwa, A. Org. Lett. 2004, 6, 3241. 13. Muroni, D.; Saba, A.; Culeddu, N. Tetrahedron: Asymmetry 2004, 15, 2609. 14. Rowlands, G. J.; Barnes, W. K. Tetrahedron Lett. 2004, 45, 5347. 15. Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron 2004, 60, 3967. 16. Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7, 47. 492

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 CCl2 Cl slow Cl3CH H2O :CCl2 OH Cl D-elimination b. Addition of dichlorocarbene and hydrolysis:

O OH O H KOH CCl H2O 2 CCl2

OClOH OCl O Cl OH CHCl H H

H OO OH CHO H

Example 1, photo Reimer–Tiemann reaction without base8

CHCl OH O 2 hv (Hg lamp)

CHCl3, 5 h, 48% CN CN 493

Example 29

OH OH CHO CHCl3, 6 eq. NaOH

2 eq. H O, reflux CO H 2 2 4 h, 64% CO2H NHBoc NHBoc

References

1. Reimer, K.; Tiemann, F. Ber. Dtsch. Chem. Ges. 1876, 9, 824. Karl L. Reimer (18451883) was born in Leipzig, Germany. He interrupted his study to serve in the Bohemian War in 1866. After the war, Reimer returned to his study and obtained his Ph.D. in 1871. He held several jobs but at the end had to resign because of poor health. The discovery of the Reimer–Tiemann reaction was the beginning of his short- lived career in organic chemistry. Johann K. F. Tiemann (18481899) was born in Rübeland, Germany. He was a student and a big fan of W. Hofmann, from whom Tiemann received his Ph.D. in 1871. Tiemann then became a Professor of Chemistry at Berlin. 2. Wynberg, H.; Meijer, E. W. Org. React. 1982, 28, 1–36. (Review). 3. Smith, K. M.; Bobe, F. W.; Minnetian, O. M.; Hope, H.; Yanuck, M. D. J. Org. Chem. 1985, 50, 790. 4. Bird, C. W.; Brown, A. L.; Chan, C. C. Tetrahedron 1985, 41, 4685. 5. Neumann, R.; Sasson, Y. Synthesis 1986, 569. 6. Cochran, J. C.; Melville, M. G. Synth. Commun. 1990, 20, 609. 7. Langlois, B. R. Tetrahedron Lett. 1991, 32, 3691. 8. Jiménez, M. C.; Miranda, M. A.; Tormos, R. Tetrahedron 1995, 51, 5825. 9. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553. 494

Reissert aldehyde synthesis Aldehyde synthesis from the corresponding acid chloride, quinoline, and KCN.

O N H N RCl KCN CN OR

H2SO4 O NH3 RH NCO2H

CN + H H

: N N Cl N H CN

RO OR OR Reissert compound

H H N N: NH O RON H R

H H O H : N NH N NH H+ O O R R H H+

OH OH N N NH2 NH O O 2 R H R H 495

+ O O H3O N H O N NH RH 2 NH2 H2O:

H O N NH3 HO NCO2H NH2

Example 14

O MeO Cl NaCN, H2O, CH2Cl2

MeO 4.5 h, 95% N OMe

O NCN 30% H SO MeO MeO 2 4 H O reflux, 1 h, 95% MeO MeO OMe OMe

Example 210

chiral Al catalyst N N O TMSCN, CH2=CHOCOCl CN Br O o CH2Cl2, 40 C, 72 h, 53% Br 73% ee 496

References

1. Reissert, A. Ber. Dtsch. Chem. Ges. 1905, 38, 1603, 3415. 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 Tiemann. Reissert later joined the faculty at Marburg in 1902. 2. McEwen, W. E.; Hazlett, R. N. J. Am. Chem. Soc. 1949, 71, 1949. 3. Popp, F. D. Adv. Heterocyclic Chem. 1979, 24, 187. (Review). 4. Schwartz, A. J. Org. Chem. 1982, 47, 2213. 5. Fife, W. K.; Scriven, E. F. V. Heterocycles 1984, 22, 2375. 6. Popp, F. D.; Uff, B. C. Heterocycles 1985, 23, 731. 7. Lorsbach, B. A.; Bagdanoff, J. T.; Miller, R. B.; Kurth, M. J. J. Org. Chem. 1998, 63, 2244. 8. Perrin, S.; Monnier, K.; Laude, B.; Kubicki, M.; Blacque, O. Eur. J. Org. Chem. 1999, 297. 9. Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 6801. 10. Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun. 2002, 1989. 11. Sieck, O.; Schaller, S.; Grimme, S.; Liebscher, J. Synlett 2003, 337. 497

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.

CO2Et CO2Et B R + R CO2Et O NO2 NO2

+ H R

H N CO2H H

H CH EtO O CH3 B 2

O OEt NO2 NO2

OH O OEt hydrolysis CO Et CO2Et NO 2 NO2 2

O H O H CO H NO 2 CO2H 2 NH2

H

CO2H CO2H N OH N H H 498

Example 13

MeO KOEt CO2Et N CO2Et 93% NO2

O CO2Et MeO MeO H2, Pd/C N EtOH, 85% N CO2Et N H NO2

Example 25

CO Et KOEt, EtOH + 2 CO2Et NO2 Et2O, 76%

CO Et 2 H2 (30 psi), PtO2 OK N CO Et NO HOAc, 42% 2 2 H

References

1. Reissert, A. Ber. 1897, 30, 1030. 2. Julian, P. C.; Meyer, E. W.; Printy, S. C. Heterocyclic Compounds; : New York, 1962; p 18. (Review). 3. Frydman, B.; Despuy, M. E.; Rapoport, H. J. Am. Chem. Soc. 1965, 87, 3530. 4. Brown, R. K. In Indoles, Part 1; Houlihan, W. J. Ed.; Wiley & Sons: New York, 1972; pp 397413. (Review). 5. Noland, W. E.; Baude, F. J. Org. Synth.; Ed, Baumgarten, H. E.; Wiley & Sons: New York, 1973; p. 567. 6. Leadbetter, G.; Fost, D. L.; Ekwuribe, N. N.; Remers, W. A. J. Org. Chem. 1974, 39, 3580. 7. Butin, A. V.; Stroganova, T. A.; Lodina, I. V.; Krapivin, G. D. Tetrahedron Lett. 2001, 42, 2031. 8. Suzuki, H.; Gyoutoku, H.; Yokoo, H.; Shinba, M.; Sato, Y.; Yamada, H.; Murakami, Y. Synlett 2000, 1196. 9. Li, J.; Cook, J. M. Reissert Indole Synthesis In Name Reactions in Heterocyclic Chem- istry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 154158. (Re- view). 499

Ring-closing metathesis (RCM)

(Cy) P Ph 3 Ph (Cy)3P F C N Cl Ru 3 Cl Cl F C Mo Ru Ph 3 OPh Cl Mes Mes O P(cy)3 NN F3C F3C Grubbs’ reagents Schrock’s reagent Mes = mesityl All three catalysts are illustrated as “LnM=CHR” in the mechanism below.

Generation of the catalyst from the precatalysts:

LnM CHR LnM the real catalyst

LnM CHR [2 + 2] LnM CHR

cycloaddition

[2 + 2] cycloreversion ML CHR n cycloaddition

cycloreversion MLn LnM

Catalytic cycle:

LnM

LnM L M [2 + 2] n cycloreversion cycloaddition 500

[2 + 2] MLn cycloaddition

cycloreversion MLn LnM

Example 14

10 mol% (PCy3)2Cl2Ru=CHPh

0.3 eq. Ti(Oi-Pr) OCO 11H23 OCO 11H23 4 o CH2Cl2, 40 C, 93%

Example 29 (Cy) P 3 Ph Cl Ru E Cl E E E Mes N N Mes

45 oC, 60 min. 100%

E = CO2Et 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. 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 Petrole 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. Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. 4. Scholl, M.; Tunka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247. 5. Morgan, J. P.; Grubbs, R. H. Org. Lett. 2000, 2, 3153. 6. Renaud, J.; Graf, C.-D.; Oberer, L. Angew. Chem., Int. Ed. 2000, 39, 3101. 7. Lane, C.; Snieckus, V. Synlett 2000, 1294. 8. Fellows, I. M.; Kaelin, D. E., Jr.; Martin, S. F. J. Am. Chem. Soc. 2000, 122, 10781. 9. Timmer, M. S. M.; Ovaa, H.; Filippov, D. V.; van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett. 2000, 41, 8635. 10. Ghosh, A. K.; Liu, C. Chem. Commun. 1999, 1743. 11. Lee, C. W.; Grubbs, R. H. J. Org. Chem. 2001, 66, 7155. 12. van Otterlo, W. A. L.; Ngidi, E. L.; Coyanis, E. M.; de Koning, C. B. Tetrahedron Lett. 2003, 44, 311. 501

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 H CCN 3 N H O 2 H

Similarly:

O H2SO4 H CCN 3 N H O 2 H

+ :N H3O E1 OH OH2 H2O

:OH2 N N nitrilium ion

+ O OH2 H OH N N N H 502

Example 14

CH3 CH3 t-BuOH, conc. H2SO4 O N N CN 7075 oC, 75 min., 97% HN

Example 28

fuming H2SO4, CH3CN, rt, 30 min., OH O o NH then H2O, 100 C, 2 h, 77% 2

References

1. Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045. 2. Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048. 3. Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213–329. (Review). 4. Schumacher, D. P.; Murphy, B. L.; Clark, J. E.; Tahbaz, P.; Mann, T. A. J. Org. Chem. 1989, 54, 2242. 5. Djaidi, D.; Leung, I. S. H.; Bishop, R.; Craig, D. C.; Scudder, M. L. J. Chem. Soc., Perkin 1 2000, 2037. 6. Jirgensons, A.; Kauss, V.; Kalvinsh, I.; Gold, M. R. Synthesis 2000, 1709. 7. Le Goanric, D.; Lallemand, M.-C.; Tillequin, F.; Martens, T. Tetrahedron Lett. 2001, 42, 5175. 8. Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 5906. 9. Nair, V.; Rajan, R.; Rath, N. P. Org. Lett. 2002, 4, 1575. 10. Reddy, K. L. Tetrahedron Lett. 2003, 44, 1453. 11. Janin, Y. L.; Decaudin, D.; Monneret, C.; Poupon, M.-F. Tetrahedron 2004, 60, 5481. 12. Concellén, J. M.; Riego, E.; Suárez, J. R.; García-Granda, S.; Díaz, M. R. Org. Lett. 2004, 6, 4499. 13. Penner, M.; Taylor, D.; Desautels, D.; Marat, K.; Schweizer, F. Synlett 2005, 212. 503

Robinson annulation Michael addition of cyclohexanones to methyl vinyl ketone followed by intramolecular aldol condensation to afford six-membered DE-unsaturated ketones.

O O Obase

R R methyl vinyl ketone (MVK)

O O enolate O Michael R H formation addition R B:

O HB aldol isomerization O R addition O O R

:B O H H O HO 2 O dehydration R

R

Example11

O O 3 TfOH, P4O10 O CH2Cl2, microwave 40 oC, 8 h, 57% 504

References

1. Rapson, W. S.; Robinson, R. J. Chem. Soc. 1935, 1285. 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, DC, 1991. 2. Gawley, R. E. Synthesis 1976, 777–794. (Review). 3. Bui, T.; Barbas, C. F., III Tetrahedron Lett. 2000, 41, 6951. 4. Jansen, B. J. M.; Hendrikx, C. C. J.; Masalov, N.; Stork, G. A.; Meulemans, T. M.; Macaev, F. Z.; de Groot, A. Tetrahedron 2000, 56, 2075. 5. Guarna, A.; Lombardi, E.; Machetti, F.; Occhiato, E. G.; Scarpi, D. J. Org. Chem. 2000, 65, 8093. 6. Tai, C.-L.; Ly, T. W.; Wu, J.-D.; Shia, K.-S,; Liu, H.-J. Synlett 2001, 214. 7. Jung, M. E.; Piizzi, G. Org. Lett. 2003, 5, 137. 8. Liu, H.-J.; Ly, T. W.; Tai, C.-L.; Wu, J.-D. et al. Tetrahedron 2003, 59, 1209. 9. Kawanami, H.; Ikushima, Y. Tetrahedron Lett. 2004, 45, 5147. 10. Singletary, J. A.; Lam, H.; Dudley, G. B. J. Org. Chem. 2005, 70, 739. 11. Jung, M. E.; Maderna, A. Tetrahedron Lett. 2005, 46, 5057. 505

Robinson–Gabriel synthesis Cyclodehydration of 2-acylamidoketones to give 2,5-di- and 2,4,5-trialkyl, aryl, heteroaryl-, and aralkyloxazoles.

R2 R2 H O HN 2 N R3 R R3 1 OO R1 O

R1, R2, R3 = alkyl, aryl, heteroaryl

H R2 R2 H N N R3 R 3 R1 O OH R1 O O

R2 H O 2 N

R3 R1 O

Example 19

OTIPS O O H MeO O N N H O HO

OH

1. Dess-Martin, CH2Cl2 OMe O 2. Ph3P, BrCCl2CCl2Br N R O N 3. DBU, CH CN 3 OMe H O 4. TBAF, THF 42% (+)-hennoxazole A 506

Example 28

O H O H N Ph3P, I2, Et3N O H N O H 55% CbzHN O O CbzHN O

References

1. Robinson, R. J. Chem. Soc. 1909, 95, 2167. 2. Gabriel, S. Chem. Ber. 1910, 43, 134, 1283. 3. Wiley, R. H.; Borum, O. H. J. Am. Chem. Soc. 1948, 70, 2005. 4. Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744. 5. Wasserman, H. H.; Vinick, F. J. J. Org. Chem. 1973, 38, 2407. 6. Meguro, K.; Tawada, H.; Sugiyama, Y.; Fujita, T.; Kawamatsu, Y. Chem. Pharm. Bull. 1986, 34, 2840. 7. Turchi, I. J. In The Chemistry of Heterocyclic Compounds, 45; Wiley: New York, 1986; pp 1342. (Review). 8. Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604. 9. Wipf, P. Lim, S. J. Am. Chem. Soc. 1995, 117, 558. 10. Brain, C. T.; Paul, J. M. Synlett 1999, 10, 1642. 11. Yokokawa, F.; Asano, T.; Shioiri, T. Org Lett 2000, 2, 4169. 12. Morwick, T.; Hrapchak, M.; DeTuri, M.; Campbell, S. Org Lett 2002, 4, 2665. 13. 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. 14. Godfrey, A. G.; Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.; Mitchell, D. J. Org. Chem. 2003, 68, 2623. 15. 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, 249253. (Re- view). 507

RobinsonSchöpf reaction Tropinone synthesis.

CO2H N CHO NH 2 O 2 CO2n 2 H2O CHO CO2H O

H O NH2: : H HN HO2CCO2H imine H2O O OH formation N CHO CHO CHO

O O

HO2CCO2H HO2CCO2H

:N :N H H OH O hemiaminal

H O

HO2CCO2H H2O

N

O H N N O decarboxylation CO2n HO C 2 O HO2C O H 508

N N N

CO2n

O O H O O O H

Example7

CHO CO H CHO 2 O NH2 CO H OH 2

O

N THF, rt, 72 h, 51%

OH

References

1. Robinson, R. J. Chem. Soc. 1917, 111, 762. 2. Büchi, G.; Fliri, H.; Shapiro, R. J. Org. Chem. 1978, 43, 4765. 3. Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H. P. J. Am. Chem. Soc. 1983, 105, 7754. 4. Royer, J.; Husson, H. P. Tetrahedron Lett. 1987, 28, 6175. 5. Bermudez, J.; Gregory, J. A.; King, F. D.; Starr, S.; Summersell, R. J. Bioorg. Med. Chem. Lett. 1992, 2, 519. 6. Langlois, M.; Yang, D.; Soulier, J. L.; Florac, C. Synth. Commun. 1992, 22, 3115. 7. Jarevång, T.; Anke, H.; Anke, T.; Erkel, G.; Sterner, O. Acta Chem. Scand. 1998, 52, 1350. 8. Amedjkouh, M.; Westerlund, K. Tetrahedron Lett. 2004, 45, 5175. 509

Rosenmund reduction

Hydrogenation reduction of acid chloride to aldehyde using BaSO4-poisoned palladium catalyst. Without poison, the resulting aldehyde may be further reduced to alcohol.

OH2 O RCl PdBaSO4 RH

Pd Pd Pd Pd HH HH

Pd Pd H Pd H HH

O Pd(0) O H Pd H Cl RCl oxidative RPd ligand exchange addition

O reductive O H Pd(0) RPd elimination RH

Example 16

Me2N N(Boc) N(Boc)2 2 Cl Cl HO CO t-Bu CO2t-Bu 2 O O

H2, 5% Pd/C N(Boc)2 2,6-lutidine H CO2t-Bu THF, 2 h, 78% O 510

Example 29

O 1. SOCl2, cat. DMF, reflux, 4 h OH 2. H2, 5% Pd/C, EtOAc, 53%

O

H

References

1. Rosenmund, K. W. Ber. Dtsch. Chem. Ges. 1918, 51, 585. 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 Insti- tute 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, 4565. 4. Burgstahler, A. W.; Weigel, L. O.; Schäfer, C. G. Synthesis 1976, 767. 5. McEwen, A. B.; Guttieri, M. J.; Maier, W. F.; Laine, R. M.; Shvo, Y. J. Org. Chem. 1983, 48, 4436. 6. Bold, V. G.; Steiner, H.; Moesch, L.; Walliser, B. Helv. Chim. Acta 1990, 73, 405. 7. Yadav, V. G.; Chandalia, S. B. Org. Proc. Res. Dev. 1997, 1, 226. 8. Chandnani, K. H.; Chandalia, S. B. Org. Proc. Res. Dev. 1999, 3, 416. 9. Chimichi, S.; Boccalini, M.; Cosimelli, B. Tetrahedron 2002, 58, 4851. 511

Rubottom oxidation D-Hydroxylation of enolsilanes.

O OSiR3 1. m-CPBA OH

2. K2CO3, H2O

Ar Ar O R3Si O O H Prilezhaev O O O R SiO O R3SiO 3 O epoxidation H

The “butterfly” transition state

R3Si H SiR3 O O + O H OH

O K2CO3, H2O OH hydrolysis

Example 15

2.5 eq m-CPBA O OSiMe3 OH ClCH CH Cl CO2Me 2 2 N N CO2Me 0 oC to rt, 1 h, 80% 512

Example 210

TMSCl, NaI

Et3N, rt, 91% O OTMS

o 1. m-CPBA, NaHCO3, pentane, 0 C OH

o 2. aq. K2CO3, 0 C, 20 h, 80% O

References

1. Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron Lett. 1974, 4319. 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 Sci- ence Foundation. 2. Brook, A. G.; Macrae, D. M. J. Organomet. Chem. 1974, 77, C19. 3. Hassner, A.; Reuss, R. H.; Pinnick, H. W. J. Org. Chem. 1975, 40, 3427. 4. Rubottom, G. M.; Gruber, J. M.; Boeckman, R. K., Jr.; Ramaiah, M.; Medwid, J. B. Tetrahedron Lett. 1978, 4603. 5. Andriamialisoa, R. Z.; Langlois, N.; Langlois, Y. Tetrahedron Lett. 1985, 26, 3563. 6. Paquette, L. A.; Lin, H.-S.; Coghlan, M. J. Tetrahedron Lett. 1987, 28, 5017. 7. Hirota, H.; Yokoyama, A.; Miyaji, K.; Nakamura, T.; Takahashi, T. Tetrahedron Lett. 1987, 28, 435. 8. Gleiter, R.; Krämer, R.; Irngartinger, H.; Bissinger, C. J. Org. Chem. 1992, 57, 252. 9. Johnson, C. R.; Golebiowski, A.; Steensma, D. H. J. Am. Chem. Soc. 1992, 114, 9414. 10. Jauch, J. Tetrahedron 1994, 50, 12903. 11. Gleiter, R.; Staib, M.; Ackermann, U. Liebigs Ann. 1995, 1655. 12. Xu, Y.; Johnson, C. R. Tetrahedron Lett. 1997, 38, 1117. 13. Paquette, L. A.; Hartung, R. E.; Hofferberth, J. E.; Vilotijevic, I.; Yang, J. J. Org. Chem. 2004, 69, 2454. 14. Christoffers, J.; Baro, A.; Werner, T. Adv. Synth. Cat. 2004, 346, 143151. (Review). 513

Rupe rearrangement Acid-catalyzed rearrangement of tertiary D-acetylenic (terminal) alcohols, leading to the formation of DE-unsaturated ketones rather than the corresponding DE- unsaturated aldehydes. Cf. MeyerSchuster rearrangement.

O OH + H , H2O

OH OH + 2 H O H 2

dehydration H

H2O: + H+ H protonation H

H

:OH O H tautomerization H H+ Example 16

O conc. H2SO4

OH CHCl3, HOAc, reflux, 1 h

Example 210 O OH H C + 3 A-252C H resin H3C H EtOAc, reflux H H H 4 h, 78% H O O 514

References

1. Rupe, H.; Kambli, E. Helv. Chim. Acta 1926, 9, 672. 2. Hennion, G. F.; Davis, R. B.; Maloney, D. E. J. Am. Chem. Soc. 1949, 71, 2813. 3. Schmidt, C.; Thazhuthaveetil, J. Tetrahedron Lett. 1970, 2653. 4. Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429. (Review). 5. Hasbrouck, R. W.; Kiessling, A. D. J. Org. Chem. 1973, 38, 2103. 6. Apparu, M.; Glenat, R. Tetrahedron 1988, 41, 2181. 7. Barre, V.; Massias, F.; Uguen, D. Tetrahedron Lett. 1989, 30, 7389. 8. An, J.; Bagnell, L.; Cablewski, T.; Strauss, C. R.; Trainor, R. W. J. Org. Chem. 1997, 62, 2505. 9. Strauss, C. R. Aust. J. Chem. 1999, 52, 83–96. (Review). 10. Weinmann, H.; Harre, M.; Neh, H.; Nickisch, K.; Skötsch, C.; Tilstam, U. Org. Proc. Res. Dev. 2002, 6, 216. 515

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 610).

AcO AcO Pd(II) OAc Me3Si Me Si O: 3 O Pd(II) OAc

Me Me

O O Pd(II) OAc E-hydride

OSiMe3 H elimination Me

O O H Pd OAc Pd(0) HOAc Me Me

Regenerating the Pd(II) oxidant:

O OH

Pd(OAc) Pd(0) 2 HOAc 2

O OH 516

Larock reported regeneration of the Pd(II) oxidant using oxygen:4

O HOAc Pd(0) O2 Pd HOOPdOAc O

O

OSiMe3 HOOSiMe3 Pd(II)(OAc)2

Example 13

OMe OMe O O O O Me3SiCl, Et3N O TMSO H H CH3OCH2CH2OCH3 OO rt, 3 h, 74% OO H H

OMe O O Pd(OAc) , p-benzoquinone 2 O H CH CN, rt, 60 oC, 53% 3 OO H

Example 28

O LDA, TBSCl O

O O HMPA-THF O 78 to 0 oC, 93% OTBS

O Pd(OAc)2, O2 O DMSO, 80 oC 48 h, 77% O 517

References

1. Ito, Y.; Hirao, T.; Saegusa, T.; J. Org. Chem. 1978, 43, 1011. 2. Dickson, J. K., Jr.; Tsang, R.; Llera, J. M.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 5350. 3. Kim, M.; Applegate, L. A.; Park, O.-S.; Vasudevan, S.; Watt, D. S. Synth. Commun. 1990, 20, 989. 4. Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng, D. Tetrahedron Lett. 1995, 36, 2423. 5. Porth, S.; Bats, J. W.; Trauner, D.; Giester, G.; Mulzer, J. Angew. Chem., Int. Ed. 1999, 38, 2015. The authors proposed sandwiched Pd(II) as a possible alternative pathway. 6. Williams, D. R.; Turske, R. A. Org. Lett. 2000, 2, 3217. 7. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596. 8. Kadota, K.; Kurusu, T.; Taniguchi, T.; Ogasawara, K. Adv. Synth. Catal. 2001, 343, 618. 9. Sha, C.-K.; Huang, S.-J.; Zhan, Z.-P. J. Org. Chem. 2002, 67, 831. 518

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 it is not part of an DE-unsaturated system (Example 2), giving rise to an alcohol.

O O TiCl4 SiMe3

TiCl4 Cl TiCl3 : complexation O O

SiMe3

TiCl O 3

Michael silicon

addition cleavage SiMe3 Cl The E-carbocation is stabilized by the silicon atom

TiCl O 3 O H2O Me3Si Cl workup

Example 12

EtAlCl2, Tol. TMS o O 0 C, 50% O 519

Example 214

O CHO Br SiMe3

OTIPS

OH O TiCl4, CH2Cl2 Br rt, 10 min., 67% 9:1 dr OTIPS

References

1. Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 1295. 2. Majetich, G.; Behnke, M.; Hull, K. J. Org. Chem. 1985, 50, 3615. 3. Hollis, T. K.; Bosnich, B. J. Am. Chem. Soc. 1995, 117, 4570. 4. Markó, I. E.; Mekhalfia, A.; Murphy, F.; Bayston, D. J.; Bailey, M.; Janousek, Z.; Do- lan, S. Pure Appl. Chem. 1997, 69, 565. 5. Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti, G.; Ricci, A.; Varchi, G. Tetrahedron: Asymmetry 1998, 9, 2979. 6. Wang, D.-K.; Zhou, Y.-G.; Tang, Y.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 1999, 64, 4233. 7. Sugita, Y.; Kimura, Y.; Yokoe, I. Tetrahedron Lett. 1999, 40, 5877. 8. Wang, M. W.; Chen, Y. J.; Wang, D. Synlett 2000, 385. 9. Organ, M. G.; Dragan, V.; Miller, M.; Froese, R. D. J.; Goddard, J. D. J. Org. Chem. 2000, 65, 3666. 10. Tori, M.; Makino, C.; Hisazumi, K.; Sono, M.; Nakashima, K. Tetrahedron: Asymme- try 2001, 12, 301. 11. Leroy, B.; Markó, I. E. J. Org. Chem. 2002, 67, 8744. 12. Itsuno, S.; Kumagai, T. Helv. Chim. Acta 2002, 85, 3185. 13. Nosse, B.; Chhor, R. B.; Jeong, W. B.; Böhm, C.; Reiser, O. Org. Lett. 2003, 5, 941. 14. Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2003, 125, 13155. 15. Knepper, K.; Ziegert, R. E.; Bräse, S. Tetrahedron 2004, 60, 8591. 16. Rikimaru, K.; Mori, K.; Kan, T.; Fukuyama, T. Chem. Commun. 2005, 394. 520

Sandmeyer reaction Haloarenes from the reaction of a diazonium salt with CuX.

CuX ArN2 Y Ar X X = Cl, Br, CN e.g.: CuCl ArN2 Cl Ar Cl

CuCl ArN2 Cl N2n Ar CuCl2 Ar Cl CuCl

Example 15

Cl

1. FeCl3 N2 Cl 2. CuCl2 Cl

Cl Cl DMSO, rt Cl N2 CuCl4 97% Cl Cl 2

Example 211

CF CF3 3 CF3

1. H2SO4 CuCN, NaCN N 2. NaNO N Na CO , 50% NH2 2 2 3 CN Cl Cl Cl

References

1. Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 1633. Traugott Sandmeyer (18541922) 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 firm J. R. Geigy, which is now part of Novartis. 2. Galli, C. J. Chem. Soc., Perkin Trans. 2 1984, 897. 521

3. Suzuki, N.; Azuma, T.; Kaneko, Y.; Izawa, Y.; Tomioka, H.; Nomoto, T. J. Chem. Soc., Perkin Trans. 1 1987, 645. 4. Merkushev, E. B. Synthesis 1988, 923–927. (Review). 5. Obushak, M. D.; Lyakhovych, M. B.; Ganushchak, M. I. Tetrahedron Lett. 1998, 39, 9567. 6. Hanson, P.; Lövenich, P. W.; Rowell, S. C.; Walton, P. H.; Timms, A. W. J. Chem. Soc., Perkin Trans. 2 1999, 49. 7. Chandler, S. A.; Hanson, P.; Taylor, A. B.; Walton, P. H.; Timms, A. W. J. Chem. Soc., Perkin Trans. 2 2001, 214. 8. Hanson, P.; Rowell, S. C.; Taylor, A. B.; Walton, P. H.; Timms, A. W. J. Chem. Soc., Perkin Trans. 2 2002, 1126. 9. Hanson, P.; Jones, J. R.; Taylor, A. B.; Walton, P. H.; Timms, A. W. J. Chem. Soc., Perkin Trans. 2 2002, 1135. 10. Daab, J. C.; Bracher, F. Monatsh. Chem. 2003, 134, 573. 11. Nielsen, M. A.; Nielsen, M. K.; Pittelkow, T. Org. Proc. Res. Dev. 2004, 8, 1059. 522

Schiemann reaction Fluoroarene formation from arylamines. Also known as the BalzSchiemann reaction.

' Ar NH2 HNO2 HBF4 ArN2 BF4 Ar F N2n BF3

N HBF4 N HO O H2O O:

N HO O H ONO N N 2 O O O

N N H O O O

: N OH

Ar N: O Ar N Ar N NH2

H+ : N OH2 H O Ar N N Ar N 2

' ArN2 BF4 N2n Ar FBF3 Ar F BF3

Example 14

F NH2 NaNO2, HBF4, H2O N N N N o N F N N 10 to 0 C, 25% F N R R

Example 210

F F NHBoc 1. HBF4 FF 2. NaNO2 HN N HN N HN N 3. hv 36% 8% 523

References

1. Balz, G.; Schiemann. G. Ber. Dtsch. Chem. Ges. 1927, 60, 1186. 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, 193228. (Review). 3. Sharts, C. M. J. Chem. Educ. 1968, 45, 185. (Review). 4. Montgomery, J. A.; Hewson, K. J. Org. Chem. 1969, 34, 1396. 5. Matsumoto, J.-i.; Miyamoto, T.; Minamida, A.; Nishimura, Y.; Egawa, H.; Nishimura, H. J. Heterocycl. Chem. 1984, 21, 673. 6. Corral, C.; Lasso, A.; Lissavetzky, J.; Alvarez-Insua, A. S.; Valdeolmillos, A. M. Het- erocycles 1985, 23, 1431. 7. Tsuge, A.; Moriguchi, T.; Mataka, S.; Tashiro, M. J. Chem. Res., (S) 1995, 460. 8. Saeki, K.-i.; Tomomitsu, M.; Kawazoe, Y.; Momota, K.; Kimoto, H. Chem. Pharm. Bull. 1996, 44, 2254. 9. Laali, K. K.; Gettwert, V. J. J. Fluorine Chem. 2001, 107, 31. 10. Dolensky, B.; Takeuchi, Y.; Cohen, L. A.; Kirk, K. L. J. Fluorine Chem. 2001, 107, 147. 11. Gronheid, R.; Lodder, G.; Okuyama, T. J. Org. Chem. 2002, 67, 693. 524

Schmidt reaction

Conversion of ketones to amides using HN3 (hydrazoic acid).

O HN3 O 1 N 1 2 2 R 2n R R + R N H H

N + H N O H O HN HO N 3 3 HO N R1 R2 1 2 R1 R2 R R R1 R2 azido-alcohol

N + R1 1 H N H2O R

H2O N N: NN R2 migration R1 R2

R1 1 R2 N HO R + N2n H N : R2 H2O nitrilium ion intermediate (Cf. Ritter intermediate)

O tautomerization R1 R2 N H

Example 1, a classic example11

O H NaN NCO2Et CO2Et 3 O MeSO3H 35% 525

Example 2, a variant15

OH TfOH, CH2Cl2 OH N O 0 oC, 79% O N3

References

1. Schmidt, K. F. Z. Angew. Chem. 1923, 36, 511. Karl Friedrich Schmidt (18871971) collaborated with Curtius at the University of Heidelberg, where Schmidt became a Professor of Chemistry after 1923. 2. Schmidt, K. F. Ber. Dtsch. Chem. Ges. 1924, 57, 704. 3. Wolff, H. Org. React. 1946, 3, 307. (Review). 4. Richard, J. P.; Amyes, T. L.; Lee, Y.-G.; Jagannadham, V. J. Am. Chem. Soc. 1994, 116, 10833. 5. Kaye, P. T.; Mphahlele, M. J. Synth. Commun. 1995, 25, 1495. 6. Krow, G. R.; Szczepanski, S W.; Kim, J. Y.; Liu, N.; Sheikh, A.; Xiao, Y.; Yuan, J. J. Org. Chem. 1999, 64, 1254. 7. Mphahlele, M. J. Phosphorus, Sulfur Silicon Relat. Elem. 1999, 144-146, 351. 8. Mphahlele, M. J. J. Chem. Soc., Perkin Trans. 1 1999, 3477. 9. Iyengar, R.; Schildknegt, K.; Aubé, J. Org. Lett. 2000, 2, 1625. 10. Pearson, W. H.; Hutta, D. A.; Fang, W.-k. J. Org. Chem. 2000, 65, 8326. 11. Tanaka, M.; Oba, M.; Tamai, K.; Suemune, H. J. Org. Chem. 2001, 66, 2667. 12. Pearson, W. H.; Walavalkar, R. Tetrahedron 2001, 57, 5081. 13. Golden, J. E.; Aubé, J. Angew. Chem., Int. Ed. 2002, 41, 4316. 14. Cristau, H.-J.; Marat, X.; Vors, J.-P.; Pirat, J.-L. Tetrahedron Lett. 2003, 44, 3179. 15. Wrobleski, A.; Sahasrabudhe, K.; Aubé, J. J. Am. Chem. Soc. 2004, 126, 5475. 16. Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260. 526

Schmidt’s trichloroacetimidate glycosidation reaction Lewis acid-promoted glycosidation of trichloroacetimidates with alcohols or phenols.

HN CCl3 O OH cat. NaH O O AcO OAc Cl3CCN AcO OAc OCH3 OCH3 trichloroacetimidate

Ar O O HO Ar

BF3xOEt2 AcO OAc

OCH3

N CCl3 H O O H O O deprotonation H2n AcO OAc AcO OAc OCH3 OCH3

AcO O

O HN CCl3 H CO H 3 OAc O O

N CCl3 AcO OAc O O OCH3 AcO OAc

OCH3 527

BF3xOEt2

HN CCl3 BF3xOEt2 neighboring O O O group assistance AcO O

CH3O

H Ar OAr: O O O O O Cl3C NH2 AcO OAc AcO O OCH3 CH3O

Example 15

HN CCl3

O O ICO2Me

AcO OAc HO OMe OCH3 OMe

ICO2Me

BF3xOEt2, 4 Å MS O O OMe

o OMe CH2Cl2, 50 C, 95% AcO OAc

OCH3 528

Example 27

BnO O OH BnO AcO BnO O NH BF3•OEt2

CCl3 CH2Cl2/hexane 20 oC, 68%

BnO O BnO O BnO AcO

References

1. Grundler, G.; Schmidt, R. R. Carbohydr. Res. 1985, 135, 203. 2. Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212. (Review). 3. Smith, A. L.; Hwang, C.-K.; Pitsinos, E.; Scarlato, G. R.; Nicolaou, K. C. J. Am. Chem. Soc. 1992, 114, 3134. 4. Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 15031531. (Review). 5. Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1993, 32, 1377. 6. Weingart, R.; Schmidt, R. R. Tetrahedron Lett. 2000, 41, 8753. 7. Furstner, A.; Jeanjean, F.; Razon, P. Angew. Chem., Int. Ed. Engl. 2002, 41, 2097. 8. Yan, L. Z.; Mayer, J. P. Org. Lett. 2003, 5, 1161. 9. Roy, S.; Sarkar, S. K.; Mukhopadhyay, B.; Roy, N. Indian J. Chem., Sect. B 2005, 44B, 130. 10. Harding, J. R.; King, C. D.; Perrie, J. A.; Sinnott, D.; Stachulski, A. V. Org. Biomol. Chem. 2005, 3, 1501. 529

Shapiro reaction The Shapiro reaction is a variant of the BamfordStevens 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 as the kinetic products, while the BamfordStevens reaction delivers the more-substituted olefins as the thermodynamic products.

1 1 R 1 R R H 2 + 2 R E 2 R N 2 n-BuLi R N Ts E 3 3 R 3 R R

Bu R1 2 1 R N R H N Ts 2 H R N R3 N Ts H Bu R3

1 1 R 1 R R 2 + 2 N2 R E R N R2 N E 3 R3 R R3

Example 13

NNHTs MeLi, Et2O-PhH

7580%

Example 22

NNHTs MeLi, Et2O

98% 2% 530

References

1. Shapiro, R. H.; Duncan, J. H.; Clopton, J. C. J. Am. Chem. Soc. 1967, 89, 471. Robert H. Shapiro was a professor at the University of Colorado. 2. Shapiro, R. H.; Heath, M. J. J. Am. Chem. Soc. 1967, 89, 5734. 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. 4. Casanova, J.; Waegell, B. Bull. Soc. Chim. Fr. 1975, 922. 5. Shapiro, R. H. Org. React. 1976, 23, 405507. (Review). 6. Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 55. (Review). 7. Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 183. (Review). 8. Corey, E. J.; Lee, J.; Roberts, B. E. Tetrahedron Lett. 1997, 38, 8915. 9. Corey, E. J.; Roberts, B. E. Tetrahedron Lett. 1997, 38, 8919. 10. Kurek-Tyrlik, A.; Marczak, S.; Michalak, K.; Wicha, J. Synlett 2000, 547. 11. Kurek-Tyrlik, A.; Marczak, S.; Michalak, K.; Wicha, J.; Zarecki, A. J. Org. Chem. 2001, 65, 6994. 12. Tormakangas, O. P.; Toivola, R. J.; Karvinen, E. K.; Koskinen, A. M. P. Tetrahedron 2002, 58, 2175. 13. Alvarez, R.; Dominguez, M.; Pazos, Y.; Sussman, F.; de Lera, A. R. Chem. Eur. J. 2003, 9, 5821. 14. Harrowven, D. C.; Pascoe, D. D.; Demurtas, D.; Bourne, H. O. Angew. Chem., Int. Ed. Engl. 2005, 44, 1221. 15. Girard, N.; Hurvois, J.-P.; Moinet, C.; Toupet, L. Eur. J. Org. Chem. 2005, 2269. 531

Sharpless asymmetric amino hydroxylation Osmium-mediated cis-addition of nitrogen and oxygen to olefins. Regioselectiv- ity may be controlled by ligand. Nitrogen sources (XNClNa) 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 ClNaNX HO NHX t-BuOH, H2O

The catalytic cycle:

OsO4 ClNX

R R1 O * HO NHX O Os NX L O

H2O O R O Os NX O L* O R1 O Os N R1 O N X X R

L*

R R ClN X O 1 O R O Os O Os N N R1 O * O * L X L X 532

Example 14

O 5 mol% (DHQD)2PHAL O NH OH 4 mol% K2OsO2(OH)4 BnO NClNa BnO n-PrOH/H2O (1:1), 63% ee

(DHQD)2-PHAL = 1,4-bis(9-O-dihydroquinidine)phthalazine (page 536).

Example 29

BnOCONH2 NaOH, t-BuOCl OH CO Et 2 (DHQD)2AQN CO2Et

K OsO (OH) NHCbz BnO 2 2 4 BnO n-PrOH/H2O (1:1) rt, 12 h, 45%, 87% ee

References

1. Herranz, E.; Sharpless, K. B. J. Org. Chem. 1978, 43, 2544. K. Barry Sharpless (USA, 1941) shared the Nobel Prize in Chemistry in 2001 with Herbert William S. Knowles (USA, 1917) and Ryoji Noyori (Japan, 1938) for his work on chirally catalyzed oxidation reactions. 2. Mangatal, L.; Adeline, M. T.; Guenard, D.; Gueritte-Voegelein, F.; Potier, P. Tetrahe- dron 1989, 45, 4177. 3. Engelhardt, L. M.; Skelton, B. W.; Stick, R. V.; Tilbrook, D. M. G.; White, A. H. Aust. J. Chem. 1990, 43, 1657. 4. Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2813. 5. Rubin, A. E.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1997, 36, 2637. 6. Kolb, H. C.; Sharpless, K. B. Transition Met. Org. Synth. 1998, 2, 243. (Review). 7. Thomas, A.; Sharpless, K. B. J. Org. Chem. 1999, 64, 8279. 8. Gontcharov, A. V.; Liu, H.; Sharpless, K. B. Org. Lett. 1999, 1, 783. 9. Nicoloau, K. C.; Li, H.; Boddy, C. N. C.; Ramajulu, J. M.; Yue, T.-Y.; Natarajan, S.; Chu, X.-J.; Bräse, S.; Rübsam, F. Chem. Eur. J. 1999, 5, 2584. 10. Demko, Z. P.; Bartsch, M.; Sharpless, K. B. Org. Lett. 2000, 2, 2221. 11. Bolm, C.; Hildebrand, J. P.; Muñiz, K. In Catalytic Asymmetric Synthesis; 2nd edn., Ojima, I., ed.; WileyVCH: New York, 2000, 399. (Review). 12. Bodkin, J. A.; McLeod, M. D. J. Chem. Soc., Perkin 1 2002, 27332746. (Review). 13. 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, 118124. (Review). 14. Lindstroem, U. M.; Ding, R.; Hidestal, O. Chem. Commun. 2005, 1773. 533

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-BuOOH, Ti(Oi-Pr)4 O OH OH L-(+)-diethyl tartrate R R2 2

1 R1 R R R t-BuOOH, Ti(Oi-Pr)4 O OH OH D-( )-diethyl tartrate R R2 2

2 The putative active catalyst, E = CO2Et:

EtO O OEt O O O Oi-Pr Ti E Ti i-PrO O O i-PrO

EtO2C Oi-Pr

The transition state:

EtO2C O CO2Et

O O Ti O O t-Bu 534

The catalytic cycle:

OiPr LnTi OiPr

tBuOOH O OH OH O LnTi O O tBu

* O O LnTi O O LnTi O tBu tBu

O * ** LnTi O O * O * tBu * * LnTi O O tBu

Example 15

Ti(O-iPr)4, 4 Å MS, (+)-DET Me OH t-BuOOH, CH2Cl2 20 °C

O crude: 88% yield, 92.3 % ee Me OH recrystallization: 73% yield, > 98% ee 535

Example 25

()-DIPT, Ti(Oi-Pr)4 O OH OH TBHP, 3 Å MS 5060%, 8892% ee

References

1. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974. 2. Williams, I. D.; Pedersen, S. F.; Sharpless, K. B.; Lippard, S. J. J. Am. Chem. Soc. 1984, 106, 6430. 3. Rossiter, B. E. Chem. Ind. 1985, 22(Catal. Org. React.), 295. (Review). 4. Pfenninger, A. Synthesis 1986, 89. (Review). 5. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765. 6. Corey, E. J. J. Org. Chem. 1990, 55, 16931694. (Review). 7. 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). 8. Woodard, S. S.; Finn, M. G.; Sharpless, K. B. J. Am. Chem. Soc. 1991, 113, 106. 9. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., ed,; VCH: New York, 1993; Chapter 4.1, pp 103158. (Review). 10. Schinzer, D. Org. Synth. Highlights II 1995, 3. (Review). 11. Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1299. (Review). 12. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; 2nd ed., Ojima, I., ed.; Wiley-VCH: New York, 2000, 231285. (Review). 13. Black, P. J.; Jenkins, K.; Williams, J. M. J. Tetrahedron: Asymmetry 2002, 13, 317. 14. Ghosh, A. K.; Lei, H. Tetrahedron: Asymmetry 2003, 14, 629. 15. Palucki, M. SharplessKatsuki Epoxidation In Name Reactions in Heterocyclic Chem- istry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 5062. (Review). 536

Sharpless asymmetric dihydroxylation Enantioselective cis-dihydroxylation of olefins using osmium catalyst in the presence of cinchona alkaloid ligands.

AD-mix-E HO OH (DHQD)2-PHAL RS RM RS RM K2OsO2(OH)4 RL H

RL H RS RM K2CO3, K3Fe(CN)6 RL H (DHQ) -PHAL 2 HO OH AD-mix-D

(DHQD)2-PHAL = 1,4-bis(9-O-dihydroquinidine)phthalazine:

N N N N O O H O O

N N

(DHQ)2-PHAL = 1,4-bis(9-O-dihydroquinine)phthalazine:

N N N N O O

O O

N N

The concerted [3 + 2] cycloaddition mechanism:

O O O O L O Os O Os Os O O O O O O L L 537

O [3 + 2]-like hydrolysis HO O Os O O cycloaddition L HO

The catalytic cycle is shown on page 539 (the secondary cycle is shut off by main- taining a low concentration of olefin):

Example 13

OH OH OH O K2OsO2(OH)4 O (DHQD)2PHAL EtO2C EtO2C

K2CO3, MeSO2NH2 OH N3 N3 t-BuOH/H2O (1:1) rt, 12 h, 90% de

Example 29

1. AD-mix-E, MeSO2NH2 CO2Et t-BuOH/H2O (1:1), rt, 12 h

BnO 2. NosCl, Et3N, CH2Cl2 0 oC, 54%, 92% ee

OH

CO2Et ONos BnO

Nos = nosylate = 4-nitrobenzenesulfonyl

References

1. Jacobsen, E. N.; Markó, I.; Mungall, W. S.; Schröder, G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968. 2. 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. 3. Kim, N.-S.; Choi, J.-R.; Cha, J. K. J. Org. Chem. 1993, 58, 7096. 4. Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 24832547. (Review). 5. Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319. (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. (Mechanism). 538

7. Rouhi, A. M. A Reaction under Scrutiny, in Chem. Eng. News 1997, November 3, 23. (Review, Mechanism). 8. Bolm, C.; Gerlach, A. Eur. J. Org. Chem. 1998, 21. 9. Nicoloau, K. C.; Li, H.; Boddy, C. N. C.; Ramajulu, J. M.; Yue, T.-Y.; Natarajan, S.; Chu, X.-J.; Bräse, S.; Rübsam, F. Chem. Eur. J. 1999, 5, 2584. 10. Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2, 863. 11. Liang, J.; Moher, E. D.; Moore, R. E.; Hoard, D. W. J. Org. Chem. 2000, 65, 3143. 12. Mehltretter, G. M.; Dobler, C.; Sundermeier, U.; Beller, M. Tetrahedron Lett. 2000, 41, 8083. 13. Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024. (Review, Nobel Prize Ad- dress). 14. Moitessier, N.; Henry, C.; Len, C.; Postel, D.; Chapleur, Y. J. Carbohydrate Chem. 2003, 22, 25. 15. Choudary, B. M.; Chowdari, N. S.; Madhi, S.; Kantam, M. L. J. Org. Chem. 2003, 68, 1736. 16. Junttila, M. H.; Hormi, O. E. O. J. Org. Chem. 2004, 69, 4816. 17. McNamara, C. A.; King, F.; Bradley, M. Tetrahedron Lett. 2004, 45, 8527. 18. Zhang, Y.; O'Doherty, G. A. Tetrahedron 2005, 61, 6337. 19. Hoevelmann, C. H.; Muniz, K. Chem. Eur. J. 2005, 11, 3951. 539

R R

O O O Os O O

R H2O R L

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 OO O O NMM NMO

H2O

R Primary cycle R OH high ee L R

R OH

high ee

O O Os O O The catalytic cycle of the Sharpless dihydroxylation 540

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 S 2 Se N Se CN CN PBu3

NO2 Se R OPBu Se 3 R PBu3 O NO2

O R R Se Se HONO2 NO2

NO2 syn-elimination Se OH R 541

Example 19

OH H 1. Bu P, o-O NPhSeCN, THF, rt H OH 3 2 2. CSA, PhH, rt to 70 oC

N 3. m-CPBA, 2,4,6-collidine o CH2Cl2, 0 C, 42% MeO

H H O

N H

Example 213

MeO 1. Bu3P, o-O2NPhSeCN O THF, rt, 6 h, 97% O O OH

OH 2. m-CPBA, Et3N, CH Cl , 78 oC OH 2 2 86%

MeO O O O

OH

OH References

1. Sharpless, K. B.; Young, M. Y.; Lauer, R. F. Tetrahedron Lett. 1973, 1979. 2. Grieco, P. A.; Miyashita, M. J. Org. Chem. 1974, 39, 120. 3. Grieco, P. A.; Miyashita, M. Tetrahedron Lett. 1974, 1869. 4. Sharpless, K. B.; Young, M. Y. J. Org. Chem. 1975, 40, 947. 5. Grieco, P. A.; Masaki, Y.; Boxler, D. J. Am. Chem. Soc. 1977, 97, 1597. 6. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485. 542

7. Grieco, P. A.; Yokoyama, Y. J. Am. Chem. Soc. 1977, 99, 5210. 8. Meade, E. A.; Krawczyk, S. H.; Townsend, L. B. Tetrahedron Lett. 1988, 29, 4073. 9. Smith, A. B., III; Haseltine, J. N.; Visnick, M. Tetrahedron 1989, 45, 2431. 10. Reich, H. J.; Wollowitz, S. Org. React. 1993, 44, 1296. (Review). 11. Krief, A.; Laval, A.-M. Bull. Soc. Chim. Fr. 1997, 134, 869874. (Review). 12. Hsu, D.-S.; Liao, C.-C. Org. Lett. 2003, 5, 4741. 13. Meilert, K.; Pettit, G. R.; Vogel, P. Helv. Chim. Acta 2004, 87, 1493. 14. Siebum, A. H. G.; Woo, W. S.; Raap, J.; Lugtenburg, J. Eur. J. Org. Chem. 2004, 2905. 15. Blay, G.; Cardona, L.; Collado, A. M.; Garcia, B.; Morcillo, V.; Pedro, J. R. J. Org. Chem. 2004, 69, 7294. The authors observed the concurrent epoxidation of a trisubsi- tuted olefin, possibly by the o-nitrophenylselenic acid via an intramolecular process. 543

Simmons–Smith reaction

Cyclopropanation of olefins using CH2I2 and Zn(Cu).

CH2I2 Zn(Cu) ICH2ZnI

Zn, Oxidative IICH2 ICH2ZnI addition SimmonsSmith reagent

2 ICH2ZnI (ICH2)2Zn 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, asymmetric version13

CONEt2

OH (1 eq) OH

OH CONEt2 6 eq Zn/Cu, 3 eq CH I MeO 2 2 o CH2Cl2, 0 C, 15 h 78%, 94% ee

OH

MeO 544

References

1. Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323. Howard E. Simmons (19291997) 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. 3. Kaltenberg, O. P. Wiad. Chem. 1972, 26, 285. 4. Takai, K.; Kakiuchi, T.; Utimoto, K. J. Org. Chem. 1994, 59, 2671. 5. Takahashi, H.; Yoshioka, M.; Shibasaki, M.; Ohno, M.; Imai, N.; Kobayashi, S. Tet- rahedron 1995, 51, 12013. 6. Nakamura, E.; Hirai, A.; Nakamura, M. J. Am. Chem. Soc. 1998, 120, 5844. 7. Kaye, P. T.; Molema, W. E. Chem. Commun. 1998, 2479. 8. Kaye, P. T.; Molema, W. E. Synth. Commun. 1999, 29, 1889. 9. Loeppky, R. N.; Elomart, S. J. Org. Chem. 2000, 65, 96. 10. Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T.; Ohishi, H.; Takemoto, Y. J. Org. Chem. 2001, 66, 81. 11. Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1415. (Review). 12. Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2003, 125, 2341. 13. Mahata, P. K.; Syam Kumar, U. K.; Sriram, V.; Ila, H.; Junjappa, H. Tetrahedron 2003, 59, 2631. 14. Long, J.; Yuan, Y.; Shi, Y. J. Am. Chem. Soc. 2003, 125, 13632. 15. Long, J.; Du, H.; Li, K.; Shi, Y. Tetrahedron Lett. 2005, 46, 2737. 545

Skraup quinoline synthesis

Quinoline from aniline, glycerol, sulfuric acid and oxidizing agent (e.g. PhNO2).

HO OH H2SO4 OH NH2 PhNO2 N

H H+ dehydration HO OH HO OH HO OH OH OH2 glycerol

H+ CHO dehydration CHO H2O OHC HO H acrolein

H+ H + O O H O conjugate H+ H NH addition N : 2 N H H

H OH OH O H intramolecular H+

: addition N N N H H H

OH2 H dehydration oxidation by N PhNO H N N H 2 2 H

For an alternative mechanism, see that of the Doebnervon Miller reaction (page 547). 546

Example 19

F H2SO4, FeSO4 F F OH H3BO3, 80 % F + HO OH SO3H F NH2 F N

NO2

Example 210

O OH + HO OH

NO NH2

O H2SO4, H3BO3 FeSO4•7H2O NO N 75 %

References

1. Skraup, Z. H. Monatsh. Chem. 1880, 1, 316. Zdenko Hans Skraup (18501910) was born in Prague, Czechoslovakia. He apprenticed under Lieben at the University of Vi- enna. 2. Skraup, Z. H. Ber. Dtsch. Chem. Ges. 1880, 13, 2086. 3. Manske, R. H. F.; Kulka, M. Org. React. 1953, 7, 80. (Review). 4. Bergstrom, F. W. Chem. Rev. 1944, 35, 152153. (Review). 5. Eisch, J. J.; Dluzniewski, T. J. Org. Chem. 1989, 54, 1269. 6. Takeuchi, I.; Hamada, Y.; Hirota, M. Chem. Pharm. Bull. 1993, 41, 747. 7. Fujiwara, H.; Okabayashi, I. Chem. Pharm. Bull. 1994, 42, 1322. 8. Fujiwara, H. Heterocycles 1997, 45, 119. 9. Oleynik, I. I.; Shteingarts, V. D. J. Fluorine Chem. 1998, 91, 25. 10. Fujiwara, H.; Kitagawa, K. Heterocycles 2000, 53, 409. 11. Theoclitou, M.-E.; Robinson, L. A. Tetrahedron Lett. 2002, 43, 3907. 12. Ranu, B. C.; Hajra, A.; Dey, S. S.; Jana, U.; Tetrahedron 2003, 59, 813. 13. 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, 488494. (Review). 547

Doebner–von Miller reaction Doebner–von Miller reaction is a variant of the Skraup quinoline synthesis (page 545). Therefore, the mechanism for the Skraup reaction is also operative for the Doebner–von Miller reaction. An alternative mechanism shown below is based on the fact that the preformed imine (Schiff base) also gives 2-methylquinoline:

HCl or OHC

NH2 ZnCl2 N

O H NH H N : 2 H N :

N OH2 H

[2 + 2] : N N cycloaddition N Ph : H N H

B: H H+ N N

N N H H

HN N H : N N H H 548

N HN H Ph N HN: H Ph

air oxidation

2 H N Example 17

CO2Me NH2 O TsOH, CH2Cl2

MeO2CCO2Me reflux, 24 h NCO2Me

Example 28 F F H F F 6 N HCl, Tol. O NHAc 100 °C, 2 h, 70% N Me

References

1. Doebner, O.; von Miller, W. Ber. Dtsch. Chem. Ges. 1883, 16, 2464. 2. Schindler, O.; Michaelis, W. Helv. Chim. Acta 1970, 53, 776. 3. Corey, E. J.; Tramontano, A. J. Am. Chem. Soc. 1981, 103, 5599. 4. Eisch, J. J.; Dluzniewski, T. J. Org. Chem. 1989, 54, 1269. 5. Zhang, Z. P.; Tillekeratne, L. M. V.; Hudson, R. A. Synthesis 1996, 377. 6. Zhang, Z. P.; Tillekeratne, L. M. V.; Hudson, R. A. Tetrahedron Lett. 1998, 39, 5133. 7. Carrigan, C. N.; Esslinger, C. S.; Bartlett, R. D.; Bridges, R. J. Bioorg. Med. Chem. Lett. 1999, 9, 2607. 8. 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. 9. Matsugi, M.; Tabusa, F.; Minamikawa, J.-i. Tetrahedron Lett. 2000, 41, 8523. 10. Fürstner, A.; Thiel, O. R.; Blanda, G. Org. Lett. 2000, 2, 3731. 11. Kavitha, J.; Vanisree, M.; Subbaraju, G. V. Indian J. Chem., Sect. B 2001, 40B, 522. 12. Li, X.-G.; Cheng, X.; Zhou, Q.-L. Synth. Commun. 2002, 32, 2477. 13. 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, 488494. (Review). 549

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 O2 2 O2S NO2 S OH

OH O

NO O NO2 O2 2 2 S OH S SNAr

OH O

O 2 NO2 O2S NO2 S

O O spirocyclic anion intermediate (Meisenheimer complex) 550

Example8

O O O Br NH2 H N 2 O HO NaOH, DMA O

O

NaOH, H2O HO N 50 oC O H

O H2O, reflux

59%, 3 steps H2N

References

1. Evans, W. J.; Smiles, S. J. Chem. Soc. 1935, 181. 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, 99215. (Review). 3. Gerasimova, T. N.; Kolchina, E. F. J. Fluorine Chem. 1994, 66, 6974. (Review). 4. Boschi, D.; Sorba, G.; Bertinaria, M.; Fruttero, R.; Calvino, R.; Gasco, A. J. Chem. Soc., Perkin Trans. 1 2001, 1751. 5. Hirota, T.; Tomita, K.-I.; Sasaki, K.; Okuda, K.; Yoshida, M.; Kashino, S. Heterocy- cles 2001, 55, 741. 6. Selvakumar, N.; Srinivas, D.; Azhagan, A. M. Synthesis 2002, 2421. 7. Kumar, G.; Gupta, V.; Gautam, D. C.; Gupta, R. R. Heterocyclic Commun. 2002, 8, 447. 8. Mizuno, M.; Yamano, M. Org. Lett. 2005, 7, 3629. 9. Bacque, E.; El Qacemi, M.; Zard, S. Z. Org. Lett. 2005, 7, 3817. 551

NewmanKwart reaction Transformation of phenol to the corresponding thiophenol, a variant of the Smile reaction (page 549).

S OH S ONMe2 Cl NMe 2 '

O SH hydrolysis SNMe2

Mechanism:

O NMe2

OS O SNMe2 Me N 2 S

Example 18

S S

OH Cl NMe2 O NMe2 OH NaH, DMF OH 85 oC, 1 h, 45%

O 275 oC, 0.8 mmHg S NMe2 OH 55% 552

Example 29

O o 1. Br2, CH2Cl2, 5 to 20 C, 90 min.

o 2. S CH2Cl2, 20 C, 16 h, 37.4% OH Cl NMe2

O O

dimethylaniline Br Br Me2N O Me N S 218 oC, 7 h, 65.7% 2 S O

O 1. KOH, MeOH, reflux, 2 h Br 2. MeI, K CO , 90% 2 3 S

References

1. Kwart, H.; Evans, E. R. J. Org. Chem. 1966, 31, 410. 2. Newman, M. S.; Karnes, H. A. J. Org. Chem. 1966, 31, 3980. 3. Newman, M. S.; Hetzel, F. W. J. Org. Chem. 1969, 34, 3604. 4. Cossu, S.; De Lucchi, O.; Fabbri, D.; Valle, G.; Painter, G. F.; Smith, R. A. J. Tetra- hedron 1997, 53, 6073. 5. Lin, S.; et al. Org. Prep. Proc. Int. 2000, 32, 547. 6. Ponaras, A. A.; Zairn, Ö. in Encyclopedia of Reagents for Organic Synthesis, Paquette, L. A. (ed.), Wiley & Sons: New York, 1995, 2174. (Review). 7. Kane, V. V.; Gerdes, A.; Grahn, W.; Ernst, L.; Dix, I.; Jones, P. G.; Hopf, H. Tetrahe- dron Lett. 2001, 42, 373. 8. Albrow, V.; Biswas, K.; Crane, A.; Chaplin, N.; Easun, T.; Gladiali, S.; Lygo, B.; Woodward, S. Tetrahedron: Asymmetry 2003, 14, 2813. 9. 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. 10. Kusch, D. Speciality Chemicals Magazine 2004, 23, 41. (Review). 553

TruceSmile rearrangement Smiles rearrangement where Y is carbon:

ZZ X base Y L L YH XH

Example 16

CF3 CF3 N N KH or NaH O O

CO2Me MO OMe

CF3 N

O OMe OM

CF3 CF3 N N

O OH O O 554

Example 28

N NaOH, H2O O2S EtOH, reflux NO2 O

NO2 N O2 H O2S S N

NO2 41% 46%

Example 39

O

O2N K2CO3, DMF

F HO reflux, 73%

O2N O2NOO OOH

References

1. Truce, W. E.; Ray, W. J. Jr.; Norman, O. L.; Eickemeyer, D. B. J. Am. Chem. Soc. 1958, 80, 3625. 2. Truce, W. E.; Hampton, D. C. J. Org. Chem. 1963, 28, 2276. 3. Bayne, D. W; Nicol, A. J.; Tennant, G. J. Chem. Soc., Chem. Comm. 1975, 19, 782. 4. Fukazawa, Y.; Kato, N.; Ito, S.; Tetrahedron Lett.1982, 23, 437. 5. Hoffman, R. V.; Jankowski, B. C.; Carr, C. S. J. Org. Chem. 1986, 51, 130. 6. Erickson, W. R.; McKennon, M. J.; Tetrahedron Lett. 2000, 41, 4541. 7. Hirota, T.; Tomita, K.; Sasaki, K.; Okuda, K.; Yoshida, M.; Kashino, S.; Heterocycles 2001, 55, 741. 8. Kimbaris, A.; Cobb, J.; Tsakonas, G.; Varvounis, G. Tetrahedron 2004, 60, 8807. 9. Mitchell, L. H.; Barvian, N. C. Tetrahedron Lett. 2004, 45, 5669. 555

Sommelet reaction Transformation of benzyl halides to the corresponding benzaldehydes with the aide of hexamethylenetetramine.

N ' N X ' CHO Ar Ar Ar X N N N N N CHCl3 N H2O hexamethylenetetramine

N X N N: SN2 N N Ar N N Ar X N

N N CH CH3 : 2 hydride H Ar N N N N N N transfer Ar :OH2

N CH3 N Ar CH3 + N N CHO H Ar N NH N N O H 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 556

Example9

F F N HOAc, H2O CHO Cl N N N ', 62% F F

References

1. Sommelet, M. Compt. Rend. 1913, 157, 852. Marcel Sommelet (18771952) 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. Le Henaff, P. Annals Chim. Phys. 1962, 367. 3. Zaluski, M. C.; Robba, M.; Bonhomme, M. Bull. Soc. Chim. Fr. 1970, 1445. 4. Smith, W. E. J. Org. Chem. 1972, 37, 3972. 5. Simiti, I.; Chindris, E. Arch. Pharm. 1975, 308, 688. 6. Stokker, G. E.; Schultz, E. M. Synth. Commun. 1982, 12, 847. 7. Armesto, D.; Horspool, W. M.; Martin, J. A. F.; Perez-Ossorio, R. Tetrahedron Lett. 1985, 26, 5217. 8. Simiti, I.; Oniga, O. Monatsh. Chem. 1996, 127, 733. 9. Malykhin, E. V.; Steingarts, V. D. J. Fluorine Chem. 1998, 91, 19. 10. Liu, X.; He, W. Huaxue Shiji 2001, 23, 237. 557

Sommelet–Hauser rearrangement [2,3]-Wittig rearrangement of benzylic quaternary ammonium salts upon treatment with alkali metal amides via the ammonium ylide intermediates.

NH N 2 NH N 3

N N [2,3]-sigmatropic NH3 H rearrangement NH2 ammonium ylide

HNH2

aromatization N N H

Example 15

DMF, reflux Ph N SiMe3 I 18 h, 94%

I CsF, HMPA NSiMe3 rt, 23 h, 86% N 558

Example 26

Br CsF, HMPA

NSiMe3 10 oC, 0.5 h, 32% AcO

N AcO N AcO 46:54

References

1. Sommelet, M. Compt. Rend. 1937, 205, 56. 2. Pine, S. H. Tetrahedron Lett. 1967, 3393. 3. Wittig, G. Bull. Soc. Chim. Fr. 1971, 1921. 4. Robert, A.; Lucas-Thomas, M. T. J. Chem. Soc., Chem. Commun. 1980, 629. 5. Shirai, N.; Sato, Y. J. Org. Chem. Soc. 1988, 53, 194. 6. Shirai, N.; Watanabe, Y.; Sato, Y. J. Org. Chem. 1990, 55, 2767. 7. Tanaka, T.; Shirai, N.; Sugimori, J.; Sato, Y. J. Org. Chem. 1992, 57, 5034. 8. Klunder, J. M. J. Heterocycl. Chem. 1995, 32, 1687. 9. Maeda, Y.; Sato, Y. J. Org. Chem. 1996, 61, 5188. 10. Endo, Y.; Uchida, T.; Shudo, K. Tetrahedron Lett. 1997, 38, 2113. 559

Sonogashira reaction Pd/Cu-catalyzed cross-coupling of organohalides with terminal alkynes. Cf. Cadiot–Chodkiewicz coupling and CastroStephens reaction. The Castro– Stephens coupling uses stoichiometric copper, whereas the Sonogashira variant uses catalytic palladium and copper.

PdCl2x(PPh3)2 RX R' RR' 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. transmetalation RC CR' iii. reductive elimination

Note that Et3N may reduce Pd(II) to Pd(0) as well, where Et3N is oxidized to iminium ion at the same time:

NEt NEt H 2 2 PdCl NEt H 2 3 HClPd PdCl 2 Cl

reductive NEt2 Cl Cl Pd H HCl Pd(0) elimination 560

Example 13 I

N CO2Et H

PdCl2•(Ph3P)2

CuI, Et3N o 60 C, 89% N CO2Et H

Example 25

Br Br SiMe3 N NBrPdCl2•(Ph3P)2, CuI SiMe3 Et3N, rt, 65–74%

References

1. Sonogashira K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467. Richard Heck discovered the same transformation using palladium but without the use of copper: J. Organomet. Chem. 1975, 93, 259. 2. McCrindle, R.; Ferguson, G.; Arsenaut, G. J.; McAlees, A. J.; Stephenson, D. K. J. Chem. Res. (S) 1984, 360. 3. Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 2248. 4. Rossi, R. Carpita, A.; Belina, F. Org. Prep. Proc. Int. 1995, 27, 129. 5. Ernst, A.; Gobbi, L.; Vasella, A. Tetrahedron Lett. 1996, 37, 7959. 6. Campbell, I. B. In Organocopper Reagents; Taylor, R. J. K. Ed.; IRL Press: Oxford, UK, 1994, 217. (Review). 7. Hundermark, T.; Littke, A.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729. 8. Dai, W.-M.; Wu, A. Tetrahedron Lett. 2001, 42, 81. 9. Alami, M.; Crousse, B.; Ferri, F. J. Organomet. Chem. 2001, 624, 114. 10. Bates, R. W.; Boonsombat, J. J. Chem. Soc., Perkin Trans. 1 2001, 654. 11. Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002, 4, 1411. 12. Balova, I. A.; Morozkina, S. N.; Knight, D. W.; Vasilevsky, S. F. Tetrahedron Lett. 2003, 44, 107. 13. Garcia, D.; Cuadro, A. M.; Alvarez-Builla, J.; Vaquero, J. J. Org. Lett. 2004, 6, 4175. 14. Li, P.; Wang, L.; Li, H. Tetrahedron 2005, 61, 8633. 15. Lemhadri, M.; Doucet, H.; Santelli, M. Tetrahedron 2005, 61, 9839. 561

Staudinger ketene cycloaddition [2 + 2] Cycloaddition of ketene and imine to form E-lactam. Other coupling part- ners for ketene also include: olefin to give cyclobutanone and carbonyl to give E- lactone.

O O X X = NR; O; CHR X

R3 R2 R3 R4 R1 R2 R4 R1 puckered transition state:

O O X R X 3 R R3 R2 4 R R R1 R2 4 1

Example 18

O O O Ot-Bu PhO PhO Ot-Bu Cl p-Tol N Et3N, CH2Cl2 N N p-Tol 10 oC to rt, 24 h ON 88%

Example 29

O AcO O Cl N N Et N, CH Cl 3 2 2 AcO 78 oC to rt, 88% 562

References

1. Staudinger, H. Ber. Dtsch. Chem. Ges. 1907, 40, 1145. Hermann Staudinger (Ger- many, 18811965) 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, 485492. (Review). 3. Snider, B. B. Chem. Rev. 1988, 88, 793811. (Review). 4. Hyatt, J. A.; Raynolds, P. W. Org. React. 1994, 45, 159646. (Review). 5. Venturini, A.; Gonzalez, Jr. J. Org. Chem. 2002, 67, 9089. 6. Orr, R. K.; Calter, M. A. Tetrahedron 2003, 59, 35453565. (Review). 7. Hevia, E.; Perez, J.; Riera, V.; Miguel, D.; Campomanes, P.; Menendez, M. I; Sordo, T. L.; Garcia-Granda, S. J. Am. Chem. Soc. 2003, 125, 3706. 8. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Mugnoli, A.; Novi, M.; Petrillo, G.; San- cassan, F.; Tavani, C. Tetrahedron 2003, 59, 10195. 9. Becker, F. F.; Banik, I.; Banik, B. K. J. Med. Chem. 2003, 46, 505. 10. Cremonesi, G.; Dalla Croce, P.; La Rosa, C. Tetrahedron 2004, 60, 93. 11. Botman, P. N. M.; David, O.; Amore, A.; Dinkelaar, J.; Vlaar, M.; Goubitz, K.; Fraanje, J.; Schenk, H.; Hiemstra, H.; van Maarseveen, J. H. Angew. Chem., Int. Ed. 2004, 43, 3471. 12. Liang, Y.; Jiao, L.; Zhang, S.; Xu, J. J. Org. Chem. 2005, 70, 334. 13. Banik, B. K.; Banik, I.; Becker, F. F. Bioorg. Med. Chem. Lett. 2005, 13, 3611. 563

Staudinger reduction Phosphazo compounds (e.g. iminophosphoranes) from the reaction of tertiary phosphine (Example Ph3P) with organic azides.

PR3 N2 X N3 XNNNPR3 XNPR3 phosphazide

XNNN XNNNPR3 XNNNPR3 :PR3 phosphazide

N PR3 N PR3 N PR3 N N N N N N X X X 4-membered ring transition state

H2O XNH2 OPR3 N2 XNPR3

Example 17

OMe OMe Ph P, THF N O N3 3

OTBDMS ', 81% OTBDMS N N 564

Example 212

N3 BnO O 1.1 eq. PMe3, 2.4 eq. Boc-ON BnO N3 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

References

1. Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635. 2. Leffler, J. E.; Temple, R. D. J. Am. Chem. Soc. 1967, 89, 5235. 3. Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron 1981, 37, 437. 4. Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353. 5. Velasco, M. D.; Molina, P.; Fresneda, P. M.; Sanz, M. A. Tetrahedron 2000, 56, 4079. 6. Balakrishna, M. S.; Abhyankar, R. M.; Walawalker, M. G. Tetrahedron Lett. 2001, 42, 2733. 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. 8. Conroy, K. D.; Thompson, A. Chemtracts 2002, 15, 514. 9. Venturini, A.; Gonzalez, Jr. J. Org. Chem. 2002, 67, 9089. 10. Chen, J.; Forsyth, C. J. Org. Lett. 2003, 5, 1281. 11. Fresneda, P. M.; Castaneda, M.; Sanz, M. A.; Molina, P. Tetrahedron Lett. 2004, 45, 1655. 12. Li, J.; Chen, H.-N.; Chang, H.; Wang, J.; Chang, C.-W. T. Org. Lett. 2005, 7, 3061. 565

Sternbach benzodiazepine synthesis Treatment of quinazoline 3-oxide with amines gives the rearrangement product, 1,4-benzodiazepine.

H N N N Cl N CH3NH2 Cl N Cl O O

chlordiazepoxide (Librium) quinazoline 3-oxide

H2N : N Cl N N CH3NH2 Cl Cl G O N Cl O

H H N H N N N concerted Cl N Cl N O slow step O

chlordiazepoxide (Librium) 566

A step-wise mechanism is also possible:

H N : H 2 N N N Cl Cl : G N Cl N OH Cl O

H N N

Cl N O

chlordiazepoxide (Librium)

References

1. Sternbach, L. H.; Kaiser, S.; Reeder, E. J. Am. Chem. Soc. 1960, 82, 475. 2. Sternbach, L. H.; Archer, G.; Reeder, E. J. Org. Chem. 1963, 28, 3013. 3. Stempel, A.; Reeder, E.; Sternbach, L. H. J. Org. Chem. 1965, 30, 4267. (Mechanism). 4. Sternbach, L. H. Angew. Chem., Int. Ed. 1971, 10, 34. (Review). 5. Sternbach, L. H. In The Benzodiazepines, Garattini, S.; Mussini, E.; Randall, L. O. eds., Raven Press: New York, 1973, pp126. (Review). 6. Sternbach, L. H. In The Benzodiazepines: From Molecular Biology to Clinical Prac- tice, Costa, Erminio, ed.; Raven Press: New York, 1983, pp 120. (Review). 567

Stetter reaction 1,4-Dicarbonyl derivatives from aldehydes and DE-unsaturated ketones. The thiazolium catalyst serves as a safe surrogate for CN. Also known as the Mi- chaelStetter reaction. Cf. Benzoin condensation.

Ph HO N O S R CHO R O NH 3 O

Ph Bn HO N deprotonation N 1 H H R S 1 S O R = HOCH2CH2CH2- :NH3 R

Bn Bn N N 1 OH OH R R1 S H S R R B O

Bn N Michael OH tautomerization R1 addition S R O

Bn O N O R1 R S R O O

Ph Ph + HO N NH4 HO N

S S 568

Example 14

OHC CHO O O

HO S I O O N (cat.) O o O O Et3N, EtOH, 80 C, 56%

Example 211 O CO2Me N H

N O

HO S CO Me Cl O 2 N N (cat.) Ph O N Et3N, DMF, 100 ºC, 75%

References

1. Stetter, H. Angew. Chem. 1973, 85, 89. Hermann Stetter (19171993), born in Bonn, Germany, was a chemist at Technische Hochschule Aachen in West Germany. 2. Stetter, H. Angew. Chem., Int. Ed. 1976, 15, 639. 3. Castells, J.; Dunach, E.; Geijo, F.; Lopez-Calahorra, F.; Prats, M.; Sanahuja, O.; Villa- nova, L. Tetrahedron Lett. 1980, 21, 2291. 4. El-Haji, T.; Martin, J. C.; Descotes, G. J. Heterocycl. Chem. 1983, 20, 233. 5. Ho, T. L.; Liu, S. H. Synth. Commun. 1983, 13, 1125. 6. Phillips, R. B.; Herbert, S. A.; Robichaud, A. J. Synth. Commun. 1986, 16, 411. 7. Stetter, H.; Kuhlmann, H.; Haese, W. Org. Synth. 1987, 65, 26. 8. Ciganek, E. Synthesis 1995, 1311. 9. Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. Helv. Chim. Acta 1996, 79, 1899. 10. Harrington, P. E.; Tius, M. A. Org. Lett. 1999, 1, 649. 11. Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.; Tai, K.; Hida, T.; Yamauchi, T.; Nagai, M. J. Med. Chem. 2000, 43, 409. 12. Kobayashi, N.; Kaku, Y.; Higurashi, K.; Yamauchi, T.; Ishibashi, A.; Okamoto, Y. Bioorg. Med. Chem. Lett. 2002, 12, 1747. 13. Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 6284. 14. Reynolds, N. T.; Rovis, T. Tetrahedron 2005, 61, 6368. 569

Still–Gennari phosphonate reaction A variant of the HornerEmmons reaction using bis(trifluoroethyl)phosphonate to give Z-olefins.

O KN(SiMe3)2, 18-Crown-6 Ph CO2CH3 (CF3CH2O)2PCO2CH3 then PhCH2CHO

O O O O CF3CH2O P CF CH O CF3CH2O OMe 3 2 P CF CH O OMe H 3 2 H SiMe3 Ph N O SiMe3

O O OCH2CF3 OCH2CF3 O P O P OCH2CF3 OCH2CF3 H H H H CO2CH3 CO CH Ph Ph 2 3 erythro isomer, kinetic adduct

Ph CO2CH3

Example 13

KN(SiMe3)2, 18-Crown-6 O 78 oC, THF, 30 min. Ph CO2CH3 (CF3CH2O)2PCO2CH3

then PhCH2CHO, 87% 570

Example 212

MeO P(OCH2CF3)2 OOOOO TBS TBS

NaH, THF CHO O OPMB 73%, Z:E 5:1 TBS OTBS

MeO

OOOO O OPMB TBS TBS TBS OTBS

References

1. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405. W. Clark Still (1946) was born in Augusta, Georgia. He was a professor at Columbia University. 2. Ralph, J.; Zhang, Y. Tetrahedron 1998, 54, 1349. 3. Nicolaou, K. C.; Nadin, A.; Leresche, J. E.; LaGreca, S.; Tsuri, T.; Yue, E. W.; Yang, Z. Angew. Chem., Int. Ed. Engl. 1994, 33, 2187. 4. Mulzer, J.; Mantoulidis, A.; Ohler, E. Tetrahedron Lett. 1998, 39, 8633. 5. Jung, M. E.; Marquez, R. Org. Lett. 2000, 2, 1669. 6. White, J. D.; Blakemore, P. R.; Browder, C. C. et al. J. Am. Chem. Soc. 2001, 123, 8593. 7. Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9535. 8. Mulzer, J.; Ohler, E. Angew. Chem., Int. Ed. Engl. 2001, 40, 3842. 9. Beaudry, C. M.; Trauner, D. Org. Lett. 2002, 4, 2221. 10. Sano, S.; Yokoyama, K.; Shiro, M.; Nagao, Y. Chem. Pharm. Bull. 2002, 50, 706. 11. Dakin, L. A.; Langille, N. F.; Panek, J. S. J. Org. Chem. 2002, 67, 6812. 12. Paterson, I.; Lyothier, I. J. Org. Chem. 2005, 70, 5494. 571

Stille coupling Palladium-catalyzed cross-coupling reaction of organostannanes with organic halides, triflates, etc. For the catalytic cycle, see Kumada coupling on page 345.

1 2 Pd(0) 1 2 RX R Sn(R )3 RR XSn(R)3

1 2 oxidative R L R Sn(R )3 RX L2Pd(0) Pd X transmetalation addition L isomerization

L L reductive 2 1 XSn(R)3 Pd 1 R R L Pd(0) R 2 R elimination

Example 16

PhO2S SnBu3 N N Cl N Br Cl N SO2Ph PdCl •(Ph P) , CuI Cl N NH2 2 3 2 Cl N NH2 THF, reflux, 92%

Example 27

Cl (MeCN)2PdCl2

Me3Sn Cl TBDPSO Br AsPh3, NMP o 80 C, 1.5 h, 55%

Cl Cl HCl

TBDPSO Cl HN Cl

Zoloft 572

References

1. Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636. John Kenneth Stille (19301989) 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. 2. Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992. 3. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. 4. Farina, V.; Krishnamurphy, V.; Scott, W. J. Org. React. 1997, 50, 1–652. (Review). 5. For an excellent review on the intramolecular Stille reaction, see, Duncton, M. A. J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1999, 1235. (Review). 6. Li, J. J.; Yue, W. S. Tetrahedron Lett. 1999, 40, 4507. 7. Lautens, M.; Rovis, T. Tetrahedron, 1999, 55, 8967. 8. Nakamura, H.; Bao, M.; Yamamoto, Y. Angew. Chem., Int. Ed. 2001, 40, 3208. 9. Heller, M.; Schubert, U. S. J. Org. Chem. 2002, 67, 8269. 10. Lin, S.-Y.; Chen, C.-L.; Lee, Y.-J. J. Org. Chem. 2003, 68, 2968. 11. Samuelsson, L.; Langstrom, B. J. Labelled Comd. Radiopharm. 2003, 46, 263. 12. 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). 13. Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 22452267. (Review). 573

StilleKelly 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 Br Pd(0) Br Me3Sn SnMe3 Br oxidative transmetalation OH OH addition OH OH

Me Sn Pd 3 Me3Sn Br reductive Br Pd(0) OH elimination OH OH OH

Me3Sn Pd(0) PdBr transmetalation

oxidative OH addition OH

Pd reductive Pd(0) elimination OH OH OH OH 574

Example8

I II I HO N N O Cl NaH, DMF, reflux, 89%

Me3Sn SnMe3 N

PdCl2•(Ph3P)2 O xylene, reflux, 92%

References

1. Kelly, T. R.; Li, Q.; Bhushan, V. Tetrahedron Lett. 1990, 31, 161. 2. Grigg, R.; Teasdale, A.; Sridharan, V. Tetrahedron Lett. 1991, 32, 3859. 3. Sakamoto, T.; Yasuhara, A.; Kondo, Y.; Yamanaka, H. Heterocycles 1993, 36, 2597. 4. Iyoda, M.; Miura, M.i; Sasaki, S.; Kabir, S. M. H.; Kuwatani, Y.; Yoshida, M. Hetero- cycles 1997, 38, 4581. 5. Fukuyama, Y.; Yaso, H.; Nakamura, K.; Kodama, M. Tetrahedron Lett. 1999, 40, 105. 6. Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999, 1505. 7. Fukuyama, Y.; Yaso, H.; Mori, T.; Takahashi, H.; Minami, H.; Kodama, M. Heterocy- cles 2001, 54, 259. 8. Yue, W. S.; Li, J. J. Org. Lett. 2002, 4, 2201. 9. Olivera, R.; SanMartin, R.; Tellitu, I.; Dominguez, E. Tetrahedron 2002, 58, 3021. 575

Stobbe condensation Condensation of diethyl succinate and its derivatives with carbonyl compounds in the presence of a base.

CO2Et O CO2Et KOt-Bu R CO2H 1 RR HOt-Bu CO2Et R1

t-BuO 1 O O enolate R H aldol O R OEt OEt formation addition CO2Et CO2Et

1 R CO Et 1 R R 2 R CO2Et lactonization O O EtO O EtO O

CO Et 1 R CO Et 2 R 2 CO2Et ring H+ R CO2H H R CO2 O opening R1 Ot-Bu R1 O

Example 112

O CHO CO2Me 1. t-BuOK, t-BuOH, reflux

2. Ac O, NaOAc, reflux O CO2Me 2 O 84%

O

CO2Me

O O OAc 576

Example 213

O O aq. NaOH, EtOH O O CHO O OH 10 oC, 5 h, 88% O O O O

References

1. Stobbe, H. Ber. Dtsch. Chem. Ges. 1893, 26, 2312. Hans Stobbe (18601938) 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. El-Rayyes, N. R.; Al-Salman, Mrs. N. A. J. Heterocycl. Chem. 1976, 13, 285. 3. Baghos, V. B.; Nasr, F. H.; Gindy, M. Helv. Chim. Acta 1979, 62, 90. 4. Welch, W. M.; Harbert, C. A.; Koe, K. B.; Kraska, A. R. US 4536518 (1985). 5. Zerrer, R.; Simchen, G. Synthesis 1992, 922. 6. Baghos, V. B.; Doss, S. H.; Eskander, E. F. Org. Prep. Proced. Int. 1993, 25, 301. 7. Moldvai, I.; Temesvari-Major, E.; Balazs, M.; Gacs-Baitz, E.; Egyed, O.; Szantay, C. J. Chem. Res., (S) 1999, 3018. 8. Moldvai, I.; Temesvari-Major, E.; Gacs-Baitz, E.; Egyed, O.; Gomory, A.; Nyulaszi, L.; Szantay, C. Heterocycles 2001, 53, 759. 9. Yvon, B. L.; Datta, P. K.; Le, T. N.; Charlton, J. L. Synthesis 2001, 1556. 10. Liu, J.; Brooks, N. R. Org. Lett. 2002, 4, 3521. 11. Moldvai, I.; Temesvari-Major, E.; Incze, M.; Platthy, T.; Gacs-Baitz, E.; Szantay, C. Heterocycles 2003, 60, 309. 12. Giles, R. G. F.; Green, I. R.; van Eeden, N. Eur. J. Org. Chem. 2004, 4416. 13. Mahajan, V. A.; Shinde, P. D.; Borate, H. B.; Wakharkar, R. D. Tetrahedron Lett. 2005, 46, 1009. 577

Stork enamine reaction A variant of the Robinson annulation, where bulky amines such as pyrrolidine are used, making the conjugate addition to methyl vinyl ketone (MVK) take place at the less hindered side of two possible enamines.

O O O N H N

methyl vinyl ketone (MVK)

N: O conjugate N O isomerization

addition

B: O O H N N O

Example 17

O N N O H H F Br PhH, 4 Å MS PhH, reflux, 12 h F reflux Br 578

O N H2O, reflux O O 1 h, 55% F Br F Br

Example 28

1. , PhH, reflux Ph N N H CH3O N H 2. MVK, cat. hydroquinone O PhH, reflux 3. NaOAc, HOAc, H2O

Ph Ph N N CH O N CH3O N 3 H H H H

O 22% 17% O O

References

1. Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76, 2029. Gilbert J. Stork (1921) was born in Brussels, Belgium. Being Jewish, he immigrated to the US due to rising antisemitism. He earned his Ph.D. at Wisconsin in 1945 and later became an assistant professor at Harvard. Since he was not awarded tenure in 1953, Stork moved to Columbia University where he has taught ever since. 2. Singerman, G.; Danishefsky, S. Tetrahedron Lett. 1964, 5, 2249. 3. Enamines: Synthesis, Structure, and Reactions; Cook, A. G., Ed.; Dekker: New York, 1969, 514. (Review). 4. Autrey, R. L.; Tahk, F. C. Tetrahedron 1968, 24, 3337. 5. Hickmott, P. W. Tetrahedron 1982, 38, 1975. (Review). 6. Hammadi, M.; Villemin, D. Synth. Commun. 1996, 26, 2901. 7. Bridge, C. F.; O'Hagan, D. J. Fluorine Chem. 1997, 82, 21. 8. Li, J. J.; Trivedi, B. K.; Rubin, J. R.; Roth, B. D. Tetrahedron Lett. 1998, 39, 6111. 9. Yehia, N. A. M.; Polborn, K.; Muller, T. J. J. Tetrahedron Lett. 2002, 43, 6907. 579

Strecker amino acid synthesis Sodium cyanide-promoted condensation of aldehyde and amine to afford D-amino nitrile, which may be hydrolyzed to D-amino acid.

2 2 O NaCN R + R R2 HN H HN H2N R1 H 1 1 AcOH R CN R CO2H

H+ H H 1 O O R

: 2 NH 1 1 R 2 R H R N NC H R : R2 H H2N iminium ion

R2 HN R2 HN tautomerization R1 NH NR1 + H OH H2O:

2 R :OH2 HN R2 H+ NH acidic amide HN R1 2 1 NH2 O hydrolysis R HO OH H+

R2 HN R2 NH HN R1 3 1 HO O R CO2H H 580

Example 16 NH CHO Cl S acetone cyanohydrin o MgSO4, 45 C, toluene, 31%

OO CN Cl Cl

N N S S Plavix

Example 213

CN NH2 O Ph Ph NaCN, NH4Cl CN NH2 i-PrOH, NH OH Ph 4 H 34% 35% H

References

1. Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 27. 2. Chakraborty, T. K.; Hussain, K. A; Reddy, G. V. Tetrahedron 1995, 51, 9179. 3. Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am. Chem. Soc. 1996, 118, 4910. 4. Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. Amino Acids 1996, 11, 259. 5. Mori, A.; Inoue, S. Compr. Asymmetric Catal. I-III 1999, 2, 983. (Review). 6. Burgos, A.; Herbert, J. M.; Simpson, I. J. Labelled. Compd. Radiopharm. 2000, 43, 891. 7. Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762. 8. Ding, K.; Ma, D. Tetrahedron 2001, 57, 6361. 9. Matsumoto, K.; Kim, J. C.; Hayashi, N.; Jenner, G. Tetrahedron Lett. 2002, 43, 9167. 10. Yet, L. Recent Developments in Catalytic Asymmetric Strecker-Type Reactions, in Or- ganic Synthesis Highlights V, Schmalz, H.-G.; Wirth, T. eds., Wiley-VCH: Weinheim, Germany, 2003, pp 187193. (Review). 11. Meyer, U.; Breitling, E.; Bisel, P.; Frahm, A. W. Tetrahedron: Asymmetry 2004, 15, 2029. 12. Huang, J.; Corey, E. J. Org. Lett. 2004, 6, 5027. 13. Cativiela, C.; Lasa, M.; Lopez, P. Tetrahedron: Asymmetry 2005, 16, 2613. 581

Suzuki coupling Palladium-catalyzed cross-coupling reaction of organoboranes with organic halides, triflates, etc. in the presence of a base (transmetalation is reluctant to occur without the activating effect of a base). For the catalytic cycle, see Kumada coupling on page 345.

L2Pd(0) 1 2 1 RX R B(R )2 R R NaOR3

oxidative R L RX L Pd(0) Pd 2 X addition L

3 NaOR OR3 1 2 R B(R )2 1 2 R B(R )2 addition of base

OR3 R L transmetalation Pd R1 B(R2) X 2 L isomerization

L L reductive 3 2 1 R OB(R)2 Pd R R R1 L2Pd(0) R elimination

Example 11

I CO Me 2 O + B CO2Me N O CO2Et

Pd(OAc)2 CO2Me Ph3P, K2CO3 CO Me THF, MeOH N 2 70 °C, 15 h, 80% CO2Et 582

Example 24

B(OH)2

I I N N N TBS I I N I N N Pd(Ph P) , Na CO , 45% SEM 3 4 2 3 SEM TBS

References

1. Tidwell, J. H.; Peat, A. J.; Buchwald, S. L. J. Org. Chem. 1994, 59, 7164. 2. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 24572483. (Review). 3. Suzuki, A. In Metal-catalyzed Cross-coupling Reactions; Diederich, F.; Stang, P. J., Eds.; WileyVCH: Weinhein, Germany, 1998, 49–97. (Review). 4. Kawasaki, I.; Katsuma, H.; Nakayama, Y.; Yamashita, M.; Ohta, S. Heterocycles 1998, 48, 748 5. Stanforth, S. P. Tetrahedron 1998, 54, 263. (Review). 6. Li, J. J. Alkaloids: Chem. Biol. Perspect. 1999, 14, 437. (Review). 7. Groger, H. J. Prakt. Chem. 2000, 342, 334. 8. Franzen, R. Can. J. Chem. 2000, 78, 957. 9. LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa, J. R., Jr. Org. Lett. 2001, 3, 1555. 10. Collier, P. N.; Campbell, A. D.; Patel, I.; Raynham, T. M.; Taylor, R. J. K. J. Org. Chem. 2002, 67, 1802. 11. Urawa, Y.; Ogura, K. Tetrahedron Lett. 2003, 44, 271. 12. 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, 211229. Wiley-VCH: Weinheim, Germany. (Review). 13. Leadbeater, N. E. Chem. Commun. 2005, 2881. 583

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 1 2 R R R R then Et3N

S O O O O O O Cl S Cl Cl S Cl Cl O O Cl O

Cl Cl H S H S O :NEt3 CO2n COn :O H 1 2 R1 R2 R R

S O Et N HCl O 3 x p 1 2 (CH3)2Sn H R R R1 R2 sulfur ylide

Example 15

OH O C H C11H23 (COCl) , DMSO 11 23 C6H13 2 C6H13

then Et3N, 89% OSiMe2t-Bu OSiMe2t-Bu 584

Example 211

OMe OMe O N3 HO N3 (COCl)2, DMSO OTBDPS OTBDPS then Et3N, 85% N N

References

1. Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1976, 41, 3329. 2. Huang, S. L.; Omura, K.; Swern, D. Synthesis 1978, 4, 297. 3. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480. 4. Tidwell, T. T. Org. React. 1990, 39, 297. (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 6. Nakajima, N.; Ubukata, M. Tetrahedron Lett. 1997, 38, 2099. 7. Harris, J. M.; Liu, Y.; Chai, S.; Andrews, M. D.; Vederas, J. C. J. Org. Chem. 1998, 63, 2407. (odorless protocol). 8. Bailey, P. D.; Cochrane, P. J.; Irvine, F.; Morgan, K. M.; Pearson, D. P. J.; Veal, K. T. Tetrahedron Lett. 1999, 40, 4593. 9. Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J. Tetrahedron Lett. 1999, 40, 5161. 10. Dupont, J.; Bemish, R. J.; McCarthy, K. E.; Payne, E. R.; Pollard, E. B.; Ripin, D. H. B.; Vanderplas, B. C.; Watrous, R. M. Tetrahedron Lett. 2001, 42, 1453. 11. 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. 12. Nishide, K.; Ohsugi, S.-i.; Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron Lett. 2002, 43, 5177. (New odorless protocols). 13. Firouzabadi, H.; Hassani, H.; Hazarkhani, H. Phosphorus, Sulfur Silicon Related Ele- ments 2003, 178, 149. 14. Nishide, K.; Patra, P. K.; Matoba, M.; Shanmugasundaram, K.; Node, M. Green Chem. 2004, 6, 142. 15. Kawaguchi, T.; Miyata, H.; Ataka, K.; Mae, K.; Yoshida, J.-i. Angew. Chem., Int. Ed. Engl. 2005, 44, 2413. 585

Takai iodoalkene synthesis Stereoselective conversion of an aldehyde to the corresponding E-vinyl iodide using CHI3 and CrCl2.

O CHI , CrCl 3 2 I R RH THF

I I CrCl CrCl2 H I 2 H I III I Cr Cl2

R O R H III Cr Cl2 CrIIICl III 2 Cl2Cr H I I III Cr Cl2

I R

A radical mechanism is recently proposed10

I I I I I H CrIIII H II Cr CrII

OCrIII O I I R H RHH I I CrIII CrII

OCrIII I OCrIII R I H I R R III CrII Cr 586

Example 12

CHI3, CrCl2

Ph CHO THF, 70% OTBS

20: 1 Ph I E:Z OTBS

Example 25

o OTES CHI3, CrCl2, 0 C

OHC CO2Me THF, 50%

OTES

I CO2Me

References

1. Takai, K.; Nitta, Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408. 2. Andrus, M. B.; Lepore, S. D.; Turner, T. M. J. Am. Chem. Soc. 1997, 119, 12159. 3. Arnold, D. P.; Hartnell, R. D. Tetrahedron 2001, 57, 1335. 4. Solsona, J. G.; Romea, P.; Urpi, F. Org. Lett. 2003, 5, 4681. 5. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2004, 45, 8717. 6. Dineen, T. A.; Roush, W. R. Org. Lett. 2004, 6, 2043. 7. Lipomi, D. J.; Langille, N. F.; Panek, J. S. Org. Lett. 2004, 6, 3533. 8. Paterson, I.; Mackay, A. C. Synlett 2004, 1359. 9. Mulzer, J.; Berger, M. J. Org. Chem. 2004, 69, 891. 10. Concellón, J. M.; Bernad, P. L.; Méjica, C. Tetrahedron Lett. 2005, 46, 569. 587

Tebbe olefination Transformation of a carbonyl compound to the corresponding exo-olefin using Tebbe’s reagent.

O Cp Ti Al(CH ) 2 3 2 1 Cl RR Tebbe’s reagent

Cp2Ti O ClAl(CH3)2 RR1

H D-hydride transmetalation Cp2Ti Cp2TiCl2 2 Al(CH3)3 CH3 abstraction titanocene dichloride

Cl Al(CH3)2 CH4n Cp2Ti CH2 Cp2Ti Al(CH3)2 coordination Cl titanocene methylidene Tebbe’s reagent

Cp2Ti CH2 dissociation Cp2Ti Al(CH3)2 1 Cl Al(CH3)2 R Cl O R

[2 + 2] Cp2Ti CH2 retro-[2 + 2] Cp Ti O O 1 1 2 cycloaddition R cycloaddition RR R oxatitanacyclobutane formation of the strong Ti=O is the driving force.

Petasis alkenylation

The Petasis reagent (Me2TiCp2, dimethyltitanocene) undergoes similar olefination reactions with ketones and aldehydes. The originally proposed mechanism5 was very different from that of Tebbe olefination. However, 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.9 588

Example 13

O Tebbe's reagent, Tol.

CO2Et CO2Et 1 then 1, THF, 0 oC to rt, 30 min., 67%

Example 24

O 1. Cp2TiCl2, AlMe3, Tol, 3 d MeO 2. 2, THF, 40 oC, 30 min. Br 2 MeO then 0 oC, 1.5 h; rt, 1 h, 93%

MeO Br

MeO

References

1. Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978, 100, 3611. 2. Chou, T. S.; Huang, S. B. Tetrahedron Lett. 1983, 24, 2169. 3. 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. 4. Winkler, J. D.; Muller, C. L.; Scott, R. D. J. Am. Chem. Soc. 1988, 101, 4831. 5. Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392. 6. Schioett, B.; Joergensen, K. A. J. Chem. Soc., Dalton Trans. 1993, 337. 7. Pine, S. H. Org. React. 1993, 43, 198. (Review). 8. Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J. Am. Chem. Soc. 1996, 118, 1565. 9. Hughes, D. L.; Payack, J. F.; Cai, D.; Verhoeven, T. R.; Reider, P. J. Organometallics 1996, 15, 663. 10. Godage, H. Y.; Fairbanks, A. J. Tetrahedron Lett. 2000, 41, 7589. 11. Hartley, R. C.; McKiernan, G. J. J. Chem. Soc., Perkin 1 2002, 27632793. (Review). 12. Jung, M. E.; Pontillo, J. Tetrahedron 2003, 59, 2729. 589

TEMPO-mediated oxidation

NaOCl, cat. TEMPO O ROH ROH KBr, NaHCO3, CH2Cl2

TEMPO = tetramethyl pentahydropyridine oxide: NHAc

N O NHAc NHAc

1/2 NaOCl N N O O

NHAc NHAc

NHAc : : N N O O N O : O Cl

NHAc NHAc NHAc

N N N OH O O 590

NHAc

NHAc N OO H N HR O : HO R AcHNN O

O O :B RH H R O Cl O Cl

OH O RO RO

Example 17

OH HO C NaOCl, cat. TEMPO 2 O O HO HO HO OMe HO OMe KBr, NaHCO3, CH2Cl2 OH OH 55%

Example 210

O cat. TEMPO, 2 eq. 2,6-lutidine

electrolysis in CH3CN/H2O (95:5) 95% 591

Example 312

OH Ormosil-TEMPO, NaOCl OH OH CO2H CH3CN, NaHCO3, 5% Cl Cl 0 oC, 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. 2. Yamaguchi, M.; Miyazawa, T.; Takata, T.; Endo, T. Pure Appl. Chem. 1990, 62, 217. 3. Adams, G. W.; Bowie, J. H.; Hayes, R. N.; Gross, M. L. J. Chem. Soc., Perkin Trans. 2 1992, 897. 4. de Nooy, A. E.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153. (Review). 5. Rychnovsky, S.D.; Vaidyanathan, R. J. Org. Chem. 1999, 64, 310. 6. Bakunov, S. A.; Rukavishnikov, A. V.; Tkachev, A. V. Synthesis 2000, 1148. 7. Fabbrini, M.; Galli, C.; Gentili, P.; Macchitella, D. Tetrahedron Lett. 2001, 42, 7551. 8. Ciriminna, R.; Pagliaro, M. Tetrahedron Lett. 2004, 45, 6381. 9. Tashino, Y.; Togo, H. Synlett 2004, 2010. 10. Breton, T.; Liaigre, D.; Belgsir, E. M. Tetrahedron Lett. 2005, 46, 2487. 11. Chauvin, A.-L.; Nepogodiev, S. A.; Field, R. A. J. Org. Chem. 2005, 47, 960. 12. Gancitano, P.; Ciriminna, R.; Testa, M. L.; Fidalgo, A.; Ilharco, L. M.; Pagliaro, M. Org. Biomol. Chem. 2005, 3, 2389. 592

ThorpeZiegler 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 N HOEt

CN EtO H CN NH NH HOEt 2

Example 1, a radical ThorpeZiegler reaction5

Bu SnH, AIBN H N CN CN 3 2 syringe pump NC Br PhH, 80 oC, 56%

Example 210

CN LDA, THF o NH 78 C to rt 2 CN N N CN 2 h, 80% Ph Ph 593

References

1. Baron, H.; Remfry, F. G. P.; Thorpe, Y. F. J. Chem. Soc. 1904, 85, 1726. 2. Ziegler, K. et al. Justus Liebigs Ann. Chem. 1933, 504, 94. Karl Ziegler (18981973), born in Helsa, Germany, received his Ph.D. in 1920 from von Auwers at the Univer- sity of Marburg. He became the director of the Max-Planck-Institut für Kohlenfor- schung at Mülheim/Ruhr in 1943. He shared the Nobel Prize in Chemistry in 1963 with Giulio Natta (19031979) for their work in polymer chemistry. The ZieglerNatta catalyst is widely used in polymerization. 3. Rodriguez-Hahn, L.; Parra M., M.; Martinez, M. Synth. Commun. 1984, 14, 967. 4. Yakovlev, M. Yu.; Kadushkin, A. V.; Solov’eva, N. P.; Granik, V. G. Heterocyclic Commun. 1998, 4, 245. 5. Curran, D. P.; Liu, W. Synlett 1999, 117. 6. Dansou, B.; Pichon, C.; Dhal, R.; Brown, E.; Mille, S. Eur. J. Org. Chem. 2000, 1527. 7. Kovacs, L. Molecules 2000, 5, 127. 8. Gutschow, M.; Powers, J. C. J. Heterocycl. Chem. 2001, 38, 419. 9. Keller, L.; Dumas, F.; Pizzonero, M.; d’Angelo, J.; Morgant, G.; Nguyen-Huy, D. Tet- rahedron Lett. 2002, 43, 3225. 10. Malassene, R.; Toupet, L.; Hurvois, J.-P.; Moinet, C. Synlett 2002, 895. 11. Malassene, R.; Vanquelef, E.; Toupet, L.; Hurvois, J.-P.; Moinet, C. Org. Biomol. Chem. 2003, 1, 547. 12. Satoh, T.; Wakasugi, D. Tetrahedron Lett. 2003, 44, 7517. 13. Wakasugi, D.; Satoh, T. Tetrahedron 2005, 61, 1245. 594

TsujiTrost reaction Palladium-catalyzed allylation using nucleophiles with allylic halides, acetates, carbonates, etc. via intermediate allylpalladium complexes, and typically with overall retention of stereochemistry.

N BnO BnO N Pd2(dba)3, dppb O O H

o 72% BnO N BnO OPh THF, 60–70 C N

Pd(0)Ln BnO BnO Pd(0)Ln O O coordination BnO OPh BnO OPh

BnO Pd(II)Ln BnO O O Pd(II)Ln H BnO N BnO N S-allyl complex

BnO O Pd(0)L BnO N n N Example 14

NH2 N N N NH2 N N OAc H AcO N AcO N NaH, Pd(Ph3P)4, DMF N 60 oC, 18 h, 79% 595

Example 27

N N N H O HO N

Pd(Ph3P)4, THF rt, 64 h, 35%

References

1. Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 6, 4387. 2. Tsuji, J. Acc. Chem. Res. 1969, 2, 144. (Review). 3. Godleski, S. A. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., eds.; Vol. 4. Chapter 3.3. Pergamon: Oxford, 1991. (Review). 4. Saville-Stones, E. A.; Lindell, S. D.; Jennings, N. S.; Head, J. C.; Ford, M. J. J. Chem. Soc., Perkin Trans. 1 1991, 2603. 5. Bolitt, V.; Chaguir, B.; Sinou, D. Tetrahedron Lett. 1992, 33, 2481. 6. Moreno-Mañas, M.; Pleixats, R. In Advances in Heterocyclic Chemistry; Katritzky, A. R., ed.; Academic Press: San Diego, 1996, 66, 73. (Review). 7. Arnau, N.; Cortes, J.; Moreno-Mañas, M.; Pleixats, R.; Villarroya, M. J. Heterocycl. Chem. 1997, 34, 233. 8. Tietze, L. F.; Nordmann, G. Eur. J. Org. Chem. 2001, 3247. 9. Sato, Y.; Yoshino, T.; Mori, M. Org. Lett. 2003, 5, 31. 10. Page, P. C. B.; Heaney, H.; Reignier, S.; Rassias, G. A. Synlett 2003, 22. 11. Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044. 596

Ugi reaction Four-component condensation (4CC) of carboxylic acids, C-isocyanides, amines, and carbonyl compounds to afford diamides. Cf. Passerini reaction.

1 2 3 RCO2H R NH2 R CHO R NC isocyanide

2 O R H N RN R3 R1 O

O 1 R2 HO H NR

N: 2 H R2 R1 R : 1 H H R NH2 imine

H NR1 R3 2 ON O R H RCO2H O N H RO : R1 R C R2 N R3

+ R3 H 2 N O R H O N RN R3 O 2 R 1 R N R O R1 597

Example 110

OMe OMOM C BnO N O I NH2 H O BocHN O OTBDPS O CO2H

OMOM NHPMP

O MeOH, ' NHBoc N O OMe 1 h, 90% O O TBDPSO I OBn

Example 213

O CO H O N NH2 HN 2 2 O2S N N OMe C OTBS CHO

O2N O2S N O MeOH, ' OO NHt-Bu 61% N HN OMe

OTBS 598

References

1. Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8. 2. Skorna, G.; Ugi, I. Chem. Ber. 1979, 112, 776. 3. Hoyng, C. F.; Patel, A. D. Tetrahedron Lett. 1980, 21, 4795. 4. Ugi, I.; Lohberger, S.; Karl, R. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 2, 1083. (Review). 5. Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (Review). 6. Ugi, I. Pure Appl. Chem. 2001, 73, 187. (Review). 7. Zimmer, R.; Ziemer, A.; Grunner, M.; Brüdgam, I.; Hartl, H.; Reissig, H.-U. Synthesis 2001, 1649. 8. Kennedy, A. L.; Fryer, A. M.; Josey, J. A. Org. Lett. 2002, 4, 1167. 9. Baldoli, C.; Maiorana, S.; Licandro, E.; Zinzalla, G.; Perdicchia, D. Org. Lett. 2002, 4, 4341. 10. Portlock, D. E.; Ostaszewski, R.; Naskar, D.; West, L. Tetrahedron Lett. 2003, 44, 603. 11. Beck, B.; Larbig, G.; Mejat, B.; Magnin-Lachaux, M.; Picard, A.; Herdtweck, E.; Doemling, A. Org. Lett. 2003, 5, 1047. 12. Hebach, C.; Kazmaier, U. Chem. Commun. 2003, 596. 13. Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7, 47. 599

Ullmann reaction 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 15

NO2 NO2 Cu powder, DMF N N N Cl 100105 oC, 4 h, 63% O2N

Example 26

O N S O N Cu NMP, rt, 88% I I

References

1. Ullmann, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174. Fritz Ullmann (18751939), born in Fürth, Bavaria, studied under Graebe at Geneva. He taught at the Technische Hochschule in Berlin and the University of Geneva. 2. Ullmann, F. Justus Liebigs Ann. Chem. 1904, 332, 38. 3. Fanta, P. E. Chem. Rev. 1946, 38, 139. (Review). 4. Fanta, P. E. Synthesis 1974, 9. (Review). 5. Dhal, R.; Landais, Y.; Lebrun, A.; Lenain, V.; Robin, J.-P. Tetrahedron 1994, 50, 1153. 600

6. Zhang, S.; Zhang, D.; Liebskind, L. S. J. Org. Chem. 1997, 62, 2312. 7. Stark, L. M.; Lin, X.-F.; Flippin, L. A. J. Org. Chem. 2000, 65, 3227. 8. Belfield, K. D.; Schafer, K. J.; Mourad, W.; Reinhardt, B. A. J. Org. Chem. 2000, 65, 4475. 9. Venkatraman, S.; Li, C.-J. Tetrahedron Lett. 2000, 41, 4831. 10. Farrar, J. M.; Sienkowska, M.; Kaszynski, P. Synth. Commun. 2000, 30, 4039. 11. Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583. 12. Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4, 1623. 13. Hameurlaine, A.; Dehaen, W. Tetrahedron Lett. 2003, 44, 957. 14. Nelson, T. D.; Crouch, R. D. Org. React. 2004, 63, 265556. (Review). 601 van Leusen oxazole synthesis 5-Substituted oxazoles through the reaction of p-tolylsulfonylmethyl isocyanide (TosMIC) with aldehydes in protic solvents at refluxing temperatures.

N OO O S NC K2CO3 H O MeOH, reflux p-tolylsulfonylmethyl isocyanide (TosMIC)

OO OO N S N S C C H B O R

OO N N Tos + S C + H O R O R

H N Tos H HHN TosH O O R H R B

Example 17

O H OO H S NC Pr N Pr

HN 602

N O H NaOMe Pr N MeOH, reflux Pr 81% HN

Example 210

O NC O N O O S K2CO3 EtO EtO H O O DMF, 80%

References

1. van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron Lett. 1972, 13, 2369. 2. Possel, O.; van Leusen, A. M. Heterocycles 1977, 7, 77. 3. Saikachi, H.; Kitagawa, T.; Sasaki, H.; van Leusen, A. M. Chem. Pharm. Bull. 1979, 27, 793. 4. van Nispen, S. P. J. M.; Mensink, C.; van Leusen, A. M. Tetrahedron Lett. 1980, 21, 3723. 5. van Leusen, A. M.; van Leusen, D. In Encyclopedia of Reagents of Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 7, 49734979. (Review). 6. Sisko, J.; Mellinger, M.; Sheldrake, P. W.; Baine, N. Tetrahedron Lett. 1996, 37, 8113; 7. 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. 8. Kulkarni, B. A.; Ganesan, A. Tetrahedron Lett. 1999, 40, 5633. 9. Kulkarni, B. A.; Ganesan, A. Tetrahedron Lett. 1999, 40, 5637. 10. Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen, M. A. J. Org. Chem. 2000, 65, 1516. 11. Barrett, A. G. M.; Cramp, S. M.; Hennessy, A. J.; Procopiou, P. A.; Roberts, R. S. Or- ganic Lett. 2001, 3, 271. 12. Herr, R. J.; Fairfax, D. J., Meckler, H.; Wilson, J. D. Org. Process Rec. Dev. 2002, 6, 677. 13. 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, 254259. (Review). 603

VilsmeierHaack 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 Cl P Cl SN2 NOPCl2 Cl NO: H Cl H

O

NO: PCl 2 NH O H Cl Cl OPCl2 Vilsmeier–Haack reagent

O O: O

H Cl H NH B Cl H N Cl N:

O O O aqueous

H : : workup O HO H HN CHO H N 604

Example 13

DMF, POCl N 3 N CHO 100 oC, 83% N N

Example 22

DMF, POCl OMe 3 MeO o OH 100 C, 14 h, 98%

OHC OMe MeO

References

1. Vilsmeier, A.; Haack, A. Ber. Dtsch. Chem. Ges. 1927, 60, 119. 2. Reddy, M. P.; Rao, G. S. K. J. Chem. Soc., Perkin Trans. 1 1981, 2662. 3. Lancelot, J.-C.; Ladureé, D.; Robba, M. Chem. Pharm. Bull. Jpn. 1985, 33, 3122. 4. Marson, C. M.; Giles, P. R. Synthesis Using Vilsmeier Reagents CRC Press, 1994. (Book). 5. Seybold, G. J. Prakt. Chem. 1996, 338, 392396 (Review). 6. Jones, G.; Stanforth, S. P. Org. React. 1997, 49, 1. (Review). 7. Jones, G.; Stanforth, S. P. Org. React. 2000, 56, 1. (Review). 8. Ali, M. M.; Tasneem; Rajanna, K. C.; Sai Prakash, P. K. Synlett 2001, 251. 9. Thomas, A. D.; Asokan, C. V. J. Chem. Soc., Perkin Trans. 1 2001, 2583. 10. Tasneem, Synlett 2003, 138. (Review of the Vilsmeier–Haack reagent). 605

Vilsmeier mechanism for acid chloride formation

Transformation of a carboxylic acid to the corresponding acid chloride using oxalyl chloride and catalytic amount of dimethyl formamide (DMF). It is a lot faster than without DMF, which generally needs reflux.

O (COCl)2, cat. DMF O

ROH CH2Cl2, rt RCl

O O NO Cl Cl Cl NO: HO O H Cl DMF oxalyl chloride

O NH NO: Cl CO2n COn H Cl Cl O Cl Vilsmeier–Haack reagent

NH

Cl NO: R O H H Cl O RO

Cl CHO O NOR N RCl H O DMF recovered, therefore only catalytic amount is required 606

Vinylcyclopropanecyclopentene rearrangement Transformation of vinylcyclopropane to cyclopentene via a diradical intermediate.

R2 ' R2

R1 R1

R2 R2

R1 R1

R2 R2

R 1 R1

Example 15

O

340 oC, 2 h O CO2Me

CO2Me 50%

Example 26

1. n-BuLi, THF-HMPT 78 to 30 oC;

2. PhCH2Br SO2Ph Ph 3. desulfonylation, 77%

References

1. Neureiter, N. P. J. Org. Chem. 1959, 24, 2044. 2. Vogel, E. Angew. Chem. 1960, 72, 4. 3. Overberger, C. G.; Borchert, A. E. J. Am. Chem. Soc. 1960, 82, 1007, 4896. 4. Flowers, M. C.; Frey, H. M. J. Chem. Soc. 1961, 3547. 5. Brule, D.; Chalchat, J. C.; Garry, R. P.; Lacroix, B.; Michet, A.; Vessier, R. Bull. Soc. Chim. Fr. 1981, 57. 607

6. Danheiser, R. L.; Bronson, J. J.; Okano, K. J. Am. Chem. Soc. 1985, 107, 4579. 7. Hudlický, T.; Kutchan, T. M.; Naqvi, S. M. Org. React. 1985, 33, 247335. (Review). 8. Goldschmidt, Z.; Crammer, B. Chem. Soc. Rev. 1988, 17, 229267. (Review). 9. Sonawane, H. R.; Bellur, N. S.; Kulkarni, D. G.; Ahuja, J. R. Synlett 1993, 875884. (Review). 10. Hiroi, K.; Arinaga, Y. Tetrahedron Lett. 1994, 35, 153. 11. Chuang, S.-C.; Islam, A.; Huang, C.-W.; Shih, H.-T.; Cheng, C.-H. J. Org. Chem. 2003, 68, 3811. 12. Baldwin, J. E. Chem. Rev. 2003, 103, 11971212. (Review). 13. Smart, B. E.; Krusic, P. J.; Roe, D. C.; Yang, Z.-Y. J. Fluorine Chem. 2004, 117, 199. 608 von Braun reaction Treatment of tertiary amines with cyanogen bromide, resulting in a substituted cyanamide and alkyl halides.

CN R Br CN Br R 1 N 1 N R R2 R R2

Cyanogen bromide (BrCN) is a counterattack reagent.

Br NC Br R SN2 CN R Br R N: CN 1 N R1 R 1 N R R2 2 R R2

Example 16

CF CF3 3

O Br-CN O CN N Tol. N

CF3

KOH, glycol O Prozac water N H

Example 27

CO2Me CO2Me CO2Me CO2Me Br-CN, THF, H2O Br N 79% N CN 609

References

1. von Braun, J. Ber. Dtsch. Chem. Ges. 1907, 40, 3914. Julius von Braun (18751940) was born in Warsaw, Poland. He was a Professor of Chemistry at Frankfurt. 2. Hageman, H. A. Org. React. 1953, 7, 198. (Review). 3. Fodor, G.; Abidi, S.-Y.; Carpenter, T. C. J. Org. Chem. 1974, 39, 1507. 4. Nakahara, Y.; Niwaguchi, T.; Ishii, H. Tetrahedron 1977, 33, 1591. 5. Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 12791300. (Review). 6. Perni, R. B.; Gribble, G. W. Org. Prep. Proced. Int. 1980, 15, 297. 7. Verboom, W.; Visser, G. W.; Reinhoudt, D. N. Tetrahedron 1982, 38, 1831. 8. McLean, S.; Reynolds, W. F.; Zhu, X. Can. J. Chem. 1987, 65, 200. 9. Cooley, J. H.; Evain, E. J. Synthesis 1989, 1. 10. Aguirre, J. M.; Alesso, E. N.; Ibanez, A. F.; Tombari, D. G.; Moltrasio Iglesias, G. Y. J. Heterocycl. Chem. 1989, 26, 25. 11. Laabs, S.; Scherrmann, A.; Sudau, A.; Diederich, M.; Kierig, C.; Nubbemeyer, U. Synlett 1999, 25. 12. Chambert, S.; Thomasson, F.; Décout, J.-L. J. Org. Chem. 2002, 67, 1898. 13. Hatsuda, M.; Seki, M. Tetrahedron 2005, 61, 9908. 610

Wacker oxidation Palladium-catalyzed oxidation of olefins to ketones.

cat. PdCl2, H2O O R R CuCl2, O2

R

oxidation olefin PdCl2 complexation

Pd(0) HCl Cl reductive elimination Pd Cl R HClPd

E-hydride : H O elimination H OH OH PdCl R nucleophilic H attack R HCl

tautomerization

O

R

Regeneration of Pd(II):

Pd(0) 2 CuCl2 PdCl2 2 CuCl

Regeneration of Cu(II):

CuCl O2 CuCl2 H2O 611

Example 16

O CO H 2 O O2, 5% Pd(OAc)2

NaOAc, DMSO, 80%

Example 210

O2, 20 mol% Cu(OAc)2 10 mol% PdCl2 OO OOO DMA/H2O (7:1) 84%

References

1. Smidt, J.; Sieber, R. Angew. Chem., Int. Ed. 1962, 1, 80. 2. Tsuji, J. Synthesis 1984, 369. (Review). 3. Miller, D. G.; Wayner, D. D. M. J. Org. Chem. 1990, 55, 2924. 4. Hegedus, L. S. In Comp. Org. Syn. Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 4, 552. (Review). 5. Tsuji, J. In Comp. Org. Syn. Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 7, 449. (Review). 6. Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298. 7. Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecule 1994, University Science Books: Mill Valley, CA, pp 199208. (Review). 8. Kang, S.-K.; Jung, K.-Y.; Chung, J.-U.; Namkoong, E.-Y.; Kim, T.-H. J. Org. Chem. 1995, 60, 4678. 9. Feringa, B. L. Wacker oxidation. In Transition Met. Org. Synth. Beller, M.; Bolm, C., eds., Wiley-VCH: Weinheim, Germany. 1998, 2, 307315. (Review). 10. 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. 11. Gaunt, M. J.; Yu, J.; Spencer, J. B. Chem. Commun. 2001, 1844. 12. Barker, D.; Brimble, M. A.; McLeod, M.; Savage, G. P.; Wong, D. J. J. Chem. Soc., Perkin Trans. 1, 2002, 924. 13. Thadani, A. N.; Rawal, V. H. Org. Lett. 2002, 4, 4321. 14. Ho, T.-L.; Chang, M. H.; Chen, C. Tetrahedron Lett. 2003, 44, 6955. 15. Hintermann, L. Wacker-type Oxidations. In Transition Met. Org. Synth. (2nd edn.) Bel- ler, M.; Bolm, C., eds., Wiley-VCH: Weinheim, Germany. 2004, 2, 379388. (Re- view). 16. Cornell, C. N.; Sigman, M. S. J. Am. Chem. Soc. 2005, 127, 2796. 612

Wagner–Meerwein rearrangement Acid-catalyzed alkyl group migration of alcohols to give more substituted olefins.

1 1 R R R R H+ H R2 OH R2 R3 R3

R 1 R + 1 R 1 R H R H2O R H H 2 H R2 R2 R OH OH 3 R3 R3 2 R

1 R 1 H+ R R H R2 R 2 3 R3 R R

Example 113

O O O O

OEt TFA, CH2Cl2 OEt HO 72 h, 76%

Example 214

Br HBr, THF OH 0 oC, 10 min., 85%

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. (Review). 3. Martinez, A. G.; Vilar, E. T.; Fraile, A. G.; Fernandez, A. H.; De La Moya Cerero, S.; Jimenez, F. M. Tetrahedron 1998, 54, 4607. 4. Birladeanu, L. J. Chem. Educ. 2000, 77, 858. 5. Kobayashi, T.; Uchiyama, Y. J. Chem. Soc., J. Chem. Soc., Perkin 1 2000, 2731. 6. Trost, B. M.; Yasukata, T. J. Am. Chem. Soc. 2001, 123, 7162. 613

7. Cerda-Garcia-Rojas, C. M.; Flores-Sandoval, C. A.; Roman, L. U.; Hernandez, J. D.; Joseph-Nathan, P. Tetrahedron 2002, 58, 1061. 8. Colombo, M. I.; Bohn, M. L.; Ruveda, E. A. J. Chem. Educ. 2002, 79, 484. 9. Román, L. U.; Cerda-Garcia-Rojas, C. M.; Guzmán, R.; Armenta, C.; Hernández, J. D.; Joseph-Nathan, P. J. Nat. Products 2002, 65, 1540. 10. Martinez, A. G.; Vilar, E. T.; Fraile, A. G.; Martinez-Ruiz, P. Tetrahedron 2003, 59, 1565. 11. Guizzardi, B.; Mella, M.; Fagnoni, M.; Albini, A. J. Org. Chem. 2003, 68, 1067. 12. Zubkov, F. I.; Nikitina, E. V.; Turchin, K. F.; Aleksandrov, G. G.; Safronova, A. A.; Borisov, R. S.; Varlamov, A. V. J. Org. Chem. 2004, 69, 432. 13. Bose, G.; Ullah, E.; Langer, P. Chem. Eur. J. 2004, 10, 6015. 14. Li, W.-D. Z.; Yang, Y.-R. Org. Lett. 2005, 7, 3107. 614

Weiss–Cook reaction Synthesis of cis-bicyclo[3.3.0]octane-3,7-dione.

EtO2C EtO2C R CO2Et O R aq. buffer O O O O R1 R1 EtO2C EtO2C CO2Et

R EtO2C EtO2C R O EtO2C H OH

O O 1 OO R O H R1 EtO2C EtO2C EtO2C

EtO C R H EtO C CO2Et 2 OH EtO C R 2 2 OH R OOO O O 1 OH 1 H H R 1 H R EtO2C R CO Et EtO2C H EtO2C 2

EtO2C R CO2Et EtO2C R CO2Et O O HO O H 1 1 H R R CO Et CO Et EtO2C 2 EtO2C 2

EtO2C R CO2Et EtO2C R CO2Et

HO O HO OH

R1 R1 EtO2C CO2Et EtO2C CO2Et 615

Example 12

CO CH 2 3 1. pH = 8.3 2. HOAc/HCl, ' O OO O CHO 90% CO CH 2 3 H

Example 23

CO2CH3 O 1. pH = 6.8 2. HOAc/HCl O OO O 80% CO2CH3

Example 36

O

MeO2C OO MeO2C O CO Me pH 5.6 2 O MeO2C CO2Me 86% MeO2C

References

1. Weiss, U.; Edwards, J. M. Tetrahedron Lett. 1968, 9, 4885. 2. Kubiak, G.; Fu, X.; Gupta, A. K.; Cook, J. M. Tetrahedron Lett. 1990, 31, 4285. 3. Wrobel, J.; Takahashi, K.; Honkan, V.; Lannoye, G.; Bertz, S. H.; Cook, J. M. J. Org Chem. 1983, 48, 139. 4. Gupta, A. K.; Fu, X.; Snyder, J. P.; Cook, J. M. Tetrahedron 1991, 47, 3665. 5. Reissig, H. U. Org. Synth. Highlights 1991, 121. (Review). 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. 7. Fu, X.; Cook, J. M. Aldrichimica Acta 1992, 25, 43. (Review). 8. Fu, X.; Kubiak, G.; Zhang, W.; Han, W.; Gupta, A. K.; Cook, J. M. Tetrahedron 1993, 49, 1511. 9. van Ornum, S. G.; Li, J.; Kubiak, G. G.; Cook, J. M. J. Chem. Soc., Perkin Trans. 1 1997, 3471. 10. Cadieux, J. A.; Buller, J. D.; Wilson, P. D. Org. Lett. 2003, 5, 3983. 616

Wharton oxygen transposition reaction Reduction of DE-epoxy ketones by hydrazine to allylic alcohols.

NH2NH2 N2n H2O O ' O OH

O OH O O NH NH2 :NH2NH2 :

:OH2 H tautomerization H H O N N H 2 N H O N O

+ + H3O Nn O OH

Example 15

O OH O

NH2NH2•H2O, MeOH N N TEOC H HOAc, rt, 52% TEOC H 617

Example 27 O

O NH2NH2•H2O, MeOH TESO OH TESO O O HOAc, rt, 59% O O

References

1. Wharton, P. S.; Bohlen, D. H. J. Org. Chem. 1961, 26, 3615. 2. Wharton, P. S. J. Org. Chem. 1961, 26, 4781. 3. Caine, D. Org. Prep. Proced. Int. 1988, 20, 1. (Review). 4. Dupuy, C.; Luche, J. L. Tetrahedron 1989, 45, 34373444. (Review). 5. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. 6. Di Filippo, M.; Fezza, F.; Izzo, I.; De Riccardis, F.; Sodano, G. Eur. J. Org. Chem. 2000, 3247. 7. Takagi, R.; Tojo, K.; Iwata, M.; Ohkata, K. Org. Biomol. Chem. 2005, 3, 2031.

618

Willgerodt–Kindler reaction Conversion of ketones to the corresponding thioamide and/or ammonium salt.

O S HN O N

TsOH, S8, ' O thioamide

In Carmack’s mechanism,8 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: SH S S S S S O N S S S S S S SS SS O NH O NH

sulfenamide

O

N: O

SH N S S S N S O N S O HS S

O N S

O O N O S N N S N H O thiirene 619

O O

N N S S

N HN O O

O O :N N S S

:N N O O

N N

O O

S S 8 N O

Example 1, the Willgerodt–Kindler reaction was a key operation in the initial synthesis of racemic Naproxen:6

O HN O O N

S8 O O O 620

1. H+ OH 2. CH3OH, H2SO4 O O 3. NaH, CH3I 4. NaOH naproxen Example 211

S O HN O N

S8, microwave O 4 min., 40%

References

1. Willgerodt, C. Ber. Dtsch. Chem. Ges. 1887, 20, 2467. Conrad Willgerodt (18411930), 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. 2. Kindler, K. Arch. Pharm. 1927, 265, 389. 3. Carmack, M. Org. React. 1946, 3, 83. (Review). 4. Schneller, S. W. Int. J. Sulfur Chem. B 1972, 7, 155. 5. Schneller, S. W. Int. J. Sulfur Chem. 1973, 8, 485. 6. Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Roskowski, A.; Tomolonis, A.; Fried, J. H. J. Med. Chem. 1970, 13, 203. 7. Schneller, S. W. Int. J. Sulfur Chem. 1976, 8, 579. 8. Carmack, M. J. Heterocycl. Chem. 1989, 26, 1319. 9. You, Q.; Zhou, H.; Wang, Q.; Lei, X. Org. Prep. Proced. Int. 1991, 23, 435. 10. Chatterjea, J. N.; Singh, R. P.; Ojha, N.; Prasad, R. J. Inst. Chem. (India) 1998, 70, 108. 11. Nooshabadi, M.; Aghapoor, K.; Darabi, H. R.; Mojtahedi, M. M. Tetrahedron Lett. 1999, 40, 7549. 12. Moghaddam, F. M.; Ghaffarzadeh, M.; Dakamin, M. G. J. Chem. Res., (S) 2000, 228. 13. Poupaert, J. H.; Bouinidane, K.; Renard, M.; Lambert, D. M.; Isa, M. Org. Prep. Pro- ced. Int. 2001, 33, 335. 14. Alam, M. M.; Adapa, S. R. Synth. Commun. 2003, 33, 59. 15. Reza Darabi, H.; Aghapoor, K.; Tajbakhsh, M. Tetrahedron Lett. 2004, 45, 4167. 16. Purrello, G. “Some aspects of the WillgerodtKindler reaction and connected reactions.” Heterocycles 2005, 65, 411449. (Review). 621

Wittig reaction Olefination of carbonyls using phosphorus ylides.

1 X R R1 base Ph3P Ph P H RX 3 R

R3 1 R 2 R3 R O 1 Ph P 2 R 3 Ph3PO R R R

X 1 R1 R Ph3P: SN2 Ph3P H RX R :B

O Ph3P 1 2 R R R1 [2 + 2] Ph3P R cycloaddition R3 R “puckered” transition state, irreversible and concerted

R3 Ph3PO 1 Ph PO 2 R R R3 3 R R1 R2 R oxaphosphetane intermediate

Example 13

NaH, Et2O; then add CHO + CH2=CHPPh3 Br

NHTs N DMF, reflux, 48 h, 50% Ts 622

Example 24

2.0 N KOH, i-PrOH Cl PPh 3 HO O o O 30 C, 1.5 h, 91.5%

CO2H

CO2H

Accutane 2-cis-4-cis-vitamin A acid

Schlosser modification of the Wittig reaction1117 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

1 Ph3P H t-BuOK R R R1 O

Br H Ph3P Ph P H Ph P H 3 3 R R R R1 O Ph phosphorus ylide

Br Br Ph3POLi Ph3POLi t-BuOH 1 RRH 1 RRLi Ph LiBr complex of E-oxo ylide 623

PPh3 Br t-BuOH R LiO R H Ph3PO LiBr t-BuOK R1 H R1 LiBr complex of threo-betaine

References 1. Wittig, G.; Schöllkopf, U. Ber. Dtsch. Chem. Ges. 1954, 87, 1318. Georg Wittig (Germany, 18971987), 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, 19122004) for their development of organic boron and phosphorous compounds. 2. Maercker, A. Org. React. 1965, 14, 270490. (Review). 3. Schweizer, E. E.; Smucker, L. D. J. Org. Chem. 1966, 31, 3146. 4. Garbers, C. F.; Schneider, D. F.; van der Merwe, J. P. J. Chem. Soc. (C) 1968, 1982 5. Murphy, P. J.; Brennan, J. Chem. Soc. Rev. 1988, 17, 130. (Review). 6. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1988, 89, 863927. (Review). 7. Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1. (Review). 8. Heron, B. M. Heterocycles 1995, 41, 2357. 9. Murphy, P. J.; Lee, S. E. J. Chem. Soc., Perkin Trans. 1 1999, 3049. 10. Blackburn, L.; Kanno, H.; Taylor, R. J. K. Tetrahedron Lett. 2003, 44, 115. 11. Schlosser, M.; Christmann, K. F. Angew. Chem., Int. Ed. Engl. 1966, 5, 126. 12. Schlosser, M.; Christmann, K. F. Justus Liebigs Ann. Chem. 1967, 708, 35. 13. Schlosser, M.; Christmann, K. F.; Piskala, A.; Coffinet, D. Synthesis 1971, 29. 14. Deagostino, A.; Prandi, C.; Tonachini, G.; Venturello, P. Trends Org. Chem. 1995, 5, 103. (Review). 15. Celatka, C. A.; Liu, P.; Panek, J. S. Tetrahedron Lett. 1997, 38, 5449. 16. Duffield, J. J.; Pettit, G. R. J. Nat. Products 2001, 64, 472. 624

[1,2]-Wittig rearrangement Treatment of ethers with alkyl lithium results in alcohols.

R2Li R1 R1 R O 2 R OH 1 2 1

R2 deprotonation R1 H RO R1 RO

1 1 [1,2]-sigmatropic R workup R rearrangement RO ROH

The radical mechanism is also possible as radical intermediates have been identi- fied.

Example 14

NOMe NOMe 2 eq. LDA, THF O o OH O 78 C, 82% O

Example 25

OTBS n-BuLi, THF TBSO O Ph

20 to 0 oC, 32%

TBSO OH TBSO Ph 625

References

1. Wittig, G.; Löhmann, L. Justus Liebigs Ann. Chem. 1942, 550, 260. 2. Tomooka, K.; Yamamoto, H.; Nakai, T. Justus Liebigs Ann. Chem. 1997, 1275. 3. Maleczka, R. E., Jr.; Geng, F. J. Am. Chem. Soc. 1998, 120, 8551. 4. Miyata, O.; Asai, H.; Naito, T. Synlett 1999, 1915. 5. Tomooka, K.; Kikuchi, M.; Igawa, K.; Suzuki, M.; Keong, P.-H.; Nakai, T. Angew. Chem., Int. Ed. 2000, 39, 4502. 6. Katritzky, A. R.; Fang, Y. Heterocycles 2000, 53, 1783. 7. Kitagawa, O.; Momose, S.; Yamada, Y.; Shiro, M.; Taguchi, T. Tetrahedron Lett. 2001, 42, 4865. 8. Barluenga, J.; Fañanás, F. J.; Sanz, R.; Trabada, M. Org. Lett. 2002, 4, 1587. 9. Lemiègre, L.; Regnier, T.; Combret, J.-C.; Maddaluno, J. Tetrahedron Lett. 2003, 44, 373. 10. Wipf, P.; Graham, T. H. J. Org. Chem. 2003, 68, 8798. 11. Miyata, O.; Koizumi, T.; Asai, H.; Iba, R.; Naito, T. Tetrahedron 2004, 60, 3893. 12. Miyata, O.; Hashimoto, J.; Iba, R.; Naito, T. Tetrahedron Lett. 2005, 46, 4015. 626

[2,3]-Wittig rearrangement Transformation of allyl ethers into homoallylic alcohols by treatment with base. Also known as StillWittig rearrangement. Cf. SommeletHauser rearrangement

2 2 3 1 1 [2,3]-sigmatropic 3 1 X Y Y rearrangement X 2 2 1

R R2Li 1 R OR1 R OH R1 = alkynyl, alkenyl, Ph, COR, CN.

R R OR1 deprotonation O H R1 R2

[2,3]-sigmatropic R R workup rearrangement OR1 HO R1

Example 13

LDA, THF 74% E

OCOH o 2 78 C, 80% HO CO2H

Example 22

KOt-Bu, HOt-Bu, THF O o O 0 C, 26 h, 22% HO O 627

References

1. Cast, J.; Stevens, T. S.; Holmes, J. J. Chem. Soc. 1960, 3521. 2. Thomas, A. F.; Dubini, R. Helv. Chim. Acta 1974, 57, 2084. 3. Nakai, T.; Mikami, K.; Taya, S.; Kimura, Y.; Mimura, T. Tetrahedron Lett. 1981, 22, 69. 4. Nakai, T.; Mikami, K. Org. React. 1994, 46, 105209. (Review). 5. Bertrand, P.; Gesson, J.-P.; Renoux, B.; Tranoy, I. Tetrahedron Lett. 1995, 36, 4073. 6. Maleczka, R. E., Jr.; Geng, F. Org. Lett. 1999, 1, 1111. 7. Tsubuki, M.; Kamata, T.; Nakatani, M.; Yamazaki, K.; Matsui, T.; Honda, T. Tetrahe- dron: Asymmetry 2000, 11, 4725. 8. Itoh, T.; Kudo, K. Tetrahedron Lett. 2001, 42, 1317. 9. Pévet, I.; Meyer, C.; Cossy, J. Tetrahedron Lett. 2001, 42, 5215. 10. Anderson, J. C.; Skerratt, S. J. Chem. Soc., Perkin 1 2002, 2871. 11. Schaudt, M.; Blechert, S. J. Org. Chem. 2003, 68, 2913. 628

Wohl–Ziegler reaction Radical-initiated allylic bromination using NBS, and catalytic AIBN as initiator or NBS under photolysis.

NBS, AIBN Br CCl4, reflux Initiation:

' NC NN CN N2n 2 CN homolytic cleavage 2,2’-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. 629

Example 13

OAc OAc OAc O

NBS, CCl4

reflux, 30 min., 48% AcO AcO

Example 213

CO2Me 1.2 eq. NBS, 0.1 eq. AIBN CO2Me Br solvent free, 60 to 65 oC 89%

References

1. Wohl, A. Ber. Dtsch. Chem. Ges. 1919, 52, 51. Alfred Wohl (18631939), born in Graudenz, Germany, 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. et al. Justus Liebigs Ann. Chem. 1942, 551, 30. Karl Ziegler (18981973), 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 (19031979) for their work in polymer chemistry. The ZieglerNatta catalyst is widely used in polymerization. 3. Djerassi, C.; Scholz, C. R. J. Org. Chem. 1949, 14, 660. 4. Wolfe, S.; Awang, D. V. C. Can. J. Chem. 1971, 49, 1384. 5. Ito, I.; Ueda, T. Chem. Pharm. Bull. 1975, 23, 1646. 6. Pennanen, S. I. Heterocycles 1978, 9, 1047. 7. Rose, U. J. Heterocycl. Chem. 1991, 28, 2005. 8. Greenwood, J. R.; Vaccarella, G.; Capper, H. R.; Mewett, K. N.; Allan, R. D.; Johns- ton, G. A. R. THEOCHEM 1996, 368, 235. 9. Allen, J. G.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 351. 10. Jeong, I. H.; Park, Y. S.; Chung, M. W.; Kim, B. T. Synth. Commun. 2001, 31, 2261. 11. Detterbeck, R.; Hesse, M. Tetrahedron Lett. 2002, 43, 4609. 12. Stevens, C. V.; Van Heecke, G.; Barbero, C.; Patora, K.; De Kimpe, N.; Verhe, R. Synlett 2002, 1089. 13. Togo, H.; Hirai, T. Synlett 2003, 702. 630

Wolff rearrangement One-carbon homologation via the intermediacy of D-diazoketone and ketene.

H O H R2 NH 2 1 N 2 N N2n CCO R R 1 2 1 R R O D-diazoketone ketene intermediate

O O O N N N2 1 N 1 N R1 R R

O alkyl N n 2 1 CH: R migration D-ketocarbene

H+ H H H 1 N 2 1 N 2 CCO H+ R R R R R1 2 O O :NH2 R H Treatment of the ketene with water would give the corresponding homologated carboxylic acid.

Example 12

O O OO ' or hv H O EtOH, dioxane (1:1) N2 >90%

Example 24

O CO2Me N2 hv, MeOH O N O 90% N 631

References

1. Wolff, L. Justus Liebigs Ann. Chem. 1912, 394, 25. Johann Ludwig Wolff (18571919) obtained 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. 3. Meier, H.; Zeller, K. P. Angew. Chem., Int. ed. Engl. 1975, 14, 32. 4. Kappe, C.; Fäber, G.; Wentrup, C.; Kappe, T. Chem. Ber. 1993, 126, 2357. 5. Podlech, J.; Linder, M. R. J. Org. Chem. 1997, 62, 5873. 6. Wang, J.; Hou, Y. J. Chem. Soc., Perkin Trans. 1 1998, 1919. 7. Müller, A.; Vogt, C.; Sewald, N. Synthesis 1998, 837. 8. Lee, Y. R.; Suk, J. Y.; Kim, B. S. Tetrahedron Lett. 1999, 40, 8219. 9. Tilekar, J. N.; Patil, N. T.; Dhavale, D. D. Synthesis 2000, 395. 10. Yang, H.; Foster, K.; Stephenson, C. R. J.; Brown, W.; Roberts, E. Org. Lett. 2000, 2, 2177. 11. Xu, J.; Zhang, Q.; Chen, L.; Chen, H. J. Chem. Soc., Perkin Trans. 1 2001, 2266. 12. Kirmse, W. “100 years of the Wolff Rearrangement” Eur. J. Org. Chem. 2002, 2193. (Review). 13. Bogdanova, A.; Popik, V. V. J. Am. Chem. Soc. 2003, 125, 1456. 14. Julian, R. R.; May, J. A.; Stoltz, B. M.; Beauchamp, J. L. J. Am. Chem. Soc. 2003, 125, 4478. 15. Zeller, K.-P.; Blocher, A.; Haiss, P. “Oxirene participation in the Photochemical Wolff Rearrangement” Mini-Reviews in Organic Chemistry 2004, 1, 291308. (Review). 632

Wolff–Kishner reduction Carbonyl reduction to methylene using basic hydrazine.

O NH2NH2 1 1 RR RRNaOH, reflux

HO O H

NH : 2 N RR1 HO NH N H 1 1 : RR RR NH NH 2 2 H H O

HO O 1 N2 H H H NR 1 N RR

R RR1

Example 111

H N O 2 N 80% NH2NH2•H2O

toluene, microwave MeO C 2 20 min., 75% MeO2C

KOH, microwave

30 min., 40% MeO2C

Example 212

OH O

85% NH2NH2•H2O, KOH OH o H2O, 0.5 h, 165 C, 87%

HO 633

OH OH O

H

1,5-hydride shift HO

OH OH H H H

HO

References

1. Kishner, N. J. Russ. Phys. Chem. Soc. 1911, 43, 582. 2. Wolff, L. Justus Liebigs Ann. Chem. 1912, 394, 86. 3. Huang-Minlon J. Am. Chem. Soc. 1946, 68, 2487. (the Huang-Minlon modification). 4. Todd, D. Org. React. 1948, 4, 378. (Review). 5. Cram, D. J.; Sahyun, M. R. V.; Knox, G. R. J. Am. Chem. Soc. 1962, 84, 1734. 6. Szmant, H. H. Angew. Chem., Int. Ed. Engl. 1968, 7, 120. 7. Murray, R. K., Jr.; Babiak, K. A. J. Org. Chem. 1973, 38, 2556. 8. Akhila, A.; Banthorpe, D. V. Indian J. Chem. 1980, 19B, 998. 9. Bosch, J.; Moral, M.; Rubiralta, M. Heterocycles 1983, 20, 509. 10. Taber, D. F.; Stachel, S. J. Tetrahedron Lett. 1992, 33, 903. 11. Gadhwal, S.; Baruah, M.; Sandhu, J. S. Synlett 1999, 1573. 12. Szendi, Z.; Forgó, P.; Tasi, G.; Böcskei, Z.; Nyerges, L.; Sweet, F. Steroids 2002, 67, 31. 13. Bashore, C. G.; Samardjiev, I. J.; Bordner, J.; Coe, J. W. J. Am. Chem. Soc. 2003, 125, 3268. 634

Yamaguchi esterification Esterification using 2,4,6-trichlorobenzoyl chloride (the Yamaguchi reagent).

Cl O Cl OOCl Cl O Cl RO

ROH Et3N, CH2Cl2 Cl Cl

HO R1 O R DMAP, Tol., reflux RO1

Cl O OClO Cl Cl Cl RO :NEt Cl O 3 Cl Cl H RO

OOCl R O OCl RO N O

: Cl Cl N Cl Cl N

N DMAP (Dimethylaminopyridine) Steric hindrance of the chloro substituents blocks attack of the other carbonyl.

OCl O

O RN N Cl Cl R1 O: H 635

R O R O 1 ON R RO1 N

Example 19

OMe I CO2H OTES

OH 2,4,6-trichlorobenzoyl chloride n-Bu Sn DMAP, Tol., Et3N 3 ODMT OMe rt, 24 h, 89%

OMe I O

OTES O n-Bu Sn 3 ODMT OMe 636

Example 211

O OOO HO CO2H

2,4,6-trichlorobenzoyl chloride Et3N, THF

then DMAP, toluene, 62%

O OOO O

O

References

1. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989. 2. Kawanami, Y.; Dainobu, Y.; Inanaga, J.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1981, 54, 943. 3. Bartra, M.; Vilarrasa, J. J. Org. Chem. 1991, 56, 5132. 4. Richardson, T. I.; Rychnovsky, S. D. Tetrahedron 1999, 55, 8977. 5. Berger, M.; Mulzer, J. J. Am. Chem. Soc. 1999, 121, 8393. 6. Paterson, I.; Chen, D. Y.-K.; Aceña, J. L.; Franklin, A. S. Org. Lett. 2000, 2, 1513. 7. Hamelin, O.; Wang, Y.; Deprés, J.-P.; Greene, A. E. Angew. Chem., Int. Ed. 2000, 39, 4314. 8. Tian, Z.; Cui, H.; Wang, Y. Synth. Commun. 2002, 32, 3821. 9. Quéron, E.; Lett, R. Tetrahedron Lett. 2004, 45, 4533. 10. Mlynarski, J.; Ruiz-Caro, J.; Fürstner, A. Chem., Eur. J. 2004, 10, 2214. 11. Lepage, O.; Kattnig, E.; Fürstner, A. J. Am. Chem. Soc. 2004, 126, 15970. 12. Nakajima, N.; Ubukata, M. Heterocycles 2004, 64, 333. 637

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 R NO2

NO2 Zincke salt

H NR

2 : Cl R N N N H H2 O2N O2N

NO2 NO2

R R N N ring- NH N H O2N H O2N opening

NO2 NO2

NH2 R NH N H NR O2N H H H 2 N N O2N R R

NO2

NO2 638

cis-trans H H N N R R R inversion NN R H

ring-

H : R R N closure NN NN Cl R H R H2 R

Example 113

Et Cl Et NO N 2 Acetone, ' Cl NO2 N overnight (79%) NO2

NO2

Et Et

N NH2 Cl n-BuOH, ' OH N NO2 Ph Cl 20 h (86%) OH Ph

NO2

Example 216

Cl NH2

NO2 NN OH OH NN OH H O, ', 16 h Cl NO2 2 OH 639

OEt EtO

H N CaCO3, H2O/THF (4:1) N O 20 oC, 3 days HO 25%, 2 steps

References

1. Zincke, T. Justus Liebigs Ann. Chem. 1903, 330, 361. 2. Zincke, Th.; Heuser, G.; Möller, W. Justus Liebigs Ann. Chem. 1904, 333, 296. 3. Zincke, Th.; Würker, W. Justus Liebigs Ann. Chem. 1905, 338, 107. 4. Zincke, Th.; Würker, W. Justus Liebigs Ann. Chem. 1905, 341, 365. 5. Zincke, Th.; Weisspfenning, G. Justus Liebigs Ann. Chem. 1913, 396, 103. 6. Marvell, E. N.; Caple, G.; Shahidi, I. Tetrahedron Lett. 1967, 8, 277. 7. Marvell, E. N.; Caple, G.; Shahidi, I. J. Am. Chem. Soc. 1970, 92, 5641. 8. Epszju, J.; Lunt, E.; Katritzky, A. R. Tetrahedron 1970, 26, 1665. (Review). 9. de Gee, A. J.; Sep, W. J.; Verhoeven, J. W.; de Boer, T. J. J. Chem. Soc., Perkin Trans. 1 1974, 676. 10. Becher, J. Synthesis 1980, 589. (Review). 11. Kost, A. N.; Gromov, S. P.; Sagitullin, R. S. Tetrahedron 1981, 37, 3423. (Review). 12. Barbier, D.; Marazano, C.; Das, B. C.; Potier, P. J. Org. Chem. 1996, 61, 9596. 13. Wong, Y.-S.; Marazano, C.; Gnecco, D.; Génisson, Y.; Chiaroni, A.; Das, B. C. J. Org. Chem. 1997, 62, 729. 14. Barbier, D.; Marazano, C.; Riche, C.; Das, B. C.; Potier, P. J. Org. Chem. 1998, 63, 1767. 15. Magnier, E.; Langlois, Y. Tetrahedron Lett. 1998, 39, 837. 16. Urban, D.; Duval, E.; Langlois, Y. Tetrahedron Lett. 2000, 41, 9251. 17. Eda, M.; Kurth, M. J. J. Chem. Soc., Chem. Commun. 2001, 723. 18. Cheng, W.-C.; Kurth, M. J. Org. Prep. Proced. Int. 2002, 34, 585. (Review). 19. Rojas, C. M. Zincke Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 355375. (Review). This page intentionally left blank 641

Subject index Allylic transposition, 1 Allylic trichloroacetamide, 436 A Allylsilanes, 518 Abnormal Claisen rearrangement, 133 Allyl trimethylsilyl ketene acetal, 137 Accutane, 622 Alpine-borane®, 386, 387 Acetone cyanohydrin, 580 Aluminum phenolate, 245 D-Acetylamino-alkyl methyl ketone, 179 Amide, 41, 116, 118, 226, 279, 302, O-Acylated hydroxamic acids, 352 348, 406, 407, 444, 501, 524, 558, Acetylation, 323, 468, 470 596 Į,ȕ-Acetylenic esters, 230 Amide acetal, 135 Acroleins, 39, 545 Amidine, 446 2-Acylamidoketones, 505 Amine synthesis, 247, 350 Acyl-o-aminobiphenyls, 399, 400 Aminoacetal, 472 Acylanilides, 376 Amino acid, 179, 579 Acyl azide, 175 D-Aminoalcohols, 350 Acylbenzenesulfonylhydrazines, 354 E-Aminoalcohols, 193 Acyl halide, 240 o-Aminobenzaldehyde, 243 Acrylic esters, 39 E-Aminocrotonate, 418 Acrylonitriles, 39 Amino hydroxylation, 531 Acylium ion, 240, 245, 259, 335 D-Aminoketone, 412 Acyl oxazolidinone, 218 2-Amino-2-methyl-1-propanol, 24 D-Acyloxycarboxamides, 444 D-Amino nitrile, 579 D-Acyloxyketones, 16 4-Aminophenol, 18 D-Acyloxythioethers, 483 Aminothiophene, 261 Acyl transfer, 65, 341, 444, 483, 511 Ammonium ylide, 557 Intramolecular acyl transfer, 454 Aniline, 55, 79, 144, 147, 180, 257, 269, AD-mix-D, 536 289, 401, 546, 637 AD-mix-E, 536 Anionic oxy-Cope rearrangement, 153 AIBN, 28, 30, 424, 628 E-Anomer, 337 Air oxidation, 206 Anomeric center, 325 Aldehyde cyanohydrins, 235 Anomeric effect, 325 Alder’s endo rule, 199 Anthracenes, 81 Alder ene reaction, 1 Appel reaction, 10 Aldol condensation, 3, 120, 189, 218, Appel’s salt, 10 243, 281, 293, 403, 454, 503, 575 Arndt–Eistert homologation, 12 Algar–Flynn–Oyamada reaction, 5 Aromatization, 339, 557 Alkenylsilanol, 299 Arylacetylene, 112 Alkyl alcohol, 237 Arylamides, 116 Alkyl cation, 242 N-Arylation,116 Alkyl migration, 14, 220, 464, 630 Aryl diazonium salt, 267 1,2-Alkyl shift, 202, 220, 335 E-Arylethylamines, 462 Alkylsilanes, 237 Aryl hydrazines, 87 Alkynylsilanol, 300 Arylhydrazones, 233 Allan–Robinson reaction, 8 O-Aryliminoethers, 118 Allylation, 518, 594 3-Arylindoles, 55 S-Allyl complex, 594 Aryl migration, 45, 177 O-Allyl hydroxylamines, 374 Arylsilanol, 300 Allylic alcohol, 139, 388, 436, 533 Aspirin, 340 Allylic amine, 456 Asymmetric aza-Mannich reaction, 362 Allylic sulfide, 388 Asymmetric hydroxylation, 185 Allylic tertiary amine-N-oxides, 374 Asymmetric epoxidation, 314 642

Asymmetric Mannich reaction, 361 Bis-acetylene, 102 Aurone, 6 Bischler–Möhlau indole synthesis, 55 Autoxidation, 48, 120 2,4-Bis-(4-methoxyphenyl)- Aza-Grob fragmentation, 273 [1,3,2,4]dithiadiphosphetane 2,4- Aza-lactone, 179 disulfide, 348 Aza-Henry reaction, 294 Bischler–Napieralski reaction, 57 Aza-MyersSaito reaction, 409 Bis(trifluoroethyl)phosphonate, 569 Aza-S-methane rearrangement, 204 Blaise reaction, 59 Azide, 63, 175, 489, 490, 564 Blanc chloromethylation, 61 Azido alcohol, 63 Blum aziridine synthesis, 63 Aziridine, 63, 157, 272 Boekelheide reaction, 65 Azirene, 412 Boger pyridine synthesis, 67, 200 2,2’-Azobisisobutyronitrile (AIBN), 28, Boranes, 85, 154, 386, 396, 582 30, 210, 628 Boronate fragmentation, 363 Borch reductive amination, 69 B Borsche–Drechsel cyclization, 71 Baeyer–Villiger oxidation, 14, 85 Boulton–Katritzky rearrangement, 73 Baker–Venkataraman rearrangement, 16 Bouveault aldehyde synthesis, 75 BalzSchiemann reaction, 522 Bouveault–Blanc reduction, 77 Bamberger rearrangement, 18 Boyland–Sims oxidation, 79 Bamford–Stevens reaction, 20 Bradsher reaction, 81 Barbier coupling reaction, 22 D-Bromination, 291 Bargellini reaction, 24 D-Bromoacid, 291 Bartoli indole synthesis, 26 Brook rearrangement, 83 Barton ester, 28 Brown hydroboration, 85 Barton–McCombie deoxygenation, 30 Bucherer carbazole synthesis, 87 Barton nitrite photolysis, 32 Bucherer reaction, 90 Barton radical decarboxylation, 28 Bucherer–Bergs reaction, 92 Barton–Zard reaction, 34 Büchner–Curtius–Schlotterbeck reac- Batcho–Leimgruber indole synthesis, 36 tion, 94 Baylis–Hillman reaction, 39 Büchner method of ring expansion, 96 9-BBN, 386 Buchwald–Hartwig C–N bond and C–O Beckmann rearrangement, 41 bond formation reactions, 98 Beirut reaction, 43 Burgess dehydrating reagent, 100, 365 1,4-Benzenediyl diradical, 49 “Butterfly” transition state, 511 Benzil, 45 Benzilic acid, 45 C Benzilic acid rearrangement, 45 Cadiot–Chodkiewicz coupling, 102 1,4-Benzodiazepine, 565 Camps quinolinol synthesis, 104 Benzofurazan oxide, 43 Cannizzaro disproportionation, 107 Benzoin, 47 Carbazole, 87 Benzoin condensation, 47 Carbene, 12, 169, 492, 630 1,4-Benzoquinone, 418 E-Carbocation, 237, 518 Benzotriazole, 322 Carbocation rearrangement, 191, 193 Bergman cyclization, 49 Carbocyclization, 425 Betaine, 623 Carbonylation, 335 cis-Bicyclo[3.3.0]octane-3,7-dione, 614 Carboxylation, 339 Biginelli pyrimidone synthesis, 51 Carmack mechanism, 618–619 Bimolecular elimination, 40 CAN, 209 BINAP, 430 Carroll rearrangement, 109 Birch reduction, 53 Castro–Stephens coupling, 112 643

3CC, 444, 456 Cyanamide, 608 4CC, 596 Cyanoacetic ester, 275 Celebrex, 332 Cyanogen bromide, 608 Chan alkyne reduction, 114 Cyclic ether, 426 Chan–Lam coupling reaction, 116 Cyclic iodonium ion, 475, 476 Chapman rearrangement, 118 Cyclic thiocarbonate, 168 Chichibabin pyridine synthesis, 120 Cyclization Chlodiazepoxide, 565 Bergman, 49 Chloroammonium salt, 304 Borsche–Drechsel, 71 Chloroiminium salt, 603 Ferrier carbocyclization, 224 Chloromethylation, 61 MyersSaito, 408 2-Chloro-1-methyl-pyridinium iodide, Nazarov, 410 406 Nicolaou hydroxy-dithioketal, 424 3-Chloropyridine, 125 Parham, 442 Chugaev reaction, 123 [2 + 2] Cycloaddition, 499, 547, 587, Chromium-vinyl ketene, 208 621 Ciamician–Dennsted rearrangement, 125 [2 + 2 +1] Cycloaddition, 448 Cinchona alkaloid, 536 [3 + 2] Cycloaddition, 536 Cinnamic acid, 454 [4+2] Cycloaddition, 199, 314 Claisen condensation, 127, 197 Cycloalkanones, 210 Claisen isoxazole synthesis, 129 Cyclobutanone, 561 Claisen rearrangement, 131 Cyclohepta-2,4,6-trienecarboxylic acid anion-assisted, 109 esters, 96 Clemmensen reduction, 141 Cyclohexadienones, 202 Collins oxidation, 318 Cyclohexanone phenylhydrazone, 71 Combes quinoline synthesis, 144 Cyclopentene, 606 Comins modification of the Bouveault Cyclopentenone, 410, 448 aldehyde synthesis, 75 Cyclopropanation, 125, 157, 358, 543 Concerted process, 151, 175 Conrad–Limpach reaction, 147 D Cope elimination reaction, 149 Dakin oxidation, 177 Cope rearrangement, 151 Dakin–West reaction, 179 Corey–Bakshi–Shibata (CBS) reduction, Danheiser annulation, 181 154 Danishefsky diene, 199 CoreyChaykovsky reaction, 157 Darzens glycidic ester condensation, 183 Corey–Fuchs reaction, 160 Davis chiral oxaziridine reagent, 185 Corey–Kim oxidation, 162 DBU, 353, 367 Corey–Nicolaou macrolactonization, DCC, 327, 395 164 DEAD, 249, 390 Corey–Seebach dithiane reaction, 166 Decarboxylation, 28, 329, 352, 507 Corey’s ylide, 157 Dehydrating agent, 11, 100, 365, 460 Corey–Winter olefin synthesis, 168 Dehydrogenation, 422 Counterattack reagent, 608 Delépine amine synthesis, 187 Coumarin, 452 de Mayo reaction, 189 Criegee glycol cleavage, 171 Demetallation, 420 Criegee mechanism of ozonolysis, 173 Demjanov rearrangement, 191 Criegee zwitterion, 173 Deoxygenation, 30 CrNi bimetallic catalyst, 432 Dess–Martin oxidation, 195, 505 Cu(III) intermediate, 102, 112 DIAD, 391 Curtius rearrangement, 175 1,2-Diaminopropanes, 24 Cyanohydrin, 92 Diastereomers, 323 644

Diazoacetates, 96 Double imine, 233 Diazo compounds, 94 Dowd–Beckwith ring expansion, 210 D-Diazoketone, 630 DPE-Phos, 99 Diazomethane, 12 Diazonium salt, 193, 316, 520 E Diazotization, 191, 193 E1, 501 Diboron reagent, 392 E1cB, 277, 365 Dibromoolefin, 160 E2, 40, 79, 100, 454, 458 Di-tert-butylazodicarbonate, 248 Eglinton coupling, 265 Dichlorocarbene, 125, 492 Ei, 100, 149 1,3-Dicyclohexylurea, 327 Electrocyclic ring closure, 208, 410 Dieckmann condensation, 197 Electrocyclic ring opening, 96 Diels–Alder reaction, 199 Electrocyclization, 49, 147, 269, 410 hetero-DielsAlder, 67 Photo-induced, 446 retro-DielsAlder, 67 Electrophilic substitution, 240, 308 Diene, 199, 200, 204, 358 E-Elimination, 285, 289, 365, 492 Dienone–phenol rearrangement, 202 syn-Elimination, 540 Dienophiles, 67, 199, 200, 358 Enamine, 67, 120, 144, 277, 281, 283, Diethyl azodicarboxylate, 390 470, 577, 592 Diethyl succinate, 575 Enediyne, 49 Diethyl tartrate, 533 Ene reaction, 1, 133 Diethyl thiodiglycolate, 295 Enol, 3 Dihydroisoquinolines, 57 Enolizable D-haloketone, 220 Dihydropyridine, 281 Enolization, 8, 197, 281, 291, 341, 343, Dihydroxylation, 475, 476, 536 361, 454, 489, 503 Diketone, 16, 189, 245, 275, 295, 438, Enolsilanes, 511, 515 440, 567 Enones, 189, 515 Dimerization, 265 Enophile, 1 Dimethylsulfide, 162 Episulfone, 485 Dimethylsulfonium methylide, 157 Epoxidation Dimethylsulfoxonium methylide, 157 CoreyChaykovsky, 157 Dimethyltitanocene, 587 Jacobsen–Katsuki, 314 Di-S-methane rearrangement, 204 Sharpless, 533 2,4-Dinitrobenzenesulfonyl chloride, Epoxide, 157 153 Epoxide migration, 450 Diol, 168 2,3-Epoxy alcohols, 450 1,3-Dioxolane-2-thione, 168 DE-Epoxy esters, 183 Diphenyl 2-pyridylphosphine, 248 DE-Epoxy ketones, 214, 616 1,3-Dipolar cycloaddition, 173, 490 DE-Epoxy sulfonylhydrazones Diradical, 49, 204, 408 ErlenmeyerPlöchl azalactone synthesis, Disproportionation reaction, 107 212 N,N-Disubstituted acetamide, 468 erythro, 306, 567 Dithiane, 166 Eschenmoser–Claisen amide acetal rear- Ditin, 573 rangement, 135 Di-vinyl ketone, 410 Eschenmoser’s salt, 361 DMFDMA, 36 Eschenmoser–Tanabe fragmentation, DMS, 162 214 DMSY, 157 Eschweiler–Clarke reductive alkylation Doebner quinoline synthesis, 206 of amines, 216 Doebner–von Miller reaction, 545 Ethyl acetoacetate, 51 Dötz reaction, 208 Ethylammonium nitrate (EAN), 330 645

Ethyl oxalate, 497 Guanidine bases, 34 Evans aldol reaction, 218 Evans chiral auxiliary, 218 H 5-Exo-trig-ring closure, 197 Hajos–Wiechert reaction, 277 6-Exo-trig-ring closure, 341, 480 Halfordinal, 236 Halichlorine, 328 F Haller–Bauer reaction, 279 Favorskii rearrangement and quasi- N-Haloamines, 304 Favorskii rearrangement, 220 D-Haloesters, 59, 183, 222, 489 Feist–Bénary furan synthesis, 222 Halogen-metal exchange, 442 Ferrier carbocyclization, 224 Halohydrin, 428 Ferrier glycal allylic rearrangement, 227 D-Haloketones, 222 Fiesselmann thiophene synthesis, 230 D-Halosulfone extrusion, 485 Fischer carbene, 208 Hantzsch dihydropyridine synthesis, 281 Fischer indole synthesis, 233 Hantzsch pyrrole synthesis, 283 Fischer oxazole synthesis, 235 Head-to-head alignment, 189 Flavol, 5 Head-to-tail alignment, 189 Flavones, 8 Heck reaction, 285 Fleming–Tamao oxidation, 237 Hegedus indole synthesis, 289 Fluoroarene, 522 Hell–Volhard–Zelinsky reaction, 291 Fluorous CoreyKim reaction, 162 Hemiaminal, 507, 555 Flustramine B, 360 Hemiketal, 426 Formamide acetals, 36 Hennoxazole, 505 Formylation, 75, 259 Henry nitroaldol reaction, 293 Four-component condensation, 596 aza-Henry reaction, 294 Friedel–Crafts reaction, 240 Heteroaryl Heck reaction, 287 Friedländer quinoline synthesis, 243 Heteroarylsulfones, 321 Fries rearrangement, 245 Hetero-DielsAlder, 67 Fukuyama amine synthesis, 247 Heterodiene, 201 Fukuyama reduction, 249 Heterodienophile, 201 Furans, 222, 440 Hexacarbonyldicobalt, 420, 448 Hexamethylenetetramine, 187, 555 G Hinsberg synthesis of thiophene deriva- Gabriel–Colman rearrangement, 255 tives, 295 Gabriel synthesis, 251 Hiyama cross-coupling reaction, 297 Gassman indole synthesis, 257 Hiyama–Denmark cross-coupling reac- Gattermann–Koch reaction, 259 tion, 299 Gewald aminothiophene synthesis, 261 Hoch–Campbell aziridine synthesis, 272 Glaser coupling, 263 Hofmann rearrangement, 302 Glycals, 229 Hofmann–Löffler–Freytag reaction, 304 Glycidic esters, 183 Homolytic cleavage, 28, 32, 210, 304, Glycol, 228 310, 354, 424, 628 Glycosidation, 325, 337, 526 Horner–Wadsworth–Emmons reaction, Gomberg–Bachmann reaction, 267, 480 306, 367 Gould–Jacobs reaction, 269 HosomiMiyaura borylation, 392 Grignard reaction, 20, 22, 271, 345, 529 Hosomi–Sakurai reaction, 518 Vinyl Grignard reagent, 26 Houben–Hoesch synthesis, 308 Grob fragmentation, 273 Intramolecular HoubenHoesch, 308 Grubbs’ reagents, 499 Hünig’s base, 368 Guareschi imide, 275 Hunsdiecker–Borodin reaction, 310 Guareschi–Thorpe condensation, 275 646

Hurd–Mori 1,2,3-thiadiazole synthesis, Isoflavones, 8 312 Isoquinoline, 206, 460, 462, 472 Hydantoin, 92 Isoquinoline 1,4-diol, 255 Hydrazine, 253, 331, 616, 632 3-Isoxazolols, 129 Hydrazoic acid, 524 5-Isoxazolone, 129 Hydrazone, 316 4-Isoxazolylsilanol, 301 E-Hydride elimination, 401, 515, 559, 610 J Hydride transfer, 30, 107, 133, 369, 386, Jacobsen–Katsuki epoxidation, 314 555, 587, 633 Japp–Klingemann hydrazone synthesis, Hydroboration, 85 316 Hydrogenation, 430, 509, 515 Johnson–Claisen (orthoester) rearran- Hydrogen atom donor, 408 gement, 139 Hydroquinone, 208 Jones modification of the Kolbe– Hydroxy-dithioketal cyclization, 424 Schmitt reaction, 340 3-Hydroxy-isoxazoles, 129 Jones oxidation, 318 Hydroxy-ketone cyclization, 424 Julia–Kocienski olefination, 321 Hydroxylamine, 129 Julia–Lythgoe olefination, 323 D-Hydroxylation, 511 5-Hydroxylindole, 418 K 2’-hydroxychalcones, 5 Kahne–Crich glycosidation, 325 2-Hydroxymethylpyridine, 65 Keck macrolactonization, 327 4-Hydroxyquinoline, 269 Ketene, 12, 208, 561, 630 D-Hydroxysilane, 83 Ketene acetal, 139, 630 E-Hydroxysilane, 458 Ketocarbene, 12, 630 Hypohalite, 257, 302 D-Ketoesters, 316 E-Ketoesters, 59, 109, 127, 129, 281, I 283, 452 IBX, 422-423 1,4-Ketones, 438, 440 Imidazolidinones, 358 J-Ketoolefin, 109 Imine, 69, 120, 144, 472, 507, 547, 592, Ketophenols, 245 596 Ketoximes, 272, 412 Iminium ion, 329, 350, 358, 468, 470, Ketyl (radical anion), 77 559, 579 Kharasch cross-coupling reaction, 345 Iminophosphoranes, 563 Kinetic products, 20 Indoles, 26, 36, 233, 257, 289, 359, 401 Kishner reduction, 1 Indole-2-carboxylic acid, 497 Knoevenagel condensation, 261, 329 2-Indolylsilanol, 300 Knorr pyrazole synthesis, 331 Ing–Manske procedure, 253 Koch–Haaf carbonylation, 335 Intramolecular HoubenHoesch reacti- Koenig–Knorr glycosidation, 337 on, 308 Kolbe–Schmitt reaction, 339 Intramolecular Nicholas reaction, 421 Kostanecki reaction, 341 Iodoalkene, 585 Kröhnke pyridine synthesis, 343 Iodonium ion, 475, 476 Kumada cross-coupling reaction, 345 o-Iodoxybenzoic acid, 420-423 Ipso, 79, 237, 371 L Ireland–Claisen (silyl ketene acetal) E-Lactam, 561 rearrangement, 137 E-Lactone, 561 Isocyanide, 444, 596 Lactonization, 575 Isocyanate, 92, 175, 302, 352 Lawesson’s reagent, 348, 438 D-Isocyanoacetates, 34 Lead tetraacetate, 171 647

Leuckart–Wallach reaction, 350 Mitsunobu reaction, 247, 390 Librium, 565 Miyaura borylation, 392 Lipitor, 334 Moffatt oxidation, 394 Liquid ammonia, 53 Montgomery coupling, 396 Lossen rearrangement, 352 Morgan–Walls reaction , 399 Morpholine, 44 M Morpholinones, 24 McFadyen–Stevens reduction, 354 Mori–Ban indole synthesis, 401 McMurry coupling, 356 Morita–Baylis–Hillman reaction, 39 MacMillan catalyst, 358 Mukaiyama aldol reaction, 403 Macrolactonization, 327 Mukaiyama Michael addition, 405 Magnesium Oppenauer oxidation, 434 Mukaiyama reagent, 406 Maleimidyl acetate, 255 Multi-component reactions, 51, 92 Mannich base, 361 MyersSaito cyclization, 408 Mannich reaction, 361 Boronic acid-Mannich, 456 N Petasis boronic acid-Mannich reacti- Naphthol, 87, 90 on, 456 E-Naphthylamines, 90 Markownikoff addition, 428 Naproxen, 620 Marasse modification of the Kolbe– Nazarov cyclization, 410 Schmitt reaction, 339 NCS, 162 Marshall boronate fragmentation, 363 Neber rearrangement, 412 Martin’s sulfurane dehydrating reagent, Nifedipine, 282 365 Nef reaction, 414 Masamune–Roush conditions, 367 Negishi cross-coupling reaction, 416 MCRs, 51, 92 Neighboring group assistance, 322, 358, Meerwein–Ponndorf–Verley reduction, 445, 475, 476, 527 369 Nenitzescu indole synthesis, 418 Meisenheimer complex, 247, 371, 549 NewmanKwart reaction, 551 MeisenheimerJackson salt, 371 Nicholas reaction, 420 [1,2]-Meisenheimer rearrangement, 372 Nickel-catalyzed coupling, 396 [2,3]-Meisenheimer rearrangement, 374 Nicolaou dehydrogenation, 422 Meldrum’s acid, 330 Nicolaou hydroxy-dithioketal cyclizati- Mesyl azide, 491 on, 424 Metallacyclobutene, 208 Nicolaou hydroxy-ketone reductive cyc- Metallacyclopentenone, 208 lic ether formation, 426 Meth–Cohn quinoline synthesis, 376 Nicolaou oxyselenation, 428 2-Methylpyridine N-oxide, 65 Nitrene, 175 Methyl vinyl ketone, 503, 577 Nitric oxide radical, 32 Meyer–Schuster rearrangement, 380 Nitrilium ion, 501, 524 Meyer’s oxazoline method, 378 Nitrite ester, 32 Michael addition, 34, 120, 277, 281, Nitroaldol reaction, 293 343, 382, 405, 418, 452, 518, 545, Nitroalkane, 412 567, 577 Nitroalkene, 34 MichaelStetter reaction, 567 Nitroarenes, 26 Michaelis–Arbuzov phosphonate syn- Nitrogen radical cation, 304 thesis, 384 Nitronates, 293, 414 Microwave, 90, 504, 620, 632 Nitronic acid, 414 Midland reduction, 386 o-Nitrophenyl selenides, 540 Migratory aptitude, 14, 464 Nitroso intermediate, 26, 32 Mislow–Evans rearrangement, 388 o-Nitrotoluene, 36, 497 648

Non-enolizable ketone, 221, 279 Sarett, 319 Noyori asymmetric hydrogenation, 430 Swern, 583 Nozaki–Hiyama–Kishi reaction, 432 TamaoKumada, 238 Nucleophilic addition, 59, 94, 293, 297, Wacker, 424 339, 378, 419, 428, 432, 466, 487, Oxidative addition, 98, 102, 112, 249, 610 283, 287, 297, 345, 392, 401, 416, 432, 487, 509, 543, 559, 571, 573, 581, 599 O syn-Oxidative elimination, 540 Octacarbonyl dicobalt, 448 Oxidative homo-coupling, 263, 265 Odorless CoreyKim reaction, 162 N-Oxide, 149 Olefin, 149, 189, 306, 321, 323, 335, Oximes, 41 356, 371, 458, 485, 531, 540, 587, J-Oximino alcohol, 32 610, 612 Oxirane, 61 Olefin complexation, 610 Oxonium ion, 325, 337 Oppenauer oxidation, 434 Oxy-Cope rearrangement, 152 Organoborane, 85, 581 Oxygen transfer, 314 Organosilanol, 299 Oxygen transposition, 616 Organosilicons, 297 Oxyselenation, 428 Organostannanes, 571 Oxyselenide, 429 Organozinc, 141, 396, 400, 416, 487 Orthoester, 139 P Osmium, 531 Paal–Knorr furan synthesis, 440 Overman rearrangement, 436 Paal–Knorr pyrrole synthesis, 333 Oxaborolidines, 154 Paal thiophene synthesis, 438 Oxalyl chloride, 605 Palladation, 289, 610 Oxaphosphetane, 621 Palladium-promoted reactions Oxatitanacyclobutane, 587 Heck, 285 Oxazete, 118 Heteroaryl Heck, 287 Oxaziridine, 185 Hiyama, 297 Oxazoles, 235, 601 Hiyama–Denmark, 299 Oxazolidinone, 218 Kumada, 345 Oxazolines, 378 Miyaura borylation, 392 Oxazolone, 179 Mori–Ban indole, 401 5-Oxazolone, 212 Negishi, 416 Oxetane, 446 Saegusa, 515 Oxidation Sonogashira, 559 Baeyer–Villiger, 14 Stille, 571 Boyland–Sims, 79 Stille–Kelly, 573 Collins, 319 Suzuki, 581 Corey–Kim, 162 Tsuji–Trost, 594 Dakin, 177 Wacker, 610 DessMartin, 109 Parham cyclization, 442 Fleming-Tamao, 237 Passerini reaction, 444 Jones, 318 Paternò–Büchi reaction, 446 Moffatt, 394 Pauson–Khand cyclopentenone synthe- Oppenauer, 434 sis, 448 PCC, 319 Payne rearrangement, 450 PDC, 320 PCC, 319 Prilezhaev, 511 PDC, 320 Rubottom, 511 Pechmann coumarin synthesis, 452 649

Periodinane, 195 Prévost trans-dihydroxylation, 475 Perkin reaction, 454 Prilezhaev epoxidation, 511 Persulfate, 77 Primary ozonide, 173 Pentacoordiante silicon intermediate, 83 Prins reaction, 478 Petasis alkenylation, 587 Progesterone, 503 Petasis reagent, 587 (L)-Proline, 362 Petasis reaction, 456 (S)-()-Proline, 277 Peterson olefination, 458 Propargyl cation, 420 PfitznerMoffatt oxidation, 394 Pschorr cyclization, 480 Phenanthridine, 399, 400 Puckered transition state, 561, 621 E-Phenethylamides, 57 Pummerer rearrangement, 483 Phenols, 202 Pyrazoles, 331 Phenoxide, 339 Pyrazolones, 331 L-Phenylalanine, 278 Pyridine synthesis, 67, 120, 281, 343 Phenylhydrazine, 233 D-Pyridinium methyl ketone salts, 343 Phenylhydrazone, 233 2-Pyridone, 275 N-Phenylhydroxylamine, 16 2-Pyridinethione, 164 4-Phenylpyridine N-oxide, 315 Pyrimidone, 51 N-Phenylselenophthalimide, 428 Pyrroles, 34, 283, 331, 333 N-Phenylselenosuccinimide, 428 Pyrrolidines, 37, 304 Phenyltetrazolyl, 321 Phosphazide, 563 Q Phosphites, 384, 389 Quasi-Favorskii rearrangement, 221 Phosphonates, 306, 367, 384 Quinoline, 144, 243, 376, 494, 545, 547 Phosphorus oxychloride, 57, 376, 399, Quinoline-4-carboxylic acid, 206 460 Quinoxaline-1,4-dioxide, 43 Phosphorous pentaoxide, 460 Quinazoline 3-oxide, 565 [2 + 2] Photochemical cyclization, 189 Quinolinol, 104 Photochemical rearrangement, 175 Quinolin-4-ones, 147 Photo-induced electrocyclization, 446 Photolysis, 32 R Photo Reimer–Tiemann, 492 Radical anion, 53, 141, 356 Phthalimide, 253 Radical coupling, 267, 480 Pictet–Gams isoquinoline synthesis, 460 Radical decarboxylation, 28 Pictet–Hubert reaction, 400 Radical reactions Pictet–Spengler tetrahydroisoquinoline Barton radical decarboxylation, 28 synthesis, 462 Barton–McCombie, 30 Pinacol rearrangement, 464 Barton nitrite photolysis, 32 (1R)-(+)-D-Pinene, 386 Dowd–Beckwith ring expansion, 210 Pinner reaction, 466 Gomberg–Bachmann, 267 Piperazinones, 24 McFadyen–Stevens reduction, 354 Piperidines, 304 McMurry coupling, 356 Plavix, 580 TEMPO-mediated oxidation, 590 Polonovski–Potier rearrangement, 470 Radical scission, 30 Polonovski reaction, 468 Radical ThorpeZiegler reaction, 592 Polyphosphoric acid, 42 Ramberg–Bäcklund reaction, 485 Pomeranz–Fritsch reaction, 472 Raney nickel, 257 Potassium phthalimide, 251 Rauhut–Currier reaction, 39 PPA, 42 Rearrangement PPTS, 145 Abnormal Claisen, 131 Precatalysts, 499 Anionic oxy–Cope, 153 650

Baker–Venkataraman, 16 Wharton, 616 Bamberger, 18 Wolff–Kishner, 632 Beckmann, 41 Reductive amination, 69, 350 Benzilic acid, 45 Reductive elimination, 96, 98, 102, 112, Brook, 83 116, 249, 345, 392, 416, 448, 509, Carrol, 109 559, 571, 573, 581, 610 Chapman, 118 Reductive methylation, 216 Claisen, 131 Reductive olefination, 168 Cope, 151 Reformatsky reaction, 487 Curtius, 175 Regitz diazo synthesis, 489 Demjanov, 191 Reimer–Tiemann reaction, 492 Dienone–phenol, 202 photo Reimer–Tiemann, 492 Di-S-methane, 204 Reissert aldehyde synthesis, 494 Eschenmoser–Claisen, 135 Reissert compound, 494 Favorskii, 220 Reissert indole synthesis, 497 Ferrier, 227 Retro-aldol reaction, 189 Fries, 245 Retro-DielsAlder, 67 Hofmann, 302 Reverse electronic demand Diels– Ireland–Claisen, 137 Alder reaction, 199 Johnson–Claisen, 139 Rhodium carbenoid, 96 Lossen, 352 Ring-closing metathesis, 499 Meisenheimer, 372 Ring expansion, 193 Meyer–Schuster, 380 Ritter reaction, 501 Mislow–Evans, 388 Robinson annulation, 277, 503 Neber, 412 Robinson–Gabriel synthesis, 505 Overman, 436 Robinson–Schöpf reaction, 507 oxy-Cope, 152 Rosenmund reduction, 509 Payne, 450 Rubottom oxidation, 511 Pinacol, 464 Rupe rearrangement, 513 Pummerer, 483 Ruthenium(II) BINAP complex, 430 Rupe, 380, 513 Quasi-Favorskii, 221 S Schmidt, 524 Saegusa enone synthesis, 515 Smiles, 549 Saegusa oxidation, 515 Sommelet–Hauser, 557 Sakurai allylation reaction, 518 Tiffeneau–Demjanov, 193 Salicylic acid, 340 Truce-Smile, 553 Sandmeyer reaction, 520 Wagner–Meerwein, 612 Sanger’s reagent, 371 Wolff, 630 Sarett oxidation, 319 Red-Al, 114 Schiemann reaction, 522 Redox addition, 432 Schiff base, 147, 547 Redox reaction, 107 Schlosser modification of the Wittig Reduction reaction, 622 Birch, 53 Schmidt reaction, 524 Bouveault–Blanc, 77 Schmidt’s trichloroacetimidate glycosi- CBS, 154 dation reaction, 526 Leuckart–Wallach reaction, 350 Schrock’s reagent, 499 McFadyen–Stevens, 354 E-Scission, 30 Meerwein–Ponndorf–Verley, 369 Secondary ozonide, 173 Midland, 386 Selenides, 429 Staudinger, 563 Selenol esters, 429 651

Selenonium, 428 Stobbe condensation, 575 Shapiro reaction, 529 Stork enamine reaction, 577 Sharpless asymmetric amino hydroxyla- Strecker amino acid synthesis, 579 tion, 531 Succinimidyl radical, 628 Sharpless asymmetric epoxidation , 533 Sulfenamide, 618 Sharpless asymmetric dihydroxylation, Sulfide reduction, 424 536 Sulfones, 323 Sharpless olefin synthesis, 540 Sulfonium ion, 257 1,2-Shift of silyl group, 181 Sulfonyl azide, 489 [1,2]-Sigmatropic rearrangement, 373, N-Sulfonyloxaziridines, 185 624 Sulfoxide, 325 [2,3]-Sigmatropic rearrangement, 257, Sulfur, 261, 438, 618 374, 388, 557, 626 Sulfur ylide, 157, 583 [3,3]-Sigmatropic rearrangement, 71, 87, Suzuki coupling, 581 131, 133, 135, 139, 151, 152, 153, Swern oxidation, 583 233, 436 Silylation, 426 T Silyl enol ether, 403, 405, 422 Takai iodoalkene synthesis, 585 Silyl ester, 137 TamaoKumada oxidation, 239 Silyl ether, 83 Tamoxifen, 217 [1,2]-Silyl migration, 83 Tautomerization, 133, 179, 208, 233, Silver carboxylate, 310 281, 380, 438, 513, 524, 567, 579, Simmons–Smith reaction, 543 610, 616 Single electron transfer, 22, 53, 77, 323, Tebbe olefination, 587 356, 422, 599 Tebbe’s reagent, 587 Singlet diradical, 446 TEMPO-mediated oxidation, 589 E-Silylalkoxide, 458 Terminal alkyne, 160, 265 Skraup quinoline synthesis, 545 Tertiary amine, 608 Sm, 23 Tertiary amine N-oxides, 373, 468, 470 SMEAH, 114 Tertiary carbocation, 335 Smiles rearrangement, 549 Tetrahydrocarbazole, 71 SN1, 325 Tetrahydroisoquinolines, 462 SN2, 61, 63, 141, 183, 187, 235, 251, Tetramethyl pentahydropyridine oxide, 253, 257, 304, 376, 384, 388, 390, 589 390, 450, 471, 475, 476, 555, 603, TFAA, 65, 470 621 Thermal aryl rearrangement, 118 SNAr, 118, 120, 371, 406, 549 Thermal Bamford-Stevens, 21 Sommelet–Hauser rearrangement, 557 Thermal elimination, 123, 149 Sommelet reaction, 555 Thermal rearrangement, 109, 175 Sonogashira reaction, 559 Thermodynamically favored, 335 Spirocyclic anion, 549 Thermodynamic products, 20 Statin side chain, 59 Thermolysis, 73 Staudinger ketene cycloaddition, 561 1,2,3-Thiadiazole, 312 Staudinger reduction, 63, 563 Thiamide, 618 Stereoselective reduction, 114 Thiazolium, 47, 567 Sternbach benzodiazepine synthesis, 565 Thiirane, 157 Stetter reaction, 567 Thiirene, 618 Still–Gennari phosphonate reaction, 569 Thiocarbonyl, 28, 30 StillWittig rearrangement, 626 1,1’-Thiocarbonyldiimidazole, 168 Stille coupling, 571 Thioglycolic acid, 230 Stille–Kelly reaction, 573 Thiol esters, 249 652

Thionium, 424 Vilsmeier mechanism for acid chloride Thiophene, 230, 261, 295, 438 formation, 605 Thiophenol, 551 Vinylcyclopropane, 204 ThorpeZiegler reaction, 592 Vinylcyclopropanecyclopentene rear- Three-component coupling, 206, 444, rangement, 606 456 Vinyl halides, 432 threo, 306 E-Vinyl iodide, 585 Tiffeneau–Demjanov rearrangement, Vinyl ketones, 39 193 Vinyl sulfones, 39 Titanium tetra-iso-propoxide, 533 von Braun reaction, 608 Titanocene methylidene, 587 Tosyl amide, 489 W Tosyl hydrazone, 312 Wacker oxidation, 515, 610 TosMIC, 601 Wagner–Meerwein rearrangement, 612 p-Tolylsulfonylmethyl isocyanide, 601 Weiss–Cook reaction, 614 Transmetalation, 116, 297, 299, 345, Wharton oxygen transposition reaction, 416, 432, 559, 571, 573, 581, 587 616 Triacetoxyperiodinane, 195 Willgerodt–Kindler reaction, 618 1,2,4-Triazines, 67 Wittig reaction, 621 Triazole, 490 Sila-Wittig reaction, 458 Trichloroacetimidate, 436, 526 [1,2]-Wittig rearrangement, 624 2,4,6-Trichlorobenzoyl chloride, 634 [2,3]-Wittig rearrangement, 626, 557 Trifluoroacetic anhydride, 65, 470 Wohl–Ziegler reaction, 628 Trimethylphosphite, 168 Wolff rearrangement, 630 Trimethylsilylallene, 181 Wolff–Kishner reduction, 632 Trimethylsilylcyclopentene, 181 Woodward cis-dihydroxylation, 476 1,3,5-Trioxane, 61 1,2,3-Trioxolane, 173 X 1,2,4-Trioxolane, 173 Xanthate, 123 Triphenylphosphine, 10, 390, 401 n, S* Triplet, 446 Y Triplet diradical, 446 Yamaguchi esterification, 634 Tropinone, 507 Yamaguchi reagent, 634 TruceSmile rearrangement, 553 Tsuji–Trost allylation, 594 Z Zimmerman rearrangement, 204 U Zinc-carbenoid, 141 Ugi reaction, 596 Zincke reaction, 637 UHP, 178 Zincke salt, 637 Ullmann reaction, 599 Zoloft, 571 DE-Unsaturated aldehydes, 513 Zwitterionic peroxide, 173 DE-Unsaturated ketone, 181, 343, 513 Urea, 51 Urea-hydrogen peroxide, 178

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