General Abbreviations

Ac acetyl DIEA =DIPEA acac acetylacetonate DIOP 2,3-O-isopropylidene-2,3-dihydroxy-1,4- AIBN 2,2-azobisisobutyronitrile bis-(diphenylphosphino)butane Ar aryl DIPEA diisopropylethylamine diphos =dppe BBN borabicyclo[3.3.1]nonane DIPT diisopropyl tartrate BCME dis(chloromethyl)ether DMA dimethylacetamide BHT butylated hydroxytoluene (2,6-di-t-butyl-p- DMAD dimethyl acetylenedicarboxylate cresol) DMAP 4-(dimethylamino)pyridine BINAL-H 2,2-dihydroxy-1,1-binaphthyl-lithium alu- DME 1,2-dimethoxyethane minum hydride DMF dimethylformamide BINAP 2,2-bis(diphenylphosphino)-1,1- dmg dimethylglyoximato binaphthyl DMPU N,N-dimethylpropyleneurea BINOL 1,1-bi-2,2-naphthol DMS dimethyl sulfide bipy 2,2-bipyridyl DMSO dimethyl sulfoxide BMS borane–dimethyl sulfide DMTSF dimethyl(methylthio) sulfonium Bn benzyl tetrafluoroborate Boc t-butoxycarbonyl dppb 1,4-bis(diphenylphosphino)butane BOM benzyloxymethyl dppe 1,2-bis(diphenylphosphino)ethane bp boiling point dppf 1,1-bis(diphenylphosphino)ferrocene Bs brosyl (4-bromobenzenesulfonyl) dppp 1,3-bis(diphenylphosphino)propane BSA N,O-bis(trimethylsilyl)acetamide DTBP di-t-butyl peroxide Bu n-butyl Bz benzoyl EDA ethyl diazoacetate EDC 1-ethyl-3-(3-dimethylaminopropyl)- CAN cerium(IV) ammonium nitrate carbodiimide Cbz benzyloxycarbonyl EDCI =EDC CDI N,N -carbonyldiimidazole ee enantiomeric excess CHIRAPHOS 2,3-bis(diphenylphosphino)butane EE 1-ethoxyethyl Chx =Cy Et ethyl cod cyclooctadiene ETSA ethyl trimethylsilylacetate cot cyclooctatetraene EWG electron withdrawing group Cp cyclopentadienyl CRA complex reducing agent Fc ferrocenyl CSA 10-camphorsulfonic acid Fmoc 9-fluorenylmethoxycarbonyl CSI chlorosulfonyl isocyanate fp flash point Cy cyclohexyl Hex n-hexyl d density HMDS hexamethyldisilazane DABCO 1,4-diazabicyclo[2.2.2]octane HMPA hexamethylphosphoric triamide DAST N,N-diethylaminosulfur trifluoride HOBt l-hydroxybenzotriazole dba dibenzylideneacetone HOBT =HOBt DBAD di-t-butyl azodicarboxylate HOSu N-hydroxysuccinimide DBN 1,5-diazabicyclo[4.3.0]non-5-ene DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC N,N-dicyclohexylcarbodiimide Im imidazole (imidazolyl) DCME dichloromethyl methyl ether Ipc isopinocampheyl DDO dimethyldioxirane IR infrared DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone de diastereomeric excess KHDMS potassium hexamethyldisilazide DEAD diethyl azodicarboxylate DET diethyl tartrate LAH lithium aluminum hydride DIBAL diisobutylaluminum hydride LD50 dose that is lethal to 50% of test subjects LDA lithium diisopropylamide PMDTA N,N,N,N,N-pentamethyldiethylene- LDMAN lithium 1-(dimethylamino)naphthalenide triamine LHMDS =LiHMDS PPA polyphosphoric acid LICA lithium isopropylcyclohexylamide PPE polyphosphate ester LiHMDS lithium hexamethyldisilazide PPTS pyridinium p-toluenesulfonate LiTMP lithium 2,2,6,6-tetramethylpiperidide Pr n-propyl LTMP =LiTMP PTC phase transfer catalyst/catalysis LTA lead tetraacetate PTSA p-toluenesulfonic acid lut lutidine py pyridine

RAMP (R)-1-amino-2-(methoxymethyl)pyrrolidine m-CPBA m-chloroperbenzoic acid rt room temperature MA maleic anhydride MAD methylaluminum bis(2,6-di-t-butyl-4- salen bis(salicylidene)ethylenediamine methylphenoxide) SAMP (S)-1-amino-2-(methoxymethyl)pyrrolidine MAT methylaluminum bis(2,4,6-tri-t- SET single electron transfer butylphenoxide) Sia siamyl (3-methyl-2-butyl) Me methyl MEK methyl ethyl ketone TASF tris(diethylamino)sulfonium MEM (2-methoxyethoxy)methyl difluorotrimethylsilicate MIC methyl isocyanate TBAB tetrabutylammonium bromide MMPP magnesium monoperoxyphthalate TBAF tetrabutylammonium fluoride MOM methoxymethyl TBAD =DBAD MoOPH oxodiperoxomolybdenum(pyridine)- TBAI tetrabutylammonium iodide (hexamethylphosphoric triamide) TBAP tetrabutylammonium perruthenate mp melting point TBDMS t-butyldimethylsilyl MPM =PMB TBDPS t-butyldiphenylsilyl Ms mesyl (methanesulfonyl) TBHP t-butyl hydroperoxide MS mass spectrometry; molecular sieves TBS =TBDMS MTBE methyl t-butyl ether TCNE tetracyanoethylene MTM methylthiomethyl TCNQ 7,7,8,8-tetracyanoquinodimethane MVK methyl vinyl ketone TEA triethylamine TEBA triethylbenzylammonium chloride n refractive index TEBAC =TEBA NaHDMS sodium hexamethyldisilazide TEMPO 2,2,6,6-tetramethylpiperidinoxyl Naph naphthyl TES triethylsilyl NBA N-bromoacetamide Tf triflyl (trifluoromethanesulfonyl) nbd norbornadiene (bicyclo[2.2.1]hepta- TFA trifluoroacetic acid 2,5-diene) TFAA trifluoroacetic anhydride NBS N-bromosuccinimide THF tetrahydrofuran NCS N-chlorosuccinimide THP tetrahydropyran; tetrahydropyranyl NIS N-iodosuccinimide Thx thexyl (2,3-dimethyl-2-butyl) NMO N-methylmorpholine N-oxide TIPS triisopropylsilyl N TMANO trimethylamine N-oxide NMP -methyl-2-pyrrolidinone NMR nuclear magnetic resonance TMEDA N,N,N ,N -tetramethylethylenediamine NORPHOS bis(diphenylphosphino)bicyclo[2.2.1]-hept- TMG 1,1,3,3-tetramethylguanidine 5-ene TMS trimethylsilyl Np =Naph Tol p-tolyl TPAP tetrapropylammonium perruthenate TBHP t-butyl hydroperoxide PCC pyridinium chlorochromate TPP tetraphenylporphyrin PDC pyridinium dichromate Tr trityl (triphenylmethyl) Pent n-pentyl Ts tosyl (p-toluenesulfonyl) Ph phenyl TTN thallium(III) nitrate phen 1,10-phenanthroline Phth phthaloyl UHP urea–hydrogen peroxide complex Piv pivaloyl PMB p-methoxybenzyl Z =Cbz Handbook of Reagents for Organic Synthesis Reagents for Heteroarene Functionalization OTHER TITLES IN THIS COLLECTION

Catalytic Oxidation Reagents Edited by Philip L. Fuchs ISBN 978 1 119 95327 2 Reagents for Silicon-Mediated Organic Synthesis Edited by Philip L. Fuchs ISBN 978 0 470 71023 4 Sulfur-Containing Reagents Edited by Leo A. Paquette ISBN 978 0 470 74872 5 Reagents for Radical and Radical Ion Chemistry Edited by David Crich ISBN 978 0 470 06536 5 Catalyst Components for Coupling Reactions Edited by Gary A. Molander ISBN 978 0 470 51811 3 Fluorine-Containing Reagents Edited by Leo A. Paquette ISBN 978 0 470 02177 4 Reagents for Direct Functionalization of C–H Bonds Edited by Philip L. Fuchs ISBN 0 470 01022 3 Reagents for Glycoside, Nucleotide, and Peptide Synthesis Edited by David Crich ISBN 0 470 02304 X Reagents for High-Throughput Solid-Phase and Solution-Phase Organic Synthesis Edited by Peter Wipf ISBN 0 470 86298 X Chiral Reagents for Asymmetric Synthesis Edited by Leo A. Paquette ISBN 0 470 85625 4 Activating Agents and Protecting Groups Edited by Anthony J. Pearson and William R. Roush ISBN 0 471 97927 9 Acidic and Basic Reagents Edited by Hans J. Reich and James H. Rigby ISBN 0 471 97925 2 Oxidizing and Reducing Agents Edited by Steven D. Burke and Rick L. Danheiser ISBN 0 471 97926 0 Reagents, Auxiliaries, and Catalysts for C–C Bond Formation Edited by Robert M. Coates and Scott E. Denmark ISBN 0 471 97924 4

e-EROS For access to information on all the reagents covered in the Handbooks of Reagents for Organic Synthesis, and many more, subscribe to e-EROS on the Wiley Online Library website. A database is available with over 200 new entries and updates every year. It is fully searchable by structure, substructure and reaction type and allows sophisticated full text searches. http://onlinelibrary.wiley.com/book/10.1002/047084289X Handbook of Reagents for Organic Synthesis Reagents for Heteroarene Functionalization

Edited by André B. Charette Université de Montréal, Montréal, QC, Canada This edition first published 2015 © 2015 John Wiley & Sons Ltd

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Library of Congress Cataloging-in-Publication Data

Handbook of reagents for organic synthesis : reagents for heteroarene functionalization / edited by André B. Charette, Université de Montréal, Montréal, QC, Canada. pages cm Includes indexes. ISBN 978-1-118-72659-4 (cloth) 1. Organic compounds–Synthesis. 2. Heterocyclic chemistry. 3. Chemical tests and reagents. I. Charette, A. B. (André B.), 1961- editor. II. Title: Reagents for organic synthesis. QD262.H2674 2015 547’.2–dc23 2015020137

A catalogue record for this book is available from the British Library.

ISBN 13: 978-1-118-72659-4

Set in 9½/11½ pt Times Roman by Thomson Press (India) Ltd., New Delhi. Printed and bound in Singapore by Markono Print Media Pte Ltd. e-EROS Editorial Board

Editor-in-Chief David Crich Institut de Chimie des Substances Naturelles (ICSN), Gif-sur-Yvette, France

Executive Editors André B. Charette Université de Montréal, Montréal, QC, Canada Philip L. Fuchs Purdue University, West Lafayette, IN, USA Tomislav Rovis Colorado State University, Fort Collins, CO, USA

Founding Editor Leo A. Paquette The Ohio State University, Columbus, OH, USA

Preface

The eight-volume Encyclopedia of Reagents for Organic Syn- Reagents for Glycoside, Nucleotide, and Peptide Synthesis thesis (EROS), authored and edited by experts in the field, and Edited by David Crich published in 1995, had the goal of providing an authoritative multivolume reference work describing the properties and re- Reagents for Direct Functionalization of C–H Bonds actions of approximately 3000 reagents. With the coming of Edited by Philip L. Fuchs the Internet age and the continued introduction of new reagents to the field as well as new uses for old reagents, the electronic Fluorine-Containing Reagents sequel, e-EROS, was introduced in 2002 and now contains in Edited by Leo A. Paquette excess of 4000 reagents, catalysts, and building blocks, making Catalyst Components for Coupling Reactions it an extremely valuable reference work. At the request of the Edited by Gary A. Molander community, the second edition of the encyclopedia, EROS-II, was published in March 2009 and contains the entire collection Reagents for Radical and Radical Ion Chemistry of reagents at the time of publication in a 14-volume set. Edited by David Crich While the comprehensive nature of EROS and EROS-II and the continually expanding e-EROS render them invaluable as Sulfur-Containing Reagents reference works, their very size limits their practicability in a Edited by Leo A. Paquette laboratory environment. For this reason, a series of inexpen- sive one-volume Handbooks of Reagents for Organic Synthesis Reagents for Silicon-Mediated Organic Synthesis (HROS), each focused on a specific subset of reagents, was in- Edited by Philip L. Fuchs troduced by the original editors of EROS in 1999: Catalytic Oxidation Reagents Reagents, Auxiliaries and Catalysts for C–C Bond Edited by Philip L. Fuchs Formation Edited by Robert M. Coates and Scott E. Denmark This series now continues with the present volume entitled Reagents for Heteroarene Functionalization, edited by André Oxidizing and Reducing Agents Charette, long-standing member of the online e-EROS Edi- Edited by Steven D. Burke and Rick L. Danheiser torial Board. This 15th volume in the HROS series, like its predecessors, is intended to be an affordable, practicable com- Acidic and Basic Reagents pilation of reagents arranged around a central theme that it is Edited by Hans J. Reich and James H. Rigby hoped will be found at arm’s reach from synthetic chemists worldwide. The reagents have been selected to give broad rel- Activating Agents and Protecting Groups evance to the volume, within the limits defined by the subject Edited by Anthony J. Pearson and William R. Roush matter. We have enjoyed putting this volume together and hope that our colleagues will find it just as enjoyable and useful to This series has continued over the last several years with the read and consult. publication of a further series of HROS volumes, each edited by a current member of the e-EROS editorial board: David Crich Centre Scientifique de Gif-sur-Yvette Chiral Reagents for Asymmetric Synthesis Institut de Chimie des Substances Naturelles Edited by Leo A. Paquette Gif-sur-Yvette, France Reagents for High-Throughput Solid-Phase and Solution-Phase Organic Synthesis Edited by Peter Wipf

Introduction

Heterocycles and, in particular, heteroarenes are among the most (Ed. Philip L. Fuchs) was published by Wiley. This volume con- prevalent structural units in natural products, pharmaceuticals, tained 80 reagents, which targeted a wide range of transformations agrochemicals, ligands for metal complexes, and electroactive and starting materials, including the formation of stereocenters. organomaterials. Consequently, a plethora of synthetic methods A search for the number of citations since 2006 for “C–H func- has appeared over the years to not only facilitate construction tionalization” produces a spectacular picture that describes this of the heteroarene motif but also to enable further modifications burgeoning field, forecasts its continual expansion, provided the employing the mildest conditions possible. Traditionally, unsub- opportunities to create and conceive novel synthetic methods, and stituted heteroarenes have been functionalized via electrophilic illustrates its important role in redefining how organic chemists aromatic substitution and regioselective metalation followed by make molecules. Given this incredible burst in popularity of C–H electrophilic trapping/transition metal-catalyzed coupling and N- functionalization, it has been a tour de force to develop a sizable alkylation and N-arylation reactions. In the last two decades, in- Handbook to include all the key reagents developed in the last 10 tensive research efforts have been geared toward developing novel years for only selective heteroarene functionalization reactions, catalytic conditions for the site-selective formation of carbon– comprising both traditional and transition metal-catalyzed C–H carbon and carbon–heteroatom bonds through direct heteroarene functionalization. Since these reactions typically involve one het- C–H functionalization. Heteroarenes are particularly good sub- eroarene, a coupling partner, and a catalyst, the Handbook not strates in these reactions since they offer good regiocontrol due only focuses on the catalyst itself but also contains other key reac- to the natural reactivity pattern of their various C–H bonds. Such tion species. To achieve this purpose, 117 reagents were selected, research endeavors have produced a significant number of alterna- including 28 new reagents and 77 updated reagents. In order to tive procedures to complement traditional methods. In particular, cover the most important heteroarene C–H transformations in a impressive achievements have been reported using various late single volume, the basic heteroarene cores of these reactions have transition metal catalysts such as Pd, Ru, Rh, Cu, and Fe. These been included and/or updated (e.g., pyridine, pyrazine, pyrrole, catalysts, in conjunction with another suitable coupling partner and N-methylindole). Furthermore, a supplementary list of rele- (e.g., halide, organometallic, and carboxylic acid), provide ac- vant reagents that could not be included in this volume, but for cess to functionalized heteroarenes without requiring conventional which relevant articles can be found in e-EROS, is also provided. double preactivation procedures (e.g., the protocols observed in As an additional resource to the reader for finding relevant in- Kumada, Suzuki–Miyaura, Stille, Hiyama, or Negishi coupling formation, a listing of Recent Reviews and Monographs follows reactions). Moreover, direct C–H functionalization reactions of- this section. ten provide complementary regioselectivities compared with tra- ditional derivatization reactions. The development and application of selective C–H functional- André B. Charette ization processes toward heteroarene synthesis is rapidly evolv- Département de Chimie, Université de Montréal ing. In 2006, the first Handbook of Reagents for Organic Syn- Montréal, (Québec) Canada thesis, Reagents for Direct Functionalization of C-H Bonds

RECENT REVIEW ARTICLES AND MONOGRAPHS xiii

Recent Review Articles and Monographs

Selected Reviews Daugulis, O. Palladium and copper catalysis in regioselective, intermolecular coupling of C–H and C–Hal bonds. Top. Curr. Ackermann, L. Metal-catalyzed direct alkylations of Chem. 2010, 292, 57–84. (hetero)arenes via C–H bond cleavages with unactivated alkyl Daugulis, O.; Do, H. Q.; Shabashov, D. Palladium- and copper- halides. Chem. Commun. 2010, 46, 4866–4877. catalyzed arylation of carbon-hydrogen bonds. Acc. Chem. Res. Ackermann, L. Carboxylate-assisted transition-metal- 2009, 42, 1074–1086. catalyzed C–H bond functionalizations: mechanism and scope. De Sarkar, S.; Liu, W. P.; Kozhushkov, S. I.; Ackermann, L. Chem. Rev. 2011, 111, 1315–1345. Weakly coordinating directing groups for ruthenium(II)-catalyzed Ackermann, L. Carboxylate-assisted ruthenium-catalyzed C–H activation. Adv. Synth. Catal. 2014, 356, 1461–1479. alkyne annulations by C–H/Het-H bond functionalizations. Acc. Gutekunst, W. R.; Baran, P. S. C–H functionalization logic in Chem. Res. 2014, 47, 281–295. total synthesis. Chem. Soc. Rev. 2011, 40, 1976–1991. Ackermann, L.; Vicente, R. Ruthenium-catalyzed direct aryla- Hartwig, J. F. Regioselectivity of the borylation of alkanes and tions through C–H bond cleavages. Top. Curr. Chem. 2010, 292, arenes. Chem. Soc. Rev. 2011, 40, 1992–2002. 211–229. Hartwig, J. F. Borylation and silylation of C–H bonds: a plat- Ackermann, L.; Vicente, R.; Kapdi, A. R. Transition-metal- form for diverse C–H bond functionalizations. Acc. Chem. Res. catalyzed direct arylation of (hetero)arenes by C–H bond cleavage. 2012, 45, 864–873. Angew. Chem., Int. Ed. 2009, 48, 9792–9826. Janin, Y. L. Preparation and chemistry of 3/5- Armstrong, A.; Collins, J. C. Direct azole amination: C–H func- halogenopyrazoles. Chem. Rev. 2012, 112, 3924–3958. tionalization as a new approach to biologically important hetero- Kakiuchi, F.; Chatani, N. Catalytic methods for C–H bond func- cycles. Angew. Chem., Int. Ed. 2010, 49, 2282–2285. tionalization: application in organic synthesis. Adv. Synth. Catal. Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Ruthenium(II)- 2003, 345, 1077–1101. catalyzed C–H bond activation and functionalization. Chem. Rev. Kakiuchi, F.; Kochi, T. Transition-metal-catalyzed carbon– 2012, 112, 5879–5918. carbon bond formation via carbon–hydrogen bond cleavage. Syn- Bandini, M.; Eichholzer, A. Catalytic functionalization of in- thesis (Stuttg) 2008, 3013–3039. doles in a new dimension. Angew. Chem., Int. Ed. 2009, 48, 9608– Kuhl, N.; Schroder, N.; Glorius, F. Formal S–N-type reactions 9644. in rhodium(III)-catalyzed C–H bond activation. Adv. Synth. Catal. Beck, E. M.; Gaunt, M. J. Pd-catalyzed C–H bond functional- 2014, 356, 1443–1460. ization on the indole and pyrrole nucleus. Top. Curr. Chem. 2010, Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Direct functional- 292, 85–121. ization of nitrogen heterocycles via Rh-catalyzed C–H bond acti- Bellina, F.; Rossi, R. Regioselective functionalization of the vation. Acc. Chem. Res. 2008, 41, 1013–1025. imidazole ring via transition metal-catalyzed C–N and C–C bond Li, B.; Dixneuf, P. H. sp2 C–H bond activation in water and cat- forming reactions. Adv. Synth. Catal. 2010, 352, 1223–1276. alytic cross-coupling reactions. Chem. Soc. Rev. 2013, 42, 5744– Boorman, T. C.; Larrosa, I. Gold-mediated C–H bond function- 5767. alisation. Chem. Soc. Rev. 2011, 40, 1910–1925. Li, B. J.; Shi, Z. J. From C(sp2) –H to C(sp3)–H: systematic Bruckl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Innate and studies on transition metal-catalyzed oxidative C–C formation. guided C–H functionalization logic. Acc. Chem. Res. 2012, 45, Chem. Soc. Rev. 2012, 41, 5588–5598. 826–839. Li, Y.; Wu, Y.; Li, G. S.; Wang, X. S. Palladium-catalyzed C–F Cacchi, S.; Fabrizi, G. Update 1 of: Synthesis and Func- bond formation via directed C–H activation. Adv. Synth. Catal. tionalization of Indoles Through Palladium-Catalyzed Reactions. 2014, 356, 1412–1418. Chem. Rev. 2011, 111, Pr215–Pr283. Lyons, T. W.; Sanford, M. S. Palladium-catalyzed ligand- Chiusoli, G. P.; Catellani, M.; Costa, M.; Motti, E.; Della directed C–H functionalization reactions. Chem. Rev. 2010, 110, Ca’, N.; Maestri, G. Catalytic C–C coupling through C–H ary- 1147–1169. lation of arenes or heteroarenes. Coord. Chem. Rev. 2010, 254, McMurray, L.; O’Hara, F.; Gaunt, M. J. Recent developments in 456–469. natural product synthesis using metal-catalysed C–H bond func- Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Recent advances tionalisation. Chem. Soc. Rev. 2011, 40, 1885–1898. in the transition metal-catalyzed twofold oxidative C–H bond ac- Mousseau, J. J.; Charette, A. B. Direct functionalization pro- tivation strategy for C–C and C–N bond formation. Chem. Soc. cesses: a journey from palladium to copper to iron to nickel to Rev. 2011, 40, 5068–5083. metal-free coupling reactions. Acc. Chem. Res. 2013, 46, 412–424.

Avoid Skin Contact with All Reagents xiv RECENT REVIEW ARTICLES AND MONOGRAPHS

Neufeldt, S. R.; Sanford, M. S. Controlling site selectivity in Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. C–H bond palladium-catalyzed C–H bond functionalization. Acc. Chem. Res. functionalization: emerging synthetic tools for natural prod- 2012, 45, 936–946. ucts and pharmaceuticals. Angew. Chem., Int. Ed. 2012, 51, Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C. Cross-coupling 8960–9009. of heteroarenes by C–H functionalization: recent progress to- wards direct arylation and heteroarylation reactions involving het- Selected Books eroarenes containing one heteroatom. Adv. Synth. Catal. 2014, C–H Activation: Topics in Current Chemistry; Springer: Berlin, 356, 17–117. 2010; Vol. 292, 384 pp. Rouquet, G.; Chatani, N. Catalytic functionalization of C(sp2) C–H and C–X Bond Functionalization: Transition Metal Medi- –H and C(sp3) –H bonds by using bidentate directing groups. ation, RSC Catalysis Series; RSC Publishing: Cambridge, 2013; Angew. Chem., Int. Ed. 2013, 52, 11726–11743. 471 pp. Shi, G. F.; Zhang, Y. H. Carboxylate-directed C–H functional- Metal Free C–H Functionalization of Aromatics: Nucleophilic ization. Adv. Synth. Catal. 2014, 356, 1419–1442. Displacement of Hydrogen: Topics in Heterocyclic Chemistry; Sun, C. L.; Li, B. J.; Shi, Z. J. Direct C–H transformation via Springer International Publishing, 2014. iron catalysis. Chem. Rev. 2011, 111, 1293–1314. Li, J. J. C–H Bond Activation in Organic Synthesis; CRC Press Wiese, S.; Badiei, Y. M.; Gephart, R. T.; Mossin, S.; Varonka, Llc, 2015. M. S.; Melzer, M. M.; Meyer, K.; Cundari, T. R.; Warren, T. H. Rousseaux, S.; Liégault, B.; Fagnou, K. C–H functionaliza- Catalytic C–H amination with unactivated amines through cop- tion: a new strategy for the synthesis of biologically active natural per(II) amides. Angew. Chem., Int. Ed. 2010, 49, 8850–8855. products. In Modern Tools for the Synthesis of Complex Bioactive Wolfe, J. P.; Thomas, J. S. Recent developments in palladium- Molecules, Cossy, J., Arseniyadis, S., Eds.; John Wiley & Sons, catalyzed heterocycle synthesis and functionalization. Curr. Org. Inc.: Hoboken, NJ, 2012. Chem. 2005, 9, 625–655.

A list of General Abbreviations appears on the front Endpapers Short Note on InChIs and InChIKeys

The IUPAC International Chemical Identifier (InChITM) and its print edition of EROS, and all derivative handbooks would compressed form, the InChIKey, are strings of letters represent- find the same information, we appreciate that the strings will ing organic chemical structures that allow for structure search- be of little use to the readers of the print editions, unless they ing with a wide range of online search engines and databases treat them simply as reminders that e-EROS now offers the such as Google and PubChem. While they are obviously an convenience of InChIs and InChIKeys, allowing the online important development for online reference works, such as users to make best use of their browsers and perform searches Encyclopedia of Reagents for Organic Synthesis (e-EROS), in a wide range of media. readers of this volume may be surprised to find printed InChI and InChIKey information for each of the reagents. If you would like to know more about InChIs and InChIKeys, please go to the e-EROS website: http://onlinelibrary.wiley. We introduced InChI and InChIKey to e-EROS in autumn com/book/10.1002/047084289X and click on the InChI and 2009, including the strings in all HTML and PDF files. While InChIKey link. we wanted to make sure that all users of e-EROS, the second

ACETIC ANHYDRIDE 1

Under these conditions, tertiary alcohols are not acylated. Most alcohols, including tertiary alcohols, can be acylated by the ad- dition of DMAP (4-dimethylaminopyridine) and acetyl chloride to the reaction containing acetic anhydride and pyridine. In gen- eral, the addition of DMAP increases the rate of acylation by 104 A (eq 2).19 N NMe , Ac O OH 2 2 OAc 1 (2) Acetic Anhydride Et3N, rt 86%

OO Recently, Vedejs found that a mixture of tributylphosphine and O acetic anhydride acylates alcohols faster than acetic anhydride with DMAP.20 However, the combination of acetic anhydride with DMAP and triethylamine proved superior. It is believed that the [108-24-7] C4H6O3 (MW 102.09) Et3N prevents HOAc from destroying the DMAP catalyst. InChI = 1/C4H6O3/c1-3(5)7-4(2)6/h1-2H3 Tertiary alcohols have been esterified in good yield using acetic InChIKey = WFDIJRYMOXRFFG-UHFFFAOYAH anhydride with calcium hydride or calcium carbide.21t-Butanol can be esterified to t-butyl acetate in 80% yield under these condi- (useful for the acetylation of alcohols,2 amines,3 and thiols,4 ox- tions. High pressure (15 kbar) has been used to introduce the ac- 22 idation of alcohols,5 dehydration,6 Pummerer7 reaction, Perkin8 etate group using acetic anhydride in methylene chloride. Yields 9 10 11 range from 79–98%. Chemoselectivity is achieved using acetic reaction, Polonovski reaction, N-oxide reaction, Thiele re- ◦ action, ether cleavage,12 enol acetate formation,13 gem-diacetate anhydride and boron trifluoride etherate in THF at 0 C. Under formation14) these conditions, primary or secondary alcohols are acetylated in the presence of phenols.23 ◦ − ◦ −3 Physical Data: bp 138–140 C; mp 73 C; d 1.082 g cm . α-d-Glucose is peracetylated readily using acetic anhydride in Solubility: sol most organic solvents. Reacts with water rapidly the presence of zinc chloride to give α-d-glucopyranose pentaac- and alcohol solvents slowly. etate in 63–72% yield (eq 3).24 Form Supplied in: commercially available in 98% and 99+% purities. Acetic anhydride-d6 is also commercially available. HO AcO Analysis of Reagent Purity: IR, NMR.15 O O Preparative Methods: acetic anhydride is prepared industrially Ac2O 1b OH OH OAc (3) by the acylation of Acetic Acid with Ketene. A labora- ZnCl2 tory preparation of acetic anhydride involves the reaction of HO AcO OAc OH OAc sodium acetate and Acetyl Chloride followed by fractional distillation.16 Purification: adequate purification is readily achieved by frac- Under basic conditions, α-d-glucose can be converted into tional distillation. Acetic acid, if present, can be removed β-d-glucopyranose pentaacetate in 56% yield (eq 4). by refluxing with CaC2 or with coarse magnesium filings at 80–90 ◦C for 5 days. Drying and acid removal can be achieved HO AcO 17 by azeotropic distillation with toluene. O OOAc Ac2O Handling, Storage, and Precautions: acetic anhydride is corro- OH OH OAc (4) NaOAc sive and a lachrymator and should be handled in a fume hood. HO AcO OH OAc

Acetylation. The most notable use of acetic anhydride is for In the food and drug industry, high-purity acetic anhydride is the acetylation reaction of alcohols,2 amines,3 and thiols.4 Acids, used in the manufacture of aspirin by the acetylation of salicylic Lewis acids, and bases have been reported to catalyze the reac- acid (eq 5).25 tions.

CO H CO H Alcohols. The most common method for acetate introduction 2 2 HO Ac O OAc is the reaction of an alcohol with acetic anhydride in the presence 2 (5) of pyridine.2 Often, Pyridine is used as the solvent and reactions proceed nearly quantitatively (eq 1).

Ac2O ROH ROAc (1) pyridine Amines. The acetylation of amines has been known since 1853 when Gerhardt reported the acetylation of aniline.3 Acetamides If the reaction is run at temperatures lower than 20 ◦C, primary are typically prepared by the reaction of the amine with acetic alcohols can be acetylated over secondary alcohols selectively.18 anhydride (eq 6).

Avoid Skin Contact with All Reagents 2 ACETIC ANHYDRIDE

O Oxidation. The oxidation of primary and secondary alcohols to the corresponding carbonyl compounds can be achieved us- NH2 NH ing dimethyl sulfoxide–acetic anhydride.5 The reaction proceeds Ac2O (6) through an acyloxysulfonium salt as the oxidizing agent (eq 12).

O– OO Me O A unique method for selective acylation of secondary amines S + S (12) in the presence of primary amines involves the use of 18-Crown- Me + Me O Me + O –OAc 6 with acetic anhydride and triethylamine.26 It is believed that the 18-crown-6 complexes primary alkylammonium salts more tightly than the secondary salts, allowing selective acetylation. The oxidations often proceed at room temperature, although In some cases, tertiary amines undergo a displacement reaction long reaction times (18–24 h) are sometimes required. A side with acetic anhydride. A simple example involves the reaction of product is formation of the thiomethyl ethers obtained from the benzyldimethylamine with acetic anhydride to give dimethylac- Pummerer rearrangement. etamide and benzylacetate (eq 7).27 If the alcohol is unhindered, a mixture of enol acetate (from ketone) and acetate results (eq 13).32 Ac2O Ph NMe2 Ph OAc + Ac NMe2 (7) O P(OEt)2 O P(OEt)2 O P(OEt)2 OH OAc OAc Allylic tertiary amines can be displaced by the reaction of acetic O DMSO O O 28 + (13) anhydride and sodium acetate. The allylic acetate is the major O Ac2O O O product, as shown in eq 8. O O O O O O 40% 30% NMe2 OAc Ac2O (8) NaOAc The oxidation of carbohydrates can be achieved by this method, as Hanessian showed (eq 14).33

Cyclic benzylic amines may undergo ring opening upon heating O O Ph O DMSO Ph O with acetic anhydride (eq 9).29 O O (14) Ac2O OH OMe O OMe

Ac N Ac O N N 2 N (9) Aromatic α-diketones can be prepared from the acyloin com- H Δ HAcO pounds; however, aliphatic diketones cannot be prepared by this method.34 The reaction proceeds well in complex systems with- out epimerization of adjacent stereocenters, as in the yohimbine 35 α-Amino acids react with acetic anhydride in the presence of example (eq 15). This method compares favorably with that of a base to give 2-acetamido ketones.30 This reaction is known dimethyl sulfoxide–dicyclohexylcarbodiimide. as the Dakin–West reaction (eq 10) and is believed to go through a oxazolone mechanism. The amine base of choice is N N 4-dimethylaminopyridine. Under these conditions, the reaction N N H H H H can be carried out at room temperature in 30 min. H Ac2O–DMSO H (15) H H R CO2H R COMe Ac2O (10) MeO2C MeO2C NH2 NHCOMe OH O

Cyclic β-amino acids rearrange to α-methylene lactams upon 31 treatment with acetic anhydride, as shown in eq 11. Dehydration. Many functionalities are readily dehydrated upon reaction with acetic anhydride, the most notable of which is CO2H 6 Ac2O the oxime. Also, dibasic acids give cyclic anhydrides or ketones, (11) depending on ring size.36 N N O An aldoxime is readily converted to the nitrile as shown in Me Me eq 16.37

NOH Thiols. S-Acetyl derivatives can be prepared by the reac- CN tion of acetic anhydride and a thiol in the presence of potassium Ac O 2 (16) bicarbonate.4 Several disadvantages to the S-acetyl group in pep- tide synthesis include β-elimination upon base-catalyzed hydrol- OMe OMe ysis. Also, sulfur to nitrogen acyl migration may be problematic. OMe OMe

A list of General Abbreviations appears on the front Endpapers ACETIC ANHYDRIDE 3

When oximes of α-tetralones are heated in acetic anhydride in OAc R Ar Ac O R Ar RCHO the presence of anhydrous phosphoric acid, aromatization occurs S+ 2 S 38 NaOAc (22) as shown in eq 17. OH O– OAc OH

NOH NHAc 2-Phenylsulfonyl ketones rearrange in the presence of acetic X X Ac2O, H3PO4 (17) anhydride–sodium acetate in toluene at reflux to give S-aryl 82–93% thioesters (eq 23).42 Upon hydrolysis, an α-hydroxy acid is ob- tained.

Oximes of aliphatic ketones lead to enamides upon treatment O with acetic anhydride–pyridine, as shown in the steroid example Ph + Ph Ac O Ph Ph Ph CO H 39 S 2 S NaOH 2 in eq 18. (23) OO– NaOAc OAc OH

Ac2O, py In the absence of sodium acetate, 2-phenylsulfonyl ketones give Δ the typical Pummerer product. Since β-keto sulfoxides are avail- HON H 94% able by the reaction of esters with the dimsyl anion, this overall process leads to one-carbon homologated α-hydroxy acids from 42 Al2O3 esters (eq 24). (18) Ac2O, py 1. NaCH SOMe Ac N AcN 2 2 H H 2. Ac2O, NaOAc RCO2H H RCO2Rʹ (24) 3. NaOH OH Upon heating with acetic anhydride, dibasic carboxylic acids lead to cyclic anhydrides of ring size 6 or smaller. Diacids longer Also, 2-phenylsulfonyl ketones can be converted to α- than glutaric acid lead to cyclic ketones (eq 19).36 phenylthio-α,β-unsaturated ketones via the Pummerer reaction using acetic anhydride and a catalytic amount of methanesulfonic 43 O acid (eq 25). C n ≤ 3 COR2 COR2 (CH2)n O Ac2O, MeSO3H C (25) CO2H 65–97% R1 +SPh R1 SPh (CH ) O (19) 2 n –O CO H 2 n ≥ 4 (CH2)n C O The Pummerer reaction has been used many times in hetero- cyclic synthesis as shown in eq 26.

N-Acylanthranilic acids also cyclize when heated with acetic O– anhydride (eq 20). The reaction proceeds in 81% yield with slow S+ S 40 Et Ac O distillation of the acetic acid formed. 2 (26) O CO H O 2 O CO2H Ac O O 2 (20) The Pummerer rearrangement of 4-phenylsulfinylbutyric acid NH N Ph with acetic anhydride in the presence of p-toluenesulfonic O Ph acid leads to butanolide formation (eq 27).44 Oxidation with m-chloroperbenzoic acid followed by thermolysis then leads to an unsaturated compound. Pummerer Reaction. In 1910, Pummerer7 reported that sul- 2 foxides react with acetic anhydride to give 2-acetoxy sulfides O– R2 PhS R + Ac2O (eq 21). The sulfoxide must have one α-hydrogen. Alternative S CO2H (27) Ph TsOH O R1 reaction conditions include using trifluoroacetic anhydride and R1 acetic anhydride. O

O– S OAc An unusual Pummerer reaction takes place with penicillin sul- R + AcOH S+ R + Ac2O (21) foxide, leading to a ring expansion product as shown in eq 28.45 R R O– PhOCH CONH H PhOCH CONH H β-Hydroxy sulfoxides undergo the Pummerer reaction upon 2 S+ 2 S Ac2O (28) addition of sodium acetate and acetic anhydride to give α,β- N N OAc diacetoxy sulfides. These compounds are easily converted to O O CO Me α-hydroxy aldehydes (eq 22).41 2 CO2Me

Avoid Skin Contact with All Reagents 4 ACETIC ANHYDRIDE

R R R This led to discovery of the conversion of penicillin V and G to Ac2O 46 + O– Ac + (35) cephalexin, a broad spectrum orally active antibiotic (eq 29). RN RN R O Me2 Me RCH CONH H PhCH(NH )CONH H 2 S 2 S (29) N N This reaction has been extended to a synthesis of 2- O O acetoxybenzodiazepine via an N-oxide rearrangement (eq 36). CO Me 2 CO2H H H O O A Pummerer-type reaction was carried out on a dithiane protect- N N 47 Ac2O ing group to liberate the corresponding ketone (eq 30). These OAc (36) were the only reaction conditions which provided any of the de- Cl N+ Cl N sired ketone. O– Ph Ph S H S 1. m-CPBA An application of the Polonovski reaction forms β- 2. Ac2O, TEA carbonylenamines. N-Methylpiperidone is reacted with m-CPBA H H2O, THF 28–37% followed by acetic anhydride and triethylamine to give the β- O carbonyl enamine (eq 37).49 OH O H O O 1. m-CPBA 2. Ac2O, Et3N H (30) (37) 50% O N N OH Me Me

Perkin Reaction. The Perkin reaction,8 developed by Perkin Reaction with N-Oxides. Pyridine 1-oxide reacts with acetic in 1868, involves the condensation of an anhydride and an alde- anhydride to produce 2-acetoxypyridine, which can be hydrolyzed hyde in the presence of a weak base to give an unsaturated acid to 2-pyridone (eq 38).10 (eq 31).

Ac2O Ac2O (31) (38) CHO AcOK CO2H O O N+ N OAc O– The reaction is often used for the preparation of cinnamic acids in 74–77% yield (eq 32). Open chain N-oxides, in particular nitrones, rearrange to CO H amides (almost quantitatively) under acetic anhydride conditions CHO Ac2O 2 (32) (eq 39).50 NaOAc O2N O2N O + Ac O Ph 2 Ph (39) Aliphatic aldehydes give low or no yields of acid. Coumarin Ph N Ph N – H can be prepared by a Perkin reaction of salicylaldehyde and acetic O anhydride in the presence of triethylamine (eq 33). Heteroaromatic N-oxides with a side chain react with acetic CHO 51 Ac2O anhydride to give side-chain acyloxylation (eq 40). (33) Et N OH 3 O O Ac O 2 (40) + OAc N N 9 Polonovski Reaction. In the Polonovski reaction, tertiary O– amine oxides react with acetic anhydride to give the acetamide of the corresponding secondary amine (eq 34). This reaction has been used in synthetic chemistry as the method –O + of choice to form heterocyclic carbinols or aldehydes. NMe2 NMeAc

Ac O Thiele Reaction. The Thiele reaction converts 1,4- 2 (34) benzoquinone to 1,2,4-triacetoxybenzene using acetic anhydride and a catalytic amount of sulfuric acid.11 Zinc chloride has In nonaromatic cases, the Polonovski reaction gives the N- been used without advantage. In this reaction, 1,4-addition to the acylated secondary amine as the major product and the deaminated quinone is followed by enolization and acetylation to give the ketone as a minor product (eq 35).48 substituted benzene (eq 41).

A list of General Abbreviations appears on the front Endpapers ACETIC ANHYDRIDE 5

O OAc The reaction occurs with inversion of configuration, as shown Ac O in eq 48. 2 (41) OAc Br O OAc (48) O 88% OAc With unhindered quinones, BF3 etherate is a more satisfactory catalyst but hindered quinones require the more active sulfuric acid Trimethylsilyl ethers are converted to acetates directly by the catalyst. 1,2-Naphthoquinones undergo the Thiele reaction with action of acetic anhydride–pyridine in the presence of 48% HF or acetic anhydride and sulfuric acid or boron trifluoride etherate boron trifluoride etherate (eq 49).56 (eq 42). Ac2O–pyr O OAc RO SMT RO cA (49) 48% HF O OAc or BF · OEt Ac2O–H2SO4 3 2 (42) 85%

OAc Miscellaneous Reactions. Primary allylic alcohols can be pre- pared readily by the action of p-toluenesulfonic acid in acetic anhydride–acetic acid on the corresponding tertiary vinyl carbinol, Ether Cleavage. Dialkyl ethers can be cleaved with acetic followed by hydrolysis of the resulting acetate.57 The vinyl anhydride in the presence of pyridine hydrochloride or anhydrous carbinol is readily available from the reaction of a ketone with Iron(III) Chloride. In both cases, acetate products are produced. As a vinyl Grignard reagent. Overall yields of allylic alcohols are shown in eq 43, the tricyclic ether is cleaved by acetic anhydride very good (eq 50). and pyridine hydrochloride to give the diacetate in 93% yield.12 1. Ac2O, HOAc HO cat TsOH OAc (50) 2. KOH, H2O OH Ac2O O (43) 55–90% py · HCl O 93% AcO Enol lactonization occurs readily on an α-keto acid using acetic 58 Simple dialkyl ethers react with iron(III) chloride and acetic an- anhydride at elevated temperatures. The reaction shown in eq 51 proceeds in 89% yield. In general, acetic anhydride is superior to hydride to produce compounds where both R groups are converted 59 to acetates (eq 44).52 acetyl chloride in this reaction. O R Rʹ Ac2O ʹ O ROAc + R OAc (44) O CO2H O FeCl3 Ac2O, 60 °C (51) 89% Cleavage of allylic ethers can occur using acetic anhydride in O O the presence of iron(III) chloride (eq 45). The reaction takes place without isomerization of a double bond, but optically active ethers Aliphatic aldehydes are easily converted to the enol acetate are cleaved with substantial racemization.53 using acetic anhydride and potassium acetate (eq 52).13 This re- Ac2O, FeCl3 action only works for aldehydes and is the principal reason for AcO 35 min AcO (45) the failure of aldehydes to succeed in the Perkin reaction. Triethy- O-t-Bu 76% OAc lamine and DMAP may also catalyze the reaction.

Cleavage of aliphatic ethers occurs with the reaction of acetic Ac2O, KOAc CHO (52) anhydride, boron trifluoride etherate, and lithium bromide (eq 46). 45–50% OAc The ethers are cleaved to the corresponding acetoxy compounds contaminated with a small amount of unsaturated product.54 In A cyclopropyl ketone is subject to homoconjugate addition us- some cases, the lithium halide may not be necessary. ing acetic anhydride/boron trifluoride etherate. Upon acetate ad- dition, the enol is trapped as its enol acetate (eq 53).60 O eM O cA Ac O, LiBr 2 OCO-t-Bu OCO-t-Bu BF3 · OEt2 H H (46) O Ac2O AcO H (53) BF3 · OEt2 Cyclic ethers are cleaved to ω-bromoacetates using Magnesium H Bromide and acetic anhydride in acetonitrile (eq 47).55 AcO

Ac2O, MgBr2 When an aldehyde is treated with acetic anhydride/anhydrous (47) O 20 °C AcO Br iron(III) chloride, geminal diacetates are formed in good to excel- 97% lent yields.14 Aliphatic and unsaturated aldehydes can be used

Avoid Skin Contact with All Reagents 6 ACETIC ANHYDRIDE in this reaction as shown in eqs 54–56. Interestingly, if an α- A condensation/cyclization reaction between an alkynyl ke- hydrogen is present in an unsaturated aldehyde, elimination of tone and a carboxylic acid in the presence of acetic anhy- the geminal diacetate product gives a 1-acetoxybutadiene. dride/triethylamine gives a butenolide (eq 62).66

Ac2O Ph CHO CH(OAc)2 (54) FeCl3 R O Ar CO H Ac2O O HC O (HC O )cA 2 R + 2 Ar (62) Et3N (55) Ph O

A few rearrangement reactions take place with acetic anhy- dride. A Claisen rearrangement is involved in the formation of the (56) aromatic acetate in eq 63.67 The reaction proceeds in 44% yield OTBS OAc even after 21 h at 200 ◦C. OAc CHO OAc O OAc Ac2O If an aldehyde is treated with acetic anhydride in the presence NaOAc (63) of a catalytic amount of cobalt(II) chloride, a diketone is formed 200 °C (eq 57).61 21 h 44% O O Ac O 2 Ph Complex rearrangements have occured using acetic anhydride (57) 68 Ph H cat CoCl2 Ph under basic conditions, as shown in eq 64. O H CO2Me N O However, if 1.5 equiv of cobalt(II) chloride is added, the gem- Ac2O N H (64) inal diacetate is formed (eq 58).62 Cl py N Cl Ph CHO CH(OAc)2 Ph 3 equiv Ac2O (58) Aromatization occurs readily using acetic anhydride. Aromati- 1.5 equiv CoCl2 zation of α-cyclohexanones occurs under acidic conditions to lead to good yields of phenols (eq 65).69 However, in totally unsubsti- Apparently, the reaction in eq 58 occurs only when the starting tuted ketones, aldol products are formed. material is polyaromatic or with compounds whose carbonyl IR frequency is less than 1685 cm−1. O OH 1. H SO Acetic anhydride participates in several cyclization reactions. R 2 4 R 2. Ac2O–HOAc For example, enamines undergo a ring closure when treated with (65) 3. H2O acetic anhydride (eq 59).63 Aromatization of 1,4- and 1,2-cyclohexanediones leads to O O OAc cresol products (eq 66) in over 90% yield.70 CO Na Ac2O 2 (59) O OH N N Ac2O, H2SO4 HOAc (66)

o-Diamine compounds also cyclize when treated with acetic O OH anhydride (eq 60).64

Me Alkynes and allenes are formed by the acylation of nitrimines NMe2 N using acetic anhydride/pyridine with DMAP as catalyst (eqs 67 Ac2O 71 (60) and 68). Nitrimines are prepared by nitration of ketoximes with N NH2 nitrous acid. NO N 2 Twistane derivatives were obtained by the reaction of a de- Ac2O (67) calindione with acetic anhydride, acetic acid, and boron trifluoride py etherate (eq 61).65 65%

H AcO • O O NNO Ac2O–HOAc 2 + (61) 76% BF3 ·OE t 2 (68) 62% H O 81% 19%

A list of General Abbreviations appears on the front Endpapers ACETIC ANHYDRIDE 7

Lastly, acetic anhydride participates in the Friedel–Crafts 25. See Ref. 1(b) and Candoros, F., Rom. Patent 85 726, 1984; reaction.72 Polyphosphoric acid is both reagent and solvent in Chem. Abstr. 1985, 103, 104 715. these reactions (eq 69). 26. Barrett, A. G. M.; Lana, J. C. A. J. Chem. Soc., Chem. Commun. 1978, 471. OMe OMe 27. Tiffeneau, M.; Fuhrer, K. Bull. Soc. Claim. Fr. 1914, 15, 162. 28. Fujita, T.; Suga, K.; Watanabe, S. Aust. J. Chem. 1974, 27, 531. Ac O 2 (69) 29. Freter, K.; Zeile, K. J. Chem. Soc., Chem. Commun. 1967, 416. PPA 84% 30. (a) Dakin, H. D.; West, R. J. Biol. Chem. 1928, 78, 745, 757 (b) Allinger, N. L.; Wang, G. L.; Dewhurst, B. B. J. Org. Chem. 1974, 39, 1730. O (c) Buchanan, G. L. Chem. Scr. 1988, 17, 91. 31. (a) Ferles, M. Collect. Czech. Chem. Commun. 1964, 29, 2323. (b) Rueppel, M. L.; Rapoport, H. J. Am. Chem. Soc. 1972, 94, 3877. 32. Glebova, Z. I.; Uzlova, L. A.; Zhdanov, Y. A. Zh. Obshch. Khim. 1985, 55, 1435; Chem. Abstr. 1986, 104, 69 072. 33. Hanessian, S.; Rancourt, G. Can. J. Chem. 1977, 55, 1111. 1. (a) Kim, D. H. J. Heterocycl. Chem. 1976, 13, 179. (b) Cook, S. L. 34. Newman, M. S.; Davis, C. C. J. Org. Chem. 1967, 32, 66. Chemical Industries 1993, 49, 145. (c) Joy, E. F.; Barnard, A. J., Jr. 35. (a) Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1965, 87, 4214. Encyclopedia of Industrial Chemical Analysis; Interscience: New York, (b) J. Org. Chem. 1965, 30, 1107. 1967; Vol. 4, p 102. 36. (a) Blanc, H. G. C.R. Hebd. Seances Acad. Sci. 1907, 144, 1356. 2. (a) Weber, H.; Khorana, H. G. J. Mol. Biol. 1972, 72, 219 (b) Zhdanov, (b) Ruzicka, L.; Prelog, V.; Meister, P. Helv. Chim. Acta 1945, 28, 1651. R. I.; Zhenodarova, S. M. Synthesis 1975, 222. 37. Beringer, F. M.; Ugelow, I. J. Am. Chem. Soc. 1953, 75, 2635, and 3. Mariella, R. P.; Brown, K. H. J. Org. Chem. 1971, 36, 735 and references references cited therein. cited therein. 38. Newnan, M. S.; Hung, W. M. J. Org. Chem. 1973, 38, 4073. 4. Zervas, L.; Photaki, I.; Ghelis, N. J. Am. Chem. Soc. 1963, 85, 1337. 39. Boar, R. B.; McGhie, J. F.; Robinson, M.; Barton, D. H. R.; Horwell, 5. Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1967, 89, 2416. D. C.; Stick, R. V. J. Chem. Soc., Perkin Trans. 1 1975, 1237. 6. (a) Buck, J. S.; Ide, W. S. Org. Synth., Coll. Vol. 1943, 2, 622. (b) White, 40. Zentmyer, D. T.; Wagner, E.C.J. Org. Chem. 1949, 14, 967. D. M. J. Org. Chem. 1974, 39, 1951. (c) Nicolet, B. H.; Pelc, J. J. J. Am. 41. Iruichijima, S.; Maniwa, K.; Tsuchihashi, G. J. Am. Chem. Soc. 1974, Chem. Soc. 1922, 44, 1145. (d) Bell, M. R.; Johnson, J. R.; Wildi, B. S.; 96, 4280. Woodward, R. B. J. Am. Chem. Soc. 1958, 80, 1001. 42. Iriuchijima, S.; Maniwa, K.; Tsuchihashi, G. J. Am. Chem. Soc. 1975, 7. (a) Pummerer, R. Biochemistry 1910, 43, 1401. (b) Parham, W. E.; 97, 596. Edwards, L. D. J. Org. Chem. 1968, 33, 4150. (c) Tanikaga, R.; Yabuki, Y.; Ono, N.; Kaji, A. Tetrahedron 1976, 2257. 43. (a) Monteiro, H. 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Chem. 1975, 40, 3571. 47. Smith, A. B., III; Dorsey, B. D.; Visnick, M.; Maeda, T.; Malamas, M. S. 13. (a) Bedoukin, P. Z. Org. Synth., Coll. Vol 1955, 3, 127. (b) Cousineau, J. Am. Chem. Soc. 1986, 108, 3110. T. J.; Cook, S. L.; Secrist, J. A., III Synth. Commun. 1979, 9, 157. 48. (a) See Ref. 9. (b) Polonovski, M.; Polonovski, M. Bull. Soc. Claim. Fr. 14. Kochhar, K. S.; Bal, B. S.; Deshpande, R. P.; Rajadhyaksha, S. N.; 1926, 39, 147. (c) Wenkert, E. Experientia 1954, 10, 346. (d) Cave, A.; Pinnick, H. W. J. Org. Chem. 1983, 48, 1765. Kan-Fan, C.; Potier, P.; LeMen, J. Tetrahedron 1967, 23, 4681. 15. For analysis by titration, see Ref. 1c. Spectra available from the Aldrich 49. Stütz, P.; Stadler, P. A. Tetrahedron 1973, 5095. Library. 50. Tamagaki, S.; Kozuka, S.; Oae, S. Tetrahedron 1970, 26, 1795. 16. Vogel’s Textbook of Practical Organic Chemistry, 4th ed.; Longman: 51. (a) Kobayashi, G.; Furukawa, S. Chem. Pharm. Bull. 1953, 1, 347. Harlow, 1978; p 499. (b) Boekelheide, V.; Lim, W. J. J. Am. Chem. Soc. 1954, 76, 1286. 17. Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of (c) Bullit, O. H., Jr.; Maynard, J. T. J. Am. Chem. Soc. 1954, 76, 1370. Laboratory Chemicals, 2nd ed.; Pergamon: Oxford, 1985; p 77. (d) Berson, J. A.; Cohen, T. J. Am. Chem. Soc. 1955, 77, 1281. 18. Stork, G.; Takahashi, T.; Kawamoto, I.; Suzuki, T. J. Am. Chem. Soc. 52. Knoevenagel, E. Justus Liebigs Ann. Chem. 1914, 402, 111. 1978, 100, 8272. 53. Ganem, B.; Small, V. R., Jr. J. Org. Chem. 1974, 39, 3728. 19. Hölfe, G.; Steglich, W.; Vorbrüggen, H. Angew. Chem. Int. Ed. Engl. 54. (a) Youssefyeh, R. D.; Mazur, Y. Tetrahedron Lett. 1962, 1287. 1978, 17, 569. (b) Narayanan, C. R.; Iyer, K. N. Tetrahedron Lett. 1964, 759. 20. Vedejs, E.; Diver, S. T. J. Am. Chem. Soc. 1993, 115, 3358. 55. Goldsmith, D. J.; Kennedy, E.; Campbell, R. G. J. Org. Chem. 1975, 40, 21. Oppenauer, R. V. Monatsh. Chem. 1966, 97, 62. 3571. 22. Dauben, W. G.; Bunce, R. A.; Gerdes, J. M.; Henegar, K. E.; 56. (a) Voaden, D. J.; Waters, R. M. Org. Prep. Proced. Int. 1976, 8, 227. Cunningham, A. F., Jr.; Ottoboni, T. B. Tetrahedron 1983, 24, 5709. (b) For conversion of ROTBS to ROAc using Ac2O and FeCl3, see 23. Nagao, Y.; Fujita, E.; Kohno, T.; Yagi, M. Chem. Pharm. Bull. 1981, 29, Ganem, B.; Small, V. R. J. Org. Chem. 1974, 39, 3728. 3202. 57. Babler, J. H.; Olsen, D. O. Tetrahedron Lett. 1974, 351. 24. Vogel’s Textbook of Practical Organic Chemistry, 4th ed.; Longman: 58. Eggette, T. A.; deBoer, J. J. J.; deKoning, H.; Huisman, H. O. Synth. Harlow, 1978; pp 454–455. Commun. 1978, 8, 353.

Avoid Skin Contact with All Reagents 8 ACETYL CHLORIDE

59. Rosenmund, K. W.; Herzberg, H.; Schutt, H., Chem. Ber. 1954, 87, 1258. present, while a purple color that persists for at least 10 min 60. (a) Rigby, J. H.; Senanayake, C. J. Am. Chem. Soc. 1987, 109, 3147. indicates that HCl is absent.1b (b) Rigby, J. H.; Senanayake, C. J. Org. Chem. 1988, 53, 440. Preparative Methods: treatment of acetic acid or sodium ac- 61. Ahmad, S.; Iqbal, J. Chem. Soc., Chem. Commun. 1987, 692. etate with the standard inorganic chlorodehydrating agents 1b,23 1a,24 1b,25 62. Fry, A. J.; Rho, A. K.; Sherman, L. R.; Sherwin, C. S. J. Org. Chem. (PCl3, SO2Cl2, or SOCl2 ) generates mate- 1991, 56, 3283. rial that may contain phosphorus- or sulfur-containing 63. Friary, R. J., Jr.; Gilligan, J. M.; Szajewski, R. P.; Falci, K. J.; Franck, impurities.1b,23a,26 Inorganic-free material can be prepared by R. W. J. Org. Chem. 1973, 38, 3487. 27 treatment of HOAc with Cl2CHCOCl (; 70%), PhCOCl (; 64. Meth-Cohn, O.; Suschitzky, H. In Advances in Heterocyclic Chemistry; 28 ◦ 29 30 88%), PhCCl3 (cat. H2SO4,90 C; 92.5%), or phosgene Katritzky, A. R.; Boulton, J., Eds.; Academic Press: New York, 1972; (optionally catalyzed by DMF,30e magnesium or other metal Vol. 14, p 213. salts,30a,b,d or activated carbon30b,c), or by addition of hy- 65. Bélanger, A.; Lambert, Y.; Deslongchamps, P. Can. J. Chem. 1969, 47, ◦ 795. drogen chloride to acetic anhydride (85–90 C; ‘practically 1a,31 66. Rao, Y. S.; Filler, R. Tetrahedron Lett. 1975, 1457. quantitative’). Purification: HCl-free material can be prepared either by dis- 67. (a) Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1. (b) Karanewsky, 11c,20 D. S.; Kishi, Y.; J. Org. Chem. 1976, 41, 3026. tillation from dimethylaniline or by standard degassing 20c,21 68. Gryer, R. I.; Brust, B.; Earley, J. V.; Sternbach, L. H. J. Chem. Soc. (C) procedures. 1967, 366. Handling, Storage, and Precautions: acetyl chloride should be 69. Kablaoui, M. S. J. Org. Chem. 1974, 39, 2126. handled only in a well-ventilated fume hood since it is volatile 22 70. Kablaoui, M. S. J. Org. Chem. 1974, 39, 3696. and toxic via inhalation. It should be stored in a sealed con- 71. Büchi, G.; Wüest, H. J. Org. Chem. 1979, 44, 4116. tainer under an inert atmosphere. Spills should be cleaned up 1a 72. Edwards, J. D.; McGuire, S. E.; Hignite, C. J. Org. Chem. 1964, 29, by covering with aq sodium bicarbonate. 3028.

Regina Zibuck Friedel–Crafts Acetylation. Arenes undergo acetylation to Wayne State University, Detroit, MI, USA afford aryl methyl ketones on treatment with acetyl chloride (AcCl) together with a Lewis acid, usually aluminum chloride3. This reaction, known as the Friedel–Crafts acetylation, is valuable as a preparative method because a single positional isomer is pro- duced from arenes that possess multiple unsubstituted electron- Acetyl Chloride1 rich positions in many instances. For example, Friedel–Crafts acetylation of toluene (AcCl/AlCl3, ethylene dichloride, rt) affords p-methyl- O acetophenone predominantly (p:m:o = 97.6:1.3:1.2; eq 1).32 Cl

AcCl/AlCl3 [75-36-5] C2H3ClO (MW 78.50) (1) ClCH2CH2Cl, rt InChI = 1/C2H3ClO/c1-2(3)4/h1H3 InChIKey = WETWJCDKMRHUPV-UHFFFAOYAQ O p:m:o = 97.6:1.3:1.2 (useful for electrophilic acetylation of arenes,2 alkenes,2a,3 alkynes,4 saturated alkanes,3a,5 organometallics, and enolates Acetylation of chlorobenzene under the same condi- (on C or O);6 for cleavage of ethers;7 for esterification of ster- tions affords p-chloroacetophenone with even higher selec- ically unhindered8 or acid-sensitive9 alcohols; for generation of tivity (p:m = 99.5:0.5).33 Acetylation of bromobenzene33 and solutions of anhydrous hydrogen chloride in methanol;10 as a fluorobenzene33 afford the para isomers exclusively. The dehydrating agent; as a solvent for organometallic reactions;11 para:meta34 and para:ortho32,34 selectivities exhibited by 12 13 for deoxygenation of sulfoxides; as a scavenger for chlorine AcCl/AlCl3 are greater than those exhibited by most other and bromine;14 as a source of ketene; and for nucleophilic Friedel–Crafts electrophiles. acetylation15) Halogen substituents can be used to control regioselectivity. For example, by introduction of bromine ortho to methyl, it is possible Physical Data: bp 51.8 ◦C;1a mp −112.9 ◦C;1a d 1.1051 g to realize ‘meta acetylation of toluene’ (eq 2).35 cm−3;1a refractive index 1.38976.1b IR (neat) ν 1806.7 cm−1;16 1 13 H NMR (CDCl3) δ 2.66 ppm; C NMR (CDCl3) δ 33.69 ppm (q) and 170.26 ppm (s); the bond angles (determined by elec- Br Br 17 ◦ ◦ AcCl/AlCl3 tron diffraction ) are 127.5 (O–C–C), 120.3 (O–C–Cl), and (2) 112.2◦ (Cl–C–C). CH2Cl2, rt O Analysis of Reagent Purity: a GC assay for potency has been described;18 to check qualitatively for the presence of HCl, a common impurity, add a few drops of a solution of crystal violet Regioselectivity is quite sensitive to reaction conditions (e.g. in chloroform;19 a green or yellow color indicates that HCl is solvent, order of addition of the reactants, concentration, and

A list of General Abbreviations appears on the front Endpapers ACETYL CHLORIDE 9 temperature). For example, acetylation of naphthalene can be di- ride (CCl4, rt; 78% yield of 5-chloro-4-methoxy-2-pentanone af- rected to produce either a 99:1 mixture of C-1:C-2 acetyl deriva- ter methanolysis),48 which are relatively immune to the effects of tives (by addition of a solution of arene and AcCl in CS2 to a acid. ◦ slurry of AlCl3 in CS2 at 0 C) or a 7:93 mixture (by addition of The acetylated products derived from higher alkenes are suscep- the preformed AcCl/AlCl3 complex in dichloroethane to a dilute tible to protonation or solvolysis which produces carbenium ions solution of the arene in dichloroethane at rt).36 Similarly, acetyla- that undergo Wagner–Meerwein hydride migrations.49 For exam- tion of 2-methoxynaphthalene can be directed to produce either a ple, on subjection of cyclohexene to standard Friedel–Crafts acety- ◦ 98:2 mixture of C-1:C-6 acetyl derivatives (using the former con- lation conditions (AcCl/AlCl3,CS2−18 C), products formed in- ditions) or a 4:96 mixture (by addition of the arene to a solution clude not only 2-chlorocyclohexyl methyl ketone (in 40% yield)50 37 2a,51 of the preformed AcCl/AlCl3 complex in nitrobenzene). Also, but also 4-chlorocyclohexyl methyl ketone. If benzene is acetylation of 1,2,3-mesitylene can be directed to produce either added to the crude acetylation mixture and the temperature is then a 100:0 mixture of C-4:C-5 isomers or a 3:97 mixture.36c increased to 40–45 ◦C for 3 h, 4-phenylcyclohexyl methyl ketone Frequently, regioselectivity is compromised by side reactions is formed in 45% yield (eq 3).49a,b catalyzed by the HCl byproduct. For example, acetylation of p- xylene by treatment with AlCl3 followed by Ac2O (CS2, ,1 O h) produces a 69:31 mixture of 2,5-dimethylacetophenone and 2,4-dimethylacetophenone, formation of the latter being indica- AcCl/AlCl3 benzene tive of competitive acid-catalyzed isomerization of p-xylene to CS2, –20 °C 40–45 °C, 3 h Cl 45% m-xylene.38 Also, although acetylation of anthracene affords 9- not isolated acetylanthracene regioselectively, if the reaction mixture is al- lowed to stand for a prolonged time prior to work-up (rt, 20 h) O isomerization to a mixture of C-1, C-2, and C-9 acetyl derivatives (3) occurs.39 These side reactions can be minimized by proper choice of re- action conditions. Isomerization of the arene can be suppressed by adding the arene to the preformed AcCl/AlCl3 complex. This order of mixing is known as the ‘Perrier modification’ of the Wagner–Meerwein rearrangement also occurs during acetyla- 40 Friedel–Crafts reaction. Acetylation of p-xylene using this order tion of methylcyclohexene, even though the rearrangement is anti- 38 of mixing affords 2,5-dimethylacetophenone exclusively. Iso- Markovnikov (β-tertiary → γ-secondary; eq 4).52 Acetylation of merization of the product aryl methyl ketone can be suppressed cis-decalin53 also produces a β-tertiary carbenium ion that un- by crystallizing the product out of the reaction mixture as it is dergoes anti-Markovnikov rearrangement. The rearrangement is formed. For example, on acetylation of anthracene in benzene at terminated by intramolecular O-alkylation of the acetyl group by ◦ 5–10 C, 9-acetylanthracene crystallizes out of the reaction mix- the γ-carbenium ion to form a cyclic enol ether in two cases.49c,53 39 ture (as its 1/1 AlCl3 complex) in pure form. Higher yields of purer products can also be obtained by substituting zirconium(IV) 41 42 O O chloride or tin(IV) chloride for AlCl3.

AcCl is not well suited for industrial scale Friedel–Crafts acety- AcCl/AlCl3 lations because it is not commercially available in bulk (only by the + CS2, –5 °C→rt drum) and therefore must be prepared on site.1 The combination of + acetic anhydride and anhydrous hydrogen fluoride, both of which 43 O are available by the tank car, is claimed to be more practical. O On laboratory scale, AcCl/AlCl is more attractive than Ac O/HF NaOH, MeOH, rt 3 2 (4) or Ac2O/AlCl3. Whereas one equivalent of AlCl3 is sufficient to activate AcCl, 1.5–2 equiv AlCl3 (relative to arene) are required H 36a,37b,38,44 Cl to activate Ac2O. Thus, with Ac2O, greater amounts endo:exo = 79:21 of solvent are required and temperature control during the quench is more difficult. Also, slightly lower isolated yields have been 36a,45 reported with Ac2O than with AcCl in two cases. However, Higher alkenes themselves are also susceptible to protonation. it should be noted that the two reagents generally afford similar The resulting carbenium ions decompose by assorted pathways 51,54 ratios of regioisomers.36a,38,46 including capture of chloride (with SnCl4 as the catalyst), ad- dition to another alkene to form dimer or polymer,5b,55 proton loss Acetylation of Alkenes. Alkenes, on treatment with (resulting in exo/endo isomerization), or skeletal rearrangement.56 AcCl/AlCl3 under standard Friedel–Crafts conditions, are trans- Higher alkenes can be acetylated in synthetically useful yield formed into mixtures of β-chloroalkyl methyl ketones, allyl by treatment with AcCl together with various mild Lewis acids. methyl ketones, and vinyl methyl ketones, but the reaction is One that deserves prominent mention is ethylaluminum dichlo- not generally preparatively useful because both the products and ride (CH2Cl2, rt), which is useful for acetylation of all classes of the starting alkenes are unstable under the hyperacidic reac- alkenes (monosubstituted, 1,2-disubstituted, and trisubstituted).57 tion conditions. Preparatively useful yields have been reported For example, cyclohexene is converted into an 82/18 mixture of 3- only with electron poor alkenes such as ethylene (dichloroethane, acetylcyclohexene and 2-chlorocyclohexyl methyl ketone in 89% 5–10 ◦C; >80% yield of 4-chloro-2-butanone)47 and allyl chlo- combined yield.

Avoid Skin Contact with All Reagents 10 ACETYL CHLORIDE

The following Lewis acids are also claimed to be supe- 1.2 equiv AcCl/AlCl3 Δ rior to AlCl3: Zn(Cu)/CH2I2 (AcCl, CH2Cl2, ), by which CH2Cl2, , 2 h cyclohexene is converted into acetylcyclohexene in 68% 58 yield (after treatment with KOH/MeOH); ZnCl2 (AcCl, ◦ ◦ + Et2O/CH2Cl2, −75 C →−20 C), by which 2-methyl-2-butene O (6) is converted into a 15:85 mixture of 3,4-dimethyl-4-penten-2-one 60% and 4-chloro-3,4-dimethyl-2-pentanone in ‘quantitative’ com- 59 bined yield; and SnCl4, by which cyclohexene (AcCl, CS2, −5 ◦C → rt) is converted into acetylcyclohexene in 50% yield (af- ◦ 60 If the reaction is carried out with excess alkane, a second hydride ter dehydrochlorination with PhNEt2 at 180 C), methylcyclo- transfer occurs, resulting in reduction of the enone to the corre- hexene (CS2, rt) is converted into 1-acetyl-2-methylcyclohexene 69,70 52 sponding saturated alkyl methyl ketone. For example, stir- in 48% yield (after dehydrochlorination), and camphene is con- ◦ verted into an acetylated derivative in ∼65% yield.49c ring AcCl/AlCl3 in excess cyclohexane (30–35 C, 2.5 h) affords 2-methyl-1-acetylcyclopentane in 50% yield (unpurified; based Conducting the acetylation in the presence of a nonnucle- 55a,69,71 on AcCl) and stirring AcCl/AlBr3 in excess cyclopen- ophilic base or polar solvent is reported to be advantageous. ◦ For example, methylenecyclohexane can be converted into 1- tane (20 C, 1 h) affords cyclopentyl methyl ketone in 60% yield (based on AcCl; eq 7).55c cyclohexenylacetone in 73% yield by treatment with AcSbCl6 in ◦ ◦ 61 the presence of Cy2NEt (CH2Cl2, −50 C →−25 C,1h) and cyclohexene can be converted into 3-acetylcyclohexene in 80% ◦ 62 O yield by treatment with AcBF4 in MeNO2 at −25 C. AcCl/AlBr3 Employment of Ac2O instead of AcCl is also advantageous (7) in some cases. For example, methylcyclohexene can be converted 20 °C, 1 h into 3-acetyl-2-methylcyclohexene in 90% yield by treatment with 60% 63 ZnCl2 (neat Ac2O, rt, 12 h). Finally, alkenes can be diacetylated to afford pyrylium salts 55b,56,64 by treatment with excess AcCl/AlCl3, albeit in low yield If the reaction is carried out with a substoichiometric amount (eq 5).64a of alkane, the product is either a 2:1 adduct (if cyclic)53b,66a or pyrylium salt (if acyclic).66b,68b Unbranched alkanes also undergo acetylation, but at higher tem- perature, so yields are generally lower. For example, acetylation of cyclohexane by AcCl/AlCl requires refluxing in CHCl and AcCl/AlCl3 3 3 (5) 55c,72 25 °C + affords 1-acetyl-2-methylcyclopentene in only 36% yield. 20% O Despite the modest to low yields, acetylation of alkanes pro- – AlCl4 vides a practical method for accessing simple methyl ketones be- cause all the input raw materials are cheap.

Coupling with Organometallic Reagents. Coupling of Acetylation of Alkynes. Under Friedel–Crafts conditions organometallic reagents with AcCl is a valuable method for prepa- ◦ (AcCl/AlCl3, CCl4, 0–5 C), acetylene undergoes acetylation to ration of methyl ketones. Generally a catalyst (either a Lewis acid afford β-chlorovinyl methyl ketone in 62% yield4 and under sim- or transition metal salt) is required. ◦ ilar conditions (AcSbF6, MeNO2, −25 C) 5-decyne undergoes Due to the large number and varied characteristics of the acetylation to afford 6-acetyl-5-decanone in 73% yield.65 organometallics, comprehensive coverage of the subject would require discussion of each organometallic reagent individually, Acetylation of Saturated Alkanes. Saturated alkanes, on which is far beyond the scope of this article. Information pertain- treatment with a slight excess of AcCl/AlCl3 at elevated temper- ing to catalyst and condition selection should therefore be accessed ature, undergo dehydrogenation (by hydride abstraction followed from the original literature; some seminal references are given in by deprotonation) to alkenes, which undergo acetylation to afford Table 1. vinyl methyl ketones. The hydride-abstracting species is believed 66 67 to be either the acetyl cation or HAlCl4, with most evidence C-Acetylation of Enolates and Enolate Equivalents. β- favoring the former. Perhaps because the alkenes are generated Diketones can be synthesized by treatment of metal enolates with slowly and consumed rapidly, and therefore are never present in AcCl. O-Acetylation is often a significant side reaction, but the high enough concentration to dimerize, yields are typically higher amount can be minimized by choosing a counterion that is bonded than those of acetylation of the corresponding alkenes.53b,68 A covalently to the enolate6 such as copper132 or zinc,133 and by 6a similar hypothesis has been offered to explain the phenomenon using AcCl rather than Ac2O. Proton transfer from the prod- that the yield from acetylation of tertiary alkyl chlorides is typ- uct β-diketone to the starting enolate is another common side ically higher than the yield from acetylation of the correspond- reaction.134 Alternative procedures for effecting C-acetylation ing alkenes.55b,64a For example, methylcyclopentane on treat- that avoid or minimize these side reactions include Lewis acid- ment with AcCl/AlCl3 (CH2Cl2, ) undergoes acetylation to af- catalyzed acetylation of the trimethylsilyl enol ether derivative 135 ford 1-acetyl-2-methylcyclopentene in an impressive 60% yield (AcCl/cat. ZnCl2,CH2Cl2 or CH2Cl2/Et2O, rt) and addition 53b,66a 136 (eq 6). of ketene to the morpholine enamine (AcCl/Et3N, CHCl3, rt).

A list of General Abbreviations appears on the front Endpapers ACETYL CHLORIDE 11

i,ii + Table 1 Catalyst Selection Chart OTBS – AcCl/Et3N O OTBS iii Organo- R = Alkyl Vinyl Aryl Alkynyl Allyl THF, rt 86% metallic OEt OEt RLi N73iv 74iv R2Mg N RMgX Fe75 TBSO O Cu76 (9) Mn76b,77 OEt D78 N79 RCuL− N80 N81 N80,82 N80,83 N84 The silyl ketene acetal strategy can also be used to effect γ- I83a acetylation of α,β-unsaturated esters (AcCl/cat. ZnBr ,CH Cl , 85,86 85 87 85 88iv 2 2 2 RZnL Pd Pd Pd Pd N rt)140 and β-ketoesters (AcCl, Et O, −78 ◦C).141 D89 D89 N90 2 N91 RCdL N91c,92 N91c,92b,d,e Enol Acetylation. Enol acetylation of ketones can be effected RHgL Al93 Al94 Al93 Al95 by formation of a metal enolate in which the metal is relatively Pd96 Ti94v Pd96,97 6 142 143 − 98 99,100vi 101vi dissociated (such as potassium or magnesium ) followed by RBL3 N N N RAlL N102 N85,102b quenching with AcCl. Alternatively, enol acetates can be synthe- 2 4,6 Cu103 Pd85 sized directly from the ketones. For example, 3-keto- -steroids − 104 85 2,4,6 R4Al Fe Pd can be converted into  -trienol acetates by treatment with Cu104 3,5,7 105 105 AcCl/PhNMe2 or into  -trienol acetates by treatment with RTlL2 N N 144 106,107 107,108,109vii 107,110 107,111,112viii, AcCl/Ac2O. RSiL3 Al Al Al Al Al113ix Acetyl bromide (AcBr) is apparently superior to AcCl as Ti114x a catalyst for enol acetylation, based on a report that 17β- 106b RGeL3 Al benzoyloxyestra-4,9(10)-dien-3-one is converted into estradiol 3- 115 115,116 117 118 119x RSnL3 Pd Pd Pd Pd Rh acetate-17-benzoate in higher yield at much lower temperature Al106b Ti120iv N117c N121,122iv 123 using AcBr rather than AcCl (87.5% yield with 1:2 AcBr:Ac O, RBiL2 Pd 2 124iv RTiL2 N CH2Cl2, rt, 1 h (eq 10) vs. 81.0% yield with 1:2 AcCl:Ac2O, , 125 145 RZrL3 N 4.5 h). 126 RVL2 N RMnL Cu127 Cu127 Cu127 Cu127 Cu127 N128 N128 N128 N128 OBz OBz RRh N129 130 130,131 RNiL N N H 1/2 AcBr/Ac2O H (10) i Codes (in headings): L = unspecified ligand and X = halogen; codes (in CH2Cl2, rt, 1 h H HH entries): N = no catalyst required, Fe = FeIII salt, Cu = CuI salt, Mn = MnI 87.5% 0 II O AcO salt, D = dipolar aprotic additive, I = LiI, Pd = Pd or Pd salt, Al = AlCl3, ii Ti=TiCl4, and Rh = ClRh(PPh3)3. Coupling occurs at metal-bearing carbon with retention of configuration to afford RCOMe unless otherwise indicated. iiiCoupling occurs at γ-carbon unless otherwise indicated. ivProduct is tertiary β-Keto esters can be converted into either trans or cis enol ac- alcohol. vCoupling occurs with inversion of configuration. viCoupling occurs etates. The trans isomer is accessible by treatment with AcCl/Et3N ◦ at β-carbon. viiCoupling occurs at δ-carbon. viiiSubstrate is allenic silane and (HMPA, rt)146 or AcCl/DBU (MeCN, 5 C → rt; eq 11),147 product is furan. ixSubstrate is propargylsilane. xCoupling occurs at α-carbon. while the cis isomer is accessible by treatment with isopropenyl acetate/HOTs.146 Each isomer couples with dialkylcuprates with retention of configuration to afford stereoisomerically enriched Analogously, esters can be C-acetylated by conversion into α,β-unsaturated esters.146,148 the corresponding silyl ketene acetal followed by treatment with 137 AcCl. Depending on the coupling conditions (neat AcCl or O O O 138 DBU AcCl/Et3N ), either the cis-β-siloxycrotonate ester or the cor- (11) OMe MeCN, 5 °C; then AcO OMe responding β,γ-isomer is produced (eqs and ). The third possi- AcCl, rt, 3 h ble isomer (trans-β-siloxycrotonate) is accessible either by sily- 53% cis:trans = 97:3 139 lation of the acetoacetic ester (TMSCl, Et3N, THF, ) or by 137 HgBr2/Et3SiBr-catalyzed equilibration of the cis isomer. Attempted enol acetylation of β-keto esters by quenching the sodium enolate146,147 or magnesium chelate149 with AcCl af- – forded C-acetylated products. + Cl OSiEt3 AcCl (neat) O OSiEt3 rt 67% Adducts with Aldehydes and Ketones. AcCl combines with OMe OMe 150 150f aldehydes (cat. ZnCl2 or AlCl3 ) to afford α-chloroalkyl acetates. The reaction is reversible,151 but at equilibrium the ratio

Et3SiO O of adduct to aldehyde is usually quite high, and the reaction is (8) otherwise clean (92% yield for acetaldehyde,150e 97% yield for OMe benzaldehyde; eq 12150f ).

Avoid Skin Contact with All Reagents 12 ACETYL CHLORIDE

O AcO 177 170 Although Ac2O/DMAP and Ac2O/Bu3P are the pre- AcCl/cat ZnCl 2 (12) ferred reagents for acetylation of most hindered alcohols, sat- H 0–10 °C, 1 h Cl (neat) isfactory results can be obtained with AcCl in combination 178 179 97% with PhNMe2 (CHCl3, ), PhNEt2 (CHCl3, ), AgCN ◦ 180 (benzene or HMPA, 80 C), magnesium powder (Et2O, ; 181 45–55% yield of t-BuOAc), and Na2CO3 (cat. PhCH2NEt3Cl, 150e,151,152 182 AcCl also adds to ketones, but the adducts are much CH2Cl2, ; 79% yield of t-BuOAc). Use of the combination of less thermodynamically stable, so significant amounts of the start- AcCl/DMAP is not recommended since unidentified byproducts ing materials are present at equilibrium.151,152a,b The equilibrium may be generated.169 can be biased in favor of the adduct by employing high concentra- Although acetylations with AcCl/pyridine produce an acidic tion, low temperature, a nonpolar solvent, excess AcCl, or AcBr or byproduct (pyridine hydrochloride), it is possible to acety- AcI instead of AcCl.151,153 For example, the acetone/AcCl adduct late highly acid-sensitive alcohols such as 2-(tributylstannyl- can be obtained in good yield (85%) by treatment of acetone with methyl)allyl alcohol (eq 13)9b and 2-(trimethylsilylmethyl)allyl ◦ 152c excess (2 equiv) AcCl (cat. ZnCl2, CCl4, −15 C). alcohol9a with AcCl/pyridine in >90% yield without competing Reduction of the aldehyde/AcBr adducts151,154 with zinc protiodestannylation or protiodesilylation by selecting a solvent 154,155 ◦ or samarium(II) iodide to α-acetoxyalkylzinc and - (CH2Cl2,0 C) in which the pyridine hydrochloride is insoluble. samarium156 compounds, respectively, completes an umpolung of the reactivity of the aldehyde. n-Bu3Sn n-Bu3Sn AcCl/pyridine Cleavage of Ethers. THF can be opened by treatment with (13) AcCl in combination with either sodium iodide (MeCN, rt, 21 h; CH2Cl2 157 90% 91% yield of 4-iodobutyl acetate) or a Lewis acid such as ZnCl2 HO AcO 158 159 (, 1.5 h; 76% yield of 4-chlorobutyl acetate), SnCl4, CoCl2 160 ◦ (rt, MeCN; 90%), ClPdCH2Ph(PPh3)2/Bu3SnCl (63 C, 48 h; 161 162 95%), Mo(CO)6 (hexane, ; 78%), KPtCl3(H2CCH2), and Alternatively, acid-sensitive alcohols may be acetylated by de- 163 ◦ 183 [ClRh(H2CCH2)2]2 (rt; 75% and 83%, respectively). Acyclic protonation with n-butyllithium (THF, −78 C) or ethylmag- 184 dialkyl ethers can also be cleaved efficiently and in many cases nesium bromide (Et2O, rt) followed by quenching with AcCl. regioselectively.159 Finally, by using a chiral tertiary amine as the base, it is Many of these methods are applicable to deprotection of ether- possible to effect enantioselective acetylations. For example, type protecting groups. For example, benzyl and allyl ethers can racemic 1-phenethyl alcohol has been partially resolved by treat- 160 be deprotected by treatment with AcCl/cat. CoCl2 or AcCl/cat. ment with AcCl in combination with (S)-(−)-N,N-dimethyl-1- 161 ◦ ClPdCH2Ph(PPh3)2/cat. Bu3SnCl. Dimethyl acetals can be phenethylamine (CH2Cl2, −78 C → rt; ee of acetate 52%, ee of cleaved selectively to aldehydes in the presence of ethylene ac- alcohol 59.5%).185 ◦ 164 etals (AcCl/cat. ZnCl2,Me2S/THF, 0 C), or to α-chloro ethers ◦ 165 166 (AcCl/cat. SOCl2,55 C). Tetrahydropyranyl (THP) ethers Generation of Solutions of Anhydrous Hydrogen Chloride and t-butyl ethers167 can be deprotected by stirring in 1:10 in Methanol. Esterification of alcohols by AcCl proceeds in the AcCl:HOAc (40–50 ◦C). absence of HCl scavengers. For example, on addition of AcCl Finally, t-alkyl esters can be cleaved to anhydrides and t-alkyl to methanol at rt, a solution of hydrogen chloride and methyl ◦ 168 10 chlorides by treatment with AcCl (MeNO2,70 C). acetate in methanol forms rapidly. This reaction provides a more practical method for access to solutions of HCl in methanol than Esterification. Although AcCl is intrinsically more reac- the apparently simpler method of bubbling anhydrous HCl into tive than Ac2O, in combination with various acylation catalysts methanol because of the difficulty of controlling the amount of the reverse reactivity order is exhibited. For example, Ac2O 4- anhydrous HCl delivered. Solutions of anhydrous HCl in acetic dimethylaminopyridine (DMAP) acetylates ethynylcyclohexanol acid can presumably be prepared analogously by addition of AcCl ◦ 169 three times faster than AcCl/DMAP (CDCl3,27 C). Also, and an equimolar amount of H2O to HOAc. ◦ 186 187 178a,188 isopropanol does not react with AcCl/Bu3P (CD3CN, −8 C; Primary, secondary, and tertiary alcohols also re- <5% conversion after 30 min), but after addition of sodium ac- act with AcCl, but the product is the alkyl chloride rather than the etate reacts rapidly to form isopropyl acetate (complete in <10 ester in most cases. Thus as a preparative esterification method 170 min). As a general rule, therefore, Ac2O is preferable for acety- this reaction has limited generality. lation of hindered alcohols while AcCl is preferable for selective AcCl also reacts with anhydrous p-toluenesulfonic acid (3–4 monoacetylation of polyols.171 equiv AcCl, ) to afford acetyl p-toluenesulfonate in 97.5% yield Examples of selective acetylations involving AcCl include: along with anhydrous HCl.189 AcCl does not react with HOAc to 31 acetylation of primary alcohols in the presence of secondary alco- generate HCl and Ac2O, at least in appreciable amounts. ◦ 8,172 hols by AcCl/2,4,6-collidine or i-PrNEt2 (CH2Cl2, −78 C); acetylation of primary alcohols in the presence of secondary Dehydrating Agent. AcCl reacts with H2O to afford HCl and alcohols,173 and secondary alcohols in the presence of tertiary HOAc rapidly and quantitatively31b and thereby qualifies as a 174 ◦ alcohols, by AcCl/pyridine (CH2Cl2, −78 C); monoacetyla- strong dehydrating agent. Examples of reactions in which AcCl tion of a 2,4-dihydroxyglucopyranose by AcCl/pyridine/−15 ◦C functions as a dehydrating agent include: cyclization of dicar- ◦ 175 190 (Ac2O/pyridine/0 C is less selective); and acetylation of boxylic acids to cyclic anhydrides (neat AcCl, ); cyclization 176 191 steroidal 5α-hydroxyls (not 5β) by AcCl/PhNMe2 (CHCl3, ). of keto acids to enol lactones (neat AcCl, ); dehydration of

A list of General Abbreviations appears on the front Endpapers ACETYL CHLORIDE 13

O nitro compounds into nitrile oxides (by treatment with NaOMe O HH 192 S followed by AcCl); and conversion of allylic hydroperoxides 0.4 equiv AcCl, 1.1 equiv SnCl2 into unsaturated ketones (AcCl/pyridine, CHCl , rt).193 The dehy- S N → 3 H N OAc MeCN/DMF, 0 °C rt drating power of AcCl has been invoked as a possible explanation O 98% 194 for its effectiveness for activation of zinc dust. O O CCl3

In Situ Generation of High-Valent Metal Chlorides. Many O HH high-valent metal chlorides are useful as reagents in organic syn- S N thesis but are difficult to handle due to their moisture sensitivity. S (16) H N OAc AcCl can be used to generate such reagents in situ from the cor- O responding metal oxides11 or acetates.195 Examples include: α- O O CCl chlorination of ketones by treatment with AcCl/manganese diox- 3 ide (HOAc, rt);196cis-1,2-dichlorination of alkenes by treatment 197 with AcCl/(Bu4N)4Mo8O26 (CH2Cl2, rt); and dichlorination Another method for deoxygenation of sulfoxides involves treat- 198 203 of alkenes by treatment with AcCl/MnO2/MnCl2 (DMF, rt). ment with two equiv AcCl (CH2Cl2, rt); the oxidized byproduct 203 Attempts to dichlorinate alkenes by treatment with AcCl/MnO2 is claimed to be gaseous chlorine. in THF, however, failed due to cleavage of THF to 4-chlorobutyl acetate.196,199 A milder reagent that can be used to activate MnO Chlorine and Bromine Scavenger. AcCl (cat. H2SO4, 2 ◦ for dichlorination of alkenes in THF is chlorotrimethylsilane.199 40–70 C) scavenges Cl2 efficiently (to afford chloroacetyl chlo- 13 ride in 87.1% yield). AcCl also scavenges Br2 efficiently at ◦ Solvent for Organometallic Reactions. Because of its cheap- 35 C.14 ness, volatility, and ability to form moisture-stable solutions of metal chlorides, AcCl is useful as a solvent for reactions involv- Source of Ketene. AcCl reacts with triethylamine at low tem- ◦ ing hygroscopic metal salts.11 For example, AcCl has been used perature (−20 C) to afford acetyltriethylammonium chloride.204 as a co-solvent for 1,2-chloroacetoxylation of alkenes by chromyl This salt functions as a source of ketene (or the functional equiv- ◦ 200 chloride (1:2 AcCl:CH2Cl2, −78 C → rt). alent). For example, it reacts with silyl ketene acetals (THF, rt) to afford silyl enol ethers of acetoacetic esters (eq 9),138 with Reaction with Heteroatom Oxides. The key step in a α-alkoxycarbonylalkylidenetriphenylphosphoranes (CH2Cl2, rt) 205 ◦ method for α-acetoxylation of aldehydes involves rearrangement to afford allenic esters, with enamines (Et2O,0 C) to afford 136a ◦ of an AcCl–nitrone adduct (eq 14).201 Analogous methods for α- cyclobutanones, with certain acyl imines (Et2O,0 C) to form benzoylation and α-pivaloylation are higher yielding. formal [4 + 2] ketene cycloadducts,206 and with certain noneno- lizable imines (Et2O, rt) to afford formal [4 + 2] diketene cy- 207 cloadducts in up to 55% yield. Also, on refluxing in Et2O in the 208 + t-Bu absence of a trapping agent, diketene is formed in 50% yield. t-BuNHOH/HOTs N AcCl/Et N O 3 AcCl/AlCl3 decomposes to acetylacetone on heating (CHCl3, – → ◦ 209 Na2SO4, CH2Cl2 O Et2O, 0 °C rt 54–61 C, 6 h; 82.5% yield after aqueous work-up). The mech- 80% anism presumably involves ketene as an intermediate. However, an attempt to trap the ketene was unsuccessful.210 OAc OAc HOAc, NaOAc (14) N-Acetylation. Primary and secondary amines can be N- N t-Bu PhH/H2O, rt O acetylated to form acetamides by treatment with AcCl under 80% from nitrone Schotten–Baumann conditions (aq NaOH),211 but hydrolysis of 212 AcCl is a significant competing side reaction. Use of Ac2O (2.5 equiv; , 10–15 min) is therefore recommended.211 β-Nitrostyrenes cyclize to indolinones on treatment with AcCl Tertiary amines react with AcCl to afford acetylammonium ◦ 202 (FeCl3,CH2Cl2,0 C; eq 15). salts. Ordinarily, these salts fragment to ketene on warming. However, those that possess a labile alkyl group fragment by loss of the alkyl group (von Braun cleavage). For example, H bis(dimethylamino)methane reacts with AcCl (Et2O, rt) to afford 213 AcCl/FeCl3 N chloromethyldimethylamine, a useful Mannich reagent, and O (15) 1,3,5-trimethylhexahydro-s-triazine reacts with AcCl (CHCl , NO CH2Cl2, 0 °C, 5 h 3 2 75% , 1 h) to afford chloromethylmethyl acetamide,214 a useful Cl amidomethylation reagent.215 Also, aziridines react with AcCl (PhH, 0 ◦C) to afford chloroethylacetamides.216 Allylic amines react with in situ-generated AcI (AcCl/CuI, THF, rt) to afford A high-yielding method for deoxygenation of sulfoxides to sul- acetamides.217 fides involves treatment with 1.1 equiv tin(II) chloride in the pres- AcCl also activates pyridines toward nucleophilic addition. ence of a catalytic amount (0.4 equiv) of AcCl (MeCN/DMF, For example, phenylmagnesium chloride adds to pyridine in the 0 ◦C → rt).12 The mildness of this method is demonstrated by its presence of AcCl (cat. CuI, THF, −20 ◦C → rt) to afford, af- usability for deoxygenation of a cephalosporin sulfoxide (eq 16). ter catalytic hydrogenation, N-acetyl-4-phenylpiperidine in 65%

Avoid Skin Contact with All Reagents 14 ACETYL CHLORIDE yield.218 Also, AcCl catalyzes the reaction between sodium iodide 10. (a) Freudenberg, K.; Jacob, W., Chem. Ber. 1941, 74, 1001. and 2-chloropyridine to afford 2-iodopyridine (MeCN, ,24h; (b) Riegel, B.; Moffett, R. B.; McIntosh, A. V. Org. Synth. 1944, 24, 41. 55%).219 (c) Fraenkel-Conrat, H.; Olcott, H. S. J. Biol. Chem. 1945, 161, 259. N-Acetylation of enolizable imines to afford enamides can be (d) Baker, B. R.; Schaub, R. E.; Querry, M. V.; Williams, J. H. J. Org. Chem. 1952, 17, 77. (e) de Lombaert, S.; Nemery, I.; Roekens, B.; accomplished by treatment with AcCl/PhNEt2. For example, treat- Carretero, J. C.; Kimmel, T.; Ghosez, L. Tetrahedron Lett. 1986, 27, ment of crotonaldehyde cyclohexylimine with AcCl followed by 5099. (f) Nashed, E. M.; Glaudemans, C. P. J. J. Org. Chem. 1987, 52, 220 PhNEt2 (toluene, rt) affords the enamide in 88% yield. 5255. Primary urethanes can be N-acetylated to afford imides by 11. (a) Chretien, A.; Oechsel, G. C.R. Hebd. Seances Acad. Sci. 1938, 206, ◦ treatment with AcCl (100 C, 1 h).221 Alternatively, urethanes 254. (b) Paul, R. C.; Sandhu, S. S. Proc. Chem. Soc. 1957, 262. (c) can be converted into acetamides by treatment with AcBr Paul, R. C.; Singh, D.; Sandhu, S. S. J. Chem. Soc 1959, 315. (d) Paul, (120–130 ◦C)221 or in situ-generated AcI222 (MeCN, 60 ◦C).223 R. C.; Singh, D.; Sandhu, S. S. J. Chem. Soc 1959, 319. (e) Maunaye, Finally, a convenient method for preparation of N- M.; Lang, J. C.R. Hebd. Seances Acad. Sci. 1965, 261, 3381, 3829. trimethylsilylacetamide (MSA), a useful trimethylsilyl transfer 12. Kaiser, G. V.;Cooper, R. D. G.; Koehler, R. E.; Murphy, C. F.; Webber, J. A.; Wright, I. G.; Van Heyningen, E.M.J. Org. Chem. 1970, 35, reagent, involves treatment of hexamethyldisilazane with AcCl 2430. (hexane, ; 88%).224 13. Scheidmeir, W.; Bressel, U.; Hohenschutz, H. U.S. Patent 3 880 923, 1975. S-Acetylation. Both aliphatic and aromatic thiols can be S- 14. Kharasch, M. S.; Hobbs, L. M. J. Org. Chem. 1941, 6, 705. 225 acetylated by treatment with AcCl (cat. CoCl2, MeCN, rt). 15. (a) Collin, J.; Namy, J.-L.; Dallemer, F.; Kagan, H. B. J. Org. Chem. 1991, 56, 3118. (b) Ruder, S. M. Tetrahedron Lett. 1992, 33, 2621. Nucleophilic Acetylation. AcCl together with SmI2 (MeCN, 16. Pouchert, C. J. The Aldrich Library of FT-IR Spectra, ed. I; Aldrich: rt) or SmCp2 delivers the acetyl anion synthon to ketones to afford Milwaukee, 1985; Vol. 1, p 723A. 15 the corresponding acyloins (eq 17). 17. Tsuchiya, S.; Kimura, M. Bull. Chem. Soc. Jpn. 1972, 45, 736. 18. Reagent Chemicals, 8th ed.; American Chemical Society: Washington, O OH 1993; p 107. O AcCl/SmI 2 (17) 19. Singh, J.; Paul, R. C.; Sandhu, S. S. J. Chem. Soc 1959, 845. MeCN, rt 20. (a) Whitmore, F. C. Recl. Trav. Chim. Pays-Bas 1938, 57, 562. (b) 80% Cason, J.; Harman, R. E.; Goodwin, S.; Allen, C. F. J. Org. Chem. 1950, 15, 860. (c) Perrin, D. 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A list of General Abbreviations appears on the front Endpapers ACETYL CHLORIDE 15

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Avoid Skin Contact with All Reagents 16 ACETYL CHLORIDE

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A list of General Abbreviations appears on the front Endpapers ACETYL CHLORIDE 17

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A.; Block, F. J. Am. Chem. Soc. 1957, 79, 952. (c) Sharma, K. K.; 163. Fitch, J. W.; Payne, W. G.; Westmoreland, D. J. Org. Chem. 1983, 48, Torssell, K. B. G. Tetrahedron Lett. 1984, 40, 1085. 751. 187. Kotsuki, H.; Kataoka, M.; Nishizawa, H. Tetrahedron Lett. 1993, 34, 164. Chang, C.; Chu, K. C.; Yue, S. Synth. Commun. 1992, 22, 1217. 4031. 165. (a) Straus, F.; Heinze, H. Justus Liebigs Ann. Chem. 1932, 493, 191. 188. Bryant, W. M. D.; Smith, D. M. J. Am. Chem. Soc. 1936, 58, 1014. (b) Quintard, J.-P.; Elissondo, B.; Pereyre, M. J. Organomet. Chem. 1981, 212, C31. (c) Quintard, J.-P.; Elissondo, B.; Pereyre, M. J. Org. 189. Karger, M. H.; Mazur, Y. J. Org. Chem. 1971, 36, 528. Chem. 1983, 48, 1559. 190. (a) Lennon, J. J.; Perkin, W. H. Jr. J. Chem. Soc 1928, 1513. (b) 166. (a) Bakos, T.; Vincze, I. Synth. Commun. 1989, 19, 523. (b) Sabharwal, Zilkha, A.; Liwschitz, Y. J. Chem. Soc 1957, 4397. (c) Bose, N. K.; A.; Vig, R.; Sharma, S.; Singh, J. Indian J. Chem., Sect. B 1990, 29, 890. Chaudhury, D. N. Tetrahedron Lett. 1964, 20, 49. 167. (a) Pop, L.; Oprean, I.; Barabas, A.; Hodosan, F. J. Prakt. Chem. 1986, 191. (a) Turner, R. B. J. Am. Chem. Soc. 1950, 72, 579. (b) Rosenmund, 328, 867. (b) Oprean, I.; Ciupe, H.; Gansca, L.; Hodosan, F. J. Prakt. K. W.; Herzberg, H.; Schutt, H., Chem. Ber. 1954, 87, 1258. (c) Vignau, Chem. 1987, 329, 283. M.; Bucourt, R.; Tessier, J.; Costerousse, G.; Nedelec, L.; Gasc, J.-C.; 168. Dutka, F.; Marton, A. F. Z. Naturforsch., Tell B 1969, 24, 1664. Joly, R.; Warnant, J.; Goffinet, B. U.S. Patent 3 453 267, 1969. 169. Hofle, G.; Steglich, W.; Vorbruggen, H. Angew. Chem. Int. Ed. Engl. 192. (a) Harada, K.; Kaji, E.; Zen, S. Chem. Pharm. Bull. 1980, 28, 3296. 1978, 17, 569. (b) Fleming, I.; Moses, R. C.; Tercel, M.; Ziv, J. J. Chem. Soc., Perkin Trans. 1 1991, 617. 170. (a) Vedejs, E.; Diver, S. T. J. Am. Chem. Soc. 1993, 115, 3358. (b) Vedejs, E.; Bennett, N. S.; Conn, L. M.; Diver, S. T.; Gingras, M.; Lin, 193. Farrissey, W. J. Jr. U.S. Patent 3 291 834, 1966. S.; Oliver, P. A.; Peterson, M. J. J. Org. Chem. 1993, 58, 7286. 194. Stirring zinc dust with AcCl and CuCl (Et2O,rt→ ) produces an 171. 1,2-Diols can be selectively monoacetylated by conversion into the active zinc couple capable of reacting with methylene bromide to form cyclic dibutylstannylidene derivative followed by treatment with the Simmons–Smith reagent: Friedrich, E. C.; Lewis, E.J. J. Org. AcCl: (a) Anchisi, C.; Maccioni, A.; Maccioni, A. M.; Podda, G. Chem. 1990, 55, 2491. Gazz. Chim. Ital. 1983, 113, 73. (b) Roelens, S. J. Chem. Soc., Perkin 195. Watt, G. W.; Gentile, P. S.; Helvenston, E.P.J. Am. Chem. Soc. 1955, Trans. 2 1988, 2105. (c) Anderson, W. K.; Coburn, R. A.; Gopalsamy, 77, 2752. A.; Howe, T. J. Tetrahedron Lett. 1990, 31, 169. (d) Getman, D. P.; 196. Bellesia, F.; Ghelfi, F.; Pagnoni, U. M.; Pinetti, A. J. Chem. Res. (S) DeCrescenzo, G. A.; Heintz, R. M. Tetrahedron Lett. 1991, 32, 5691. 1990, 188.

Avoid Skin Contact with All Reagents 18 ALUMINUM CHLORIDE

197. Nugent, W. A. Tetrahedron Lett. 1978, 3427. Aluminum Chloride1 198. Bellesia, F.; Ghelfi, F.; Pagnoni, U. M.; Pinetti, A. Synth. Commun. 1991, 21, 489. 199. Bellesia, F.; Ghelfi, F.; Pagnoni, U. M.; Pinetti, A. J. Chem. Res. (S) AlCl3 1989, 108. 200. Backvall, J. E.; Young, M. W.; Sharpless, K. B. Tetrahedron Lett. [7446-70-0] AlCl3 (MW 133.34) 1977, 3523. InChI = 1/Al.3ClH/h;3*1H/q+3;;;/p-3/fAl.3Cl/h;3*1h/ 201. Cummins, C. H.; Coates, R. M. J. Org. Chem. 1983, 48, 2070. qm;3*-1 202. (a) Demerseman, P.; Guillaumel, J.; Clavel, J.-M.; Royer, R. InChIKey = VSCWAEJMTAWNJL-GZMOREBICG Tetrahedron Lett. 1978, 2011. (b) Guillaumel, J.; Demerseman, P.; Clavel, J.-M.; Royer, R.; Platzer, N.; Brevard, C. Tetrahedron Lett. 1980, 36, 2459. (Lewis acid catalyst for Friedel–Crafts, Diels–Alder, [2 + 2] cy- 203. Numata, T.; Oae, S. Chem. Ind. (London) 1973, 277. cloadditions, ene reactions, rearrangements, and other reactions) 204. (a) Adkins, H.; Thompson, Q. E. J. Am. Chem. Soc. 1949, 71, 2242. ◦ ◦ (b) Paukstelis, J. V.; Kim, M. J. Org. Chem. 1974, 39, 1503. Physical Data: mp 190 C (193–194 C sealed tube); sublimes ◦ −3 205. (a) Lang, R. W.; Hansen, H.-J. Helv. Chim. Acta 1980, 63, 438. (b) at 180 C; d 2.44 g cm . Lang, R. W.; Hansen, H.-J. Org. Synth. 1984, 62, 202. (c) Abell, A. D.; Solubility: sol many organic solvents, e.g. benzene, nitroben- Morris, K. B.; Litten, J. C. J. Org. Chem. 1990, 55, 5217. zene, carbon tetrachloride, chloroform, methylene chloride, 206. (a) Burger, K.; Huber, E.; Sewald, N.; Partscht, H. Chem.-Ztg. 1986, nitromethane, and 1,2-dichloroethane; insol carbon disulfide. 110, 83. (b) Sewald, N.; Riede, J.; Bissinger, P.; Burger, K. J. Chem. Form Supplied in: colorless solid when pure, typically a gray Soc., Perkin Trans. 1 1992, 267. or yellow-green solid; also available as a 1.0 M nitrobenzene 207. Maujean, A.; Chuche, J. Tetrahedron Lett. 1976, 2905. solution. 208. Sauer, J. C. J. Am. Chem. Soc. 1947, 69, 2444. Handling, Storage, and Precautions: fumes in air with a strong 209. Hunt, C. F. U.S. Patent 2 737 528, 1956. odor of HCl · AlCl3 reacts violently with H2O. All containers 210. Matoba, K.; Tachi, M.; Itooka, T.; Yamazaki, T. Chem. Pharm. Bull. should be kept tightly closed and protected from moisture.1c 1986, 34, 2007. Use in a fume hood. 211. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Longman/Wiley: New York, 1989; pp 916, 1273. Original Commentary 212. (a) Sonntag, N. O.V. Chem. Rev. 1953, 52, 237. (b) To minimize the amount of hydrolysis, the acetylation should be run at pH=(x + 13.25)/2, where x is the pKa of the protonated amine: King, Paul Galatsis J. F.; Rathore, R.; Lam, J. Y. L.; Guo, Z. R.; Klassen, D. F. J. Am. University of Guelph, Ontario, Canada Chem. Soc. 1992, 114, 3028. 213. (a) Bohme, H.; Hartke, K., Chem. Ber. 1960, 93, 1305. (b) Kinast, G.; Friedel–Crafts Chemistry.1,2 AlCl has traditionally been Tietze, L.-F. Angew. Chem. Int. Ed. Engl. 1976, 15, 239. 3 used in stoichiometric or catalytic3 amounts to mediate Friedel– 214. Kritzler, H.; Wanger, K.; Holtschmidt, H. U.S. Patent 3 242 202, 1966. Crafts alkylations and acylations of aromatic systems (eq 1). 215. (a) Ikeda, K.; Morimoto, T.; Sekiya, M. Chem. Pharm. Bull. 1980, 28, 1178. (b) Ikeda, K.; Terao, Y.; Sekiya, M. Chem. Pharm. Bull. 1981, O 29, 1156. R 216. Okada, I.; Takahama, T.; Sudo, R. Bull. Chem. Soc. Jpn. 1970, 43, 2591. RCl RCOCl R 217. Caubere, P.; Madelmont, J.-C. C.R. Hebd. Seances Acad. Sci., Ser. C (1) AlCl3 AlCl3 1972, 275, 1305. 218. Comins, D. L.; Abdullah, A. H. J. Org. Chem. 1982, 47, 4315. This is a result of the Lewis acidity of AlCl3 which complexes 219. Corcoran, R. C.; Bang, S. H. Tetrahedron Lett. 1990, 31, 6757. strongly with carbonyl groups.4 Adaptations of these basic reac- Tetrahedron Lett. 1979 220. (a) Oppolzer, W.; Bieber, L.; Francotte, E. , 981. tions have been reported.5 In chiral systems, inter- and intramole- (b) Ng, K. S.; Laycock, D. E.; Alper, H. J. Org. Chem. 1981, 46, 2899. cular acylations have been achieved without the loss of optical 221. Ben-Ishai, D.; Katchalski, E. J. Org. Chem. 1951, 16, 1025. activity (eq 2).6 222. Hoffmann, H. M. R.; Haase, K. Synthesis 1981, 715. 223. Ihara, M.; Hirabayashi, A.; Taniguchi, N.; Fukumoto, K. Heterocycles O O 1992, 33, 851. AlC3 224. (a) Pump, J.; Wannagat, U. Monatsh. Chem. 1962, 93, 352. (b) Bowser, Cl (2) benzene J. R.; Williams, P. J.; Kurz, K. J. Org. Chem. 1983, 48, 4111. NHCO2Me 50–60% MeO2CHN 225. Ahmad, S.; Iqbal, J. Tetrahedron Lett. 1986, 27, 3791. O O AlC3 Bruce A. Pearlman Cl NHCO2Me The Upjohn Company, Kalamazoo, MI, USA 55–75% NHCO2Me >98% ee

Friedel–Crafts chemistry at an asymmetric center generally pro- ceeds with racemization, but the use of mesylates or chlorosul- fonates as leaving groups has resulted in alkylations with excellent

A list of General Abbreviations appears on the front Endpapers ALUMINUM CHLORIDE 19

7 O O control of stereochemistry. The reactions proceed with inversion 1 1. AlCl , HC CH R of configuration (eq 3). Cyclopropane derivatives have been used R1 3 Cl 2. Zn (10) as three-carbon units in acylation reactions (eq 4).8 In conjunc- 45–70% 2 tion with triethylsilane, a net alkylation is possible under acylation R2 R conditions (eq 5).9 These conditions are compatible with halogen atoms present elsewhere in the molecule. Acylation reactions of SO2Ph phenolic compounds with heteroaromatic systems have also been accomplished (eq 6).10 O O AlCl3 AlCl3

CO2Me AlCl3 PhH CO2Me 78% 90% (3) X 50–80% Ph >97% (S)(S) O X = OSO2Me, OSO2Cl (11) O

AlCl3 PhH The use of silyl derivatives in Friedel–Crafts chemistry has not CO2Et (4) 93% only improved the regioselectivity but extended the scope of these reactions. Substitution at the ipso position occurs with aryl silanes (eq 12).20 The ability of silyl groups to stablize β-carbenium ions RCOCl, AlCl R 3 (5) (β-effect) affords acylated products with complete control of re- Et3SiH giochemistry (eq 13).21 R 43–94% R O TMS O OH Cl TMS TMS HO OH AlCl Cl Cl Cl + 3 N AlCl3 + (6) 75% N 63% N TMS OH N TMS (12) Cl Cl O TMS AcCl Treatment of aryl azides with AlCl has been reported to give AlCl3 3 (13) polycyclic aromatic compounds (eq 7),11 or aziridines when the 77% reactions are run in the presence of alkenes (eq 8).12 The use of silylacetylenes gives ynones (eq 14),22 cyclo- 23 AlCl3 pentenone derivatives (eq 15), and α-amino acid derivatives (7) 24 89% (eq 16). N3 N H O O AlCl3 + TMS TMS (14) N3 ClR 85–94% R TMS AlCl + 3 (8) O n 63–93% n N Ar Cl AlCl R Cl 3 O + TMS (15) n = 1, 2 63%

The scope of Friedel–Crafts chemistry has been expanded TMS beyond aromatic systems to nonaromatic systems, such as alkenes 13 TMS and alkynes and the mechanistic details have been investigated. HCl TMS 14 15 The Friedel–Crafts alkylation and acylation of alkenes pro- AlCl3 + H (16) vide access to a variety of organic systems (eq 9). The acylation of EtO2CNH CO2Me 65% 16 alkynes provides access to cyclopentenone derivatives (eq 10). TMS EtO2CNH CO2Me In addition, one can use this chemistry to access indenyl systems17 18 and vinyl chlorides. Allylic sulfones can undergo allylation Propargylic silanes undergo acylation to generate allenyl 19 chemistry (eq 11). ketones (eq 17),25 while alkylsilanes afford cycloalkanones (eq 18).26 Ac AcCl H AlCl3 • (9) R AcCl R 48% TMS (17) AlCl3 Cl H O

Avoid Skin Contact with All Reagents 20 ALUMINUM CHLORIDE

O R R COCl AlCl OH AlCl 3 (18) O 3 (25) 60–87% + CO2Me 40–55% TMS OO

Several name reactions are promoted by AlCl3. For example, + the Darzens–Nenitzescu reaction is simply the acylation of NH3 O AlCl3 alkenes. The Ferrario reaction generates phenoxathiins from + (26) 27 diphenyl ethers (eq 19). The rearrangement of acyloxy aro- N matic systems is known as the Fries rearrangement (eq 20).28 Aryl aldehydes are produced by the Gatterman aldehyde synthe- sis (eq 21).29 The initial step of the Haworth phenanthrene syn- O O thesis makes use of a Friedel–Crafts acylation.30 The acylation of phenolic compounds is called the Houben–Hoesch reaction AlCl3 (27) (eq 22).31 The Leuckart amide synthesis generates aryl amides 68% from isocyanates (eq 23).32

S S 1 AlCl3 R1 R (19) 2 R2 87% RCl AlCl O O 3 O (28) N O N O R R

AlCl3 (20) O 85% CCl OAc O OH 3 OAc OH AlCl3 (29) CCl4 OR OR 37–42% OH O AlCl3 (21) HCl HCN

CHO Diels–Alder Reactions. There is some evidence that AlCl3 catalysis of Diels–Alder reactions changes the transition state OH OH from a synchronous to an asynchronous one.39 This also enhances AlCl3 asymmetric induction by increasing steric interactions at one end RCN (22) of the dieneophile. There are many examples of AlCl3 promoted HCl OH OH Diels–Alder reactions (eq 30).40 Hetero-Diels–Alder reactions can be used to generate oxygen (eq 31)41 and nitrogen (eq 32)42 O R containing heterocycles.

O OMe OMe AlCl 3 NHR (23) AlCl3 RNCO + 62% H CO3Et O O Amides can also be obtained by AlCl catalyzed ester amine H H 3 CO2Et exchange which proceeds primarily without racemization of (30) chiral centers (eq 24).33 The reaction of phenols with β-keto esters is known as the Pechmann condensation (eq 25).34 Aryl amines are used in the Riehm quinoline synthesis (eq 26).35 Aromatic 36 AlCl3 systems may be coupled via the Scholl reaction (eq 27) and + O CN (31) 37 70% indole derivatives are prepared in the Stolle synthesis (eq 28). O In the Zincke-Suhl reaction, phenols are converted to dienones (eq 29).38 Ph H Cl N Cl AlCl Ph AlCl3 + Ph 3 CO Me CONEt2 (24) (32) 2 NPh 60% Et2NH 77% OTMS (S) 98% S:R = 82:18 OTMS

A list of General Abbreviations appears on the front Endpapers