NAME REACTIONSAND REAGENTSIN ORGANIC SYNTHESISSecond EditionBradford P. MundyProf. of Chemistry, EmeritusColby CollegeWaterville, MEMichael G. EllerdMaxim TechnologiesBozeman, MTFrank G. Favaloro, Jr.Helicon TherapeuticsFarmingdale, NYWILEYINTERSCIENCEA JOHN WILEY & SONS, INC., PUBLICATION

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NAME REACTIONSAND REAGENTSIN ORGANIC SYNTHESISSecond EditionBradford P. MundyProf. of Chemistry, EmeritusColby CollegeWaterville, MEMichael G. EllerdMaxim TechnologiesBozeman, MTFrank G. Favaloro, Jr.Helicon TherapeuticsFarmingdale, NYWILEYINTERSCIENCEA JOHN WILEY & SONS, INC., PUBLICATION

Copyright 02005 by John Wiley & Sons, Inc. All rights reserved.Published by John Wiley & Sons, Inc., Hoboken, New Jsersey.Published simultaneously in Canada.No part of this publication may be reproduced, stored in a retrieval system, or transmitted in anyform or by any means, electronic, mechanical, photocop:ying, scanning, or otherwise, except aspermitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the priorwritten permission of the publisher, or authorization throsugh payment of the appropriate per-copyfee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923,978-7508400, fax 978-646-8600, or on the web at Requests to the publisher forpermission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 11 1 RiverStreet, Hoboken, NJ 07030. (201) 748-6008, fax (201) 748-6008.Limit of LiabilitylDisclaimer of Warranty: While the publisher and author have used their bestefforts in preparing this book, they make no representations or warranties with respect to theaccuracy or completeness of the contents of this book and specifically disclaim any impliedwarranties of merchantability or fitness for a particular piurpose. No warranty may be created orextended by sales representatives or written sales The advice and strategies containedherin may not be suitable for your situation. You should consult with a professional whereappropriate. Neither the publisher nor author shall be lialble for any loss of profit or any commercialdamages, including but not limited to special, incidental, consequential, or other damages.For general information on our products and services contact our Customer Care Department withinthe U.S. at 877-762-2974, outside the U S . at 317-572-3993 or fax 317-572-4002.Wiley also publishes its books in a variety of electronic formats. Some content that appears in print,however, may not be available in electronic format.Library of Congress Cataloging-in-PublicationData is available.ISBN 0-471-22854-0Printed in the United States of America10987654321

PrefaceIt has been a long haul. The start for this revision came almost the same way that the originaledition started. For the fnst edition it was Mike Ellerd, then an undergraduate at Montana State, whoorganized my crude Name Reaction handouts so well that others encouraged the conversion into abook. At Colby College, Frank Favaloro did the same thing, making “study sheets” and adding tothe list of Name Reactions. He graduated in 1996 and I started reformatting and expanding. Withencouragement from Darla Henderson, this became a project. By then Frank had finished graduateschool and was enthusiastic about participating. I had also retired from formal teaching and foundmuch more time for creative work. The three of us started to work in earnest!This edition differs substantially from the fmt by the inclusion of many modem NameReactions instead of sticking exclusively with the old, tried and true. There are many reactions notcovered; indeed, we ultimately eliminated those that had little contemporary use. We generallyapplied a “rule of thumb” that a newer name had to be cited by multiple authors. Therefore there aresome relatively new protocols that have not stood the test of time; however the breadth of recent usewarranted inclusion. As for reagents, we have focused on both Name Reagents and those whoseacronyms are often used in place of the actual name. We have noted the common use of these formsin current literature.First and foremost, this is a book to be used. Feel free to write in the text. . . use any availableblank space to add your own notes. Transform this intoyow book of Name Reactions! It isintended to serve as a starting point. Within a two page format for reactions and one page forreagents, the reader will fmd a basic, generalized defmition / formula, a mechanism that conveys apossible course from starting material to product, notes which describe a few of the major highlightsof the reaction or which points the reader to related reactions (by name or similarity) and recentexamples of use. We have tried to convey the current mechanistic thinking with special care to showintermediatesteps, point out proton exchanges, and sometimes suggest transition states, but withoutgoing through kinetics, isotope effects, etc.Wherever appropriate, we have included references to selected secondary sources. Theycontain more detailed discussions on the topics introduced in this book. In all cases, we recommenduse of the primary literature. The examples in the following pages are but a small taste of the detail,variation, scope and experimental detail available. Our choices reflect our personal interests; there isno “better or worse” implied! We tried to use current examples from journals that seem to be mostcommonly accessible, both in paper form and electronically,to student and professional alike.When recent references were difficult to come by, we made use of the abstracts and reaction-searchengine of SciFinder (American Chemical Society). In these cases, we supplied a number [AN year:XXXX] that will allow ready access to the abstract. To the authors of the works we have chosen todescribe, we hold the most sincere gratitude and we hope we have faithfully represented your work.Colby CollegeWaterville, MEFeb 1,2005

ACKNOWLEDGMENTSAs always, completion of a project requires more than just the work of the authors. Without theconsideration, support and patience of spouses: Margaret (Brad), Mary (Mike) and Michelle (Frank),this probably could not have been completed.Special thanks goes to the chemistry community for their endless development of newmethods for creating C-C and C-heteroatom bonds. It has been an enlightening experience tochronicle the explosion of new “named” reactions and protocols. We have not lost view of theobvious new participation of the world chemical community.Each of us can thank mentors and spe’cialpeople that have given us encouragement:Brad:I still owe much to my formal mentors:Richard F. Smith who first provided the excitement of chemistry, A.Paul Krapcho, graduate mentorand friend, and the late Henry Rapoport, postdoctoral advisor.I thank my colleagues from Colby College, Dasan Thamattoor and Jeff Katz, for theirhelp in reading parts of this manuscript. And, of c:ourse my former graduate and undergraduatestudents . . . two of the latter are now coauthors, who were the reason for my continued interest inthe academic life. Special thanks goes to Prof.Tom Poon (Claremont McKenna, Pitzer, & ScrippsColleges) for a great two years as a Dreyfus Fellow with me at Colby. He taught me much, andworked closely with Frank Favaloro.I would like to thank several Colby staff that made my working easier: Susan W. Cole ofthe Science Library could always be depended on to solve any library problem that developed in theabsolutely great electronic resources of Colby College, and patiently put up with my many requests,piled up books and journals and general use of the library. The Colby College ITS staff wasextremely good-natured and helpfd for computer questions. Their help was greatly appreciated.Mike:My appreciation goes out to all of my professors at Montana State, who,years ago sparked myinterest in chemistry, and to those who still today keep that interest very much alive.Frank:I would like to thank all of those who not only taught me organic chemistry, but also to be excitedfor the art it contains: Gordon W. Gribble, Tadashi Honda, Thomas Spencer, Peter Jacobi, DavidLemal, Thomas Poon, Philip Previte and, most i,mportantly, Brad Mundy. Thank you to the manyfriends and co-workers who provided support, advice and the occasional reference: Erin Pelkey,Janeta Popovici-Muller, Tara Kishbaugh, Jeanese Badenock, Alison Rinderspacher and ChaoyangDai.Of course a project with a publisher requires interaction. Darla Henderson, Amy Byers,Camille Carter and Dean Gonzalez were the peoplle who kept the ball rolling and the project infocus.Colby CollegeWaterville, MEFeb 1,2005vi

CONTENTSAcronyms and Abbreviations / viiiNameReactions / 1Name Reagents and Acronyms / 714Index /872vii

ACRONYMS nateAcOH(HOAc)Acetic acidMe -COOHAIBN2,2’-AzobisisobutyronitrileNC MeACNMeMeN N-LCN\Me1,l . o)-l,1’binaphththyl1,l ’-bi-2,2’-naphtholBinolKitanium isopropoxideTi(iPr0)4 / BINOLBromomagnesium DiisopropylamideBorane DimethylsulfideviiiBH3-Me2S

EMSBorane tylstannaneBzBenzoylCANCeric ammonium nitrateCASCeric ammonium sulfateCbz-CarbobenzyloxyCDI1,l ylMeMe&.MeCSACamphorsulfonic thylenediamine3HO,S-H,Me

Acronyms and AbbreviationsDiethylamino)sulfur trifluorideEt,N cyano1,4benzoquinoneNCNc CI0MeDimethyldioxiraneMeDEIPSDETDiethyl AzodicarboxylateEtOOC-N N-COOEtDiethylisopropylsilylEti-Pr -hiE(Dietkyl tartrate- YHEtOOC -CHCH-COOEtIHOin R-, S, and mesoformsDZBALDZBAL-HDisobutylaluminum hydrideh dMeMeMeDIPEADiisopropylethylamineHunip's baseMe 1MeMe--(MeMe-(NJMeOHDiisopropyl tartrateIiPrOOC -CHCH -COOiPrIHOin R-, S, and mesoformsDiplvmeDiethylene glycol dimethyl etherMeO-O-OMe

cronyms and lfoxide5Me0OMeMeMe.Me Ph-PPh-Peeenantiomeric excess % major enantiomer - % minorenantiomerFmoc9-Fluoren ylmethoxycarbonylIAp-phnPhpiIP-PhIPhPh

Acronyms and Abbreviationsxii2-(6-Chloro- 1H-benzotriazole- 00Hexamethylphosphoric sy1oxy)-iodobcnzenerImidazoylIcLI BHLN-3DiisopinocampheylboraneLead tetraacetateh?AcAcO -Pb -0AcIOAcLTMpLiTMPLithium 2,2,6,6tetramethylpiperidideMethylaluminum eroxybenzoic acidFAcetonitrile2-MethoxyethoxymethylMsMesyl ,MethanesulfonylMe-CzN

.xonyms and Abbreviat nsMethylthiomethylWTMXlll WVKMethyl Vinyl MPN-Methylpynolidone0or:IMePCCPyridinium chlorochromateCorey's ReagentO CIHPDC00Pyridinium h ! e N O 2Polyphosphoric AcidpTT{PTAB)Phenvltrimethvlammoniumtribrdmide .PhenyltrimethylammoniumperbromideUnspecified mixture withHigh concentration of0";'"Ph-N-Me\Me0Br3

"Acronyms and AbbreviationsMePyridinium para-toluenesulfonatep-Toluenesulfonic acid;rosic rrolidine(S)- 1-Amino-2MethoxymethylpyrrolidineEnder's 'MeISi-042Sodium Bis(2methoxyethoxy)aluminum HydrideTetrabutylammonium fluorideTBDPStert-Butyldipheny lsilylPht-Bu--\SiPh'-5t-Butyl ethylamineTEBATEBACBenzyltriethylammonium chlorideTEMPO2,2,6,6-Tetramethylpiperidin- 1-oxyl0

xvcronyms and Abbreviat PTetrah ydropyranylTIPSTriisopropylsilyli-Pr‘ -2i-Pr tePr4N’RuO4TPPTriphenyl rifluoromethanesulfonateTriphenylsilylPhIPh-PPh -‘siPh‘Trt- TritylP h T tPhTsTOS-Tosylp-toluenesulfonylN-MeMe

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NAME REACTIONSIn this section we provide a summary of Name Reactions. The format is slightly modified from ourprevious book, but maintains the essential features:Reaction:Summary reaction.Proposed Mechanism:Currently accepted mechanisms. We have tried to be complete in showing steps, intermediatesand the necessary curly arrow notations.Notes:Additional comments and references from key sources.Examples:Current examples if possible.When a term is underlined, (for example, AIdol Condensation) it means that the concept can befound under an independent heading in the book.General Bibliography:B. P. Mundy, M. G. Ellerd, Name Reactions and Reagents in Organic Synthesis, John Wiley andsons, Inc., New York, 1988;M. B. Smith, J. March in March's Advanced Organic Chemistv, 51h ed., John Wiley and Sons, Inc.,New York, 2001;T. Laue, A. Plagens, Named Organic Reactions, John Wiley and Sons, Inc., New York, 1998;V. K. Ahluwalia, R. K. Parashar, Organic Reaction Mechanisms, Alpha Science International Ltd.,Pangbourne, U.K., 2002;J. J. Li, Name Reactions, Springer, Berlin, 2002;Comprehensive Organic Synthesis, B. M. Trost, editor-in-chief, Pergamon Press, Oxford, 1991;M. B. East, D. J. Ager, Desk Referencefor Organic Chemists, Krieger Publishing Company,Malabar, FL, 1995;M. Orchin, F. Kaplan, R. S. Macomber, R. M. Wilson, H. Zimmer, The Vocabulary of OrganicChemistv, John Wiley and Sons, Inc., New York, 1980;A. Hassner, C. Stumer, Organic Syntheses Based on Name Reactions and UnnamedReactions,Pergamon, Oxford, 1994;The Merck Index, Merck & CO., Inc., Whitehouse Station, N. J. (now in the 13" Edition) Eachedition has an updated list of Named Reactions.See also: ndex ameReactions/TOC.asDOther URL's to Name Reaction or chem.chem.uconn.eddnamereact/nlSome references are provided with a SciFinder (American Chemical Society) number so that one canaccess the abstract if needed.1

Name Reaction2Acetoacetic Ester SynthesisThe Reaction:1. Base2. K-xuOEt04. R"-xU Rzo RlEhydrolysistdecarboxylationProposed Mechanism:The methylene protons are the most acidicby influence from both carbonyls.1. Base2. R"-xX can be CI, Br, I,OTs, etc.I. HO-, HZOR R "OEtAllcylation can be done a second time(with a different R) if desired.2. HfAK R "Ester hydrolysiskaponification, then withheat, the P-keto acid decarboxylates to give an enolketo-enol tautomerismNotes:Acetoacetic Ester can be prepared by the condensation of ethyl acetate, called theAcetoacetic Ester Condensation Reaction, a CIaisen Condensation:J. K. H. Inglis and K. C. RobertsBaseOrganic Syntheses .m,235O'EtuOEt-See M. B. Smith, J. March in March's Advanced Organic Chemistty, 51h ed., John Wiley and Sons,Inc., New York, 2001, p 549; and C. R. Hauser, B. E. Hudson, Jr., Organic Reactions 1 , 9Weiler Modtjicaiion: By using very strong bases, a dianion can be formed that will preferentiallyalkylate at the methyl group:0000NaH, n-BuLiBr f83%Me OEtTHF,30min * [H2CuOEt]/S. N. Huckin, L. Weiler Journal ofthe American Chemical Socieg 1974,1082ooon Me ester shows theHOMO corresponding tothe reactive intermediate

3Name ReactionExamples:001. NaOEt, EtOH *2. n-Bu-BrL c o 2 tMeMe CO2EtBu72%C. S. Marvel, F. D. Hager, Organic Syntheses 1941,1,248Mefi1. NaH, DMF0L C 0 2 M e2.C02Me MeMeMe77%MeK. A. Parker, L. Resnick, Journal of Organic Chemistry 1995,&l, 57261. NaOMe, MeOH2. Me1C02Me8 MeO- ?Ce-82%fieY.-Q.Lu, C.-J. Li, Tetrahedron Letters 1996, , 471kOzMeK. Mori, Tetrahedron 1974,30,42230 H00t-BuL90%uMe0" MeTsOH'OHHOAc75%W. L. Meyer, M. J. Brannon, C. da G. Burgos, T. E. Goodwin, R. W. Howard, Journal of OrganicChemistry 1985,3,438

Name Reaction4Acyloin CondensationThe Reaction:0RAORAprotic Solv.No02 OR H OR H2. [email protected] Mechanism:Na,-Two of these radicalanions react.An electron adds to theLUMO of the ester.Alkoxide leaves to give a 1.2 dione thatfurther reacts with electrons in solution.Notes:M. B. Smith, J. March in March's Advanced Organic Chemistry, 51h ed., John Wiley and Sons, Inc.,New York, 2001, p 1562; T. Laue, A. Plagens, Named Organic Reactions, John Wiley and Sons,Inc., New York, 1998, pp. 1-3; S. M. McElvain, Organic Reactions, 4,4; J. P. Schaefer, J. J.Bloomfield, Organic Reactions, 4, 15; J. J. Bloomsfield, J. M. Owsley, J. M . Nelke, OrganicReactions 23,2The Riihlmann modification (Bouveault-Blanc Condensation or Ruhlmann Reaction) traps thedienolate as a TMS derivative. This protocol generally results in improved yields.0K0RRNaGowoO- TMsoHmMsTMSClEtOH-RRRRThis reaction is better than either the Dieckmann or Thome-Zeialer reactions for preparing largerings.Examples:-*0N. L. Allinger, Organic Synfheses 1963,&.840COOMeCooMemso''OTMSE. Butkus, A. Ilinskasa, S. Stoniusa, R. Rozenbergasa, M. urbanovab, V. Setnikac, P. BOUC,K.Volkac, Tetrahedron: Asymmetry 2002,l3,633

Name Reaction5Na-K tolueneTMSCltaken to next step w/o punficationJ. A. Marshall, J. C. Peterson, L Lebioda, Journal of the American Chemical Society 1984,106,6006%COWC0,Me1. Na, TMSCl, toluene2 dil HC13 Ac20,pyndine-%o*c076%G. Mehta, R. Vidya, Journal of Organic Chemstry 2001,66,6913/oj-""Me0MeNa,TMSCI toluene88%Me0MeM. J. Meyers, J. Sun, K. E. Carlson, B. S. Katzenellenbogen, J. A. Katzenellenbogen,Journal of Medicinal Chemistry 1999,42,2456C02Et.Na / tolueneTMSClMeondC02Et97%MeA. N. Blanchard, D. J. Bumell, Tetrahedron Letters 2001,42,4779oms

Name Reaction6Acyloin RearrangementRh;,-The Reaction:acid or base.0HOProposed Mechanism:In acid:In base:Examples:BrBrMeMeP. A. Bates, E. J. Ditzel, M. P. Hartshom, H. T. Ing, K. E. Richards, W. T. Robinson, TetrahedronLetters 1981,22, 2325MHOe R H o OEtEt benzene0OEtR i-Pr 43%R P h 80%T. Sate, T. Nagata, K. Maeda, S . Ohtsuka, Tetrahedron Letters 1994,35, 5027

Name ReactionKOHMeLMeOHH&;OH 'MeOHquant.a mixture of acyl estersM. Rentzea, E. Hecker, Tetrahedron Letters 1982,23, 1785MOMONaH, MeOHCH2ClzMOMO84%J. Liu, L. N. Mander, A. C. Willis, Tetrahedron 1998,a 11637OH7

8Name ReactionAdamantane Rearrangement (Schleyer Adamantization)The Reaction:Proposed Mechanism:P. von R. Schleyer, P. Grubmcller, W. F. Maier, 0.Vostrowsky, Tetrahedron Letters 1980,& 921M . Farcasiu, E. W. Hagaman, E. Wenkert, P. von R. Schleyer Tetrahedron Letters 1981,22, 1501E. M. Engler, M. Farcasiu, A. Sevin, J. M. Cense, P. V. R. Schleyer, Journal ofthe AmericanChemical [email protected] 1973,95,5769M . A. McKervey, Tetrahedron 1980,s,971 provides a useful review:This reaction consists of a series of deprotonations, protonations, hydride transfers and WagnerMeenvein rearrangements. There are postulated to be 2897 possible routes between startingmaterial and product! A few of the steps have been tested experimentally; most of the data arecomputational. The following structural features seem to be supported:Notes:Tricyclic molecules having 10 carbon atoms are converted to adamantane with Lewis acids.Additional carbon atoms become alkyl appendages:MeM. A. McKervey, Tetrahedron 1980,%, 971

Name ReactionExamples:9 1. SbF SOOH- 80%p-]H. W. Whitlock, Jr., M. W. Siefken, Journal of the American Chemical Socieq 1968,%, 4929Verification of the first steps:Jb998-100% HNO3HNo3 0zn-0n&a.NZo*65%P. A. Krasutsky, I. R. Likhotvorik, A. L. Litvyn, A. G. Yurchenko, D. Van Engen TetrahedronLetters 1 9 9 0 , a , 3973

10Name ReactionAldehyde Syntheses&Arens-van Dorp Cinnamaldehyde SynthesisRORLindar Reduction *RO-Bodrozu-Chichibabin Aldehyde SynthesisOEtJ-\RMgXy OEtOEt-0EtOEtacetalR0OH0.-EtOHEtBouveault Aldehyde SynthesisDMSO-based OxidationsAlbright-Goldman Oxidation / Albrieht-Goldman Reapent

11Name ReactionCorey-Kim Oxidation / Corm-Kim ReaeentNCSN-ChloroSuccinimideKornblum Aldehvde Svnthesis1.AgTsR H2.DMSO3. NEt3, NaHC03X I, Br, OTsOnodera OxidationDMSOphosphorous pentoxidePfitzner-MoffattOxidationO'HDCC, HXDMSO *HRiHalso for ketonesSwern OxidationOxalyl chloride, DMSOHalso for ketonesCH2C12* H'R

Name Reaction12Dess-Martin OxidationAcO OAcR,""-0CH,CI,,25 C0*R4also for ketonesDuffReactionhexamethylenetetramineHFukuyama ReductionM. Kimura, M. Seki, Tetrahedron Letters 2004, 45, 3219

13Name ReactionGanem OxidationH'helped by DMSO*@[email protected] RAH M e - i ,Me ,N-MeMe @MeMe.N,Me MeTMNOGattermann Reaction (Gatterman Aldehyde Synthesis) / Gattermann Reagent0G alkyl, ORGatterman-Koch Reaction (see under Gatterman Reaction)There seems to be agreement that the product-forming part of the mechanism is:However, the details of the formation of the formyl cation seem to be less assured.b'1110HC1,AlCb *(?c u0HSee S. Raugei, M. L. Klein, Journal of Physical Chemisrty B, 2001,105,8213 for pertinentreferences to experiment, and their computational study of the formyl cation.C-.Grundmann Aldehyde Synthesis

Name Reaction14-0RA, CO Pb(OAc),Huss-Bender ReactionNO,ArAX0ArKHMcFudven-Stevens Aldehyde SynthesisR Ar or alkyl with no a-protons

Name ReactionMevers Aldehvde Svnthesis /Mevers ReagentsA G H H c H3OHK,,RPolonovski ReactionACZOorAcClR RR"6ds-1H 3HOAcorHC1Reimer- Tiemann ReactiontCHC13f3 KOH-tHzOt3 KCI

16Name ReactionReissert Reaction (Grosheintz-Fischer-ReissertAldehyde Synthesis)Rosenmund Reduction0RACIH2Pd.BaSO,Sommelet Reaction0 HCI0

Name Reaction17Sonn-Muller Method-Stephen Reduction (Stephen Aldehyde Synthesis)R e N :F H C lutVilsmeier-HuackReaction:GWNKH0 IMenucleophilic aromaticcompounds onlyWucker Oxidation Reactionc1---HCI) N;RH6".GOC1HRH) [email protected]

Name Reaction18Alder-Rickert ReactionThe Reaction:Proposed Mechanism:This reaction is a reverse DieZs-Alder Reaction. The orbital considerations controlling the“backward: reaction are the same as the ‘‘forward” reaction.Notes:It seems accepted that almost any “retro-Diels-Alder“reaction can be included in the MeJ. W. Patterson, Tetrahedron 1993,49,478959% for the two steps.Me

Name Reaction1948%R. N Warrener, J.-M. Wang, K. D. V. Weerasuria, R. A. Russell, Tetrahedron Letters 1990,2,7069LO/OMeeRD. W. Landry, Tetrahedron 1983,a 2761Ne- CHOheattoluene85%R*-OcAAcO-pD. Schomburg, M. Thielmann, E. Winterfeldt, Tetrahedron Letters 1985,26, 1705tolueneA100%dqMe,,-c1MeM. E. Jung, L. J. Street, Journal of the American Chemical Society 1984,106,8327

Name Reaction20Aldol Type ReactionsThe Reaction:This reaction has become an extremely important tool in the reaction toolbox of organic chemists.Because of the variety of approaches to the aldol products, this summary section is prepared.Most synthetically useful approaches use a preformed enolate as one of the reactants.00Strong Base RJCH3*Ketone added to base R J c H ,"Kinetic enolate"With a weaker base and / o r slow additionof base to the ketone, an equilibrium will beestablished and a "ihermodynamic enolate"will predominate.The most useful approach is when the enolate can be trapped and used in a configurationally stableform.A generic analysis of enolate addition to an aldehyde:A similar exercise can be provided for the E-enolate.Zimmerman- Trader modelAn analysis of the steric effects in a chair-transition state for the reaction:

Name Reaction21A directed aldol reaction requires that one partner provides a preformed enolate (or chemicallyequivalent reactive species) and is then added to the second carbonyl-containing molecule.When one of the reactants is chiral, asymmetric induction can provide enantioselective products:Cram’s Rule and Related Views on Asymmetric InductionThis rule was developed to rationalize the steric course of addition to carbonyl compounds.’ Theconformations of the molecules are shown in their Newman structures, and a preferredconformation is selected in which the largest group, L, is situated anti to the carbonyl oxygen. Thisconformation assumes a model having a large oxygen, sometimes referred to as the ”big 0”model.’Examination of steric hindrance to nucleophile trajectory determined the major product? We mightpoint out, at the start, that Reetz has recently reported that “how” the reaction is carried out; forexample “slow” vs. “fast” mixing, can dramatically alter product ratios4RLess steric effects1LOHOHMajor productMinor productIn cases where the alpha-carbon is chiral, attack at the carbonyl carbon introduces a new stereogeniccenter. The two carbonyl faces are diastereotopic and attack at the re and se faces are differentd&bS O MThe two faces are diastereotopicA modification of the Cram model, in which the medium sized group, M, eclipsed the carbonyloxygen, was developed by Karabatsos’; however, it generally predicted the same product as theCram model. In this model, which assumes two major conformations, the major product is thatwhich is derived from attack at the less hindered side of the more stable conformer.1. a. See J. D. Morrison, H. S. Mosher, Asymmetric Organic Reactions, Prentice-Hall, EnglewoodCliffs, 1971, Chapter 3, for a somewhat dated, but excellent account of this concept.b Cram‘s first work, (D. J. Cram, F. A. Abd Elhafez, Journal of the American Chemical Society1952,74, 5828) set the stage for intense studies that have spanned 50 years.2. The original thought included the notion that there was a large steric bulk associated with theoxygen by nature of metal complexing.3. Application of the Curtin-Hammett Principle would suggest that the different ground stateconformers have minimal influence on the product composition. It is the difference in activationenergies for the two different isomers that controls the reaction, and the diastereomeric transitionstates would be attained from either ground state conformation.4. M. T. Reetz, S. Stanchev, H. Haning, Tetrahedron 1992,48,68135. a G. J. Karabatsos Journal of the American Chemical Sociew 1967, B, 1367;b. G. J. Karabatsos, D. J. Fenoglio, Topics in Stereochemistry 1970, , 167

22Name ReactionPrefemdS'Felkin-Cherest-Anh RuleLike Cram's Rule, the Felkin-Cherest-Anh model, developed by Felkin and coworkers6,is an attempt to understand and predict the stereochemistry of addition to a carbonyl group. Thismodel requires a "small 0 interpretation in which the largest group is oriented anti to the attackingnucleophile's trajectory. One should note that the Felkin-Cheresf-Anh model neglects thedominate.interaction of the carbonyl oxygen. In this approach, the R/S or &'Minteractions.I?HRMO; 0LThis is the important interaction that must beminimized. Note that in this approach thecarbonyl substituent plays an important role.Calculations in this model are based on an orbital interaction as described below. It should also benoted that the trajectory of delivery of nucleophile to the carbonyl carbon is defined by an angle ofabout 109".Prefemd conformation.We see in this coformer anLess interaction betweenincreased interactionthe small group and thebetween the mediumR-group. We also notegroup and R. Also,that this model "feels" thethere is more interactioninfluence of increasing size with the nucleophile.of R.This model often leads to the same conclusions obtained from the other models. It does,however, recognize the nonpassive role of the R-group in ketones. In this model onewould predict an increase of stereodifferentiation as the size of R- increases. This hasbeen found experimentally.For aldehydes the transition state model will be:MI.6 . M. Cherest, H. Felkin, N. Prudent, Tetrahedron Letters, 1968,9, 2199

Name Reaction23A usehl orbital approach by Cieplak' has suggested that the nucleophile will attack the carbonyl antito the best donor ligand.ECases for Modification of the ModelsSometimes the Lewis acid that coordinates with the carbonyl oxygen is sufficiently bulkythat it seriously influences the stereochemistry of attack. Sometimes these reaction products, whichseem opposite of the expected Cram Rule analysis, are termed "anti-Cram"products. Compare the"normal" situation with the influence of a sterically bulky Lewis acid:Dipolar ModelThere is evidence to suggest that competing dipole effects will alter the preferredconformation. Thus, for example, halogens will prefer a conformation in which the dipoles are antito one another. This is often described as the Cornforth model? In this model the highly polarizedgroup will take the place of the L-group of the Cram model.7. a. A. S. Cieplak, B. D. Yait, C. R. Johnson, Journal ofthe American Chemical Society 1989 111,8447A. S. Cieplak, Journal of the American Chemical Society 1981,103,4548b.8. J. W. Cornforth, R. H. Cornforth, K. K. Methew, Journal ofthe Chemical Society 1959, 112

24Name ReactionChelation ContropNeighboring heteroatoms can provide a site for complexing.Het,, .,oL k RML& O\\ vetIPreferreddirectionofattackfPh2cCIC1 t I., 0rT1, 1A1RHet heteroatomh4M metalProduct stereochemistries can be greatly influenced by these chelation control effects.This was first observed by Cram.” There are many controversies about this topic, and the issueremains a topic of investigative interest.” Without kinetic data, it has been suggested that it isimpossible to distinguish the following two mechanistic types:”Chelate Ketone MgMe,product(Non-chelation)Ket

8400, fax 978-646-8600, or on the web at Requests to the publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 11 1 River Street, Hoboken, NJ 07030. (201) 748-6008, fax (201) 748-6008. Limit of LiabilitylDisclaimer of Warranty: While the publisher and author have used their best