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Organic Reactions

ADVISORY BOARD

John E. Baldwin Michael J. MartinelliPeter Beak Stuart W. McCombieDale L. Boger Jerrold MeinwaldAndré B. Charette Scott J. MillerEngelbert Ciganek Larry E. OvermanDennis Curran Leo A. PaquetteSamuel Danishefsky Gary H. PosnerHuw M. L. Davies T. V. RajanBabuJohn Fried Hans J. ReichJacquelyn Gervay-Hague James H. RigbyHeinz W. Gschwend William R. RoushStephen Hanessian Scott D. RychnovskyLouis Hegedus Martin SemmelhackPaul J. Hergenrother Charles SihRobert C. Kelly Amos B. Smith, IIIAndrew S. Kende Barry M. TrostLaura Kiessling James D. WhiteSteven V. Ley Peter WipfJames A. Marshall

FORMER MEMBERS OF THE BOARDNOW DECEASED

Roger Adams Louis F. FieserHomer Adkins Ralph F. HirshmannWerner E. Bachmann Herbert O. HouseA. H. Blatt John R. JohnsonRobert Bittman Robert M. JoyceVirgil Boekelheide Willy LeimgruberGeorge A. Boswell, Jr. Frank C. McGrewTheodore L. Cairns Blaine C. McKusickArthur C. Cope Carl NiemannDonald J. Cram Harold R. SnyderDavid Y. Curtin Milán UskokovicWilliam G. Dauben Boris WeinsteinRichard F. Heck

Organic ReactionsV O L U M E 95

EDITORIAL BOARDScott E. Denmark, Editor-in-Chief

Jeffrey Aubé Donna M. HurynDavid B. Berkowitz Jeffrey S. JohnsonCarl Busacca Marisa C. KozlowskiJin K. Cha Gary A. MolanderP. Andrew Evans John MontgomeryPaul L. Feldman Albert PadwaDennis G. Hall Steven M. Weinreb

Jeffery B. Press, SecretaryPress Consulting Partners, Brewster, New York

Robert M. Coates, Proof-Reading EditorUniversity of Illinois at Urbana-Champaign, Urbana, Illinois

Danielle Soenen, Editorial Coordinator

Dena Lindsay, Secretary and Editorial Assistant

Landy K. Blasdel, Editorial Assistant

Linda S. Press, Editorial Consultant

Engelbert Ciganek, Editorial Advisor

ASSOCIATE EDITORS

Paul R. BlakemoreSelena Milicevic Sephton

Engelbert CiganekClaudio PalomoMikel Oiarbide

Aitor LandaAntonia Mielgo

Copyright © 2018 by Organic Reactions, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New JerseyPublished simultaneously in Canada

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INTRODUCTION TO THE SERIESROGER ADAMS, 1942

In the course of nearly every program of research in organic chemistry, the inves-tigator finds it necessary to use several of the better-known synthetic reactions. Todiscover the optimum conditions for the application of even the most familiar one to acompound not previously subjected to the reaction often requires an extensive searchof the literature; even then a series of experiments may be necessary. When the resultsof the investigation are published, the synthesis, which may have required months ofwork, is usually described without comment. The background of knowledge andexperience gained in the literature search and experimentation is thus lost to thosewho subsequently have occasion to apply the general method. The student of prepar-ative organic chemistry faces similar difficulties. The textbooks and laboratory manu-als furnish numerous examples of the application of various syntheses, but only rarelydo they convey an accurate conception of the scope and usefulness of the processes.

For many years American organic chemists have discussed these problems. Theplan of compiling critical discussions of the more important reactions thus wasevolved. The volumes of Organic Reactions are collections of chapters each devotedto a single reaction, or a definite phase of a reaction, of wide applicability. Theauthors have had experience with the processes surveyed. The subjects are presentedfrom the preparative viewpoint, and particular attention is given to limitations,interfering influences, effects of structure, and the selection of experimental tech-niques. Each chapter includes several detailed procedures illustrating the significantmodifications of the method. Most of these procedures have been found satisfactoryby the author or one of the editors, but unlike those in Organic Syntheses, theyhave not been subjected to careful testing in two or more laboratories. Each chaptercontains tables that include all the examples of the reaction under consideration thatthe author has been able to find. It is inevitable, however, that in the search of theliterature some examples will be missed, especially when the reaction is used as onestep in an extended synthesis. Nevertheless, the investigator will be able to use thetables and their accompanying bibliographies in place of most or all of the literaturesearch so often required. Because of the systematic arrangement of the material inthe chapters and the entries in the tables, users of the books will be able to findinformation desired by reference to the table of contents of the appropriate chapter.In the interest of economy, the entries in the indices have been kept to a minimum,and, in particular, the compounds listed in the tables are not repeated in the indices.

The success of this publication, which will appear periodically, depends upon thecooperation of organic chemists and their willingness to devote time and effort tothe preparation of the chapters. They have manifested their interest already by thealmost unanimous acceptance of invitations to contribute to the work. The editors willwelcome their continued interest and their suggestions for improvements in OrganicReactions.

v

INTRODUCTION TO THE SERIESSCOTT E. DENMARK, 2008

In the intervening years since “The Chief” wrote this introduction to the second ofhis publishing creations, much in the world of chemistry has changed. In particular,the last decade has witnessed a revolution in the generation, dissemination, andavailability of the chemical literature with the advent of electronic publication andabstracting services. Although the exponential growth in the chemical literaturewas one of the motivations for the creation of Organic Reactions, Adams couldnever have anticipated the impact of electronic access to the literature. Yet, as oftenhappens with visionary advances, the value of this critical resource is now evengreater than at its inception.

From 1942 to the 1980’s the challenge that Organic Reactions successfullyaddressed was the difficulty in compiling an authoritative summary of a prepara-tively useful organic reaction from the primary literature. Practitioners interestedin executing such a reaction (or simply learning about the features, advantages,and limitations of this process) would have a valuable resource to guide theirexperimentation. As abstracting services, in particular Chemical Abstracts andlater Beilstein, entered the electronic age, the challenge for the practitioner was nolonger to locate all of the literature on the subject. However, Organic Reactionschapters are much more than a surfeit of primary references; they constitute adistillation of this avalanche of information into the knowledge needed to correctlyimplement a reaction. It is in this capacity, namely to provide focused, scholarly, andcomprehensive overviews of a given transformation, that Organic Reactions takeson even greater significance for the practice of chemical experimentation in the 21st

century.Adams’ description of the content of the intended chapters is still remarkably

relevant today. The development of new chemical reactions over the past decadeshas greatly accelerated and has embraced more sophisticated reagents derived fromelements representing all reaches of the Periodic Table. Accordingly, the successfulimplementation of these transformations requires more stringent adherence to impor-tant experimental details and conditions. The suitability of a given reaction for anunknown application is best judged from the informed vantage point provided byprecedent and guidelines offered by a knowledgeable author.

As Adams clearly understood, the ultimate success of the enterprise depends on thewillingness of organic chemists to devote their time and efforts to the preparation ofchapters. The fact that, at the dawn of the 21st century, the series continues to thrive isfitting testimony to those chemists whose contributions serve as the foundation of thisedifice. Chemists who are considering the preparation of a manuscript for submissionto Organic Reactions are urged to contact the Editor-in-Chief.

vi

PREFACE TO VOLUME 95

For various reasons, many organic reactions have come to be knownby the names of their discoverers or early champions. Thus, organic

chemists commonly speak and write of Friedel-Crafts reactions,Diels-Alder reactions, and the like, rather than referring to the

reactions by more descriptive terms. This makes for efficiency incommunication, particularly when the descriptive term would be

long and involved.

J. F. Bunnett, Science 1965, 147, 726

Already in the prefaces to Volumes 77 and 90, the significance of “name reactions”in organic chemistry was described in great detail. Now, as Yogi Berra would have it,“It’s déjà vu all over again!!” The two chapters in Volume 95 feature reactions thathave achieved the apotheosis of being baptized as reactions of sufficient utility, gen-erality and uniqueness to be identified by their inventors/developers. As was the casein the previous 104 chapters on name reactions in this series, the question naturallyarises “Who are/were those individuals”? Chemistry, like all endeavors in scienceand the arts, is a quintessentially human activity. Accordingly we are compelled torecognize the individuality of those who bring new creations to light.

The first chapter in this volume, authored by Paul R. Blakemore, Selena Milice-vic Sephton and Engelbert Ciganek, represents a unique species of name reaction,namely one that was initially attributed to a single investigator, but then upon signifi-cant enhancement by a second, became a hyphenated name reaction. Unlike hyphen-ated name reactions that acknowledge co-developers (e.g. Diels-Alder Reaction), thistype recognizes a substantial contribution that markedly improves on the original, nomean feat.

The Julia-Kocienski olefination reaction acknowledges the important contribu-tions of Sylvestre Julia and Philip Kocienski in the development of a modification ofthe “classical” Julia olefination introduced by Marc Julia, Sylvestre’s brother. MarcJulia was one of the most influential organic chemists in France in the second halfof the twentieth century. Among Marc Julia’s many contributions is his developmentof a reaction to make alkenes and polyenes by the action of lithiated sulfones oncarbonyl compounds. One of the limitations of this original process is the lack ofcontrol over double bond geometry resulting from the intermediacy of a radical dur-ing desulfurization. This problem and the elimination of the need for dissolving metalreduction were addressed in a most ingenious way, first by brother Sylvestre and thenby Kocienski. These investigators recognized that the addition of a sulfonyl anion toa carbonyl compound and elimination of the resulting alcohol could be streamlinedinto a single step if the sulfone bore an activating group for the alcohol. That group

vii

viii PREFACE TO VOLUME 95

could transfer via a Smiles Rearrangement and expel sulfur dioxide in a single step.Thus, the Julia-Kocienski reaction was born. Moreover, it is no accident that Prof.Blakemore has agreed to author this chapter as he carried out his doctoral studieswith Prof. Kocienski in Southampton.

Prof. Blakemore is intimately familiar with all aspects of this process and togetherwith his student Selena Milicevic Sephton has composed an outstanding and thoroughtreatise on the various combinations of sulfone and carbonyl component that userswould need to know. They also provide a critical summary of the best methods (i.e.which sulfonyl activating group and conditions) for a given type of alkene product.With the help of our longtime Board Member and author of multiple Organic Reac-tions chapters, Engelbert Ciganek, the authors compiled an extremely user-friendlyand comprehensive Tabular Survey which is organized by the structure and substitu-tion pattern found on the product alkene or polyene.

The second chapter represents a reaction attributed to such an influential figurein organic chemistry that more than one name reaction bears his name. HermannStaudinger was a pioneering German organic chemist who is widely recognized as thefather of polymer chemistry for which he was awarded a Nobel Prize in Chemistry in1953. Staudinger is also well known for having first discovered ketenes as well as forthe first preparation of phosphine imines by combination of phosphines with azides.The latter reaction, also known as a Staudinger Reaction, figures significantly todayin bioconjugation, but also interestingly serves as a curious historical anomaly. In1919 Staudinger combined his phosphine imines with ketenes to form carbodiimides,which predates the use of phosphorus ylides in carbonyl olefination by Wittig by35 years! Among the most significant developments in the chemistry of ketenes byStaudinger was his discovery that they react with imines to generate β-lactams, theStaudinger Reaction that is the topic of Chapter 2 in this Volume. It is interesting tonote that this reaction was included in Chapter 6 of Volume 9 in this series, publishedin 1957 and authored by none other than John C. Sheehan and E. J. Corey. It wasalso included in Chapter 3 of Volume 82 published in 2013, which covered catalytic,asymmetric cycloadditions of ketenes.

We are now pleased to present a chapter wholly dedicated to the Staudinger Reac-tion with the primary focus being the stereoselective synthesis of β−lactams usingboth auxiliary and catalyst control. This chapter by Aitor Landa, Antonia Mielgo,Mikel Oiarbide, and Claudio Palomo comprehensively details the construction ofβ−lactams bearing alkyl and heteroatom substituents on C(3) which derives from theketene component. The critical features of generation of the ketene and successfulinterception by the imine are described. The relative configuration of the substituentson C(3) and C(4) is established by the geometry of the precursor imine and the orbitalsymmetry controlled, conrotatory closure of the four-membered ring. Furthermorethe attachment of chiral auxiliaries on the imine nitrogen, carbon and ketene carbonare all presented and the relative merits of each approach are compared. Given thetherapeutic importance of β−lactams, the Staudinger Reaction has found ample appli-cation in synthetic endeavors, which are generously illustrated. Finally, the TabularSurvey compiles a comprehensive listing of all examples organized by location of thestereocontrolling group and substituent type on the ketene.

PREFACE TO VOLUME 95 ix

It is appropriate here to acknowledge the expert assistance of the entire editorialboard, in particular Jeffrey Johnson and P. Andrew Evans (Chapter 1) and StevenWeinreb (Chapter 2) who shepherded this volume to completion. The contributions ofthe authors, editors, and publisher were expertly coordinated by the board secretary,Dena Lindsay. In addition, the Organic Reactions enterprise could not maintain thequality of production without the dedicated efforts of its editorial staff, Dr. DanielleSoenen, Dr. Linda S. Press, Dr. Landy Blasdel and Dr. Robert Coates. Insofar as theessence of Organic Reactions chapters resides in the massive tables of examples, theauthors’ and editorial coordinators’ painstaking efforts are highly prized.

Scott E. DenmarkUrbana, Illinois

CONTENTS

chapter page

1. The Julia–Kocienski OlefinationPaul R. Blakemore, Selena Milicevic Sephton, andEngelbert Ciganek . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2. Asymmetric Synthesis of β-Lactams by the Staudinger ReactionAitor Landa, Antonia Mielgo, Mikel Oiarbide, andClaudio Palomo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423

Cumulative Chapter Titles by Volume . . . . . . . . . . . . . . . . . . . . . . 595

Author Index, Volumes 1–95 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613

Chapter and Topic Index, Volumes 1–95 . . . . . . . . . . . . . . . . . . . . . . 619

xi

CHAPTER 1

THE JULIA–KOCIENSKI OLEFINATION

Paul R. Blakemore

Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, USA

Selena Milicevic Sephton

Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, Universityof Cambridge, Cambridge, UK

Engelbert Ciganek

121 Spring House Way, Kennett Square, Pennsylvania 19348, USA

CONTENTS

Page

Acknowledgments and Author Contributions . . . . . . . . 3Introduction . . . . . . . . . . . . . . . . . 3Mechanism and Stereochemistry . . . . . . . . . . . . 4

Mechanism . . . . . . . . . . . . . . . . . 5Factors Influencing Stereoselectivity . . . . . . . . . . . 6

Stereoselectivity in Type I Reactions: Neither Component Conjugated . . . 7Stereoselectivity in Type II Reactions: Conjugated Sulfone Anions . . . . 10Stereoselectivity in Type III Reactions: Conjugated Carbonyl Compounds . . 12Stereoselectivity in Type IV Reactions: Both Components Conjugated . . . 14

Scope and Limitations . . . . . . . . . . . . . . . 14Methods for Introducing Sulfone Activators . . . . . . . . . . 14

Via Oxidation of Intermediate Thioethers . . . . . . . . . 14Via Sulfone Derivatization . . . . . . . . . . . . . 18

Generation of Sulfone Anions and Strategies to Avoid Self-Condensation . . . 19Optimal Targeting of Different Classes of Alkene . . . . . . . . 22

Monosubstituted and 1,1-Disubstituted Alkenes . . . . . . . . 22Non-Conjugated 1,2-Disubstituted Alkenes . . . . . . . . . 23Conjugated 1,2-Disubstituted Alkenes . . . . . . . . . . 26Trisubstituted and Tetrasubstituted Alkenes . . . . . . . . . 32Vinyl Halides . . . . . . . . . . . . . . . . 35Miscellaneous Alkene Classes . . . . . . . . . . . . 38

[email protected] Reactions, Vol. 95, Edited by Scott E. Denmark et al.© 2018 Organic Reactions, Inc. Published in 2018 by John Wiley & Sons, Inc.

1

2 ORGANIC REACTIONS

Functional-Group Tolerance of Olefination and Epimerization Possibilities . . 39Reaction Variants . . . . . . . . . . . . . . . . 42

Comparison with Other Methods . . . . . . . . . . . . 46Julia–Lythgoe Olefination . . . . . . . . . . . . . . 46Wittig Reaction and Other Phosphorus-Based Olefination Methods . . . . 49Miscellaneous Methods for Alkene Synthesis . . . . . . . . . 51

Experimental Conditions . . . . . . . . . . . . . . 53Experimental Procedures . . . . . . . . . . . . . . 54

1-tert-Butyl-1H-tetrazole-5-thiol [Preparation of TBTSH] . . . . . . 545-Ethylsulfonyl-1-phenyl-1H-tetrazole [Sulfone Preparation via Alkylation/

Oxidation: PTSH, RBr, KOH/m-CPBA] . . . . . . . . . 55Ethyl (Benzothiazol-2-ylsulfonyl)acetate [Sulfone Preparation via

Alkylation/Oxidation: BTSH, RCl, K2CO3/Mo(VI), H2O2] . . . . 553,5-Bis(trifluoromethyl)phenyl Isopropyl Sulfone [Sulfone Preparation via

Alkylation/Oxidation: BTFPSH, RBr, NaH/Mn(II), H2O2] . . . . 56(E,2S,6S,7R,8S)-1-(1,3-Benzothiazol-2-ylsulfanyl)-8-(tert-butyldimethylsilyloxy)-7-

methoxy-2,4,6-trimethylnon-4-ene [Mitsunobu Thioetherification] . . . 57(E,2S,6S,7R,8S)-1-(1,3-Benzothiazol-2-ylsulfonyl)-7-methoxy-2,4,6-trimethylnon-4-

en-8-ol [Thioether Oxidation: Catalytic Mo(VI), H2O2] . . . . . 57N-(tert-Butoxycarbonyl)-4-methylenepiperidine [Methylenation of a Ketone: TBT

Sulfone, Barbier, Cs2CO3, THF–DMF] . . . . . . . . . 585,5-Dimethyl-2-[(E,S)-3-methylhex-4-enyl]-1,3-dioxane [Synthesis of a

Non-Conjugated 1,2-Disubstituted (E) Alkene: PT Sulfone, Barbier, KHMDS,DME] . . . . . . . . . . . . . . . . . 59

(S,E)-tert-Butyldiphenyl(5-methylhex-3-en-2-yloxy)silane [Synthesis of aNon-Conjugated 1,2-Disubstituted (E) Alkene: PT Sulfone, Premetalation, KHMDS,18-crown-6, THF] . . . . . . . . . . . . . . 59

Ethyl (2E,4E,7S,10E,15S)-15-(tert-Butyldiphenylsilyloxy)-7-methoxy-2-methylhexadeca-2,4,10-trienoate [Synthesis of a Non-Conjugated 1,2-Disubstituted(E) Alkene: PT Sulfone, Premetalation, LiHMDS, THF–HMPA] . . . 60

(Z)-6-Phenyl-1,3-hexadiene [Synthesis of a Conjugated 1,2-Disubstituted (Z)Alkene via a Type II Olefination: PT Sulfone, Premetalation, KHMDS,DMF–TDA] . . . . . . . . . . . . . . . 61

Ethyl (E)-4-Ethylhex-2-enoate [Synthesis of a Conjugated 1,2-Disubstituted (E) Enoatevia a Type II Olefination: BT Sulfone, Barbier, DBU, CH2Cl2] . . . 61

18-O-(4-Chlorobenzoyl)herboxidiene, Allyl Ester [Synthesis of a Conjugated1,2-Disubstituted (E) Alkene via a Type III Olefination: BT Sulfone, Premetalation,LDA, THF] . . . . . . . . . . . . . . . 62

1,4-Dimethoxy-2-methyl-5-(6-methylhept-5-en-2-yl)benzene [Synthesis of aTrisubstituted Alkene: PT Sulfone, LiHMDS, THF] . . . . . . 63

1-(4-Chlorophenyl)-2-methyl-1-phenylpropene [Synthesis of a Tetrasubstituted Alkene:BTFP Sulfone, Barbier, P4-t-Bu, THF] . . . . . . . . . 64

Tabular Survey . . . . . . . . . . . . . . . . 64Table 1. Synthesis of Monosubstituted Alkenes. . . . . . . . . 66Table 2. Synthesis of 1,1-Disubstituted Alkenes. . . . . . . . . 71Table 3. Synthesis of Non-Conjugated 1,2-Disubstituted Alkenes. . . . . 79Table 4. Synthesis of 1,3-Dienes. . . . . . . . . . . . 200Table 5. Synthesis of 1,3,5-Trienes and Higher Conjugated Polyenes. . . . 247Table 6. Synthesis of 1,3-Enynes. . . . . . . . . . . . 266Table 7. Synthesis of Allenes. . . . . . . . . . . . . 270Table 8. Synthesis of Vinyl Halides. . . . . . . . . . . . 271Table 9. Synthesis of Vinyl Ethers, Vinyl Esters, and Vinyl Amides. . . . 313Table 10. Synthesis of Vinyl Silanes. . . . . . . . . . . . 325Table 11. Synthesis of α, β-Unsaturated Esters. . . . . . . . . 326

THE JULIA–KOCIENSKI OLEFINATION 3

Table 12. Synthesis of α, β-Unsaturated Amides. . . . . . . . . 329Table 13. Synthesis of α, β-Unsaturated Ketones and Their Derivatives. . . . 330Table 14. Synthesis of Vinyl Arenes and Vinyl Heteroarenes. . . . . . 332Table 15. Synthesis of 1,2-Diaryl/Heteroaryl Alkenes. . . . . . . . 367Table 16. Synthesis of Trisubstituted Alkenes. . . . . . . . . 379Table 17. Synthesis of Tetrasubstituted Alkenes. . . . . . . . . 402Table 18. Intramolecular Reactions. . . . . . . . . . . . 404

References . . . . . . . . . . . . . . . . . 406

ACKNOWLEDGMENTS AND AUTHOR CONTRIBUTIONS

The authors gratefully acknowledge the guidance and assistance of the editorialstaff of Organic Reactions that was provided during the preparation of this chapter.Paul R. Blakemore wrote the main chapter and helped to compile tabular surveyentries for literature from 1991 through 2013. Selena Milicevic Sephton compiledtabular survey entries for literature from 1991 through 2013 and performed literaturesearches for all years. Engelbert Ciganek compiled tabular survey entries for litera-ture from 2014 through early 2016 and was responsible for the overall organizationof the tabular survey.

INTRODUCTION

The Julia–Kocienski olefination, also known as the modified Julia olefination, orthe one-pot Julia olefination, is a connective synthesis of alkenes involving the reac-tion of an α-metalated aryl alkyl sulfone (sulfone anion) such as 2 with a carbonylcompound (Scheme 1).1 The aryl group is necessary to permit ipso substitution nextto the sulfonyl moiety such that the initially generated addition adduct 3 may undergoa spontaneous Smiles rearrangement (i.e., 3 to 4).2 The elimination of sulfur dioxideand an aryloxide anion from the Smiles rearrangement product 4 affords alkene 5 andmetalated benzothiazole 6. The reaction was first described using benzothiazol-2-yl(BT) sulfones (1 in Scheme 1),1 but it has since been extended to include a variety of

S R1

HN

S

1

R2N–M

S R1

MN

S

2

R2CHO

R1

S

R2

OM

S

N

3

R1

S

O

4

R2

R1 R2

S

N

O O M

OMS

N+

65

– SO2 *

O O O O

OO

Scheme 1

4 ORGANIC REACTIONS

alternative aromatic activating groups, each of which has its own merits (Figure 1).3–6

To avoid confusion, it is worth noting at the outset that the Julia–Kocienski olefination(discovered by S. A. Julia)1 is distinct from the older Julia–Lythgoe olefination (dis-covered by M. Julia),7 which is an indirect alkene synthesis that involves the additionof phenyl sulfone anions to carbonyl compounds followed by a separate reductivedesulfonylation step (see “Comparison with Other Methods”).8–12 Throughout thisreview an asterisk indicates the site of a newly introduced alkene.

S

N

N

pyrid-2-yl(PYR)

CF3

CF3

NN

N

N

Ph

NN

N

N

t-Bu

benzothiazol-2-yl(BT)

1-phenyl-1H-tetrazol-5-yl (PT)

1-tert-butyl-1H-tetrazol-5-yl (TBT)

3,5-bis(trifluoromethyl)phenyl (BTFP)

Figure 1. Five aromatic activators (Act) commonly used in the Julia–Kocienski olefination.

The outcome of the Julia–Kocienski olefination is sensitive to all variables, andan informed selection of coupling partner types (sulfone and carbonyl component,choice of bond disconnection in polyenes, type of activator) and reaction conditions(protocol for sulfone anion generation, type of base, base countercation, solvent,additives) is critical to obtain a high yielding alkene synthesis with the desired con-figuration. Providing that the coupling of interest is optimized and properly executed,the Julia–Kocienski olefination is capable of generating a wide variety of complexalkene targets, in which it is especially well suited to the production of trans-1,2-disubstituted double bonds. The olefination process itself and the methods availablefor installing the activating sulfone moiety generally exhibit broad functional-grouptolerance, and consequently, the Julia–Kocienski reaction has enjoyed widespreadadoption as a reliable tool for the coupling of multifunctional sulfone and carbonylcompounds during total synthesis efforts. This review focuses on how to achieveoptimal results from the Julia–Kocienski olefination by a consideration of its the-oretical and operational aspects, in what situations it is best applied, and when analternative carbonyl olefination tactic is perhaps better suited. Notable variants of theprocess leading to non-alkene targets are also briefly surveyed. The Julia–Kocienskiolefination has been previously reviewed, and these accounts should be consulted fordiscourse on the historical development of the process.2,9,11–14

MECHANISM AND STEREOCHEMISTRY

The broader aspects of the mechanism for the Julia–Kocienski olefination are wellunderstood; however, a rigorous framework to fully explain the influence of sub-stituents and other parameters on the stereochemical outcome of the process is not yetavailable. Nonetheless, extensive experimental findings reveal substrate-dependentstereoselectivity traits, most of which can be rationalized on at least an empiricallevel.3 A more complete understanding of the mechanistic origin of stereoselectivityin some special cases has been obtained by a combination of control experiments andcomputational studies.13,15–18


Mechanism

The current mechanistic understanding of the Julia–Kocienski olefination is sum-marized below and illustrated for the synthesis of a 1,2-disubstituted alkene from ametalated BT-sulfone and an aldehyde (Scheme 2; solid arrows depict the defaultpathway that is followed when R1 and R2 are non-conjugating substituents). Analo-gous pathways will be followed for alternative activators and for substrates leading toother classes of alkenes. Addition of the metalated sulfone nucleophile to the carbonylelectrophile generates the expected pair of diastereomeric syn and anti β-alkoxy sul-fone intermediates 7; diastereoselectivity for this step is strongly dependent on reac-tion conditions and activator type. The initial adducts, syn-7 and anti-7, are formedirreversibly if the sulfone anion is not stabilized (e.g., R1 = alkyl) but are capable ofequilibration via a retroaddition/re-addition mechanism (pathway A) if the sulfoneanion is equipped with an anion-stabilizing group (e.g., R1 = vinyl, aryl, carbonyl,etc.). Smiles rearrangement occurs by way of spirocyclic intermediates trans-8 andcis-8 (an example of which has been isolated),19 which open to generate syn and antiβ-aryloxy sulfinates 9, respectively. Spirocyclization occurs more rapidly from syn-7than from anti-7 because the spirocycle derived from the latter isomer (cis-8) exhibitshigher strain.15 This accounts for the observation of (Z)-selective Julia–Kocienskiolefination in certain cases, in which the initial addition reaction is reversible and the

H

BTO R2

R1 SO2M

H

R2

BTO H

R1 SO2M

H

R1 R2

R2R1– BTOM

– SO2

– SO2

– BTOM

R1R2

O

SO2BT

M

R1R2

O

SO2BT

M

O

HR2

O2S

HR1

NS M

O

R2

H

O2S

HR1

NS M

cis-8

anti-9

trans-8

syn-9

anti-7

R1

SO2BT

M+ R2CHO

syn-7

kanti

slow

ksyn

fast

(E) alkene

(Z) alkene

R1

SO2–

HCH R2

A

A

R2

OBT

HCH R1

M+

10 11

C, – SO2B– BTOM

– BTOMB C, – SO2

– SO2 – BTOM

– BTOM– SO2D

*

*

–+

Scheme 2

6 ORGANIC REACTIONS

Curtin–Hammett principle operates (i.e., equilibration between syn-7 and anti-7 isfaster than spirocyclization).

A variety of mechanistic pathways have been identified, or at least inferredby indirect evidence, for the production of alkenes from β-aryloxy sulfinates 9.Loss of the aryloxide anion (BTOM) and sulfur dioxide from sulfinates 9 isstereospecific only when R1 and R2 are non-conjugating substituents (e.g., simplealkyl); in such cases, elimination is a concerted E2-like process occurring fromthe illustrated conformers, wherein the β-C–OAct and α-C–SO2

– bonds have anantiperiplanar alignment, and anti-9 leads to the (E) alkene whereas syn-9 affordsthe (Z) alkene. The validity of this pathway for the reaction of metalated PTSO2Etwith acetaldehyde is supported by a recent DFT computational study, albeit whetherspirocycle 8 is a true intermediate along the reaction coordinate or merely a transitionstructure was questioned.18 Unsaturation in either R1 or R2 potentially enables thenon-stereospecific conversion of β-aryloxy sulfinate isomers 9 to alkene products:where R2 is a cation-stabilizing substituent (aryl, vinyl, etc.), the suggestion of anE1-type elimination (from 9 or 8) via zwitterion 10 was noted in Julia’s originalwork (pathway B),3 and when R1 is a strongly electron-withdrawing group (e.g.,carbonyl), an E1cB-type elimination via carbanion 11 (i.e., an enolate) is consistentwith some relevant data (pathway C).14,16,20 Conformational relaxation via rotationabout the central C–C bond in intermediates 10 and 11 prior to respective electrofuge(SO2) or nucleofuge (BTO–) release leads preferentially to the (E) alkene in bothcases. More recent work casts doubt on the veracity of Julia’s ad hoc zwitterion(10) hypothesis, at the very least for reactions involving R2 = aryl; a concertedsyn E2-like elimination mechanism from syn-9 (R2 = aryl) via a conformationwith synperiplanar β-C–OAct and α-C–SO2

– bonds (not illustrated) was identifiedcomputationally and suggested by experiment (pathway D).17 Related syn elimi-nation pathways from spirocycles 8 that bypass β-aryloxy sulfinate intermediatesaltogether and lead directly to alkene products have been located by computationalstudies for reactions involving 3,5-bis(trifluoromethyl)phenyl (BTFP) sulfonylacetates.16 Results that support the various mechanistic pathways posited above andthe relationship between the substituent and other parameters on the stereochemicaloutcome of the Julia–Kocienski olefination are now considered.

Factors Influencing Stereoselectivity

Substituent effects play a major role in determining the stereochemical out-come of the Julia–Kocienski olefination, and intrinsic selectivity trends can beaccentuated or sometimes reversed by the use of different activators. Selectivityis further influenced in most cases by the base used to form the sulfone anion, thecountercation, solvents, and any added cosolvents or cation-complexing agents. Thepresence or absence of conjugation in each coupling partner has the most profoundeffect on stereoselectivity, and reactions are usefully divided into four substrate pairclasses according to this principle.3 Examples within the same class share relatedstereochemical behaviors that can be rationalized within the mechanistic frameworkadvanced above (Scheme 2). The four classes are: (I) reactions of sulfone anions thatare not β,γ-unsaturated with carbonyl compounds that are not α,β-unsaturated, (II)


reactions of sulfone anions that are β,γ-unsaturated with carbonyl compounds that arenot α,β-unsaturated, (III) reactions of sulfone anions that are not β,γ-unsaturated withcarbonyl compounds that are α,β-unsaturated, and (IV) reactions of sulfone anionsthat are β,γ-unsaturated with carbonyl compounds that are α,β-unsaturated. Thesebroad reaction classes are now considered in turn within the context of 1,2-disubstituted alkene synthesis. Similar principles apply for tri- and tetrasubstitutedalkene synthesis, but these types of products generally cannot be obtained withhigh levels of stereoselectivity via the Julia–Kocienski olefination because thesteric interactions that differentiate the competing diastereomeric pathways are lessenergetically distinguished in higher-substituted cases (see “Scope and Limitations”).

Stereoselectivity in Type I Reactions: Neither Component Conjugated. Thestereochemical outcome of a Type I reaction is determined by the kinetic diastereo-selectivity in the initial addition step: the formation of β-alkoxy sulfone intermediates7 is irreversible in such cases, and their subsequent breakdown to alkene productsis stereospecific. This fact was established experimentally for alkyl BT, pyrid-2-yl(PYR), and 1-phenyl-1H-tetrazol-5-yl (PT) sulfones by studying the base-mediatedelimination of alkyl-substituted, stereodefined β-alkoxy sulfones.15,21 For example,treatment of anti β-hydroxy sulfone 12 (generated from trans-7-tetradecene oxideby ring-opening with PTSH followed by oxidation of the resulting thioether) withKHMDS (HMDS = hexamethyldisilazane) leads exclusively to (E)-7-tetradecene(Scheme 3). By contrast, in situ generation of the corresponding syn β-alkoxy sulfoneanion via desilylation of syn β-silyloxy-PT-sulfone 13 with TBAF provides exclu-sively (Z)-7-tetradecene (Scheme 4).21

OH

S

KHMDS, DME

–60° to rt, 1.5 h

(91%) (E)/(Z)* > 98:212

*

HMDS = hexamethyldisilazane

OPTO

Scheme 3

TESO

S

n-Bu4NF, DME

–60° to rt, 3 h

(95%) (E)/(Z)* < 2:9813

*

OPTO

Scheme 4

Type I reactions generally result in poor stereoselectivity under the reactionconditions for olefination that were first described by Julia and coworkers (BTor PYR sulfones, LDA, THF, –78∘ to room temperature).3 The inference of lowdiastereoselectivity in the sulfone anion addition step was confirmed in the case

8 ORGANIC REACTIONS

of lithiated alkyl PYR sulfones by the isolation of β-hydroxy sulfones with dr∼50:50 directly from reactions with non-conjugated aldehydes.15 Early effortsto apply the nascent Julia–Kocienski olefination to target-directed synthesesrevealed that variations in base countercation and solvent polarity markedly affectstereoselectivity.22–24 Building on these findings, Kocienski and coworkers system-atically investigated the role of base countercation, solvent polarity, and aromaticactivator on the stereochemical outcome of simple Type I reactions.4 Conditionsthat promote the dissociation of the metal cation from the sulfone anion (e.g., K+

countercation in a polar solvent) favor (E) alkene products, which is particularlypronounced when PT sulfones are employed. As seen in Figure 2, an excellent levelof trans selectivity can be obtained using PT sulfones, regardless of the degree ofchain branching, using KHMDS as base in 1,2-dimethoxyethane.4 Other reactionconditions that also favor a “naked” PT sulfone anion have the same effect; forexample, LiHMDS in dimethylformamide with hexamethylphosphoramide as thecosolvent,25 and KHMDS in tetrahydrofuran with added 18-crown-6.26

(E)/(Z)*

60:4075:25

Act = BT

Act = PT

MLiK

SolventTHFDME

(E)/(Z)*

66:3476:24

MLiK

SolventTHFDME

(E)/(Z)*

72:2836:64

MLiK

SolventTHFDME

(E)/(Z)*

75:2594:6

MLiK

SolventTHFDME

(E)/(Z)*

69:3199:1

MLiK

SolventTHFDME

(E)/(Z)*

53:4799:1

MLiK

SolventTHFDME

* * *

Figure 2. Stereoselectivity of alkene formation via addition of R1CHMSO2Act to R2CHO(−78∘ or −60∘, increasing to rt); sulfone anions are generated via premetalation with(TMS)2NM bases; the group to the left of the double bond originated from the sulfone (R1).

A credible stereocontrol model has been proposed to account for the high antidiastereoselectivity (and ultimately the (E)-selective olefination) for the addition ofmetalated sulfones to aldehydes under conditions favoring cation dissociation.14 Anextension of the model to explain both high and low stereoselectivity scenarios isnow delineated. Sulfones do not stabilize adjacent negative charge density by 2p–3dπ-bonding resonance, but rather by a combination of inductive, polarization, andhyperconjugative effects.27,28 Solid-state and solution-phase studies of alkyl aryl sul-fone metalates indicate the existence of species such as 14 or comparable dimers(Figure 3), wherein the metal cation is associated with the sulfone oxygen atoms,and a pyramidalized sp3-hybridized carbanion is oriented to allow for nC → σ*S–Arorbital overlap.29 For addition reactions in which the cation is expected to be tightlybound to the metalated sulfone, e.g., M = Li and tetrahydrofuran (or a less coor-dinating solvent), closed chair-like transition states 15 and 16 are more likely the


dominant species (Scheme 5).30,31 There is little to differentiate energetically betweenthese two assemblies because significant 1,3-diaxial interactions do not exist to dis-tinguish the axial disposition of R1 in 16 from its equatorial placement in 15. Theobservation of poor stereocontrol for Type I olefinations under Julia’s original reac-tion conditions (LDA, THF, –78∘ to rt) is understandable on this basis. By contrast,protocols that favor cation dissociation, e.g., M = K and 1,2-dimethoxyethane sol-vent or M = Li and dimethylformamide–hexamethylphosphoramide solvent, allowfor open transition states such as 18 and 19. The second transition state (19) is oflower energy because it lacks the gauche interaction between R1 and R2 that is presentin the alternative transition state (18). Progression of the olefination process via thefavored transition state 19 leads to anti β-alkoxy sulfone 17 and thence to the (E)alkene. Thus, a plausible hypothesis is at hand to account for the finding of hightrans selectivity under conditions involving “naked” sulfone anions. A recent DFTcomputational study draws a similar conclusion and offers additional insights.18 Inaddition, the reason why PT sulfones offer intrinsically higher anti selectivity thanBT sulfones has been the source of speculation;14 however, no definitive conclusioncan yet be drawn. Taken as a whole, the mechanistic origin of diastereoselectivity inthe addition of sulfone anions to carbonyl compounds warrants further studies.

SAr

O O

R1H

Msolv solv

Ar

O O

R1H

M+

solv solv

14

+

––

Figure 3. The structure of an alkyl aryl sulfone metalate.

O

S

OMR2

O

Ar

R1R2

R1

S

OM

S

OO

O

Ar

R1

R2

M+(solv)n

δ–

δ–

15

18 (disfavored)

O H

R2SO2ArR1

Hδ–

δ–

syn-17

vs

vs

16

19 (favored)

H O

R2HArO2S

R1 δ–

δ–

anti-17

M+(solv)n

H

O

S

OMR1

closed transition structure

open transition structure

R2

O

Ar R1

R2

OM

S

O

S

R1

O

O

Ar

H

R2

δ–

δ–

H

H

H

HH

H

ArO

O

OArO

Scheme 5

10 ORGANIC REACTIONS

Stereoselectivity in Type II Reactions: Conjugated Sulfone Anions. The useof stabilized (e.g., R1 = carbonyl) or semi-stabilized (e.g., R1 = vinyl, alkynyl, aryl)conjugated sulfone anions provides the possibility of equilibration between inter-mediate β-alkoxy sulfones 7 via a retroaddition/re-addition mechanism (pathway A,Scheme 2). Conditions under which retroaddition operates in the case of metalatedbenzylic BT and PT sulfones have been identified experimentally using crossoverexperiments with 2-sulfonyl-2-phenylethanols 20 (Scheme 6).13,17,21,32 Treatment ofβ-hydroxy sulfones 20 with base in the presence of 4-nitrobenzaldehyde generatesthe direct elimination product 21 if no fragmentation of the alkoxide anion occurs.However, if the intermediate alkoxide undergoes retroaddition, a competition willexist between re-addition of the resulting sulfone anion PhCHMSO2Act to RCHOor to 4-nitrobenzaldehyde. The isolation of the “crossover” product 22 thereforeprovides evidence that some degree of retroaddition occurs. In the case of antiβ-hydroxy sulfones 20 (R = Ph), lithium alkoxides of both BT and PT variantsexperience significant retroaddition between –78∘ and room temperature.13,21

In the case of the less-substituted BT sulfone 20 (R = H), retroaddition fromthe derived lithium alkoxide does not occur to any measureable extent at –60∘,in which the inducement of significant fragmentation requires generation of thepotassium alkoxide in the presence of potassium-selective complexing agents suchas 18-crown-6 or tris[2-(2-methoxyethoxy)ethyl]amine (TDA).32 The potassiumalkoxide of the analogous PT sulfone 20 (R = H) exhibits a much higher propensityto fragment under the same reaction conditions.

RPh

OH

S

20

Temp–78° to rt–78° to rt

–60°–55°–60°–60°

RPhPhHHHH

ActBTPTBTBTBTPT

Yield (%)4035

>98a

34a

22a

<2a

(E)/(Z)*

≥98:287:13

nananana

Yield (%)6060<2a

66a

7293

(E)/(Z)*

92:869:31

————

PhR

Ph

NO2

NO2

OHC

21direct product

22cross-over product

aBased on HPLC analysis.

+**

Cross-Over ProductDirect ProductBaseLDALDALiHMDSKHMDSKHMDSKHMDS

SolventTHFTHFDMF–HMPA (3:1)18-crown-6, DMFDMF–TDA (3:1)DMF–TDA (3:1)

TDA = tris[2-(2-methoxyethoxy)ethyl]amine na = not applicable

ActO

O

Scheme 6

In Type II reactions in which a retroaddition mechanism operates, the ulti-mate stereochemical outcome of olefination is not a simple consequence ofdiastereoselectivity in the initial step. Furthermore, because syn β-alkoxy sulfone


intermediates 7 cyclize faster than their anti counterparts, the preferred formationof cis alkenes is anticipated in cases where retroaddition is more facile than spiro-cyclization, and the elimination from β-aryloxysulfinates 9 follows a stereospecificanti pathway (see Scheme 2). Indeed, potentially useful (Z) selectivity has been doc-umented for many Type II reactions, particularly for examples involving propargylicsulfones (Scheme 7);3 however, this outcome is by no means certain, and the cisbias is generally overridden when α-branched aldehydes are utilized (Scheme 8).3

Less reactive aromatic activators such as PYR3 and 1-tert-butyl-1H-tetrazol-5-yl(TBT)5 raise the energy barrier for the Smiles rearrangement (by lower activatorelectrophilicity in the former, and by increased steric hindrance to ipso substitutionin the latter), thereby promoting (Z) selectivity by enhancing equilibration betweensyn and anti β-alkoxy sulfone intermediates. As illustrated in Scheme 9, this kind ofactivator effect can be significant enough to result in the reversal in stereoselectivity.5

1. LDA, THF, –78°, 1 h

2. n-C8H17CHO, –78° to rt, 4 h

(E)/(Z)* 37:6340:60<1:99

R S Rn-C8H17

*RPhCH2=CHn-C4H9

Yield (%)816626

BT

O O

Scheme 7

1. LDA, THF, –78°, 1 h

2. i-PrCHO, –78° to rt, 4 h

(51%) (E)/(Z)* = 90:10

Ph SPh

*O

BT

O

Scheme 8

1. KHMDS, DME, –60°, 30 min

2. n-C9H19CHO, –60° to rtSn-C9H19

*ActPTTBT

Yield (%)3960

(E)/(Z)*

67:334:96

O

Act

O

Scheme 9

An alternative strategy to enhance (Z) selectivity from semi-stabilized sulfoneanions utilizes the more common BT or PT activators under the reaction conditionsnoted above in Scheme 6 for optimal retroaddition (Scheme 10).32 The presenceof α-branching on the aldehyde leads to (E) alkenes, which has been ascribed tothe difficulty of generating syn β-alkoxy sulfones via an open transition state (18,Scheme 5) in which R2 is bulky.32 Steric effects are evidently not the only cause oflosing cis selectivity, because non-branched α-oxygenated aldehydes also afford (E)alkene products under these conditions.32


1. KHMDS, DMF–TDA (3:1), –60°, 2 min

Sn-PrPh

*n-Pr

ActBTPT

Yield (%)7340

(E)/(Z)*

17:8313:87

2. Ph(CH2)2CHO, –60° to rt, 7 h

O

Act

O

Scheme 10

Type II reactions involving highly stabilized sulfone anions (e.g., R1 = carbonyl)follow the same trends highlighted above for semi-stabilized cases; thus, (Z) α,β-unsaturated carbonyl compounds can be prepared from non-conjugated unbranchedaldehydes, but (E) selectivity is observed in all other cases.20 The sense ofstereoselectivity is dependent on reaction temperature, in which any inherent (Z)selectivity is accentuated at low temperature, and (E) selectivity is obtained uponheating (Scheme 11).20 It has been suggested that at higher temperatures, loss of SO2and the aryloxide anion from β-aryloxy sulfinates 9 is non-concerted and followsan E1cB-type mechanism via 11 (pathway C, Scheme 2).14 In this case (i.e., R1 =carbonyl or with other strongly electron-withdrawing groups), the formation of the(E) alkene would be anticipated if the stabilized carbanion (enolate) 11 eliminatesActO– from the lower-energy conformer. The synthesis of α,β-unsaturated carbonylcompounds and related alkenes, including fluorinated examples,33 is discussed inmore detail below (see “Scope and Limitations”).

O

EtO

n-C5H11CHO, DBU

CH2Cl2, –78°, 16 h

O

EtO

n-C5H11

(47%) (E)/(Z)* = 8:92S

O

EtO n-C5H11

n-C5H11CHO, NaHMDS

THF, 0–65°, 2 h

(31%) (E)/(Z)* = 95:5

*

*

O

BT

O

Scheme 11

Stereoselectivity in Type III Reactions: Conjugated Carbonyl Compounds.Julia–Kocienski olefinations involving non-conjugated primary BT or PT sulfoneanions and α,β-unsaturated aldehydes (including aryl aldehydes) result in the pre-ferential formation of (E)-configured 1,2-disubstituted alkenes in a vast majority ofcases.3 The level of stereoselectivity obtained is usually high [(E)/(Z) ratios well inexcess of 4:1 are typical], and the stereochemical outcome is not particularly sensi-tive to solvent, cation, or additive effects, making these kinds of reactions reliableand easy to perform. As is the case for Type II reactions, kinetic diastereoselectivityin the initial addition step is not the determinant of alkene configuration in Type IIIreactions,15 but for the latter type, this fact is attributed to the mechanistic complex-ity of the elimination from β-aryloxy sulfinate intermediates rather than to issues of


reversibility.17 Prompted by the (E) selectivity in Type III reactions and the correlationbetween product (E)/(Z) ratio and the electron richness of substituted benzaldehydesubstrates (Scheme 12), Julia and coworkers proposed the zwitterionic pathway out-lined in Scheme 2 (pathway B).3 It was reasoned that zwitterionic intermediates 10can be formed in cases where R2 is capable of stabilizing an adjacent carbocation;loss of SO2 from the lower-energy conformer of 10 leads to the (E) alkene regard-less of the original syn or anti configuration of the precursor β-aryloxy sulfinate 9.Substituents that can stabilize the positively charged center are anticipated to pro-mote the zwitterionic pathway and so accentuate the stereoselectivity of the reaction.Although the zwitterion hypothesis has predictive value, experimental proof has notbeen forthcoming, and its validity is dubious given the poor nucleofugality of aryl-oxide anions (e.g., BTO–) and the expected high energy of zwitterions 10 in therelatively non-polar ethereal solvent media.

SR

CHO+

R

LDA, THF

–78° to rt, 4 h

*

RHMeOCl

Yield (%)689551

(E)/(Z)*

94:699:177:23

BT

O O

Scheme 12

Recently performed calculations also fail to locate zwitterions as credible inter-mediates in Type III (or Type IV) reactions and reveal stereoconvergence in the elim-ination of β-aryloxy sulfinates 9 (M = Li, R1 = Me, R2 = Ph) such that both possiblediastereoisomers preferentially generate the (E) alkene product but via distinct, con-certed mechanisms.17 The lowest-energy pathway for loss of SO2 and BTOLi fromanti-9 (M = Li, R1 = Me, R2 = Ph) is via antiperiplanar elimination, whereas forsyn-9 (M = Li, R1 = Me, R2 = Ph), the synperiplanar elimination pathway is lowerin energy (pathway D, Scheme 2). Lending credence to the major conclusions ofthis important computational study, generation of stereodefined, isotopically labeledβ-aryloxy sulfinates 24 from sulfones 23 leads predominantly to (E)-alkene products25 predicted by a syn elimination pathway (Scheme 13).17 Given that the (E)- and(Z)-alkene products 25 in this case differ only by isotopic substitution, these find-ings are incompatible with the zwitterionic pathway hypothesis, which would affordalkenes 25 with (E)/(Z) ∼ 50:50. Significantly, the dependence of the (E)/(Z) ratio onthe aryl moiety mirrors the trend found previously for Type III Julia–Kocienski olefi-nations involving aryl aldehydes (c.f., Scheme 12), indicating that electron-releasingR2 substituents stabilize the transition state of the synperiplanar elimination path-way (which is precluded for anti β-aryloxy sulfinates 7 with non-trivial substituentsbecause of an eclipsing interaction between R1 and R2). It waits to be seen whetheror not stereoconvergence is also the cause of (E) selectivity in Type III olefinationsinvolving non-aromatic α,β-unsaturated aldehydes.


23D

OBTS

R

EtSLi,THF, –78°

24

D

OBTLiO2S

RD

R

25

– SO2

– BTOLi

*

RPh4-MeOC6H4

4-ClC6H4

Yield (%)928789

(E)/(Z)*

90:1094:681:19

– BTSEt

OBT

O

Scheme 13

Although most Type III reactions are (E)-selective, some exceptions are known.For example, in a limited focus study, it was found that the potassium metalate of anon-conjugated PYR sulfone reacts with (E)-configured α,β-unsaturated aldehydes toprovide the (E,Z)-diene products (Scheme 14).34,35 The mechanistic origin of selec-tivity for this reaction is unknown, as is its potential generality for the synthesis ofconjugated (Z)-configured alkenes.

OTIPSS

1. KHMDS, toluene, rt, 3 min

2. (E)-cinnamaldehyde, 1 h

OTIPSPh

*

(70%) (E)/(Z)* = 8:92

O

PYR

O

Scheme 14

Stereoselectivity in Type IV Reactions: Both Components Conjugated. Forscenarios in which both R1 and R2 are conjugating substituents, all of the mechanisticpossibilities discussed above for Type II and Type III reactions come into play. Pre-diction of the stereochemical outcome of Type IV olefination reactions is difficultunless one has knowledge of the behavior of closely related examples. Some specificcases are discussed below.

SCOPE AND LIMITATIONS

Methods for Introducing Sulfone Activators

Via Oxidation of Intermediate Thioethers. An attractive feature of theJulia–Kocienski olefination is the ease with which the activating sulfone moietycan be introduced into a fragment of interest. Sulfones are generally prepared viaoxidation of the corresponding thioethers which are, in turn, typically produced bythe alkylation of the appropriate thiol ActSH (Act = BT, PT, PYR, etc.) via an SN2substitution. It is worth noting from the standpoint of operational convenience thatthe heterocyclic thiols most commonly employed as starting materials are odorlesssolids. For simple R groups (R = primary or secondary alkyl), thioether formation is


most economically achieved by direct alkylation of the thiol with an alkyl halide oralkyl sulfonate ester in the presence of a base (e.g., step 1, Schemes 15–17).20,34–36

Br1. BTSH (1.2 equiv), Et3N, THF, 0° to rt, 2 h S(O)nBT

step 1: (95%) n = 0step 2: (90%) n = 2

2. m-CPBA (2.1 equiv), CH2Cl2, 0° to rt, 4 h

Scheme 15

EtOCl

O1. BTSH, K2CO3, acetone, heat, 20 h

EtOS

O(71%)

2. (NH4)6Mo7O24•4H2O (cat.), aq H2O2 (30% wt/wt), EtOH, rt, 40 h

O

BT

O

Scheme 16

OMs S(O)nPYR

step 1: (71%) n = 0step 2: (>95%) n = 2

1. PYRSH, NaH, DMF

2. Na2WO4•2H2O (10 mol %), aq H2O2 (30% wt/wt) (4–10 equiv), MeOH, rt, 3–12 h

Scheme 17

For more complex R groups, wherein preparation of the alkyl halide or sulfonatewould necessitate unwelcome additional operations, thioethers are convenientlyproduced from alcohol precursors with ActSH using the Mitsunobu reaction.37 TheMitsunobu method is compatible with a wide range of aprotic functional groups(including common protecting groups), and it has been successfully applied to thesynthesis of many late-stage polyfunctional intermediates en route to natural producttargets (Scheme 18).38 As expected, thioetherification of stereogenic secondaryalcohols proceeds with inversion of configuration (Scheme 19).39 An alternative andless-explored approach to thioethers to prepare Julia–Kocienski reagents involvesan SNAr reaction of a substrate thiol with an ActX type species (Scheme 20).40

1. PTSH, PPh3, i-PrO2CN=NCO2i-Pr, THF, rt, 24 hO

HO

OO OTBS

OH

OTBS

S(O)nPT

step 1: (88%) n = 0step 2: (96%) n = 2

OMeO 2. (NH4)6Mo7O24•4H2O (cat.), aq H2O2 (30% wt/wt), EtOH, rt, 12 h

H

Scheme 18


1. BTSH, PPh3, i-PrO2CN=NCO2i-Pr, THF, 0° to rt, 12 h

step 1: (72%) n = 0step 2: (73%) n = 2

H

HBT(O)nS

H

HHO

2. (NH4)6Mo7O24•4H2O (cat.), aq H2O2 (30% wt/wt), EtOH, rt, 10 d

Scheme 19

HS

1. BTCl, NaH, THF, rt to 65°, 14 h

step 1: (63%) n = 0step 2: (80%) n = 2

H

OO

BT(O)nSH

OO

2. (NH4)6Mo7O24•4H2O (cat.), aq H2O2 (30% wt/wt), EtOH, rt, 30 h

Scheme 20

A wide variety of oxidants are capable of converting thioethers into the corres-ponding sulfones (e.g., m-CPBA, Oxone, transition-metal oxo complexes etc.);however, before implementing a particular method one must consider any relevantchemoselectivity issues. For example, the use of peroxyacid reagents (e.g., m-CPBA)may result in competitive alkene epoxidation during the attempted conversion ofan alkenyl thioether into a sulfone. Protocols based on the use of transition-metaloxo complexes are available that achieve chemoselective oxidation at sulfur whileminimizing unwanted transformations at other sites. An ammonium molybdatehydrate catalyst [(NH4)6Mo7O24•4H2O] in the presence of aqueous hydrogenperoxide (30 wt %) as the terminal oxidant has enjoyed widespread use for thesynthesis of sulfones for the Julia–Kocienski olefination (e.g., step 2, Schemes18–20).38–40 Finally, catalytic thioether oxidation with sodium tungstate dihydratehas been reported to be superior to molybdenum(VI) catalysts for sulfone productionwith particularly sensitive substrates (Scheme 17).34,35

Regardless of the oxidation procedure employed, it should be noted that theconversion of thioethers to sulfones is an indirect process that proceeds via inter-mediate sulfoxides. Production of the sulfoxide from the thioether is rapid, andfurther oxidation of the sulfoxide to the sulfone is considerably slower. Monitoringthe extent of oxidation by TLC analysis is recommended, since it is generally foundthat the sulfoxide is more polar than the thioether, and that the sulfone has a polaritybetween those of the thioether and the sulfoxide (usually closer to the thioetherthan to the sulfoxide). The NMR signature of the α-methylene unit in compoundsActS(O)nCH2CH2R (where R is achiral) undergoes diagnostic changes as the

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