Organic Reactions, Volume 95

Introduction to the Series Roger Adams, 1942

In the course of nearly every program of research in organic chemistry, the investigator finds it necessary to use several of the better-known synthetic reactions. To discover the optimum conditions for the application of even the most familiar one to a compound not previously subjected to the reaction often requires an extensive search of the literature; even then a series of experiments may be necessary. When the results of the investigation are published, the synthesis, which may have required months of work, is usually described without comment. The background of knowledge and experience gained in the literature search and experimentation is thus lost to those who subsequently have occasion to apply the general method. The student of preparative organic chemistry faces similar difficulties. The textbooks and laboratory manuals furnish numerous examples of the application of various syntheses, but only rarely do they convey an accurate conception of the scope and usefulness of the processes.

For many years American organic chemists have discussed these problems. The plan of compiling critical discussions of the more important reactions thus was evolved. The volumes of Organic Reactions are collections of chapters each devoted to a single reaction, or a definite phase of a reaction, of wide applicability. The authors have had experience with the processes surveyed. The subjects are presented from the preparative viewpoint, and particular attention is given to limitations, interfering influences, effects of structure, and the selection of experimental techniques. Each chapter includes several detailed procedures illustrating the significant modifications of the method. Most of these procedures have been found satisfactory by the author or one of the editors, but unlike those in Organic Syntheses, they have not been subjected to careful testing in two or more laboratories. Each chapter contains tables that include all the examples of the reaction under consideration that the author has been able to find. It is inevitable, however, that in the search of the literature some examples will be missed, especially when the reaction is used as one step in an extended synthesis. Nevertheless, the investigator will be able to use the tables and their accompanying bibliographies in place of most or all of the literature search so often required. Because of the systematic arrangement of the material in the chapters and the entries in the tables, users of the books will be able to find information 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 the cooperation of organic chemists and their willingness to devote time and effort to the preparation of the chapters. They have manifested their interest already by the almost unanimous acceptance of invitations to contribute to the work. The editors will welcome their continued interest and their suggestions for improvements in Organic Reactions.

Introduction to the Series Scott E. Denmark, 2008

In the intervening years since The Chief wrote this introduction to the second of his publishing creations, much in the world of chemistry has changed. In particular, the last decade has witnessed a revolution in the generation, dissemination, and availability of the chemical literature with the advent of electronic publication and abstracting services. Although the exponential growth in the chemical literature was one of the motivations for the creation of Organic Reactions, Adams could never have anticipated the impact of electronic access to the literature. Yet, as often happens with visionary advances, the value of this critical resource is now even greater than at its inception.

From 1942 to the 1980's the challenge that Organic Reactions successfully addressed was the difficulty in compiling an authoritative summary of a preparatively useful organic reaction from the primary literature. Practitioners interested in executing such a reaction (or simply learning about the features, advantages, and limitations of this process) would have a valuable resource to guide their experimentation. As abstracting services, in particular Chemical Abstracts and later Beilstein, entered the electronic age, the challenge for the practitioner was no longer to locate all of the literature on the subject. However, Organic Reactions chapters are much more than a surfeit of primary references; they constitute a distillation of this avalanche of information into the knowledge needed to correctly implement a reaction. It is in this capacity, namely to provide focused, scholarly, and comprehensive overviews of a given transformation, that Organic Reactions takes on 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 decades has greatly accelerated and has embraced more sophisticated reagents derived from elements representing all reaches of the Periodic Table. Accordingly, the successful implementation of these transformations requires more stringent adherence to important experimental details and conditions. The suitability of a given reaction for an unknown application is best judged from the informed vantage point provided by precedent and guidelines offered by a knowledgeable author.

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

Preface to Volume 95

For various reasons, many organic reactions have come to be known by 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 in communication, 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 that have achieved the apotheosis of being baptized as reactions of sufficient utility, generality and uniqueness to be identified by their inventors/developers. As was the case in the previous 104 chapters on name reactions in this series, the question naturally arises Who are/were those individuals? Chemistry, like all endeavors in science and the arts, is a quintessentially human activity. Accordingly we are compelled to recognize the individuality of those who bring new creations to light.

The first chapter in this volume, authored by Paul R. Blakemore, Selena Milicevic Sephton and Engelbert Ciganek, represents a unique species of name reaction, namely one that was initially attributed to a single investigator, but then upon significant enhancement by a second, became a hyphenated name reaction. Unlike hyphenated name reactions that acknowledge co-developers (e.g. Diels-Alder Reaction), this type recognizes a substantial contribution that markedly improves on the original, no mean feat.

The Julia-Kocienski olefination reaction acknowledges the important contributions of Sylvestre Julia and Philip Kocienski in the development of a modification of the classical Julia olefination introduced by Marc Julia, Sylvestre's brother. Marc Julia was one of the most influential organic chemists in France in the second half of the twentieth century. Among Marc Julia's many contributions is his development of a reaction to make alkenes and polyenes by the action of lithiated sulfones on carbonyl compounds. One of the limitations of this original process is the lack of control over double bond geometry resulting from the intermediacy of a radical during desulfurization. This problem and the elimination of the need for dissolving metal reduction were addressed in a most ingenious way, first by brother Sylvestre and then by Kocienski. These investigators recognized that the addition of a sulfonyl anion to a carbonyl compound and elimination of the resulting alcohol could be streamlined into a single step if the sulfone bore an activating group for the alcohol. That group 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 studies with Prof. Kocienski in Southampton.

Prof. Blakemore is intimately familiar with all aspects of this process and together with his student Selena Milicevic Sephton has composed an outstanding and thorough treatise on the various combinations of sulfone and carbonyl component that users would 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 Reactions chapters, Engelbert Ciganek, the authors compiled an extremely user-friendly and comprehensive Tabular Survey which is organized by the structure and substitution pattern found on the product alkene or polyene.

The second chapter represents a reaction attributed to such an influential figure in organic chemistry that more than one name reaction bears his name. Hermann Staudinger was a pioneering German organic chemist who is widely recognized as the father of polymer chemistry for which he was awarded a Nobel Prize in Chemistry in 1953. Staudinger is also well known for having first discovered ketenes as well as for the first preparation of phosphine imines by combination of phosphines with azides. The latter reaction, also known as a Staudinger Reaction, figures significantly today in bioconjugation, but also interestingly serves as a curious historical anomaly. In 1919 Staudinger combined his phosphine imines with ketenes to form carbodiimides, which predates the use of phosphorus ylides in carbonyl olefination by Wittig by 35 years! Among the most significant developments in the chemistry of ketenes by Staudinger was his discovery that they react with imines to generate β-lactams, the Staudinger Reaction that is the topic of Chapter 2 in this Volume. It is interesting to note that this reaction was included in Chapter 6 of Volume 9 in this series, published in 1957 and authored by none other than John C. Sheehan and E. J. Corey. It was also 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 Reaction with the primary focus being the stereoselective synthesis of β−lactams using both auxiliary and catalyst control. This chapter by Aitor Landa, Antonia Mielgo, Mikel Oiarbide, and Claudio Palomo comprehensively details the construction of β−lactams bearing alkyl and heteroatom substituents on C(3) which derives from the ketene component. The critical features of generation of the ketene and successful interception by the imine are described. The relative configuration of the substituents on C(3) and C(4) is established by the geometry of the precursor imine and the orbital symmetry controlled, conrotatory closure of the four-membered ring. Furthermore the attachment of chiral auxiliaries on the imine nitrogen, carbon and ketene carbon are all presented and the relative merits of each approach are compared. Given the therapeutic importance of β−lactams, the Staudinger Reaction has found ample application in synthetic endeavors, which are generously illustrated. Finally, the Tabular Survey compiles a comprehensive listing of all examples organized by location of the stereocontrolling group and substituent type on the ketene.

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

Scott E. Denmark

Urbana, Illinois

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, University of Cambridge, Cambridge, UK

Engelbert Ciganek

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

Acknowledgments and Author Contributions

Introduction

Mechanism and Stereochemistry

Mechanism

Factors Influencing Stereoselectivity

Stereoselectivity in Type I Reactions: Neither Component Conjugated

Stereoselectivity in Type II Reactions: Conjugated Sulfone Anions

Stereoselectivity in Type III Reactions: Conjugated Carbonyl Compounds

Stereoselectivity in Type IV Reactions: Both Components Conjugated

Scope and Limitations

Methods for Introducing Sulfone Activators

Via Oxidation of Intermediate Thioethers

Via Sulfone Derivatization

Generation of Sulfone Anions and Strategies to Avoid Self-Condensation

Optimal Targeting of Different Classes of Alkene

Monosubstituted and 1,1-Disubstituted Alkenes

Non-Conjugated 1,2-Disubstituted Alkenes

Conjugated 1,2-Disubstituted Alkenes

Trisubstituted and Tetrasubstituted Alkenes

Vinyl Halides

Miscellaneous Alkene Classes

Functional-Group Tolerance of Olefination and Epimerization Possibilities

Reaction Variants

Comparison with Other Methods

Julia–Lythgoe Olefination

Wittig Reaction and Other Phosphorus-Based Olefination Methods

Miscellaneous Methods for Alkene Synthesis

Experimental Conditions

Experimental Procedures

1-tert-Butyl-1H-tetrazole-5-thiol [Preparation of TBTSH].⁵, ⁶², ¹⁶⁴

5-Ethylsulfonyl-1-phenyl-1H-tetrazole [Sulfone Preparation via Alkylation/Oxidation: PTSH, RBr, KOH/m-CPBA].⁶⁰

Ethyl (Benzothiazol-2-ylsulfonyl)acetate [Sulfone Preparation via Alkylation/Oxidation: BTSH, RCl, K2CO3/Mo(VI), H2O2].²⁰

3,5-Bis(trifluoromethyl)phenyl Isopropyl Sulfone [Sulfone Preparation via Alkylation/Oxidation: BTFPSH, RBr, NaH/Mn(II), H2O2].⁹⁵

(E,2S,6S,7R,8S)-1-(1,3-Benzothiazol-2-ylsulfanyl)-8-(tert-butyldimethylsilyloxy)-7-methoxy-2,4,6-trimethylnon-4-ene [Mitsunobu Thioetherification].⁶⁰

(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].⁶⁰

N-(tert-Butoxycarbonyl)-4-methylenepiperidine [Methylenation of a Ketone: TBT Sulfone, Barbier, Cs2CO3, THF–DMF].⁶²

5,5-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].⁶⁰

(S,E)-tert-Butyldiphenyl(5-methylhex-3-en-2-yloxy)silane [Synthesis of a Non-Conjugated 1,2-Disubstituted (E) Alkene: PT Sulfone, Premetalation, KHMDS, 18-crown-6, THF].²⁶

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].¹⁶⁵

(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].³²

Ethyl (E)-4-Ethylhex-2-enoate [Synthesis of a Conjugated 1,2-Disubstituted (E) Enoate via a Type II Olefination: BT Sulfone, Barbier, DBU, CH2Cl2].²⁰

18-O-(4-Chlorobenzoyl)herboxidiene, Allyl Ester [Synthesis of a Conjugated 1,2-Disubstituted (E) Alkene via a Type III Olefination: BT Sulfone, Premetalation, LDA, THF].⁶⁰

1,4-Dimethoxy-2-methyl-5-(6-methylhept-5-en-2-yl)benzene [Synthesis of a Trisubstituted Alkene: PT Sulfone, LiHMDS, THF].¹⁶⁶

1-(4-Chlorophenyl)-2-methyl-1-phenylpropene [Synthesis of a Tetrasubstituted Alkene: BTFP Sulfone, Barbier, P4-t-Bu, THF].⁹⁵

Tabular Survey

Table 1 Synthesis of Monosubstituted Alkenes

Table 2 Synthesis of 1,1-Disubstituted Alkenes

Table 3 Synthesis of Non-Conjugated 1,2-Disubstituted Alkenes

Table 4 Synthesis of 1,3-Dienes

Table 5 Synthesis of 1,3,5-Trienes and Higher Conjugated Polyenes

Table 6 Synthesis of 1,3- Enynes

Table 7 Synthesis of Allenes

Table 8 Synthesis of Vinyl Halides

Table 9 Synthesis of Vinyl Ethers, Vinyl Esters, and Vinyl Amides

Table 10 Synthesis of Vinyl Silanes

Table 11 Synthesis of α,β-Unsaturated Esters

Table 12 Synthesis of α,β-Unsaturated Amides

Table 13 Synthesis of α,β-Unsaturated Ketones and Their Derivatives

Table 14 Synthesis of Vinyl Arenes and Vinyl Heteroarenes

Table 15 Synthesis of 1,2-Diaryl/Heteroaryl Alkenes

Table 16 Synthesis of Trisubstituted Alkenes

Table 17 Synthesis of Tetrasubstituted Alkenes

Table 18 Intramolecular Reactions

References

Acknowledgments and Author Contributions

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

Introduction

The Julia–Kocienski olefination, also known as the modified Julia olefination, or the one-pot Julia olefination, is a connective synthesis of alkenes involving the reaction of an α-metalated aryl alkyl sulfone (sulfone anion) such as 2 with a carbonyl compound (Scheme 1).¹ The aryl group is necessary to permit ipso substitution next to the sulfonyl moiety such that the initially generated addition adduct 3 may undergo a spontaneous Smiles rearrangement (i.e., 3 to 4).² The elimination of sulfur dioxide and an aryloxide anion from the Smiles rearrangement product 4 affords alkene 5 and metalated 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 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 (discovered by M. Julia),⁷ which is an indirect alkene synthesis that involves the addition of phenyl sulfone anions to carbonyl compounds followed by a separate reductive desulfonylation step (see Comparison with Other Methods).⁸–¹² Throughout this review an asterisk indicates the site of a newly introduced alkene.

Scheme 1

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, and an 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 configuration. Providing that the coupling of interest is optimized and properly executed, the Julia–Kocienski olefination is capable of generating a wide variety of complex alkene 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 available for installing the activating sulfone moiety generally exhibit broad functional-group tolerance, and consequently, the Julia–Kocienski reaction has enjoyed widespread adoption as a reliable tool for the coupling of multifunctional sulfone and carbonyl compounds during total synthesis efforts. This review focuses on how to achieve optimal results from the Julia–Kocienski olefination by a consideration of its theoretical and operational aspects, in what situations it is best applied, and when an alternative carbonyl olefination tactic is perhaps better suited. Notable variants of the process leading to non-alkene targets are also briefly surveyed. The Julia–Kocienski olefination has been previously reviewed, and these accounts should be consulted for discourse 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 well understood; however, a rigorous framework to fully explain the influence of substituents and other parameters on the stereochemical outcome of the process is not yet available. Nonetheless, extensive experimental findings reveal substrate-dependent stereoselectivity traits, most of which can be rationalized on at least an empirical level.³ A more complete understanding of the mechanistic origin of stereoselectivity in some special cases has been obtained by a combination of control experiments and computational studies.¹³, ¹⁵–¹⁸

Mechanism

The current mechanistic understanding of the Julia–Kocienski olefination is summarized below and illustrated for the synthesis of a 1,2-disubstituted alkene from a metalated BT-sulfone and an aldehyde (Scheme 2; solid arrows depict the default pathway that is followed when R¹ and R² are non-conjugating substituents). Analogous pathways will be followed for alternative activators and for substrates leading to other classes of alkenes. Addition of the metalated sulfone nucleophile to the carbonyl electrophile generates the expected pair of diastereomeric syn and anti β-alkoxy sulfone intermediates 7; diastereoselectivity for this step is strongly dependent on reaction conditions and activator type. The initial adducts, syn-7 and anti-7, are formed irreversibly if the sulfone anion is not stabilized (e.g., R¹ = alkyl) but are capable of equilibration via a retroaddition/re-addition mechanism (pathway A) if the sulfone anion is equipped with an anion-stabilizing group (e.g., R¹ = vinyl, aryl, carbonyl, etc.). Smiles rearrangement occurs by way of spirocyclic intermediates trans-8 and cis-8 (an example of which has been isolated),¹⁹ which open to generate syn and anti β-aryloxy sulfinates 9, respectively. Spirocyclization occurs more rapidly from syn-7 than from anti-7 because the spirocycle derived from the latter isomer (cis-8) exhibits higher strain.¹⁵ This accounts for the observation of (Z)-selective Julia–Kocienski olefination in certain cases, in which the initial addition reaction is reversible and the Curtin–Hammett principle operates (i.e., equilibration between syn-7 and anti-7 is faster than spirocyclization).

Scheme 2

A variety of mechanistic pathways have been identified, or at least inferred by indirect evidence, for the production of alkenes from β-aryloxy sulfinates 9. Loss of the aryloxide anion (BTOM) and sulfur dioxide from sulfinates 9 is stereospecific only when R¹ and R² are non-conjugating substituents (e.g., simple alkyl); in such cases, elimination is a concerted E2-like process occurring from the illustrated conformers, wherein the β-C–OAct and α-C–SO2– bonds have an antiperiplanar alignment, and anti-9 leads to the (E) alkene whereas syn-9 affords the (Z) alkene. The validity of this pathway for the reaction of metalated PTSO2Et with acetaldehyde is supported by a