Organic Reactions, Volume 98

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 98

It has long been recognized that, in a molecule containing a system of conjugated double linkages, the influence of a functional group may sometimes be propagated along the chain and make itself apparent at a remote point in the molecule.

Reynold C. Fuson

Chem. Rev. 1935, 16, 1

In 1935, Reynold Clayton Fuson (University of Illinois) articulated the Principle of Vinylogy to formalize the empirical observation that the electronic properties of functional groups are transmitted through vinylene residues (i.e. double bonds). The manifestation of those electronic properties can be enhancement of both electrophilic character and nucleophilic character, terms introduced just the year prior by Ingold (Chem. Rev. 1934, 16, 225). Although this phenomenon is easily understood from contemporary theory of organic chemistry, it is instructive to remember that the foundation of this principle originates in Robinson's electronic theory of organic reactions published in two lectures in 1932 (Institute of Chemistry, London, pp. 1–52). Robinson's illustration of conjugated electromeric systems are of tremendous historical significance as it introduces the use of curly arrow notation to signify the movement of electrons under the mandates of the anionoid or cationoid characteristics of the functional groups. The two chapters that comprise Volume 98 represent both manifestations of the principle of vinylogy, though not in the same way.

Although the reaction covered in the first chapter does not illustrate the principle of vinylogy, it does create the substrates that are essential for the manifestation of the vinylogous cationoid character of unsaturated carbonyl compounds. Chapter 1 in this volume, entitled The Saegusa Oxidation and Related Procedures by Jean Le Bras and Jacques Muzart, provides a comprehensive treatment of the catalytic dehydrogenation of enoxysilane derivatives to form α,β‐unsaturated carbonyl compounds. This transformation pioneered by Ito, Hirato and Saegusa has achieved the enviable status of a name reaction owing to its mildness, generality and ease of operation. Although many methods exist for the desaturation of native carbonyl compounds, these suffer from the need for stoichiometric amounts of strong oxidants and also the lack of site selectivity in case of ketones. By harnessing the ability to control the position of enolization and subsequent silylation, the Saegusa method solves a key limitation of earlier methods. Moreover, after initially requiring stoichiometric amounts of a palladium(II) oxidant, recent modifications have reduced the palladium loading considerably and have simultaneously introduced inexpensive and atom‐economical terminal oxidants to render the process highly efficient. In the spirit of the Organic Reactions style, the authors have done an outstanding job in compiling tables in the text portion that summarize the best methods for a given type of carbonyl compound and a given type of oxidant. Furthermore, in the Comparison with Other Methods section, the authors list representative cases wherein other methods are superior to the catalytic dehydrogenation and those for which the Saegusa protocol is superior. The Tabular Survey is organized by the carbonyl function that undergoes dehydrogenation, making the discovery of the best set of conditions for the interested reader extremely easy.

On the other hand, the second chapter is squarely in the domain of manifesting the principle of vinylogy for anionoid reactivity of enol ethers. Chapter 2 in this volume entitled The Asymmetric Vinylogous Mukaiyama Aldol Reaction by Martin H. C. Cordes and Markus Kalesse constitutes a tour de force treatment of another eponymous reaction. The 1973 report by Mukaiyama, Narasaka and Banno was a watershed event in the evolution of the aldol addition reaction. These authors demonstrated the ability to preordain one carbonyl component as the nucleophile by preforming the derived silyl enol ether, thus addressing one of the greatest disadvantages of this reaction, namely the inability to control the identity of donors and acceptors. The historical development of this reaction has been extensively chronicled but perhaps nowhere better than in Chapter 3 of Volume 28 entitled Directed Aldol Reactions by Teruaki Mukaiyama. It will therefore come as no surprise that Prof. Mukaiyama was also the pioneer of the vinylogous extension of his own invention. Cordes and Kalesse have composed an outstanding overview of the various modes of activation of vinylogous enol ethers derived from a myriad of different carbonyl precursors and have expertly described the stereochemical model for relative and absolute stereoselection. A reaction of this scope and generality has been extensively applied in complex molecule syntheses, particularly in recent years with the advent of catalytic, enantioselective variants. Perhaps the most impressive component of this chapter is the extraordinary resolution of the Tabular Survey. The primary rubric for tabular organization is the structure of the nucleophile and comprises ten tables for all of the different functional groups involved. However, each of these tables is further subdivided according to a secondary rubric that represents all of the different electrophiles employed with that nucleophile. In the case of β‐keto ester derived dienolates, this collection comprises 26 different electrophile types! Accordingly, readers will easily locate the pairwise combination of reactants of greatest interest to their particular goal. Truly, a field guide of the first rank for executing this reaction.

The organic chemistry community mourns the passing of Professor Teruaki Mukaiyama who died on 17 November 2018 at the age of 91. In honor of his towering contributions to our discipline and his authorship of two chapters in the Organic Reactions series, we felt it fitting to dedicate Volume 98 to his memory.

It is appropriate here to acknowledge the expert assistance of the entire editorial board, in particular Jin K. Cha (Chapter 1) and Gary A. Molander (Chapter 2) who shepherded these chapters 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. Engelbert Ciganek, and Dr. Robert M. Coates, Dr. Landy Blasdel, and Dr. Devra Dolliver. 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 SAEGUSA OXIDATION AND RELATED PROCEDURES

Jean Le Bras and Jacques Muzart

Institute of Molecular Chemistry of Reims, UMR 7312, The National Center for Scientific Research (CNRS) and University of Reims Champagne‐Ardenne, B.P. 1039, 51687, Reims Cedex, 2, France

Introduction

Mechanism and Stereochemistry

Silyl Enol Ethers or Silyl Ketene Acetals as Substrates

1,4‐Benzoquinone as the Oxidant

Oxygen, Oxygen and a Copper Salt, or Oxygen and Oxone as the Oxidant

Oxygen and tert‐Butyl Hydroperoxide as the Oxidant

Allyl Carbonate as the Oxidant

Enol Acetates as Substrates

Alkyl Enol Ethers and Vinyl Halides as Substrates

Allyl Enol Carbonates, Allyl β‐Keto Carboxylates, or Allyl Malonates as Substrates

α‐Chloro Ketones as Substrates

Scope and Limitations

Silyl Enol Ethers or Silyl Ketene Acetals as Substrates

Palladium(II) and 1,4‐Benzoquinone or Copper Salt (Methods A and B)

Palladium Acetate, DMSO, and Oxygen (Method C)

Palladium(0)/SiO2 and Oxygen (Method D)

Palladium(II) Acetate, Oxone, and Oxygen (Method E)

Palladium(II) Hydroxide, tert‐Butyl Hydroperoxide, Oxygen, and a Base (Method F)

Palladium(0) Complexes and Diallyl Carbonate (Method G)

Atypical Dehydrogenation Reactions

Comparison of the Aforementioned Procedures

Enol Acetates as Substrates

Alkyl Enol Ethers as Substrates

Allyl Enol Carbonates, Allyl β‐Keto Carboxylates, or Allyl Malonates as Substrates

α‐Chloro Ketones as Substrates

Applications to Synthesis

Desymmetrization/Palladium‐Mediated Dehydrosilylation Reaction Sequence

Enones as Intermediates in Natural Product Synthesis

Tandem Reactions Involving Enones

Saegusa Reaction on an Industrial Scale

Comparison with Other Methods

Experimental Conditions

Silyl Enol Ethers as Substrates

Enol Acetates as Substrates

Allyl Enol Carbonates as Substrates

Allyl β‐Keto Carboxylates as Substrates

Experimental Procedures

5,5‐Dimethyl‐3a′,4′‐dihydro‐1′H‐spiro[[1,3]dioxane‐2,2′‐pentalen]‐5′(3′H)‐one [Stoichiometric Dehydrogenation of a Ketone via a Silyl Enol Ether].

4‐Isopropylcyclohex‐2‐enone [Dehydrogenation of a Ketone in the Presence of Benzoquinone via a Silyl Enol Ether].

1,4‐Dioxaspiro[4.5]dec‐6‐en‐8‐one [Catalytic Dehydrogenation of a Silyl Enol Ether in the Presence of an Allyl Carbonate].

Bicyclo[4.1.0]hept‐3‐en‐2‐one [Catalytic Dehydrogenation of a Silyl Enol Ether in the Presence of tert‐Butyl Hydroperoxide and Oxygen]

(4R,5S)‐5‐Ethyl‐4,5‐dihydroxycyclohex‐2‐enone [Catalytic Dehydrogenation of a Silyl Enol Ether in the Presence of Oxygen]

(1R,5R)‐1‐[(((1,1‐Dimethylethyl)dimethylsilyloxy)methyl)]bicyclo[3.1.0]hex‐3‐en‐2‐one [Catalytic Dehydrogenation of a Ketone in the Presence of Oxygen via a Silyl Enol Ether]

4‐Cyano‐4‐(3,4‐dichlorophenyl)cyclohex‐2‐enone [Catalytic Dehydrogenation of an Enol Acetate in the Presence of an Allyl Carbonate]

(4R,5S)‐2‐Allyl‐4,5‐bis((benzyloxy)methyl)‐4,5‐dimethylcyclopent‐2‐enone [Catalytic Decarboxylative Dehydrogenation of an Allyl β‐Keto Carboxylate]

6‐[(Z)‐7‐[(Tetrahydropyranyl)oxy]hept‐1,5‐diyn‐3‐ene]‐6‐[(tert‐butyldimethylsilyl)oxy]cyclohex‐2‐en‐1‐one [Catalytic Decarboxylative Dehydrogenation of an Allyl Enol Carbonate]

(E)‐6‐Oxohex‐4‐en‐1‐yl Acetate [Catalytic Dehydrogenation of an Alkyl Enol Ether in the Presence of Benzoquinone]

(E)‐4‐Phenyl‐2‐butenal [Catalytic Dehydrogenation of an Alkyl Enol Ether in the Presence of Cu(II)]

Tabular Survey

Table 1A. Acyclic α,β‐Unsaturated Ketones

Table 1B. Cyclic 2,3‐En‐1‐ones

Table 1C. Heterocyclic 2,3‐En‐1‐ones

Table 1D. Cross‐Conjugated Dienones

Table 1E. Phenolic Systems

Table 2. α,β‐Unsaturated Aldehydes

Table 3. α,β‐Unsaturated Esters

Table 4. α,β‐Unsaturated Lactones and Lactams

Table 5. α,β,γ,δ‐Unsaturated Ketones, Esters, and Amides

References

Introduction

α,β‐Unsaturated carbonyl compounds are highly useful synthetic materials in organic synthesis,1–4 and regioselective dehydrogenation of carbonyl compounds to the corresponding α,β‐unsaturated carbonyl compounds is an important transformation in synthetic chemistry.5,6 One‐pot, palladium‐mediated dehydrogenation reactions of ketones, aldehydes, esters, lactones, and amides are known, but such reactions are limited primarily to simple substrates.7–11 Moreover, they suffer from lack of regiocontrol in the case of unsymmetrical ketones. In 1977, Ito, Hirato, and Saegusa reported the conversion of silyl enol ethers to the corresponding α,β‐unsaturated ketones and aldehydes using stoichiometric or substoichiometric amounts of palladium(II) salts.12 Although silyl enol ethers are easily prepared from saturated ketones or aldehydes, 12 several years passed before the first application of the Saegusa Reaction was reported. Studies to improve on the original procedure by using lower catalyst loadings have since appeared. A brief review of the Saegusa Reaction concerning the literature up to 1998 is available,13 and related methods devised primarily by the Tsuji and Larock groups are discussed in reviews14–16 and books. 6 17–19

This review concerns the Saegusa Reaction and related methods. In addition to enol silanes, enol acetates, alkyl enol ethers, allyl enol carbonates, allyl β‐keto carboxylates, allyl malonates, and α‐chloro ketones have been transformed into α,β‐unsaturated carbonyl products. This chapter covers the literature through August 2018.

Mechanism and Stereochemistry

The mechanism of the formation of α,β‐unsaturated carbonyl compounds using palladium‐mediated procedures related to the Saegusa Reaction is substrate‐dependent, but a majority of known examples involve a palladium enolate as the key intermediate. Catalytic reactions have been developed under various conditions.

Silyl Enol Ethers or Silyl Ketene Acetals as Substrates

Most palladium‐mediated, oxidative dehydrogenation reactions of silyl enol ethers and silyl ketene acetals use a palladium(II) salt. The coordination of the C=C bond to the palladium species results in transmetalation, which leads to loss of the silyl group and formation of a palladium enolate. 13 The latter compound exists as an equilibrium between the oxo‐η³‐allyl palladium and the C‐ and O‐enolate tautomers (Scheme 1).20 Subsequent β‐hydride elimination affords the α,β‐unsaturated carbonyl compound and a hydridopalladium complex. Although the stability of palladium hydrides is ligand‐dependent,21 they are converted, in most cases, to palladium(0) species. Because addition/elimination of hydridopalladium species to olefins is reversible, (E)‐α,β‐unsaturated carbonyl compounds are usually produced selectively from acyclic substrates.

Scheme 1

To achieve a catalytic process, the Saegusa Reaction is carried out in the presence of an oxidant—often 1,4‐benzoquinone or oxygen—to regenerate the active palladium(II) species. The proposed catalytic cycle generates AcOSiR3 and acetic acid (i.e., YSiR3 and HY of Scheme 1) as the byproducts of the first turnover and hydroquinone or peroxides as the stoichiometric byproducts. However, palladium(0) species can form relatively stable palladium(0)–alkene complexes, which can impede the catalytic cycle (Scheme 2).22 Such complexes can be decomposed on heating or treatment with silica gel.

Scheme 2

1,4‐Benzoquinone as the Oxidant

Coordination of 1,4‐benzoquinone to palladium(0) in the presence of acetic acid generates 4‐hydroxyphenoxypalladium acetate (Scheme 3).23,24 This intermediate reacts with AcOSiR3 to regenerate palladium(II) acetate. A mixture of 4‐trimethylsilyloxyphenol and 1,4‐bis(trimethylsilyloxy)benzene has been isolated. 12 It is also possible that HPdOAc reacts directly with 1,4‐benzoquinone, rather than undergoing reductive elimination to form palladium(0) first.25

Scheme 3

Oxygen, Oxygen and a Copper Salt, or Oxygen and Oxone as the Oxidant

The use of oxygen as the oxidant in DMSO leads to formation of a peroxopalladacycle.26 Addition of acetic acid affords a hydroperoxypalladium complex, which reacts with AcOSiR3 to regenerate palladium(II) acetate (Scheme 4).27 The mechanism of the formation of active palladium(II) species from hydridopalladium intermediates and oxygen remains unknown.28–31

Scheme 4

In the presence of both oxygen and a copper salt, the catalyst can be regenerated in a manner analogous to the Wacker oxidation (Scheme 5).32

Scheme 5

A recently developed catalytic procedure involves the use of Oxone under an oxygen or air atmosphere.33 The exact role of oxygen under these conditions has not been elucidated.

Silica‐supported palladium(0) has been used as a catalyst under an oxygen atmosphere primarily in NMP; acetonitrile is a poor solvent for this method.34,35 The dispersion of oxygen on palladium(0) is proposed to oxidize part of the supported palladium(0) into palladium(II), and the silyl ether is adsorbed onto the catalytic surface. 35

Oxygen and tert‐Butyl Hydroperoxide as the Oxidant

Cycloalkenyloxy triisopropylsilyl ethers can be used to prepare cyclic α,β‐enones; this process employs palladium(II) hydroxide on carbon as the catalyst and is performed in the presence of oxygen, a base (disodium hydrogen phosphate or triethylamine), and excess amounts of tert‐butyl hydroperoxide.36,37 The catalyst is believed to initiate a radical process by palladium‐mediated homolytic cleavage of the O–H bond of the hydroperoxide (Scheme 6). However, because tert‐butyl hydroperoxide is capable of generating active palladium(II) species from palladium(0),38 a catalytic cycle similar to that shown in Scheme 1 cannot be ruled out.

Scheme 6

Allyl Carbonate as the Oxidant

An alkyl allyl carbonate or a diallyl carbonate reacts with a palladium(0) catalyst to afford an η³‐allyl palladium complex (Scheme 7, R³ = alkyl or allyl, Z = (R⁴)3Si).39 This palladium(II) species reacts with a silyl enol ether to form the η³‐allyl palladium enolate, which provides the unsaturated carbonyl compound and an η³‐allyl palladium hydride. The latter complex then releases propene and regenerates palladium(0).

Scheme 7

Enol Acetates as Substrates

Enones can also be obtained from enol acetates using an excess of an alkyl allyl carbonate and catalytic amounts of both palladium(II) acetate and tributyltin methoxide. The proposed mechanism is depicted in Scheme 7 (R³ = alkyl, Z = Bu3Sn). The role of tributyltin methoxide is to form the tin enolate, which easily transmetalates with the palladium species to afford the η³‐allyl palladium enolate with concomitant generation of the tributyltin alkoxide.

Oxidative dehydroacetoxylation of enol acetates can also be accomplished with silica‐supported palladium(0) in the presence of oxygen (9 atm). Under these conditions, oxygen is dispersed over the heterogeneous catalyst and takes part in the reaction.40

Alkyl Enol Ethers and Vinyl Halides as Substrates

The palladium‐mediated formation of enals from alkyl enol ethers is carried out under aqueous conditions with either stoichiometric or catalytic amounts of palladium(II) acetate. Under catalytic conditions, either copper(II) acetate41 or 1,4‐benzoquinone42 is typically employed as the stoichiometric oxidant. The proposed mechanism parallels the catalytic cycle of the Wacker oxidation,43 wherein the key step is addition of water to the C=C bond that is activated by coordination to palladium(II) acetate (Scheme 8). 41 The resulting intermediate undergoes regioselective β‐hydride elimination, in preference to β‐OH