Organic Reactions, Volume 98 -  - ebook

Organic Reactions, Volume 98 ebook

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The 98th volume in this series for organic chemists in academia and industry presents critical discussions of widely used organic reactions or particular phases of a reaction. The material is treated from a preparative viewpoint, with emphasis on limitations, interfering influences, effects of structure and the selection of experimental techniques. The work includes tables that contain all possible examples of the reaction under consideration. Detailed procedures illustrate the significant modifications of each method.

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Table of Contents

Cover

Introduction to the Series Roger Adams, 1942

Introduction to the Series Scott E. Denmark, 2008

Preface to Volume 98

Chapter 1: The Saegusa Oxidation and Related Procedures

Introduction

Mechanism and Stereochemistry

Scope and Limitations

Applications to Synthesis

Comparison with Other Methods

Experimental Conditions

Experimental Procedures

Tabular Survey

REFERENCES

Chapter 2 The Asymmetric Vinylogous Mukaiyama Aldol Reaction

Acknowledgments

Introduction

Mechanism and Stereochemistry

Scope and Limitations

Applications to Synthesis

Comparison with Other Methods

Experimental Conditions

Experimental Procedures

Tabular Survey

References

Cumulative Chapter Titles by Volume

Author Index, Volumes 1-98

Chapter and Topic Index, Volumes 1–98

End User License Agreement

List of Illustrations

Chapter 1

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Scheme 6

Scheme 7

Scheme 8

Scheme 9

Scheme 10

Scheme 11

Scheme 12

Scheme 13

Scheme 14

Scheme 15

Figure 1 Substrates leading to inefficient reactions under Saegusa's conditions...

Scheme 16

Scheme 17

Scheme 18

Figure 2 Substrates leading to inefficient Pd(OAc)

2

/O

2

/DMSO reactions.

Scheme 19

Figure 3 Substrates leading to inefficient reactions under Pd(OH)

2

/

t

‐BuOOH cond...

Scheme 20

Scheme 21

Scheme 22

Scheme 23

Figure 4 Substrates leading to inefficient reactions under Pd(0)/allyl carbonat...

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Scheme 28

Figure 5 α,β‐Enones obtained from silyl enol ethers using Methods A–G.

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Scheme 33

Figure 6 Allyl malonates leading to inefficient reactions.

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Chapter 2

Scheme 1

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Scheme 4

Figure 1 Comparison of orbital coefficients and electrophilic susceptibility of...

Scheme 5

Figure 2 Binding modes of the carbonyl group to the Lewis acid.

Scheme 6

Scheme 7

Scheme 8

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Scheme 10

Figure 3 X‐ray crystal structure

N

and other reactive conformations of activate...

Scheme 11

Scheme 12

Figure 4 Diels‐Alder‐like transition‐state model

Q

versus open‐chain model

R

.

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Guide

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Advisory Board

John E. Baldwin

James A. Marshall

Peter Beak

Michael J. Martinelli

Dale L. Boger

Stuart W. McCombie

André B. Charette

Scott J. Miller

Engelbert Ciganek

John Montgomery

Dennis Curran

Larry E. Overman

Samuel Danishefsky

T. V. RajanBabu

Huw M. L. Davies

Hans J. Reich

John Fried

James H. Rigby

Jacquelyn Gervay-Hague

William R. Roush

Heinz W. Gschwend

Tomislav Rovis

Stephen Hanessian

Scott D. Rychnovsky

Louis Hegedus

Martin Semmelhack

Paul J. Hergenrother

Charles Sih

Jeffrey S. Johnson

Amos B. Smith, III

Robert C. Kelly

Barry M. Trost

Laura Kiessling

James D. White

Marisa C. Kozlowski

Peter Wipf

Steven V. Ley

Former Members of the Board Now Deceased

Roger Adams

Ralph F. Hirschmann

Homer Adkins

Herbert O. House

Werner E. Bachmann

John R. Johnson

A. H. Blatt

Robert M. Joyce

Robert Bittman

Andrew S. Kende

Virgil Boekelheide

Willy Leimgruber

George A. Boswell, Jr.

Frank C. McGrew

Theodore L. Cairns

Blaine C. McKusick

Arthur C. Cope

Jerrold Meinwald

Donald J. Cram

Carl Niemann

David Y. Curtin

Gary H. Posner

William G. Dauben

Harold R. Snyder

Richard F. Heck

Milán Uskokovic

Louis F. Fieser

Boris Weinstein

Organic Reactions

Volume 98

Editorial Board

Scott E. Denmark, Editor-in-Chief

Jeffrey Aubé

Jeffrey B. Johnson

David B. Berkowitz

Gary A. Molander

Jin K. Cha

Albert Padwa

P. Andrew Evans

Jennifer M. Schomaker

Paul L. Feldman

Kevin H. Shaughnessy

Dennis G. Hall

Steven M. Weinreb

Donna M. Huryn

Jeffery B. Press, Secretary

Press Consulting Partners, Brewster, New York

Robert M. Coates, Proof-Reading Editor

University of Illinois at Urbana-Champaign, Urbana, Illinois

 

Danielle Soenen, Editorial Coordinator

Dena Lindsay, Secretary and Processing Editor

Landy K. Blasdel, Processing Editor

Debra Dolliver, Processing Editor

Linda S. Press, Editorial Consultant

Engelbert Ciganek, Editorial Advisor

ASSOCIATE EDITORS

Martin H. C. Cordes Markus Kalesse Jean LeBras Jacques Muzart

COPYRIGHT

Copyright © 2019 by Organic Reactions, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

ISBN: 978-1-119-45658-2

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 1THE 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)/SiO

2

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]

(4

R

,5

S

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

(1

R

,5

R

)‐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]

(4

R

,5

S

)‐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 or β‐OR elimination,44 to afford the enal. A similar reaction is also possible with vinyl halides.45

Scheme 8

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

The palladium‐catalyzed transformation of allyl enol carbonates, allyl β‐keto carboxylates, and allyl malonates into α,β‐unsaturated carbonyl compounds also involves a palladium enolate as the key intermediate (Scheme 9).46 The latter arises from the initial formation of an η3‐allyl palladium carbonate or an η3‐allyl palladium carboxylate, followed by subsequent decarboxylation. In agreement with this proposed mechanism, treatment of sodium 2‐oxocyclohexanecarboxylate with a stoichiometric amount of PdCl2(PPh3)2 and an excess of sodium acetate at room temperature affords cyclohex‐2‐enone (Scheme 10). A catalytic process is possible by including copper(II) chloride as the oxidant.47

Scheme 9

Scheme 10

α‐Chloro Ketones as Substrates

The synthesis of enones from α‐chloro ketones proceeds by oxidative insertion of palladium(0) into the C–Cl bond to afford a chloropalladium enolate, which then likely follows the catalytic cycle shown in Scheme 11.48

Scheme 11

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)

The seminal report by Ito, Hirato, and Saegusa describes the synthesis of α,β‐unsaturated ketones and aldehydes from trimethylsilyl enol ethers using either a stoichiometric amount of palladium(II) acetate (Method AS) or 0.5 equivalents each of palladium(II) acetate and 1,4‐benzoquinone (Method AC) at room temperature in acetonitrile. 12 Both procedures are well documented. Trimethylsilyl enol ethers are obtained from the corresponding saturated carbonyl compounds (Scheme 12)49 and are often used without purification owing to their hydrolytic instability. More stable silyl enol ethers such as triethylsilyl (TES),50–59 TBS, 27 ,5360–68 or TIPS ethers 59 69–72 can be employed as well, though these products are also typically used without purification.

Scheme 12

Saegusa's original conditions are effective for the synthesis of α,β‐unsaturated lactones, dienones, and heterocyclic 2,3‐en‐1‐ones. Some reactions are, however, carried out with stoichiometric or excess amounts of both palladium(II) acetate and 1,4‐benzoquinone.64,65,73 Saegusa Reactions are compatible with halides74 and ethers, but acid‐catalyzed hydrolysis of the trimethylsilyl enol ethers may compete with the desired reaction, resulting in isolation of the original saturated ketones.75

Another possible side reaction is cyclization onto a tethered alkene (Scheme 13).76,77 This pathway likely involves the coordination of the tethered alkene to the palladium enolate78,79 or addition of the silyl enol ether to the palladium‐complexed pendant alkene.80,81 This cyclization reaction is sensitive to crowding around the C=C bond, as shown in the reaction of silyl enol ether 1, which affords only the enone (Scheme 14).82 By comparison, silyl enol ether 2 affords a mixture of cyclohexenones 3–5 (Scheme 15). 82 This cycloalkenylation procedure has been utilized in the synthesis of a variety of natural products. 80 83–90

Scheme 13

Scheme 14

Scheme 15

When subjected to the original Saegusa conditions, a number of substrates afford none of the expected α,β‐unsaturated carbonyl compounds or form them only in low yields. These problematic substrates are summarized in Figure 1. The nature of the silyl group or the troublesome step (silylation or palladation) is not always specified, and consequently, the problematic substrates may be depicted as either the silyl enol ether or the carbonyl compound. In some cases, strong complexation of the catalyst to basic groups such as an isoquinoline moiety precludes the Saegusa Reaction.91

Figure 1