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- Herausgeber: John Wiley & Sons
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- Serie: Organic Reactions
- Sprache: Englisch
A carefully curated review of the scientific literature, Volume 115 of Organic Reactions presents critical discussions of widely used organic reactions or particular steps 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.
Launched in 1942, the Organic Reactions series today is a leading secondary- and tertiary-level source for organic chemists across the world.
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Table of Contents
Cover
Table of Contents
Title Page
Copyright
INTRODUCTION TO THE SERIES BY ROGER ADAMS, 1942
INTRODUCTION TO THE SERIES BY SCOTT E. DENMARK, 2008
PREFACE TO VOLUME 115
John Edwin Baldwin 1937–2024
Chapter 1: (4+3) CYCLOADDITIONS OF ALLYLIC AND RELATED CATIONS
ACKNOWLEDGMENTS
INTRODUCTION
MECHANISM AND STEREOCHEMISTRY
SCOPE AND LIMITATIONS
APPLICATIONS TO SYNTHESIS
COMPARISON WITH OTHER METHODS
EXPERIMENTAL CONDITIONS
EXPERIMENTAL PROCEDURES
LIST OF ABBREVIATIONS
TABULAR SURVEY
REFERENCES
SUPPLEMENTAL REFERENCES
2 THE MEYER–SCHUSTER REARRANGEMENT
INTRODUCTION
MECHANISM AND STEREOCHEMISTRY
SCOPE AND LIMITATIONS
APPLICATIONS TO SYNTHESIS
COMPARISON WITH OTHER METHODS
EXPERIMENTAL CONDITIONS
EXPERIMENTAL PROCEDURES
LIST OF ABBREVIATIONS
TABULAR SURVEY
REFERENCES
SUPPLEMENTAL REFERENCES
CUMULATIVE CHAPTER TITLES BY VOLUMECUMULATIVE CHAPTER TITLES BY VOLUME
Volume 1 (1942)
Volume 2 (1944)
Volume 3 (1946)
Volume 4 (1948)
Volume 5 (1949)
Volume 6 (1951)
Volume 7 (1953)
Volume 8 (1954)
Volume 9 (1957)
Volume 10 (1959)
Volume 11 (1960)
Volume 12 (1962)
Volume 13 (1963)
Volume 14 (1965)
Volume 15 (1967)
Volume 16 (1968)
Volume 17 (1969)
Volume 18 (1970)
Volume 19 (1972)
Volume 20 (1973)
Volume 21 (1974)
Volume 22 (1975)
Volume 23 (1976)
Volume 24 (1976)
Volume 25 (1977)
Volume 26 (1979)
Volume 27 (1982)
Volume 28 (1982)
Volume 29 (1983)
Volume 30 (1984)
Volume 31 (1984)
Volume 32 (1984)
Volume 33 (1985)
Volume 34 (1985)
Volume 35 (1988)
Volume 36 (1988)
Volume 37 (1989)
Volume 38 (1990)
Volume 39 (1990)
Volume 40 (1991)
Volume 41 (1992)
Volume 42 (1992)
Volume 43 (1993)
Volume 44 (1993)
Volume 45 (1994)
Volume 46 (1994)
Volume 47 (1995)
Volume 48 (1995)
Volume 49 (1997)
Volume 50 (1997)
Volume 51 (1997)
Volume 52 (1998)
Volume 53 (1998)
Volume 54 (1999)
Volume 55 (1999)
Volume 56 (2000)
Volume 57 (2001)
Volume 58 (2001)
Volume 59 (2001)
Volume 60 (2002)
Volume 61 (2002)
Volume 62 (2003)
Volume 63 (2004)
Volume 64 (2004)
Volume 65 (2005)
Volume 66 (2005)
Volume 67 (2006)
Volume 68 (2007)
Volume 69 (2007)
Volume 70 (2008)
Volume 71 (2008)
Volume 72 (2008)
Volume 73 (2008)
Volume 74 (2009)
Volume 75 (2011)
Volume 76 (2012)
Volume 77 (2012)
Volume 78 (2012)
Volume 79 (2013)
Volume 80 (2013)
Volume 81 (2013)
Volume 82 (2013)
Volume 83 (2014)
Volume 84 (2014)
Volume 85 (2014)
Volume 86 (2015)
Volume 87 (2015)
Volume 88 (2015)
Volume 89 (2015)
Volume 90 (2016)
Volume 91 (2016)
Volume 92 (2016–2017)
Volume 93 (2017)
Volume 94 (2017)
Volume 95 (2018)
Volume 96 (2018)
Volume 97 (2019)
Volume 98 (2019)
Volume 99 (2019)
Volume 100 (2019)
Volume 101 (2020)
Volume 102 (2020)
Volume 103 (2020)
Volume 104 (2020)
Volume 105 (2021)
Volume 106 (2021)
Volume 107 (2021)
Volume 108 (2021)
Volume 109 (2022)
Volume 110 (2022)
Volume 111 (2022)
Volume 112 (2022)
Volume 113 (2023)
Volume 114 (2024)
AUTHOR INDEX, VOLUMES 1–115
CHAPTER AND TOPIC INDEX, VOLUMES 1–115
End User License Agreement
List of Tables
Chapter 2
Table A Characteristics of the different methods for the Meyer–Schuster rea...
List of Illustrations
Chapter 1
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Figure 1 The transition structure for the reaction in Scheme 8.
Scheme 8
Scheme 9
Figure 2 The transition structure for the reaction of allylic cation
22
with...
Scheme 10
Scheme 11
Figure 3 The transition structures for the reaction of
24
with two substitut...
Figure 4 Heterobenzylic cations that engage in (4+3) cycloadditions.
Scheme 12
Scheme 13
Scheme 14
Scheme 15
Scheme 16
Scheme 17
Scheme 18
Scheme 19
Scheme 20
Scheme 21
Scheme 22
Scheme 23
Scheme 24
Scheme 25
Scheme 26
Scheme 27
Scheme 28
Figure 5 Selected chiral furan dienes used in (4+3) cycloadditions.
Scheme 29
Scheme 30
Scheme 31
Scheme 32
Scheme 33
Scheme 34
Scheme 35
Scheme 36
Scheme 37
Scheme 38
Scheme 39
Scheme 40
Scheme 41
Scheme 42
Scheme 43
Scheme 44
Scheme 45
Scheme 46
Scheme 47
Scheme 48
Scheme 49
Scheme 50
Scheme 51
Scheme 52
Scheme 53
Scheme 54
Scheme 55
Scheme 56
Scheme 57
Scheme 58
Scheme 59
Scheme 60
Scheme 61
Scheme 62
Scheme 63
Scheme 64
Scheme 65
Figure 6 The elusive “parent” oxyallylic cation.
Scheme 66
Scheme 67
Scheme 68
Scheme 69
Scheme 70
Scheme 71
Scheme 72
Scheme 73
Scheme 74
Scheme 75
Scheme 76
Scheme 77
Scheme 78
Scheme 79
Scheme 80
Figure 7 Regiochemical outcomes of several (4+3) cycloaddition reactions.
Scheme 81
Scheme 82
Scheme 83
Scheme 84
Scheme 85
Scheme 86
Figure 8 Selected dioxolanes used in (4+3) cycloadditions.
Scheme 87
Scheme 88
Scheme 89
Scheme 90
Scheme 91
Scheme 92
Scheme 93
Scheme 94
Scheme 95
Scheme 96
Scheme 97
Scheme 98
Scheme 99
Scheme 100
Scheme 101
Scheme 102
Scheme 103
Scheme 104
Scheme 105
Scheme 106
Scheme 107
Scheme 108
Scheme 109
Scheme 110
Figure 9 Examples of (4+3) cycloadducts from a two‐component reaction.
Scheme 111
Scheme 112
Scheme 113
Scheme 114
Scheme 115
Scheme 116
Scheme 117
Scheme 118
Scheme 119
Scheme 120
Scheme 121
Scheme 122
Scheme 123
Scheme 124
Scheme 125
Scheme 126
Scheme 127
Scheme 128
Scheme 129
Scheme 130
Scheme 131
Scheme 132
Scheme 133
Scheme 134
Scheme 135
Scheme 136
Scheme 137
Scheme 138
Scheme 139
Scheme 140
Scheme 141
Scheme 142
Scheme 143
Scheme 144
Scheme 145
Scheme 146
Scheme 147
Scheme 148
Scheme 149
Scheme 150
Scheme 151
Figure 10 (4+3) Cycloadducts derived from 1,3‐cyclohexadiene.
Figure 11 Other cycloadducts obtained by the process detailed in the previou...
Scheme 152
Scheme 153
Scheme 154
Scheme 155
Scheme 156
Scheme 157
Scheme 158
Scheme 159
Scheme 160
Scheme 161
Scheme 162
Scheme 163
Figure 12 Selected examples of (4+3) cycloadducts prepared as in Scheme 163....
Scheme 164
Scheme 165
Scheme 166
Scheme 167
Scheme 168
Scheme 169
Scheme 170
Scheme 171
Scheme 172
Scheme 173
Scheme 174
Scheme 175
Scheme 176
Scheme 177
Scheme 178
Scheme 179
Scheme 180
Scheme 181
Scheme 182
Scheme 183
Scheme 184
Scheme 185
Scheme 186
Scheme 187
Scheme 188
Scheme 189
Scheme 190
Scheme 191
Scheme 192
Scheme 193
Scheme 194
Scheme 195
Chapter 2
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
Scheme 16
Scheme 17
Scheme 18
Figure 1 Structures of common NHC ligands.
Scheme 19
Scheme 20
Scheme 21
Scheme 22
Scheme 23
Scheme 24
Scheme 25
Scheme 26
Scheme 27
Scheme 28
Scheme 29
Scheme 30
Scheme 31
Scheme 32
Scheme 33
Scheme 34
Scheme 35
Scheme 36
Scheme 37
Scheme 38
Scheme 39
Scheme 40
Scheme 41
Scheme 42
Scheme 43
Scheme 44
Scheme 45
Scheme 46
Scheme 47
Scheme 48
Scheme 49
Scheme 50
Scheme 51
Scheme 52
Scheme 53
Scheme 54
Scheme 55
Scheme 56
Scheme 57
Scheme 58
Scheme 59
Scheme 60
Scheme 61
Scheme 62
Scheme 63
Scheme 64
Scheme 65
Scheme 66
Scheme 67
Scheme 68
Scheme 69
Scheme 70
Scheme 71
Scheme 72
Scheme 73
Scheme 74
Scheme 75
Scheme 76
Scheme 77
Scheme 78
Scheme 79
Scheme 80
Scheme 81
Scheme 82
Scheme 83
Scheme 84
Scheme 85
Scheme 86
Scheme 87
Scheme 88
Scheme 89
Scheme 90
Scheme 91
Scheme 92
Scheme 93
Scheme 94
Scheme 95
Scheme 96
Scheme 97
Scheme 98
Scheme 99
Scheme 100
Scheme 101
Scheme 102
Scheme 103
Scheme 104
Scheme 105
Scheme 106
Scheme 107
Scheme 108
Scheme 109
Scheme 110
Scheme 111
Scheme 112
Scheme 113
Scheme 114
Scheme 115
Scheme 116
Scheme 117
Scheme 118
Scheme 119
Scheme 120
Scheme 121
Scheme 122
Scheme 123
Scheme 124
Scheme 125
Scheme 126
Scheme 127
Scheme 128
Scheme 129
Scheme 130
Scheme 131
Scheme 132
Scheme 133
Scheme 134
Scheme 135
Scheme 136
Scheme 137
Scheme 138
Scheme 139
Scheme 140
Scheme 141
Scheme 142
Scheme 143
Scheme 144
Guide
Cover
Table of Contents
Series Page
TITLE PAGE
COPYRIGHT
INTRODUCTION TO THE SERIES BY ROGER ADAMS, 1942
INTRODUCTION TO THE SERIES BY SCOTT E. DENMARK, 2008
PREFACE TO VOLUME 115
John Edwin Baldwin 1937–2024
Begin Reading
CUMULATIVE CHAPTER TITLES BY VOLUME
AUTHOR INDEX, VOLUMES 1–115
CHAPTER AND TOPIC INDEX, VOLUMES 1–115
END USER LICENSE AGREEMENT
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FORMER MEMBERS OF THE BOARD OF EDITORS AND DIRECTORS
JEFFREY AUBÉ
DAVID B. BERKOWITZ
DALE L. BOGER
JIN K. CHA
ANDRÉ B. CHARETTE
ENGELBERT CIGANEK
DENNIS CURRAN
SAMUEL DANISHEFSKY
HUW M. L. DAVIES
SCOTT E. DENMARK
VICTOR FARINA
PAUL FELDMAN
JOHN FRIED
JACQUELYN GERVAY‐HAGUE
STEPHEN HANESSIAN
LOUIS HEGEDUS
PAUL J. HERGENROTHER
DONNA M. HURYN
JEFFREY S. JOHNSON
LAURA KIESSLING
MARISA C. KOZLOWSKI
STEVEN V. LEY
JAMES A. MARSHALL
MICHAEL J. MARTINELLI
STUART W. MCCOMBIE
SCOTT J. MILLER
JOHN MONTGOMERY
LARRY E. OVERMAN
T. V. RAJANBABU
JAMES H. RIGBY
WILLIAM R. ROUSH
TOMISLAV ROVIS
SCOTT D. RYCHNOVSKY
MARTIN SEMMELHACK
CHARLES SIH
AMOS B. SMITH, III
BARRY M. TROST
PETER WIPF
FORMER MEMBERS OF THE BOARDNOW DECEASED
ROGER ADAMS
HOMER ADKINS
WERNER E. BACHMANN
JOHN E. BALDWIN
PETER BEAK
ROBERT BITTMAN
A. H. BLATT
VIRGIL BOEKELHEIDE
GEORGE A. BOSWELL, JR.
THEODORE L. CAIRNS
ARTHUR C. COPE
DONALD J. CRAM
DAVID Y. CURTIN
WILLIAM G. DAUBEN
LOUIS F. FIESER
HEINZ W. GSCHWEND
RICHARD F. HECK
RALPH F. HIRSCHMANN
HERBERT O. HOUSE
JOHN R. JOHNSON
ROBERT M. JOYCE
ROBERT C. KELLY
ANDREW S. KENDE
WILLY LEIMGRUBER
FRANK C. MCGREW
BLAINE C. MCKUSICK
JERROLD MEINWALD
CARL NIEMANN
LEO A. PAQUETTE
GARY H. POSNER
HANS J. REICH
HAROLD R. SNYDER
MILÁN USKOKOVIC
BORIS WEINSTEIN
JAMES D. WHITE
Organic Reactions
VOLUME 115
EDITORIAL BOARD
P. ANDREWEVANS, Editor‐in‐Chief
STEVEN M. WEINREB, Executive Editor
PAUL
R.
BLAKEMORE
BO
QU
REBECCA
L.
GRANGE
IAN
J.
ROSENSTEIN
DENNIS
G.
HALL
KEVIN
H.
SHAUGHNESSY
JEFFREY
B.
JOHNSON
STEVEN
D.
TOWNSEND
JEFFREY
N.
JOHNSTON
BEN
W. H.
TURNBULL
ALBERT
PADWA
CHRISTOPHER
D.
VANDERWAL
JOSHUA
G.
PIERCE
MARY
P.
WATSON
BARRY B. SNIDER, Secretary
JEFFERY B. PRESS, Treasurer
DANIELLESOENEN, Editorial Coordinator
DENALINDSAY, Secretary and Processing Editor
LANDY K.BLASDEL, Processing Editor
TINAGRANT, Processing Editor
ENGELBERTCIGANEK,Editorial Advisor
ASSOCIATE EDITORS
DEBORA CHIODI
MADISON M. CLARK
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ALESSIO PORTA
JIANZHUO TU
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INTRODUCTION TO THE SERIES BY 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 BY 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 115
Einstein: “What I most admire about your art is its universality. You do not say a word, yet the world understands you.”
Chaplin: “It's true. But your fame is even greater. The world admires you, when no one understands you.”
This exchange highlights a profound truth that resonates within the world of synthetic organic chemistry, in which creativity and complexity are evident even when underlying processes are not fully understood. The preparation and identification of functional molecules remain ongoing challenges. Despite the intricate and often unclear mechanisms of the reactions involved, the creativity and innovation they embody are universally appreciated. The Organic Reactions series epitomizes the intuitive elegance and scientific rigor essential for new reaction development. Just as Chaplin's silent films communicated universally without words, the outcomes of these reactions speak volumes through their applications to challenging synthetic problems, even if the mechanistic nuances are unclear—much like Einstein's groundbreaking theories. Organic chemistry combines creativity with complexity, like the arts and sciences appreciated by Chaplin and Einstein. This dual nature allows the appreciation of sophisticated transformations and a deeper understanding of the reaction mechanisms, making the field accessible and admirable to a diverse audience. Studying cycloadditions and rearrangements captures the essence of this synergy. While detailed mechanisms may be challenging to grasp fully, the elegant transformations they enable are universally appreciated, reflecting the harmonious blend of scientific rigor and innovative thinking in organic chemistry.
The Organic Reactions series is unique in its meticulous curation of information on specific transformations, offering an unparalleled method for the proverbial “finding a needle in a haystack.” When Roger Adams founded the series over eighty years ago, he identified a critical issue: while much of the relevant information and expertise existed, it was scattered and challenging to access uniformly across the chemical research landscape at that time. Adams foresaw the immense value of chemical informatics by consistently organizing this data in a database. The series addresses this need by systematically tabulating important examples of each transformation, thereby permitting researchers to evaluate the feasibility of a proposed process on a specific substrate. Consequently, despite the advent of countless electronic platforms, Organic Reactions remains an invaluable resource that can readily identify specific tactics and thereby accelerate “Eureka” moments because of how it presents the information. Each chapter compiles comprehensive data and delves into the mechanistic and experimental details essential for practicing synthetic organic chemists. This detailed documentation facilitates the development of new adaptations, broadening the scope and defining the limitations of various reactions. The two chapters in this Organic Reactions volume describe higher‐order cycloadditions and rearrangement reactions of allylic cations and propargylic alcohols, respectively.
The first chapter by Michael Harmata, Jianzhuo Tu, and Madison M. Clark provides an excellent treatise on the (4+3) cycloadditions of allylic and related cations, updating an earlier chapter by James H. Rigby and F. Christopher Pigge (Vol. 51, Ch. 3, p 351), which covered the literature up to 1997. Hoffmann, Föhlisch, and Noyori independently pioneered the reaction, which is the formal combination of a neutral 1,3‐diene with an allyl‐type cation, most commonly an oxyallyl cation, to provide an intermediary cycloheptenyl cation that collapses to afford functionalized cycloheptenones. The process is symmetry‐allowed and analogous to the Diels‐Alder reaction, and as such, it can be envisioned as a [4π (4 atoms) + 2π (3 atoms)] cycloaddition reaction, wherein the allyl cation provides a 2π dienophile. Notably, there are relatively few general methods for the stereoselective synthesis of seven‐membered rings.
The Mechanism and Stereochemistry section outlines the intricate pathways involved in allylic cation chemistry, addressing the debate as to whether these reactions proceed via concerted or stepwise mechanisms. Supported by computational and experimental studies, the discussion extends to understanding the regioselectivity observed with unsymmetrical dienes and dienophiles, shedding light on how specific substitution patterns influence reaction outcomes. The section also explores simple and induced diastereoselectivities, documenting how subtle changes in reaction conditions or substrate structure can impact the level of stereocontrol. Although the formation of mixtures of diastereoisomers is often problematic, it can be advantageous in fields like drug discovery, where different stereoisomers provide insight into the origin of biological activity.
The Scope and Limitations section is meticulously organized by the type of allylic cation and the nature of the reaction—inter‐ or intramolecular. For acyclic allylic cations, both unsubstituted and carbon‐substituted species are examined. The discussion on intermolecular reactions highlights the versatility of these cations, particularly those derived from α‐halo ketones, strained‐ring precursors, allylic alcohols, and propargylic esters. Each substrate class provides unique reactivity profiles that can be exploited in synthetic applications. In contrast, intramolecular reactions of allylic cations derived from the same precursors, including allenes and alkylidenecyclopropanes, emphasize their utility in constructing complex polycyclic structures. The discussion extends to heteroatom‐substituted allylic cations in both inter‐ and intramolecular contexts. Halogen‐, nitrogen‐, oxygen‐, and sulfur‐substituted allylic cations showcase the breadth of functional‐group compatibility and the potential for incorporating diverse heteroatoms into target molecules. These transformations are particularly valuable for accessing heterocyclic compounds prevalent in unnatural and natural products. Cyclic allylic cations, both unsubstituted and carbon‐substituted, are also discussed in the context of inter‐ and intramolecular reactions. The section on intermolecular reactions covers allylic cations derived from cyclic α‐pseudohalo‐ and α‐halo ketones and the Nazarov cyclization, highlighting the importance of ring strain and electronic effects in these processes. In contrast, the intramolecular reactions include allylic cations derived from allylic alcohols and sulfones to facilitate the synthesis of polycyclic frameworks, which is crucial for natural‐product synthesis. Heteroatom‐substituted cyclic allylic cations, including those derived from dihalo ketones and oxidopyridinium ions, are also discussed, showcasing their unique reactivities. A section on benzylic and related cations delves into both inter‐ and intramolecular reactions of heterobenzylic cations derived from pyrroles, indoles, furans, benzofurans, thiophenes, and benzothiophenes. These reactions are instrumental in constructing complex, polycyclic structures and incorporating heteroatoms into aromatic systems.
The Applications to Synthesis section provides selected examples of how this type of cycloaddition has been utilized to prepare an array of challenging and important natural products. These case studies illustrate the practical utility of allylic cation cycloaddition chemistry in complex‐molecule synthesis and will likely inspire future developments in this area. The Comparison with Other Methods section compares allylic cation strategies with alternative synthetic approaches, such as cycloadditions of vinyl diazo compounds, the Claisen rearrangement, (5+2) cycloadditions of vinyl cyclopropanes, and ring‐closing alkene metathesis. Each method offers unique advantages and limitations, underscoring the versatility and robustness of allylic cation chemistry in the broader context of synthetic organic chemistry. The Tabular Survey mirrors the Scope and Limitations section, wherein the tables are differentiated by inter‐ and intramolecular reactions, the substitution on the dienophile, and whether it is cyclic or acyclic to permit the identification of a specific reaction combination of interest. This is an outstanding chapter on an important cycloaddition reaction that will be a valuable resource to the synthetic community, particularly given its utility for target‐directed synthesis.
The second chapter by Giovanni Vidari, Debora Chiodi, Alessio Porta, and Giuseppe Zanon describes the Meyer‐Schuster rearrangement, which involves the formal conversion of secondary and tertiary propargylic alcohols to an array of α,β‐unsaturated carbonyl compounds. The original process was discovered in the early 1920s by Meyer and Schuster, who discovered that propargylic carbinols rearrange using simple Brønsted acids. Although the direct conversion of the propargylic alcohol to the α,β‐unsaturated carbonyl compound is atom‐economical, the strongly acidic and harsh reaction conditions commonly employed in early versions of the Meyer–Schuster reaction are incompatible with many acid‐labile substrates. Hence, relatively few examples that afford acid‐labile products were reported in the first 70 years following its discovery. Moreover, the reaction frequently produces a mixture of (E)‐ and (Z)‐stereoisomers in addition to several competing side reactions, the most notable of which is the Rupe rearrangement, which yields a different constitutional isomer for tertiary alcohol substrates. Nevertheless, this reaction is a conceptually simple and practical method for generating α,β‐unsaturated carbonyl groups present in many important intermediates and bioactive molecules. Therefore, the search for milder and more selective methods has been the focus of ongoing developments in this area, which are nicely captured in this chapter.
The Mechanism and Stereochemistry section explores the array of mechanistic pathways available for effecting the Meyer–Schuster rearrangement, focusing on how various conditions and catalysts influence the reaction mechanism. For instance, the classic acid‐promoted Meyer–Schuster rearrangement of propargylic alcohols follows an ionic mechanism. In contrast, the rearrangement under basic conditions is relatively rare and is thought to involve a prototropic rearrangement. The discussion also covers the rearrangement of propargylic alcohols activated as oxo complexes of transition metals, emphasizing the role of metal coordination in facilitating these transformations. In addition, this section also describes the rearrangement of propargylic esters and alcohols using gold and other transition metals, including cases involving C‐H bond activation of terminal propargylic alcohols via transition‐metal insertion. These variations in the mechanism highlight the complex interplay between substrate, catalyst, and reaction conditions.
The Scope and Limitations section provides a comprehensive overview of substrate preparation and the diversity in reaction conditions that facilitate the Meyer–Schuster rearrangement. Both catalyzed and uncatalyzed rearrangements are discussed for propargylic alcohols, with particular attention to those promoted by Brønsted and Lewis acids. The use of oxo complexes of transition metals and transient carbonate intermediates is described, highlighting their influence on reaction efficiency and selectivity. Gold and other transition‐metal‐based catalysts play a crucial role in these transformations, often leading to enhanced reactivity and selectivity. The Meyer–Schuster rearrangement of propargylic esters and ethers highlights the versatility of this transformation, including the rearrangement of α‐allenols, propargylic hemiaminals, and sulfides. The aza‐Meyer–Schuster rearrangement offers a pathway for rearranging propargylic amines, hydrazine derivatives, γ‐amino ynamides, and propargylic hydroxylamines. The versatility of the Meyer–Schuster rearrangement is further showcased in tandem and consecutive reactions that involve a Meyer–Schuster rearrangement in conjunction with a carbon–carbon bond‐forming reactions such as aldol‐type condensation, Michael addition, Friedel–Crafts, and Diels–Alder reactions. The utility of these rearrangements is demonstrated in the formation of an array of important heterocyclic scaffolds. These transformations can also readily access aliphatic oxa‐ and azacyclic derivatives.
The section on the electrophilic and nucleophilic interception of Meyer–Schuster rearrangement intermediates delineates a series of methods that diversify the products. Consecutive reactions involving the interception of an allenyl carbocation or an allenol intermediate are explored, in which the latter are further subdivided into propargylic alcohol and ester precursors, with examples including α‐halogenation, α,α‐dihalogenation, electrophilic α‐arylation, α‐trifluoromethylation, aldol‐type and Mannich‐type addition reactions, and α‐allylation. Alternatively, the interception processes from propargylic esters permit the synthesis of diverse structures, such as tetrahydrofurans, tetrahydropyrans, and halo‐Meyer–Schuster rearrangement products. In contrast, the dehydrogenative Meyer–Schuster rearrangement produces alkynyl ketones, while its alkylative variant leads to alkyl‐α,β‐unsaturated ketones. Knoevenagel‐type derivatives permit the preparation of α‐ylidene‐1,3‐diones and α‐ylidene β‐keto esters, broadening the scope of accessible products. Intramolecular Michael addition reactions, Myers–Saito cyclizations, and cycloisomerization reactions further demonstrate the versatility of these pathways. The section culminates with a discussion on intermolecular α‐alkylation and α‐allylation reactions, emphasizing the interception of Meyer–Schuster rearrangement intermediates involving allenol intermediates with reversed reactivity, further illustrating the broad applicability and innovative potential of these rearrangements in modern organic synthesis.
The Applications to Synthesis section describes selected applications for preparing several bioactive natural and unnatural products. For example, this process has featured in the synthesis of alkaloids, carotenoids, prostaglandins, sesquiterpenes, etc., in addition to an array of other bioactive agents, each highlighting a unique aspect of the transformation. The Comparison with Other Methods section evaluates other approaches, including elimination, olefination, cross‐coupling, alkyne‐carbonyl metathesis, cycloadditions, and carbocyclizations reactions that afford α,β‐unsaturated carbonyl compounds. The Tabular Survey delineates selected examples, making this the first example of using the condensed tables, which are organized by starting material for the classical reactions and by the product for the tandem and intercepted reactions to permit the identification of a specific reaction combination of interest. The chapter is meticulously crafted to provide both the seasoned chemist and the novice with a thorough understanding of this reaction's potential and place within the broader context of organic synthesis.
As I pen my final preface as the Editor‐in‐Chief of Organic Reactions, I reflect on the remarkable journey over 15 volumes. During my tenure, we have implemented numerous changes to ensure that Organic Reactions remains a leading reference text in organic chemistry. We launched a new, user‐friendly website, expanded our visibility by being abstracted in SciFinder, and cultivated a robust social‐media presence on Twitter and LinkedIn. Additionally, we championed diversity, significantly enhancing the representation on our Boards of Directors and Editors. Recognizing the need for sustainable leadership, we created the role of Executive Editor held by Steven M. Weinreb and divided the President/Editor‐in‐Chief position to ease its demands. While I will continue to serve as President, I am confident that under Kevin Shaughnessy's capable leadership as Editor‐in‐Chief, Organic Reactions is well‐positioned for continued success and excellence in organic chemistry.
I would be remiss if I did not acknowledge the entire Organic Reactions Editorial Board for guiding this volume through the editorial process and their collective efforts throughout my tenure as Editor‐in‐Chief. I extend my gratitude to Dr. Al Padwa (Chapters 1 and 2) and Dr. Steven M. Weinreb (Chapter 1), who served as the Responsible Editors for marshaling the chapters through the various phases of development. I am also deeply indebted to Dr. Danielle Soenen for her continued and ongoing contributions to the success of Organic Reactions as the Editorial Coordinator: her knowledge is critical to maintaining consistency in the series. Dr. Dena Lindsay ( Secretary to the Editorial Board) is thanked for coordinating the contributions of the authors, editors, and publishers. In addition, the Organic Reactions enterprise could not maintain the quality of production without the efforts of Dr. Steven M. Weinreb (Executive Editor), Dr. Engelbert Ciganek (Editorial Advisor), Dr. Landy Blasdel (Processing Editor), and Dr. Tina Grant (Processing Editor). I would also like to acknowledge Dr. Barry B. Snider (Secretary) for keeping everyone on task and Dr. Jeffery Press (Treasurer) for ensuring we remain fiscally solvent!
I am also indebted to past and present members of the Board of Editors and Directors for ensuring the enduring quality of Organic Reactions. The specific format of the chapters, in conjunction with the collated tables of examples, makes this series of reviews not just unique but exceptionally valuable to the practicing synthetic organic chemist, a testament to their collective expertise and dedication.
P. Andrew Evans
Kingston
Ontario, Canada
John Edwin Baldwin
1937–2024
John Edwin Baldwin was born in Berwyn, Illinois on September 10, 1937 and grew up in Oak Park. He excelled in sports and was valedictorian of his high school graduating class. Baldwin did his undergraduate studies at Dartmouth College, graduating as valedictorian in 1959. He then pursued his doctoral studies in chemistry and physics under Jack Roberts at California Institute of Technology, earning his PhD in 1963.
After five years on the faculty of the University of Illinois he moved in 1968 to the University of Oregon as a professor. During his sixteen‐year tenure there, he also served five years as Dean of Arts and Sciences. John moved in 1984 to Syracuse University where he spent his final decades of teaching and research. He co‐led the eight‐year creation of the 230,000 square foot Life Sciences Complex and chaired the Department of Chemistry with immense distinction. He invested in mentoring other scholars and academic leaders; his colleagues and students are making an impact throughout the world. He was the William Rand Kenan Jr. Professor of Science and was named one of the few Distinguished Professors at Syracuse, also earning a Chancellor's Citation for Excellence. His research was supported by the NSF and by awards, such as those from the John Simon Guggenheim and the Alexander von Humboldt Foundations. Baldwin served on national boards and scientific advisory committees, including the President's Science Advisory Committee; the NIH Medicinal Chemistry Study Section; the NSF's Chemistry Division Standing Review Panel; the executive committee of the ACS Division of Organic Chemistry; and the Advisory Board of the ACS Petroleum Research Fund. He served on the Board of Editors of Organic Reactions from Volume 20 (1973) to Volume 25 (1978).
Deeply interested in physical organic chemistry and dedicated to the universities where he worked, as well as to his broader scholarly community, Baldwin developed a reputation as a gifted and meticulous scholar, researcher, collaborator, and legendary teacher and mentor. John's research contributions were diverse and highly influential and his complex experiments were considered ambitious, elegant, and insightful: one mark of that work was his receipt of the American Chemical Society's James Flack Norris Award in Physical Organic Chemistry in 2010. The citation highlights his original mathematical approaches and ingenious isotopic labeling to solve the most challenging problems.
He was one of the first to use density‐functional theory and other emerging quantum calculations to gain insights into chemical bonding and reaction mechanisms. He published over 150 articles and continued to publish important works up until his retirement in 2014 focused on mechanistic studies of structural isomerizations and stereomutations, including those in cyclopropanes and vinylcyclopropanes. Small molecules, especially those in the gas phase, were always of particular interest, since the energy levels of these molecules could be calculated using the programs and computational capabilities of the time. He summarized this work and its history and development in a 2003 Chemical Reviews article.
John had a passion for learning that extended beyond his primary professional field. He read broadly, especially in history and philosophy, and studied many foreign languages, including Russian, Swedish, and German. He embraced the professional and personal opportunities to travel and held visiting professor appointments at Heidelberg, Munich and Hamburg, Germany; Krakow, Poland; Stockholm and Göteborg, Sweden; and at his alma mater Cal Tech. His friends and colleagues treasured his intense interest in their work, no matter how far afield it was from his. He loved music and enjoyed being on the board of the Chamber Music Society and supporting the work of the Society for New Music in Syracuse. John and Anne held concerts of those societies in their home and frequently hosted visiting musicians. He was an athlete on the football, lacrosse, track, and ski teams at Dartmouth. He remained an avid runner and took pleasure in running with friends.
John died on May 26, 2024 and is survived by his wife, Anne, three children, and eight grandchildren.
Chapter 1(4+3) CYCLOADDITIONS OF ALLYLIC AND RELATED CATIONS
Michael Harmata Jianzhuo Tu and Madison M. Clark
Department of Chemistry, University of Missouri–Columbia, Columbia, Missouri, 65211
Edited by Albert Padwa and Steven Weinreb
CONTENTS
ACKNOWLEDGMENTS
INTRODUCTION
MECHANISM AND STEREOCHEMISTRY
Concerted or Stepwise? Computational and Experimental Studies
Regioselectivity: Unsymmetrical Dienes and Dienophiles
Diastereoselectivity: Simple and Induced
SCOPE AND LIMITATIONS
Acyclic Allylic Cations: Unsubstituted and Carbon‐Substituted Species
Intermolecular Reactions
Allylic Cations Derived from α‐Halo Ketones
Allylic Cations Derived from Strained‐Ring Precursors
Allylic Cations Derived from Allylic Alcohols
Allylic Cations Derived from Propargylic Esters
Intramolecular Reactions
Allylic Cations Derived from α‐Halo Ketones
Allylic Cations Derived from Allylic Sulfones
Allylic Cations Derived from Strained‐Ring Precursors
Allylic Cations Derived from Propargylic Esters
Allylic Cations Derived from Allenes
Allylic Cations Derived from Alkylidenecyclopropanes
Acyclic Allylic Cations: Heteroatom‐Substituted Species
Intermolecular Reactions
Halogen‐Substituted Allylic Cations
Nitrogen‐Substituted Allylic Cations
Oxygen‐Substituted Allylic Cations
Sulfur‐Substituted Allylic Cations
Intramolecular Reactions
Halogen‐Substituted Allylic Cations
Nitrogen‐Substituted Allylic Cations
Oxygen‐Substituted Allylic Cations
Sulfur‐Substituted Allylic Cations
Cyclic Allylic Cations: Unsubstituted and Carbon‐Substituted Species
Intermolecular Reactions
Allylic Cations Derived from Cyclic α‐Pseudohalo Ketones and α‐Halo Ketones
Allylic Cations Derived from the Nazarov Cyclization
Intramolecular Reactions
Allylic Cations Derived from Cyclic α‐Halo Ketones
Allylic Cations Derived from the Nazarov Cyclization
Allylic Cations Derived from Allylic Alcohols and Sulfones
Cyclic Allylic Cations: Heteroatom‐Substituted Species
Intermolecular Reactions
Allylic Cations Derived from Dihalo Ketones
Aromatic Oxyallylic Cations: Oxidopyridinium Ions
Intramolecular Reactions
Allylic Cations Derived from Allylic Alcohols
Aromatic Oxyallylic Cations: Oxidopyridinium Ions
Benzylic and Related Cations
Intermolecular Reactions
Heterobenzylic Cations Derived from Pyrroles and Indoles
Heterobenzylic Cations Derived from Furans and Benzofurans
Heterobenzylic Cations Derived from Thiophenes and Benzothiophenes
Intramolecular Reactions
APPLICATIONS TO SYNTHESIS
(+)‐Hedyosumin A
(±)‐Cortistatin J
(–)‐Englerin A
(±)‐Urechitol A
(±)‐Sterpurene
(±)‐Spatol
(+)‐Dactylol
Imerubrine
(±)‐Lasidiol
(±)‐Aphanamol I
(±)‐Widdrol
(±)‐Frondosin B
COMPARISON WITH OTHER METHODS
Cycloadditions of Vinyl Diazo Compounds
Claisen Rearrangement
(5+2) Cycloadditions of Vinyl Cyclopropanes
Ring‐Closing Alkene Metathesis
EXPERIMENTAL CONDITIONS
EXPERIMENTAL PROCEDURES
(1
S*
,2
S*
,4
S*
,5
R*
)‐1‐Methoxy‐2,4‐dimethyl‐8‐oxabicyclo[3.2.1]oct‐6‐en‐3‐one and (1
S*
,2
R*
,4
R*
,5
R*
)‐1‐Methoxy‐2,4‐dimethyl‐8‐oxabicyclo[3.2.1]oct‐6‐en‐3‐one [Reductive Approach to an Acyclic Carbon‐Substituted Oxyallylic Cation and Intermolecular (4+3) Cycloaddition].
(1
R
,2
R
,5
R
)‐2‐((
R
)‐3‐((
tert
‐Butyldiphenylsilyl)oxy)‐1‐hydroxypropyl)bicyclo[3.2.1]oct‐6‐en‐3‐one and (1
S
,2
R
,5
S
)‐2‐((
R
)‐3‐((
tert
‐Butyldiphenylsilyl)oxy)‐1‐hydroxypropyl)bicyclo[3.2.1]oct‐6‐en‐3‐one [Ring‐Opening of a Vinyl Epoxide and Intermolecular (4+3) Cycloaddition].
(Benzyl)‐(
E
)‐[(1
R*
,5
S*
,8
S*
)‐7,7‐dimethyl‐11‐oxatricyclo[6.2.1.01, 5]undec‐9‐en‐6‐ylidene]amine [Activation of an Alkylidene Aziridine and Intramolecular (4+3) Cycloaddition].
(3a
R
,8a
R
)‐3a,5‐Dimethyl‐2‐(4‐tolylsulfonyl)‐2‐aza‐1,2,3,3a,6,8a‐hexahydroazulene [Gold‐Catalyzed Activation of an Allene and Intramolecular (4+3) Cycloaddition].
1‐[(Benzyloxy)methyl]‐2,2,4,4‐tetrachloro‐8‐oxabicyclo[3.2.1]oct‐6‐en‐3‐one [Base‐Mediated Halogen‐Substituted Oxyallylic Cation Formation and Intermolecular (4+3) Cycloaddition].
(1
R
,2
S
,5
R
)‐1,5‐Dimethyl‐3‐oxo‐8‐oxabicyclo[3.2.1]oct‐6‐en‐2‐yl)acetaldehyde [Activation of a Dienal Catalyzed by a Chiral Amine and Intermolecular (4+3) Cycloaddition].
(1
R
,2
S
,5
R
)‐2‐((
S
)‐1‐Phenylethoxy)‐8‐oxabicyclo[3.2.1]oct‐6‐en‐3‐one and (1
S
,2
R
,5
S
)‐2‐((
S
)‐1‐Phenylethoxy)‐8‐oxabicyclo[3.2.1]oct‐6‐en‐3‐one [Vinyl Oxocarbenium Ion from an Allylic Acetal and Intermolecular (4+3) Cycloaddition].
(2
R*
,7
R*
)‐2‐Benzyl‐7‐((
tert
‐butyldimethylsilyl)oxy)cyclohept‐4‐en‐1‐one [Activation of a 2‐Silyloxy Enal and Intermolecular (4+3) Cycloaddition of an Oxygen‐Substituted Oxyallylic Cation].
(1
R*
,2
S*
,5
R*
,8
R*
)‐6‐Oxo‐4‐(
p
‐tolylsulfonyl)‐11‐oxa‐4‐azatricyclo[6.2.1.01, 5]undec‐9‐en‐2‐yl 2,2‐Dimethylpropionate [Amidoallene Oxidation Route to a Nitrogen‐Substituted Oxyallylic Cation and Intramolecular (4+3) Cycloaddition].
(1
S*
,6
S*
,8
R*
,9
S*
)‐2,2,6,9‐Tetramethyl‐8‐(phenylthio)‐12‐oxatricyclo[7.2.1.01, 6]dodec‐10‐en‐7‐one and (1
S*
,6
R*
,8
R*
,9
S*
)‐2,2,6,9‐Tetramethyl‐8‐(phenylthio)‐12‐oxatricyclo [7.2.1.01, 6]dodec‐10‐en‐7‐one [Sulfur‐Substituted Oxyallylic Cation from an Allylic Sulfone Followed by an Intramolecular (4+3) Cycloaddition].
11‐Oxatricyclo[4.3.1.12, 5]undec‐3‐en‐10‐one [Silver‐Mediated Cyclic Aminoallylic Cation from an Allylic Chloride and Intermolecular (4+3) Cycloaddition].
(1
R*
,2
R*
,10
S*
,11
S*
)‐8‐[(
tert
‐Butyldimethylsilyl)oxy]‐1‐methyl‐12‐methylene‐11‐phenyltricyclo[8.2.12, 7]tridec‐7‐en‐13‐one [Nazarov Cyclization to Form a Cyclopentenyl Oxyallylic Cation and Intermolecular (4+3) Cycloaddition].
(1
S*
,6
S*
,10
S*
,12
R*
)‐6,10‐Dimethyl‐12‐phenyltricyclo[8.2.1.01, 6]tridec‐7‐en‐13‐one [Nazarov Cyclization to Form a Cyclopentenyl Oxyallylic Cation and Intramolecular (4+3) Cycloaddition].
Methyl (2
R
*,6
R
*)‐3‐Methyl‐11‐oxo‐1,2,3,6,7,8,9,10‐octahydro‐2,6‐methanocyclopenta[
d
]azonine‐5‐carboxylate [Intermolecular (4+3) Cycloaddition with an Oxidopyridinium Ion].
5,8‐Dimethyl‐10‐phenyl‐5,6,9,10‐tetrahydrocyclohepta[
b
]indole [Three‐Component (4+3) Cycloaddition of an Indole‐Derived Cation].
(4
S*
,7
R*
)‐2,8,8‐Trimethyl‐7,8‐dihydro‐4
H
‐4,7‐ethanocyclohepta[
b
]furan [Intermolecular Cycloaddition of a Furanylmethyl Cation].
LIST OF ABBREVIATIONS
TABULAR SURVEY
Chart 1. Ligands Used in the Tables
Chart 2. Catalysts Used in the Tables
Table 1. Intermolecular Cycloadditions of Acyclic Unsubstituted and Carbon-Substituted Allylic Cations
Table 2. Intermolecular Cycloadditions of Acyclic Heteroatom-Substituted Allylic Cations
Table 3. Intermolecular Cycloadditions of Cyclic Unsubstituted and Carbon-Substituted Allylic Cations
Table 4. Intermolecular Cycloadditions of Cyclic Heteroatom-Substituted Allylic Cations
Table 5. Intermolecular Cycloadditions of Benzylic and Related Cations
Table 6. Intramolecular Cycloadditions of Acyclic Unsubstituted and Carbon-Substituted Allylic Cations
Table 7. Intramolecular Cycloadditions of Acyclic Heteroatom-Substituted Allylic Cations
Table 8. Intramolecular Cycloadditions of Cyclic Unsubstituted and Carbon-Substituted Allylic Cations
Table 9. Intramolecular Cycloadditions of Cyclic Heteroatom-Substituted Allylic Cations
Table 10. Intramolecular Cycloadditions of Benzylic and Related Cations
REFERENCES
SUPPLEMENTAL REFERENCES
ACKNOWLEDGMENTS
Our work in the area of (4+3) cycloaddition chemistry has been supported by the National Science Foundation, to whom we are very grateful. A portion of this manuscript was prepared at the Justus Liebig Universität in Giessen, Germany, courtesy of the Alexander von Humboldt Foundation. We thank Professor Peter R. Schreiner for his gracious hospitality. Proofreading assistance by Ms. Judy L. Snyder and Mr. Alexander S. Harmata is gratefully acknowledged.
INTRODUCTION
The (4+3) cycloaddition is defined as the reaction between a diene and a cation that is stabilized by a π system. The initial adduct is formally a cycloheptenyl cation, and the process generally terminates by electron donation from a substituent (Z) on the 2‐position of the starting allylic cation (Scheme 1). Several interesting variations on this theme are emerging. This review is a continuation of where the previous Organic Reactions chapter in this area ended in 1997,1 and thus covers papers published through June 2018. A supplemental list of references is provided at the end of the bibliography, with papers published in the period of 2018–2023. Also note that any ratios of isomers missing in schemes reflect their omission in the primary literature.
Scheme 1
The foundations of this reaction were first laid by Hoffmann, Föhlisch, and Noyori, whose contributions have been summarized in a number of reviews2–8 and the previous Organic Reactions chapter on this subject.1 It is worth noting that IUPAC rules recommend the use of brackets and parentheses in the description of cycloaddition reactions.9 The former descriptor refers to the number of electrons involved in each unit in the bond formation process. Therefore, the reactions described herein would be characterized as [4+2] cycloadditions, as the allylic cation has only 2 π electrons, just as a “normal” dienophile in a Diels–Alder reaction. Parentheses refer to the number of atoms involved in each of the components of the cycloaddition. In this case, the processes described herein are referred to as (4+3) cycloadditions.
MECHANISM AND STEREOCHEMISTRY
Concerted or Stepwise? Computational and Experimental Studies
There are two possible mechanistic extremes for the (4+3) cycloaddition: stepwise and concerted. Computational examination of certain (4+3) cycloadditions indicates that both pathways are feasible. Stepwise reactions tend to be favored when the dienophile is more reactive (i.e., electrophilic) and the diene is more electron‐rich or nucleophilic.
Calculations involving the reaction of the “parent” oxyallylic cation and its protonated congener, the 2‐hydroxyallylic cation, with selected dienes provide some insight into the fundamental reactivity and mechanistic issues in (4+3) cycloaddition chemistry. For example, the parent, unsubstituted oxyallylic cation 1 preferentially reacts in silico with s‐cis‐1,3‐butadiene via an exo concerted, but asynchronous, transition state. Only slightly higher in energy is a competing, concerted (3+2) cycloaddition leading to dihydrofuran 2, which then undergoes a [3,3] sigmatropic (Claisen) rearrangement with a barrier of 7.6 kcal/mol to produce the formal (4+3) cycloaddition product 3 (Scheme 2).10
Scheme 2
Cycloadditions of various congeners of the parent oxyallylic cation having a metal cation or a proton associated with the formally negatively charged oxygen were calculated to proceed along paths that are generally experimentally observable. Increasing the electrophilicity of the dienophile by decreasing the formal charge on oxygen leads to either stepwise reactions or concerted (3+2) cycloaddition reactions that could be followed by a Claisen rearrangement to afford (4+3) cycloadducts. Similarly, as the nucleophilicity of the diene increases, stepwise reaction paths are favored.11 In the most extreme case examined, the reaction of the 2‐hydroxyallylic cation with pyrrole gives a σ‐complex intermediate, for which any mode of further cyclization is unfavorable. Proton loss from such an intermediate affords the product from a net electrophilic aromatic substitution, which is a common side reaction in this type of chemistry.
In the same vein, calculations indicate that the intramolecular cyclization of oxyallylic cation 4 to tricycle 5 proceeds by a barrierless, stepwise process (Scheme 3).12 Moreover, the same calculations suggest that the formation of product 5 is reversible, albeit this has apparently not yet been experimentally verified.
Scheme 3
The idea that divergent reactivity is to be expected based on the electrophilicity of the dienophile is supported by the calculated reaction paths of the cyclic oxyallylic cation 6 and its protonated counterpart 8. Although the former is predicted to afford the endo (4+3) cycloadduct 7 from a barrierless reaction with cyclopentadiene, the latter is calculated to proceed to a cationic intermediate 9 that undergoes an intramolecular hydride transfer to produce 10, followed by the loss of a proton to form 11 (Scheme 4).13 Experimental evidence supports the hydride transfer pathway; however, it still is not clear whether 6 and 8 uniquely form 7 and 11, respectively.
Scheme 4
In a related analysis, the oxyallylic cation 12 is calculated to afford exo and endo intramolecular (4+3) cycloaddition products 13 and 14 via concerted, asynchronous transition states, in which a nonpolar medium favors the endo adduct and a polar environment favors the exo adduct. Notably, the computational predictions were substantiated by experimental studies (Scheme 5).14
Scheme 5
In a study of cyclic allylic cations like 15, formed as the result of Nazarov cyclizations of vinyl allenyl ketones, computations suggest that, generally, a subsequent (4+3) cycloaddition should occur with an exo preference in a concerted, asynchronous fashion.15 Dienes that are more electron‐rich or sterically hindered kinetically favor stepwise processes that result in either (3+2) cycloaddition or addition/elimination pathways. These calculations were validated by experimental results (Scheme 6).16
