Organic Reactions, Volume 89 E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Serie: Organic Reactions
- Sprache: Englisch
The latest volume in this series for organic chemists in 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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Veröffentlichungsjahr: 2016
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Table of Contents
Cover
Title Page
Copyright
Introduction to the Series Roger Adams, 1942
Introduction to the Series Scott E. Denmark, 2008
Preface to Volume 89
Chapter 1: Olefin Ring-Closing Metathesis
Introduction
Mechanism
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 1-89
Chapter and Topic Index, Volumes 1-89
End User License Agreement
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Guide
Cover
Table of Contents
Preface to Volume 89
Begin Reading
List of Illustrations
Chapter 1: Olefin Ring-Closing Metathesis
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
Scheme 19
Scheme 20
Scheme 21
Schemes 22
Scheme 23
Scheme 24
Scheme 25
Scheme 26
Scheme 27
Scheme 28
Scheme 29
Scheme 30
Scheme 31
Scheme 32
Schemes 33
Scheme 34
Scheme 35
Scheme 36
Scheme 37
Scheme 38
Scheme 39
Scheme 40
Scheme 41
Scheme 42
Schemes 43
Scheme 44
Scheme 45
Scheme 46
Scheme 47
Scheme 48
Schemes 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
Schemes 64
Scheme 65
Scheme 66
Scheme 67
Scheme 68
Scheme 69
Scheme 70
Scheme 71
Scheme 72
Scheme 73
Scheme 74
Schemes 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
Schemes 110
Scheme 111
Scheme 112
Scheme 113
Scheme 114
Schemes 115
Scheme 116
Schemes 117
Scheme 118
Schemes 119
Scheme 120
Scheme 121
Scheme 122
Scheme 123
Scheme 124
Scheme 125
Scheme 126
Scheme 127
Schemes 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
Scheme 152
Scheme 153
Scheme 154
Scheme 155
Scheme 156
Scheme 157
Scheme 158
Scheme 159
Scheme 160
Scheme 161
Scheme 162
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
Schemes 180
Scheme 181
Scheme 182
Scheme 183
Scheme 184
Scheme 185
Scheme 186
Scheme 187
Schemes 188
Scheme 189
Scheme 190
Scheme 191
Schemes 192
Scheme 193
Scheme 194
Scheme 195
Scheme 196
Schemes 197
Scheme 198
Schemes 199
Scheme 200
Schemes 201
Scheme 202
Schemes 203
Scheme 204
List of Tables
Chapter 1: Olefin Ring-Closing Metathesis
Table A Reviews of Applications of the Ring-Closing Metathesis Reaction
Chart 1 Catalysts Used in Tables
Chart 2 Ligands Used in Tables
Table 1 Synthesis of Carbocycles
Table 2A Synthesis of Cyclic Amines
Table 2B Synthesis of Cyclic Ethers
Table 2C Synthesis of Phosphorus-Containing Heterocycles
Table 2D Synthesis of Phosphorus-Containing Heterocycles
Table 2E Synthesis of Sulfur-Containing Heterocycles
Table 2F Synthesis of Sulfonamide-Containing Heterocycles
Table 2G Synthesis of Boron-Containing Derivatives
Table 2H Synthesis of Unsaturated Lactams
Table 2I Synthesis of Cyclic Peptides
Table 2j Synthesis of Unsaturated Lactones
Table 2K Synthesis of other Heterocycles Containing Multiple Heteroatoms
Table 3 Synthesis of Supramolecular Compounds
Table 4 Tandem Methathesis Reactions
ADVISORY BOARD
John E. Baldwin
Peter Beak
Dale L. Boger
George A. Boswell, Jr.
André B. Charette
Engelbert Ciganek
Dennis Curran
Samuel Danishefsky
Huw M. L. Davies
John Fried
Jacquelyn Gervay-Hague
Heinz W. Gschwend
Stephen Hanessian
Richard F. Heck
Louis Hegedus
Robert C. Kelly
Andrew S. Kende
Laura Kiessling
Steven V. Ley
James A. Marshall
Michael J. Martinelli
Stuart W. McCombie
Jerrold Meinwald
Scott J. Miller
Larry E. Overman
Leo A. Paquette
Gary H. Posner
T. V. RajanBabu
Hans J. Reich
James H. Rigby
William R. Roush
Scott D. Rychnovsky
Martin Semmelhack
Charles Sih
Amos B. Smith, III
Barry M. Trost
Milán Uskokovic
James D. White
Peter Wipf
FORMER MEMBERS OF THE BOARD NOW DECEASED
Roger Adams
Homer Adkins
Werner E. Bachmann
A. H. Blatt
Robert Bittman
Virgil Boekelheide
Theodore L. Cairns
Arthur C. Cope
Donald J. Cram
David Y. Curtin
William G. Dauben
Louis F. Fieser
Ralph F. Hirshmann
Herbert O. House
John R. Johnson
Robert M. Joyce
Willy Leimgruber
Frank C. McGrew
Blaine C. McKusick
Carl Niemann
Harold R. Snyder
Boris Weinstein
Organic Reactions
Volume 89
Editorial Board
Scott E. Denmark, Editor-in-Chief
Jeffrey Aubé
Jin K. Cha
André Charette
Vittorio Farina
Paul L. Feldman
Dennis G. Hall
Paul J. Hergenrother
Jeffrey S. Johnson
Marisa C. Kozlowski
Gary A. Molander
John Montgomery
Steven M. Weinreb
Robert M. Coates, Secretary University of Illinois at Urbana-Champaign, Urbana, Illinois
Jeffery B. Press, Secretary Press Consulting Partners, Brewster, New York
Linda S. Press, Editorial Coordinator
Dena Lindsay, Editorial Assistant
Associate Editor
Larry Yet
Copyright © 2016 by Organic Reactions, Inc. All rights reserved.
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Published simultaneously in Canada.
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Library of Congress Catalog Card Number: 42-20265
ISBN: 978-1-119-21121-1
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 89
The Prefaces to Volumes 76, 80, and 84 highlighted the enormous impact of transition metal catalysis in synthetic organic chemistry. Three of the last 14 Nobel Prizes in Chemistry have been awarded for the discovery and development of transition metal catalyzed reactions that fundamentally changed the practice of organic synthesis (2001: reduction/oxidation (Knowles, Noyori and Sharpless); 2005: olefin metathesis (Chauvin, Grubbs, Schrock); 2010: cross coupling (Heck, Negishi, Suzuki)). Of the 17 chapters published in the Organic Reactions series since the diamond anniversary Volume 75 (2011), 12 have involved transition metal catalyzed transformations! The impact of catalysis using transition metal complexes and reagents on the practice of synthetic organic chemistry cannot be overstated and continues to grow exponentially. In fact, the research in this field is so intense that the resulting literature quickly becomes too massive to compile in the comprehensive fashion characteristic of Organic Reactions.
Of the three major topics celebrated by Chemistry Nobel Prizes, reduction/oxidation as well as cross-coupling are well-represented in the volumes of Organic Reactions. However, not surprisingly given the vast literature in the field, no chapter on any aspect of olefin metathesis has appeared. In fact, such a chapter had been commissioned more than a decade ago when it was still conceivable to cover one of the more important versions of olefin metathesis in organic synthesis, namely ring-closing metathesis (RCM). However, that chapter languished as the author changed locations and the literature ballooned. Much to my amazement, shortly after beginning my tenure as Editor in Chief, that author expressed renewed interest in completing the chapter and true to his word, Volume 89 comprises the results of those heroic efforts.
Dr. Larry Yet has composed the most definitive review of the family of olefin ring-closing metathesis reactions ever to appear in the! literature. Despite the appearance of literally dozens of journal reviews, book chapters, and encyclopedia entries, this contribution stands out for its comprehensive coverage of ring-closing metathesis reactions that create carbocycles, heterocycles, macrocycles, supramolecular assemblies, and polypeptides. In view of the enormous number of synthesis endeavors that construct natural products and therapeutic agents, Dr. Yet has provided an extensive overview of how RCM has revolutionized the ability to disconnect target molecules in fundamentally different ways. Some of the most recent advances in ring-closing metathesis such as enantioselective processes using chiral catalysts, solid phase transformations, and tandem metathesis reactions are covered as well. True to the spirit of Organic Reactions chapters, Dr. Yet has provided critical guidance for the selection of an appropriate catalyst for a given class of substrate and important insights in the role of olefin substitution for the most successful pairwise combination of addends.
Compiling the comprehensive Tabular Survey represented a monumental undertaking for a single author. Although the Tables cover the literature up to 2010, Dr. Yet has provided Supplemental References at the end of the chapter, organized by Table, that bringe the literature coverage through 2013.
Volume 89 represents the tenth single chapter volume to be produced in our 74-year history. Such single-chapter volumes represent definitive treatises on extremely important chemical transformations. The organic chemistry community owes an enormous debt of gratitude to the authors of such chapters for the generous contribution of their time, effort, and insights on reactions that we clearly value. Moreover, this volume also represents the largest single chapter every produced in the Organic Reactions series and we are very grateful to Anita Lekhwani and her colleagues at Wiley for their assistance in accommodating this massive work in a single bound volume.
It is appropriate here to acknowledge the expert assistance of the entire editorial board, in particular André Charette who shepherded this massive chapter to completion. The contributions of the author, editors, and the publisher were expertly coordinated by the board secretary, Robert M. Coates. In addition, the Organic Reactions enterprise could not maintain the quality of production without the dedicated efforts of its editorial staff, Dr. Linda S. Press, Dr. Danielle Soenen, and Ms. Dena Lindsey. Insofar as the essence of Organic Reactions chapters resides in the massive tables of examples, the author's and editorial coordinators' painstaking efforts are highly prized.
Scott E. DenmarkUrbana, Illinois
Richard F. Heck
August 15, 1931–October 10, 2015
Richard F. Heck, a giant in the field of organic chemistry, died on October 9, 2015. Beginning in the late 1950's, Heck envisioned that as the art of organic synthesis grew there would be a need for catalytic, organometallic-mediated bond-forming reactions that were tolerant of a wide range of functional groups. Research investigations led him to the Pd(0)/Pd(II) cycle of oxidative addition and reductive elimination, by which carbon-X bonds are catalytically converted to carbon-carbon and carbon-heteroatom bonds. His investigations laid the groundwork for all catalytic, organometallic, bond-forming processes that are used currently in modern organic synthesis.
The epic importance of catalytic palladium-mediated, carbon-carbon bond formation only slowly became apparent to the organic synthesis community. When his Organic Reactions chapter appeared in 1982, coverage of all the literature required only 45 pages (including tables!). By 2002, applications of his chemistry in synthesis had grown to the extent that the Organic Reactions chapter published that year, limited to the subset of intramolecular Heck Reactions, covered 377 pages. Moreover, the original 45 page chapter, despite its size, it is the most highly cited chapter in the Organic Reactions series with over 1500 citations!
Professor Heck received number of awards for his seminal contributions to chemistry, most notably sharing the Chemistry Nobel Prize in 2010. Among his many professional activities, he served as a member of the Editorial Board of Organic Reactions, Inc. from 1973–1985.
On a personal note, Dick Heck had already been publishing on palladium-catalyzed carbon-carbon bond formation for ten years, at the time that I joined the chemistry faculty of the University of Delaware in 1982. It was apparent that the intramolecular Heck reaction could be a powerful transformation. I sketched out some possible applications to Dick and offered to help his students, but he was not interested. He preferred to continue exploring new reactivity, initiating both “Suzuki coupling” and the “Sonogashira reaction”. Although he was the first to fully characterize a π-allylmetal complex and to elucidate the mechanism of cobalt-catalyzed alkene hydroformylation, he most enjoyed discussing the addition of formate to the palladium-catalyzed carbonylation reaction, leading to the formation of aldehydes. Even in retirement, Dick was eager to keep up with the literature, so I would send a selection of the most interesting articles every few months. He found the Catellani protocol particularly intriguing. He had thought that the carbon-palladium bond would be far too labile to allow such cascade transformations.
Dick is remembered for the key role he played as a pioneer in applying transition metal catalysis to the synthesis of complex organic molecules, both in academics and in industry. Before Grubbs, Schrock, Buchwald or Hartwig–indeed, before Stille, Suzuki, Negishi, Tsuji, Trost or Sonogashira–there was Heck pointing the way. From the late 1950's on, his contributions provided the creative spark that ignited this essential subdiscipline of synthetic methodology. In the words of Professor E. J. Corey: “Of all the individuals who have contributed to the spectacular progress in palladium catalyzed synthesis, there is no one whose work is as seminal or significant than that of Richard F. Heck.”
Douglass F. Taber, University of DelawareNovember 10, 2015
Chapter 1Olefin Ring-Closing Metathesis
Larry Yet
Department of Chemistry, University of South Alabama, Mobile, Alabama 36688-0002
Contents
Introduction
Mechanism
Scope and Limitations
Catalyst Selection
Effects of Olefin Substitution
Synthesis of Carbocycles
Synthesis of Heterocycles
Synthesis of Nitrogen-Containing Heterocycles
Synthesis of Oxygen-Containing Heterocycles
Synthesis of Phosphorus-Containing Heterocycles
Synthesis of Silicon-Containing Heterocycles
Synthesis of Sulfur-Containing Heterocycles
Synthesis of Boron-Containing Heterocycles
Synthesis of Unsaturated Lactams
Synthesis of Unsaturated Lactones
Synthesis of Macrocycles
Synthesis of Cyclic Amino Acids and Peptidomimetics
Synthesis of Supramolecular Compounds
Enantioselective Synthesis with Chiral Catalysts
Tandem Metathesis Reactions
Solid-Phase Synthesis of Cyclic Alkenes
Ring-Closing Metathesis Reactions under Microwave Irradiation
Applications to Synthesis
Comparison with Other Methods
Experimental Conditions
General Reaction Conditions
Special Reaction and Purification Conditions
Experimental Procedures
3-Cyclopentene-1,1-dicarboxylic Acid Diethyl Ester [Ring-Closing Metathesis of Diethyl Diallylmalonate and Various Methods for Removal of Ruthenium Byproducts].
500
[Removal of Ruthenium Byproducts with Tris(hydroxymethyl)phosphine].
499
[Removal of Ruthenium Byproducts with Silica Gel/Activated Carbon].
502
4,4-Dicarboethoxy-1,2-dimethylcyclopentene [Ring-Closing Metathesis of a Sterically Hindered Diene Ester].
51, 68
(1
S
,2
S
,3
S
)-4-Cyclohexen-1,2,3-triol [Ring-Closing Metathesis of a Diene Triol].
508
(
R
)-2-Isopropenyl-3-methyl-5,6-dihydro-2
H
-pyran [Asymmetric Ring-Closing Metathesis of an Achiral Diene with a Chiral Molybdenum Catalyst].
319
1-Tosyl-2,3-dihydro-1
H
-pyrrole [Ring-Closing Metathesis of a Dienesulfonamide].
125
1,1-Dioxo-2,3,6,7-tetrahydro-1
H
-[1,2]thiazepine-7-carboxylic Acid Isopropyl Ester [Ring-Closing Metathesis of a Diene Sulfonamide with a Polymer-Bound Ruthenium Catalyst].
509
tert
-Butyl (
S
)-1-[(
S
)-5-Oxo-2,5-dihydrofuran-2-yl]-2-phenylethylcarbamate [Ring-Closing Metathesis in the Presence of a Lewis Acid to Form a γ-Lactone].
221
tert
-Butyl (3
S
,6
S
,
E
)-3-(Methoxycarbonyl)-5,12-dioxo-1-oxa-4-azacyclododec-8-ene-6-carbamate [Ring-Closing Metathesis of a Dipeptide Analog].
263
2-(3-Butenyl)-4-methyl-2,5-dihydrofuran [Ring-Opening Metathesis/Ring-Closing Metathesis Sequence in the Presence of Ethylene].
510
1-Isopropyl-2-pyrrolidinone [Tandem Metathesis/Hydrogenation Sequence of an
N
-Allyl α,β-Unsaturated Amide].
511
Tabular Survey
Chart 1 Catalysts Used in Tables
Chart 2 Ligands Used in Tables
Table 1 Synthesis of Carbocycles
Table 2A Synthesis of Cyclic Amines
Table 2B Synthesis of Cyclic Ethers
Table 2C Synthesis of Phosphorus-Containing Heterocycles
Table 2D Synthesis of Phosphorus-Containing Heterocycles
Table 2E Synthesis of Sulfur-Containing Heterocycles
Table 2F Synthesis of Sulfonamide-Containing Heterocycles
Table 2G Synthesis of Boron-Containing Derivatives
Table 2H Synthesis of Unsaturated Lactams
Table 2I Synthesis of Cyclic Peptides
Table 2J Synthesis of Unsaturated Lactones
Table 2K Synthesis of other Heterocycles Containing Multiple Heteroatoms
Table 3 Synthesis of Supramolecular Compounds
Table 4 Tandem Methathesis Reactions
References
Introduction
Olefin metathesis was defined for the first time by Calderon in 1967 as a catalytically induced reaction wherein olefins undergo bond reorganization resulting in a redistribution of alkylidene moieties.1, 2 The first observation of the metathesis of propene at high temperature was reported in 1931; the first catalyzed metathesis reactions were discovered in the 1950's when industrial chemists at Du Pont, Standard Oil, and Phillips Petroleum reported that propene led to ethylene and 2-butenes when it was heated with molybdenum on alumina.3, 4 The first polymerization of norbornene by the WCl6/Et2AlCl system was independently reported in 1960 by Eleuterio4 and by Truett.5
The number of applications of olefin metathesis in organic synthesis has increased exponentially in the last two decades. Many reviews and monographs have documented the significant advances in this field.6–25 Olefin metathesis, a process in which alkylidene groups are exchanged by the scission of carbon–carbon double bonds of alkenes, can be organized into four main categories: (1) cross-metathesis (CM),26 in which two different alkenes undergo an intermolecular reaction to form new olefinic products; (2) ring-opening metathesis polymerization (ROMP), which involves the ring-opening of strained olefins to afford polymeric olefin compounds; (3) ring-opening metathesis (ROM), which also involves ring-opening of strained olefins in the presence of an alkene to generate a diene product; and (4) ring-closing metathesis (RCM), a procedure in which a diene undergoes cyclization to afford cyclic alkenes (Scheme 1). Many examples of each of the four types of olefin metathesis reactions are reported, and each occupies a prominent and useful place in organic synthesis. This chapter focuses on the olefin ring-closing metathesis reaction.
Scheme 1
Olefin ring-closing metathesis (RCM) was first applied in organic synthesis in 1980, but the catalysts employed at that time were undefined and poorly characterized.27, 28 These early catalysts showed high activity but poor compatibility with polar functional groups, making them unattractive for the synthesis of complex molecules. Ruthenium catalysts that could polymerize functionalized monomers via metathesis were discovered in the late 1980's, although these catalysts were still undefined.29, 30
The discovery of well-defined metal alkylidene complexes with excellent functional-group tolerance, such as Schrock's molybdenum complex 131 and Grubbs's ruthenium complexes 2 and 3,32, 33 allowed applications of RCM in organic synthesis to increase at a rapid pace. The reaction can now be carried out under mild conditions with alkene precursors containing many common functional groups. Moreover, it has achieved strategy-level status in the total syntheses of many natural products and therapeutic agents that bear alkenes, and alkene synthons. This chapter will focus on developments in ring-closing metathesis reactions up to 2010.
Mechanism
The original mechanism, proposed in 1971 by Yves Chauvin, for the ring-closing metathesis reaction of dienes with ruthenium and molybdenum complexes is now generally accepted.34 Chauvin convincingly demonstrated that metal-catalyzed olefin metathesis is the result of a non-pair-wise exchange of alkylidene fragments. The process consists of a sequence of formal [2+2] cycloadditions/cycloreversions involving alkenes, metal carbenes, and metallacyclobutane intermediates. Thus, diene 4 first reacts with the active metal carbene species [M]=CH2 to generate metallacyclobutane 6 via a [2+2] cycloaddition process, which leads to the formation of alkylidene 7 (Scheme 2). Alkylidene 7 then undergoes a further [2+2] cycloaddition to generate metallacyclobutane 8, which upon cycloreversion affords cyclic alkene 5 and regenerates the metal carbene.
Scheme 2
In principle, each of the individual steps in the catalytic cycle is reversible, and an equilibrium mixture of olefins can be obtained. The forward reaction can be entropically driven because RCM transforms one substrate molecule into two products, where a volatile alkene (often ethene or propene) is removed as it is formed. The reaction can be driven by carrying it out at a high reaction temperature and/or by bubbling an inert gas through the reaction mixture to assist removal of the volatile alkene byproduct. The reverse reaction is also slowed if the product has a more highly substituted double bond than the substrate, because most metathesis catalysts are sterically sensitive. The use of high dilution conditions favors ring-closing metathesis of a diene substrate over competing polymerization via acyclic diene metathesis (ADMET).
Mechanistic studies employing 31P NMR magnetization transfer experiments and other 1H NMR and UV–vis spectroscopic techniques suggest that the overall catalytic cycle for ruthenium complexes proceeds according to the mechanism outlined in Scheme 3.35–37 The first step, catalyst initiation, involves dissociation of one PCy3 ligand to afford the highly reactive 14-electron monophosphine intermediate 9. The reaction of intermediate 9 with an olefinic substrate generates the metal monophosphine/olefin complex 10 in the second step. Finally, coupling of the olefin and alkylidene ligands within the coordination sphere of the ruthenium metal produces metallacyclobutane intermediate 11. Metallacyclobutane 11 can break down productively to form a new olefin and a new metal alkylidene product or unproductively to regenerate the starting materials.
Scheme 3
The overall catalytic activity of the ruthenium complex as outlined in Scheme 3 is dictated by the relative rates of three processes: (1) phosphine dissociation (initiation, k1), (2) phosphine recoordination (k–1), and (3) olefin binding (k2). When catalyst initiation is efficient (k1 is large), high catalytic activity is seen. The 14-electron intermediate 9 reacts rapidly with olefinic substrates relative to reaction with the free phosphine (k2/k–1 is large). These relative rates allow many catalyst turnovers to take place before phosphine recoordination.
The factors governing the catalytic activity of ruthenium carbenes of the general formula (PR13)2(X)2Ru=CHR2 have been examined in great detail.36, 37 Electron-donating phosphines with large cone angles lead to particularly active catalysts (PPh3 ≪ P(i-Pr)2Ph < PCy2Ph, P(i-Pr)3, PCy3). The bis(triphenylphosphine) complex is essentially unreactive toward a diene substrate. In contrast, the order of increasing activity for the anionic ligand is X = I < Br < Cl; the smaller and more electron-withdrawing chloride leads to a more active species. Catalyst activity is influenced dramatically by the nature of the alkylidene moiety (R2 = H < Ph < alkyl < CO2R).
Computational studies have contributed significantly to the understanding of intermediate species such as 1138–41 and the experimental evidence to support these proposed intermediates has been reported independently by several groups. The phosphonium alkylidene 12 is combined with 2.2 equivalents of ethylene in CD2Cl2 at –50° to allow the first direct observation of a 14-electron ruthenacyclobutane 13 (Scheme 4).42, 43 NMR spectroscopic data indicates that compound 13 has a C2v-symmetric structure with a flat, kite-shaped ruthenacyclobutane ring. Significant Cα–Cβ agostic interactions with the ruthenium center are also observed and are verified in another study.44 Furthermore, a NMR analysis of the reaction of phosphonium alkylidene 12 with one equivalent of ethylene at –78° in the presence of 2 equivalents of a trapping olefin reveals the formation of ruthenacyclobutane 14 which is relevant to the olefin metathesis catalytic cycle.45, 46 This ruthenacyclobutane derived from a cyclopentene derivative is more relevant to RCM than is the original spectroscopic characterization of intermediate 13. The dynamic behavior of ruthenacyclobutane-derived species 14 has been evaluated using the powerful two-dimensional NMR technique EXSY (exchange spectroscopy).
Scheme 4
The postulated scenarios for olefin binding to intermediate 15 include (1) binding preferentially trans (complex 16, bottom-face pathway) or cis (complex 17, side-on pathway) to the L-type ligand or (2) binding nonpreferentially through both intermediates 16 and 17 (Scheme 5). Upon addition of 1,2-divinylbenzene to a solution of metal alkylidene 18 in benzene, two new species in a ratio of 3:2 are observed initially by 1H NMR spectroscopy (Scheme 6).47, 48 The two ruthenium–olefin adducts undergo dynamic interconversions and on the basis of observed NOEs and a low-temperature crystal dissolution experiment, the two isomers were assigned as side-bound olefin adducts 19 (major) and 20 (minor). No evidence of a trans ruthenium–olefin adduct is observed.
Scheme 5
Scheme 6
Second-generation ruthenium complexes 21,49, 5022,51, 52 and 2353 all contain stable N-heterocyclic carbene (NHC) ligands. Compared to phosphine ligands, NHC ligands are stronger σ-donors and are much less labile. N-Heterocyclic carbene complexes 21–23 enhance the dissociation of the trans phosphine ligand from the ruthenium center to generate the active metal species that can then coordinate an olefin substrate.54, 55 The larger steric bulk and excellent electron-donating properties of the NHC ligands stabilize both the 14-electron catalyst species and the 16-electron olefin complex more effectively, thus promoting olefin metathesis.
Scope and Limitations
Catalyst Selection
The scope of the olefin metathesis reaction has expanded significantly since the initial discovery of Schrock's molybdenum complex 131 and Grubbs's ruthenium complexes 2 and 3.32, 33 The importance of these complexes derives from their activity, stability, and functional group tolerance.56, 57 In general, complexes 1–3 are all capable of catalyzing the formation of simple five-, six-, seven-, and eight-membered mono- and bicyclic ring systems. Macrocyclic rings can also be formed in a facile reaction with either Schrock's or Grubbs's complexes. Schrock's molybdenum complex 1 is air- and moisture-sensitive and is also thermally unstable. Rigorously purified and dried substrates and degassed solvents are usually required for this catalyst to mediate productive RCM reactions. In contrast, Grubbs's ruthenium complexes 2 and 3 are remarkably tolerant of oxygen and moisture. Molybdenum complex 1 is more reactive than ruthenium complex 2 but does not tolerate carboxylic acids, alcohols, or aldehydes. Conversely, catalyst 2 can usually tolerate a wider range of functional groups such as ketones, esters, amides, epoxides, alcohols, acetals, silyl ethers, carboxylic acids, aldehydes, and phosphorus-containing groups. The use of ruthenium complex 2 is problematic with functional groups such as sulfides, disulfides, and enol ethers. Molybdenum complex 1 is capable of mediating the formation of tri- and tetrasubstituted olefins, whereas ruthenium complexes 2 and 3 are most effective with di- and trisubstituted olefins.
Second-generation ruthenium complexes 2149, 50, 2251, 52 and 2353 exhibit significantly higher activities than those of the parent Grubbs carbene complexes 2 and 3. The reactivities of complexes 21–23 are similar to that of Schrock molybdenum complex 1. Furthermore, catalysts 21–23 display exceptional thermal stability, resistance toward oxygen and moisture, and compatibility with many functional groups. One of the most outstanding features of these second-generation ruthenium complexes is the ease with which tri- and tetrasubstituted olefins are formed, as these systems were not previously accessible with ruthenium complexes 2 or 3. Ruthenium complex 22 can also promote ring-closing metathesis reactions in aqueous media without any additives or cosolvents.58
A new class of ruthenium-based catalysts has allowed unique levels of reactivity in a variety of ring-closing metathesis reactions.59 Ruthenium complex 24 featuring a bidentate ligand shows good activity and is especially attractive because it can be recycled in good yield. The lateral isopropoxy group stabilizes the complex in its resting state, but opens a metal coordination site in the presence of the olefin substrate. However, complex 24 only participates in efficient metathesis reactions with terminal alkenes. Ruthenium complex 25, which does not have a phosphine ligand, displays even higher reactivity and excellent air stability, and is effective in the synthesis of tri- and tetrasubstituted alkenes.60, 61 This catalyst can also participate in ring-closing metathesis reactions in aqueous media, DME, or acetone.62 The ease of storage, handling, and the possibility of reuse and immobilization are additional advantages of this catalyst. Ruthenium alkylidene complexes 26a and 26b, bearing N-heterocyclic carbene ligands with substituted N-phenyl rings, are resistant to decomposition and are two of the most efficient catalysts for ring-closing metathesis to form tetrasubstituted olefins.63
In addition to the systems described above, many other ruthenium complexes have been developed for olefin ring-closing metathesis reactions. Many of these new catalysts have not been employed in syntheses other than those described in the original reports. Despite all these new developments, commercially available ruthenium complexes 2, 22, and 25 are those most commonly used in synthetic endeavors.
Highly active, water-soluble ruthenium complexes bearing a PEG-tagged group like catalyst 27 or a quaternary ammonium group such as catalysts 28 and 29a–c show good activity in the ring-closing metathesis of neutral and polar dienes.64 Examples of these catalysts in benchmark reactions are shown in the Tables.
Complexes 1–3
