Organic Reactions, Volume 97 E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: Organic Reactions
• Sprache: Englisch

Seitenzahl: 376

Veröffentlichungsjahr: 2019

Beschreibung

The 97th 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.

Leseprobe

Table of Contents

Cover

Introduction to the Series Roger Adams, 1942

Preface to Volume 97

Jerrold Meinwald

Introduction to the Series Scott E. Denmark, 2008

1 [2+2+2] Cycloadditions of Alkynes with Heterocumulenes and Nitriles

Acknowledgments

Introduction

Mechanism and Stereochemistry

Scope and Limitations

Applications to Synthesis

Comparison With Other Methods

Experimental Conditions

Experimental Procedures

Tabular Survey

References

Supplemental References for Table 1B

Supplemental References for Table 1C

Supplemental References for Table 3

Supplemental References for Table 5

Supplemental References for Table 6

Supplemental References for Table 7

Supplemental References for Table 8A

Supplemental References for Table 8B

Supplemental References for Table 8C

Supplemental References for Table 8E

Supplemental References for Table 8F

2 Amide‐Forming Ligation Reactions

Introduction

Mechanism and Stereochemistry

Scope and Limitations

Comparison with Other Methods

Experimental Conditions

Experimental Procedures

Tabular Survey

References

Supplemental References for Table 1: Capture/Rearrangement Strategy for Ligation

Supplemental References for Table 2: Native Chemical Ligation

Supplemental References for Table 3: Staudinger Ligation

Supplemental References for Table 4: α‐Ketoacid–Hydroxylamine Ligation

Supplemental References for Table 5: Potassium Acyltrifluoroborate–Hydroxylamine Ligation

Supplemental References for Table 6: Synthesis of Peptides and Proteins with Orthogonal Ligation Strategies

Cumulative Chapter Titles by Volume

Author Index, Volumes 1-97

CHAPTER AND TOPIC INDEX, VOLUMES 1–97

End User License Agreement

List of Illustrations

Chapter 1

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Chapter 2

Figure 1 Concept of chemoselective amide ligation for peptide and protein synt...

Figure 2 Cartoon illustrating advantages of chemoselective ligation of unprotec...

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Figure 3 Structures of templates used for prior thiol capture ligation.

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Figure 5 Cysteine surrogates successfully utilized in native chemical ligation.

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Figure 7 Homoserine as a surrogate for selected canonical amino acids.

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Figure 8 Functional groups that emulate α‐ketoacid and hydroxylamine groups.

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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

Leo A. Paquette

Huw M. L. Davies

T. V. RajanBabu

John Fried

Hans J. Reich

Jacquelyn Gervay-Hague

James H. Rigby

Heinz W. Gschwend

William R. Roush

Stephen Hanessian

Tomislav Rovis

Louis Hegedus

Scott D. Rychnovsky

Paul J. Hergenrother

Martin Semmelhack

Jeffrey S. Johnson

Charles Sih

Robert C. Kelly

Amos B. Smith, III

Laura Kiessling

Barry M. Trost

Marisa C. Kozlowski

James D. White

Steven V. Ley

Peter Wipf

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 97

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

Jeffrey W. Bode Janis Louie Ayodele O. Ogunkoya Vijaya R. Pattabiraman Nicholas D. Staudaher Ryan M. Stolley

Copyright

Copyright © 2018 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: 978-1-119-37454-1

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.

Preface to Volume 97

Multicomponent reactions (MCRs) are generally defined as reactions in which three or more starting materials react to form a product, where basically all or most of the atoms contribute to the newly formed product.

Ivar Ugi, Alexander Dömling and Werner Hörl

Endeavor1994, 18, 115

One of the most powerful strategies for creating molecular complexity from simple building blocks is to leverage the power of multicomponent reactions (MCRs). The highly modular nature of MCRs allows for the production of large collections (libraries in common parlance) of compounds through the combinatorial assembly of common components. Many types of chemical reactions have been developed that constitute MCRs such as the Strecker, Hantzsch, Biginelli, Passerini, Mannich, and Bucherer‐Bergs Reactions, and of course the most famous of all, the Ugi Reaction. All of these reactions have the common theme of being derived from the chemistry of carbonyl groups. The first chapter in this Volume is a rare breed of MCR that arises from the combination of alkynes, nitriles and heterocumulenes in [2+2+2] cycloadditions to produce a diverse family of six‐membered ring products.

“[2+2+2] Cycloadditions of Alkynes with Heterocumulenes and Nitriles” provides a thorough illustration of the diversity of avenues available to just a few simple building blocks composed by one of the leading authorities, Professor Janis Louie together with her students Nicholas D. Staudaher and Ryan M. Stolley. These authors provide a unifying mechanistic scheme that is operative for a wide variety of transition‐metal catalysts including nickel, cobalt, rhodium, ruthenium, iron and iridium. Particular attention is given to the recent use of low‐valent titanium(II) complexes to overcome the problems of chemoselectivity when two different alkynes are combined with a nitrile. The heterocumulenes that eagerly participate in this process include carbon disulfide, carbon dioxide, isocyanates, isothiocyanates, carbodiimides and ketenes. One needs little imagination to realize the diversity of hexacyclic products that will arise from these combinations. Moreover, the synthetic utility of these reactions is greatly increased by combining two of the components into a single molecule, thus preordaining the connectivity and constitution of the products. The authors provide excellent guidance for the selection of catalysts that are preferred for each combination of precursors and also illustrate recent advances that employ chiral catalysts for the control of newly formed stereogenic centers in the hexacyclic products. Some truly impressive applications are featured that involve multiple [2+2+2] cycloaddition cascades from tetraynes together with nitriles to produce highly substituted biisoquinolines. Not surprisingly, reaction manifolds that allow for the construction of many bonds in a single operation have been used in complex molecule total synthesis and the authors have provided awe‐inspiring illustrations in the synthesis of various families of alkaloids. The comprehensive Tabular Survey (updated through 2017) is nicely organized by the reaction components thus facilitating easy discovery of the target products one may wish to prepare by this unusual family of MCRs.

The second chapter in this Volume does not feature a MCR, but rather constitutes multi‐reaction components! In a slight departure from the long‐standing policy that Organic Reactions chapters describe a single reaction type, we have chosen to feature a class of reactions that lead to a very specific functional group. To justify this departure, clearly that functional group must be extremely important and indeed, the amide linkage qualifies as such a privileged functional group. It is impossible to overstate the significance of the amide bonds that form the basis for all oligopeptides and proteins nor is it possible to overstate the importance of these biopolymers to the entire domain of biology. For chemists to enable research directed toward understanding the foundations of structural biology, biosynthesis, metabolism, cellular function and regulatory process, they must be able to provide access to custom‐designed proteins. Surely, traditional solid‐phase synthesis has revolutionized the ability to generate research quantities of peptides in the 35‐45 residue range and modern molecular biological methods have also made great strides in providing access to unique sequences. However, these methods face limitations in producing peptides in hundred‐kilogram quantities and specifically large peptides in ultra‐high purity. Moreover, incorporation of non‐natural amino acids or isotopically labeled amino acids represent additional challenges. To address these challenges, the field of chemical ligation has emerged as a powerful solution to link together in a convergent fashion oligopeptide building blocks by enabling highly site selective amide bond formation.

We are very fortunate that one of the world's experts in developing imaginative chemical ligation methods, Professor Jeffrey W. Bode has agreed to compose this non‐traditional chapter together with his students Vijaya R. Pattabiraman and Ayodele O. Ogunkoya. “Amide‐Forming Ligation Reactions” is a brilliant survey of the state of the art of these ingenious solutions to the superficially mundane problem of forming an amide bond. The authors provide a clear analysis of the challenges associated with engineering reaction partners that will find each other with exquisite selectivity in the sea of other reactive functions on side chains and of course with many other peptide linkages. From the clear formulation of the boundary conditions, the reader is prepared to appreciate the remarkable successes accomplished by the insightful tactics such as native chemical ligation using cysteine residues and the modification of amino acids other than cysteine to enable unions at different sites. From the authors' own laboratories, the extremely clever α‐ketoacid hydroxylamine (KAHA) ligation and potassium acyltrifluoroborate‐hydroxylamine (KAT) ligation are described in detail. The illustration of all of the different methods in highly challenging syntheses of proteins comprised of more than 200 amino acid residues makes the compelling case of the success of these chemical methods. Because of the non‐traditional coverage, the Tabular Survey is organized by ligation method as the first rubric but within each overarching protocol, different classes of peptides and proteins are subdivided. We hope that researchers in biologically intensive fields will be alerted to the utility of these methods and especially the value of coverage offered in our series.

It is appropriate here to acknowledge the expert assistance of the entire editorial board, in particular Gary A. Molander (Chapter 1) and Paul Hergenrother (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, Dr. Robert M. Coates, Dr. Landy Blasdel, and Dr. Debra 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

Jerrold Meinwald

(January 26, 1927 – April 23, 2018)

Jerrold (Jerry) Meinwald was born in New York City in 1927. At a very early age, Jerry developed a passion for chemistry after reading a biochemistry textbook on the beach. Together with his good friend, Michael Cava, the two were producing homemade fireworks displays for their neighbors and began performing experiments in a home laboratory, acquiring the necessary chemicals from drug stores and supply houses. Jerry graduated from Stuyvesant High School, and briefly attended Brooklyn College and Queens College. During 1945–46 he served as an electronics technician in the US Navy, then earned a Ph.B. (1947) and B.S. (1948) in Chemistry at the University of Chicago. At Harvard University he completed M.A. (1950) and Ph.D. (1952) degrees, working with R.B. Woodward. Jerry joined the Cornell faculty in 1952 and spent most of his subsequent career in Ithaca. He was named Goldwin Smith Professor of Chemistry (1980–2005) and held the Andrew Mellon Foundation Professorship (1993–95). Jerry served on the Board of Editors of Organic Reactions for Volumes 18–25 (1970–77) and stayed on the Editorial Advisory Board until his death.

Jerry Meinwald's work was widely recognized across the world. He was elected to the National Academy of Sciences (1969), the American Academy of Arts and Sciences (1970, serving as secretary from 2005–16), and the American Philosophical Society (1987). He was an Alfred P. Sloan Foundation Fellow (1958–62) and twice a John Simon Guggenheim Foundation Fellow (1960–61 and 1976–77). His awards include the Tyler Prize in Environmental Achievement (1990), the Heyrovsky Medal of the Academy of Sciences of the Czech Republic (1996), the American Chemical Society's Roger Adams Award in Organic Chemistry (2005), the Grand Prix de la Fondation de la Maison de la Chimie (2006), the Benjamin Franklin Medal in Chemistry (2013), and the Nakanishi Award of the Chemical Society of Japan (2014). In 2014, President Obama presented him the 2012 National Medal of Science.

It is difficult to overstate the impact of Meinwald's work in the field of chemical ecology, since as its earliest practitioner, he set the standards of excellence by which all others in the field are judged. By focusing on biotic interactions and their mediating molecules – on the signals of courtship, defense, and parental maintenance – Jerry (along with Tom Eisner) established beyond any doubt that both the theoretical and the practical value of nature lies in its molecules. Through discoveries that have become landmarks, he has elucidated the intricacies of countless natural interactions involving insects and plants. Acutely aware of the long‐range implications of species loss, he and Tom Eisner argued persuasively, through their extensive publications and lectures worldwide, for the preservation of nature and the chemical capital it provides.

Jerry's first major plant‐related chemical discovery was to establish the structure of nepetalactone, the component in “catnip” that attracts and intrigues cats. Returning to plants again years later in a spectacular study of the chemistry of lepidopteran courtship, Jerry showed how female moths use compounds from a plant dietary source to screen for the most fit male sexual partners. In essence, the female tiger moth, Utetheisa ornatrix, emits a mixture of C18 trienes and tetraenes that attracts males from a distance. A courting male then signals the female at close range with a pheromone biosynthesized from a plant‐derived pyrrolizidine alkaloid that the male has sequestered from his diet.

Females avoid mating with a male who does not provide this chemical cue. However, the male with the appropriate pheromone is accepted, and transmits to the female a spermatophor (up to 10% of his body weight!) containing not only sperm, but also residual alkaloid. Some of the alkaloid is retained by the female and some is incorporated into her fertilized eggs, rendering the female and her eggs unpalatable to predators and parasites.

During his long career at Cornell, Jerry trained generations of chemists, including many leading researchers in both organic chemistry and chemical ecology. He published over 400 journal articles with some 200 collaborators. In the early 1970s, he was a founding Research Director of the International Center for Insect Physiology and Ecology headquartered in Nairobi, Kenya.

Jerry Meinwald was also a superbly gifted teacher, and taught Cornell's legendary “Introduction to Organic Chemistry” for many years. He went on to create the highly innovative course, “The Language of Chemistry,” which helped many hundreds of “nonscientist” Cornell undergraduates meet their science requirement while learning a significant amount of contemporary organic chemistry. Educating nonscientists was important to Jerry; he strived to boost scientific literacy among non‐science majors at the college and university level. In 2010 he co‐headed an American Academy of Arts and Sciences study of “Science in the Liberal Arts Curriculum,” which was aimed at examining what science requirements our institutions of higher learning have established for their non‐science majors, why they have these requirements, whether those requirements actually produced the desired results, and whether current curricula might be modernized and strengthened to produce a more science‐literate citizenry.

Jerry was a talented flutist. He studied flute with Arthur Lora, James Pappoutsakis, and Marcel Moyse. Throughout his life, he enjoyed playing music with (and for) colleagues, friends, and family members, often with wife Charlotte Greenspan at the keyboard. One of his friends recounts traveling with him when a flight to a chemical meeting was delayed. He sat down in the midst of an impatient crowd, took out his flute and started practicing. He and his wife were present, it seems, at every Cornell musical event.

Jerry Meinwald is survived by Charlotte Greenspan, his wife of 37 years; their daughter, Julia; and Constance and Pamela, daughters of his first marriage. He is also survived by his first wife, Yvonne Chu, who was his earliest long‐term chemical collaborator.

To everyone, not just his colleagues, Jerry was a sweet man. It is impossible to think of him without a smile. And that is how he will be remembered.

Bruce Ganem

Cornell University

Ithaca, New York

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.

1[2+2+2] Cycloadditions of Alkynes with Heterocumulenes and Nitriles

Nicholas D. Staudaher Ryan M. Stolley and Janis Louie

Department of Chemistry, University of Utah, Salt Lake City, UT, 84112

Acknowledgments

Introduction

Mechanism and Stereochemistry

Transition‐Metal‐Catalyzed Cycloadditions

Cycloadditions of Alkenyl Isocyanates and Alkynes

Low Valent Titanium‐Mediated Cycloadditions of Alkynes and Nitriles

Nucleophile‐Catalyzed Cycloadditions

Isocyanate Trimerization

Cycloaddition of Carbon Disulfide with Two Ketenes

Scope and Limitations

Cycloadditions of Isocyanates

Diynes and Isocyanates

Alkynes and Isocyanates

Alkenyl Isocyanates

Multiple Isocyanates

Cycloadditions of Other Heterocumulenes

Carbodiimides

Carbon Disulfide

Isothiocyanates

Carbon Dioxide

Ketenes

Ketenes and Carbon Disulfide

Diynes and Ketenes

Cycloadditions of Nitriles and Oximes

Alkynes and Nitriles

Diynes and Nitriles

Alkyne–Nitriles and Alkynes

Alkyne–Nitriles and Nitriles

Alkyne–Alkyne–Nitriles

Diynes and Oximes

Applications to Synthesis

Comparison With Other Methods

Experimental Conditions

Experimental Procedures

4,7‐Dimethyl‐5‐phenyl‐2‐(toluene‐4‐sulfonyl)‐1,2,3,5‐tetrahydropyrrolo[3,4‐

c

]pyridin‐6‐one [Ni–NHC Catalyzed Cycloaddition of a Diyne and an Isocyanate]. 36

5‐

n

‐Butyl‐4‐methyl‐7‐phenylfuro[3,4‐

c

]pyridine‐3,6(1

H

,5

H

)‐dione [Ir–Biphosphine Catalyzed Cycloaddition of an Unsymmetrical Diyne and an Isocyanate]. 39

(

Z

)‐11‐Phenyl‐11,12‐dihydro‐6,10‐dioxa‐1(4,6)‐pyridina‐8(1,2)‐benzenocyclotetradecaphan‐12‐one and (13

Z

,15

Z

)‐11‐Phenyl‐11,12‐dihydro‐6,10‐dioxa‐1(3,6)‐pyridina‐8(1,2)‐benzenocyclotetradecaphan‐12‐one [Synthesis of Pyridoneophanes by Co‐Catalyzed Cycloaddition of an Isocyanate and a Diyne with a Long Tether]. 41

1‐Ethyl‐4,6‐di((

E

)‐prop‐1‐en‐1‐yl)‐3,5‐bis(trimethylsilyl)pyridin‐2(1

H

)‐one [Regioselective Ni‐Catalyzed Cycloaddition of Two Molecules of an Enyne and an Isocyanate]. 47

1‐Benzyl‐4,5‐di(cyclohex‐1‐en‐1‐yl)pyridin‐2(1

H

)‐one [Rh‐Catalyzed Regioselective Cycloaddition of a Terminal Monoalkyne and an Isocyanate]. 37

(

R

)‐5‐Phenyl‐2,3,8,8a‐tetrahydroindolizin‐7(1

H

)‐one (major) and (

S

)‐7‐Phenyl‐2,3,8,8

a

‐tetrahydroindolizin‐5(1

H

)‐one (minor) [Enantioselective Rh‐Catalyzed Cycloaddition of a Terminal Monoalkyne with an Alkenyl Isocyanate]. 52

1,3,5‐Tris(4‐methoxyphenyl)‐1,3,5‐triazinane‐2,4,6‐trione [NHC‐Catalyzed Trimerization of an Isocyanate]. 32

2,4‐Tolyl‐3,4‐tolylimino‐2,3,5,7‐tetrahydro[2]pyrindine‐6,6‐dicarboxylic Diacid, Dimethyl Ester [Rh‐Catalyzed Cycloaddition of a Diyne and a Carbodiimide]. 60

6,6‐Bis((benzyloxy)methyl)‐1,4‐dimethyl‐6,7‐dihydrocyclopenta[

c

]pyran‐3(5

H

)‐one [Ni‐Catalyzed Cycloaddition of Carbon Dioxide and a Diyne]. 65

Tetramethyl 6‐Ethyl‐6‐(4‐methoxyphenyl)‐5,8‐dimethyl‐7‐oxo‐1,4,6,7‐tetrahydronaphthalene‐2,2,3,3‐tetracarboxylate [Ni‐Catalyzed Cycloaddition of a Diyne and a Ketene]. 68

3,6‐Bis(4‐fluorophenyl)‐

N

,

N

‐dimethylpyridin‐2‐amine [Cycloaddition of a Terminal Monoalkyne and a Cyanamide Catalyzed by Fe]. 73

Diethyl 3‐Methyl‐1‐phenyl‐4‐trimethylsilyl‐5,7‐dihydro‐6

H

‐cyclopenta[

c

]pyridine‐6,6‐dicarboxylate [Cycloaddition of an Unsymmetrical Diyne and a Nitrile Catalyzed by a Co‐Catalyst Generated in Situ]. 82

1,4‐Dimethyl‐3‐phenyl‐6,7‐dihydro‐5

H

‐cyclopenta[

c

]pyridine [Ni–Xantphos Catalyzed Cycloaddition of a Diyne and a Nitrile]. 88

Dimethyl 3‐(Fluoromethyl)‐5,7‐dihydro‐6

H

‐cyclopenta[

c

]pyridine‐6,6‐dicarboxylate [Ru‐Catalyzed Cycloaddition of a Terminal Diyne with a Halonitrile]. 91

Dimethyl 2,3‐Diethyl‐4‐methyl‐5,7‐dihydro‐6

H

‐cyclopenta[

b

]pyridine‐6,6‐dicarboxylate [Fe–PDAI Catalyzed Cycloaddition of an Alkyne–Nitrile and an Alkyne]. 94

Benzyl 6‐Tosyl‐5‐(trimethylsilyl)‐1,3,6,7,8,9‐hexahydro‐2

H

‐pyrrolo[3,4‐

f

][1,7]naphthyridine‐2‐carboxylate [Co‐Catalyzed Intramolecular Cycloaddition of an Alkyne–Alkyne–Nitrile]. 96

Tabular Survey

Acknowledgments

We thank Gary Molander, Tom Rovis, Linda Press, and the other members of the Organic Reactions Editorial Board for useful input at all stages in the preparation of this article. We are also grateful to Wenxing Guo for detailed English translations of several German journal articles.

Introduction

The [2+2+2] cycloaddition of unsaturated systems has proven to be an atom‐economical way to create carbocycles and heterocycles rapidly. In 1866, Berthelot discovered that acetylene could be thermally converted to benzene.1 Over 80 years later, in 1948, nickel complexes were found to catalyze the same trimerization at much lower temperatures.2 The first examples of [2+2+2] cycloadditions using heterocumulenes emerged in the 1970s, and the number of publications in this area has increased dramatically over the last decade. The heterocumulenes that have been utilized as substrates include isocyanates, isothiocyanates, carbodiimides, carbon dioxide, carbon disulfide, and ketenes. Although a wide array of 6‐membered heterocycles can be prepared, little is known about how transition‐metal catalysts facilitate the cycloaddition reactions. In contrast, reactions of nitriles, a class of substrates believed to undergo cycloadditions with alkynes by a similar mechanism as heterocumulene substrates, have been mechanistically well‐explored. Overall, these reactions typically create six‐membered heterocycles from two alkynes and a heterocumulene. The types of heterocycles that can be constructed with this chemistry are quite broad (Scheme 1). In addition, these heterocyclic products are useful synthetic building blocks because they are prevalent in a wide array of natural products, pharmacologically important compounds, transition‐metal ligands, and organic light‐emitting diode materials.

Scheme 1

This chapter is limited to the [2+2+2] cycloadditions involving heterocumulenes with one exception: the cycloadditions of nitriles are included. Several reviews on [2+2+2] cycloadditions have appeared recently. These reviews tend to be general to [2+2+2] cycloadditions,3–6 or specific to a substrate, product, or catalyst. For example, metal‐catalyzed pyridine synthesis has been reviewed in depth.7–13 Construction of macrocycles has been reviewed,14 as well as enantioselectivity in [2+2+2] cycloadditions.15,16 The rhodium‐catalyzed cycloaddition of alkenyl isocyanates and alkynes has also been reviewed.17 Tanaka has written a thorough treatment of [2+2+2] cycloadditions.18 No reviews specifically on [2+2+2] cycloaddition of heterocumulenes are extant. In this chapter the literature from the 1970s through early 2014 is covered in the case of heterocumulenes. Cycloadditions of nitriles are reviewed in a separate Organic Reactions chapter,19 which covers the literature through 2004. This chapter will therefore include the literature from 2004 to early 2014 where nitriles are concerned.

Mechanism and Stereochemistry

Transition‐Metal‐Catalyzed Cycloadditions

Owing to the broad scope of transition‐metal‐catalyzed cycloadditions, the specific details of each reaction mechanism can vary greatly. Yet, despite the large number of catalysts (Ni, Co, Rh, Ru, Fe, and Ir), the number and identity of nitriles or heterocumulenes (isocyanates, carbodiimides, carbon disulfide, isothiocyanates, carbon dioxide, ketenes) incorporated into the product, the identity of the coupling partners (alkenes or alkynes), and whether two or more coupling partners are tethered, all reactions follow the same general mechanism. For simplicity, we will illustrate a general reaction in which two equivalents of acetylene are coupled with one equivalent of acetonitrile by a nondescript metal catalyst, forming 2‐methylpyridine (Scheme 2). Two pathways are possible in such a scheme. The first one, called the homocoupling pathway, is thought to be operative with Co,20 Ru,21 and Ir.22 It is initiated by coordination of two alkynes to the metal, affording bis‐alkyne complex 1, which undergoes oxidative coupling of the alkynes, forming metallacycle 2. Complex 2 can react with the nitrile either by [4+2] cycloaddition to form 3, [2+2] cycloaddition to form 4, or 5 can be produced by insertion of the nitrile into one of the metal–carbon bonds of 2. Reductive elimination then occurs to afford pyridine 6 and to regenerate the catalyst. 21 Conversely, Ni is believed to promote an alternative heterocoupling pathway, which is initiated by formation of alkyne–nitrile complex 7 following coordination of one alkyne and one nitrile to the metal.23,24 This complex undergoes a heterooxidative coupling, affording azametallacycle 8. This metallacycle can undergo [4+2], [2+2], and insertion reactions with an alkyne similar to those for intermediate 2 in the homocoupling pathway, forming 9, 10, or 11, respectively. Again, reductive elimination forms pyridine 6 and regenerates the reduced metal species. 21

Scheme 2

According to calculations of oxidative coupling of two alkenes on a Fe(CO)3 fragment25 and experimental observations of oxidative coupling of two alkynes on a CpCo fragment, 20 these events can be controlled by electronic or steric effects (Scheme 3). The computational study indicates that the π substituent atom with the largest LUMO (lowest unoccupied molecular orbital) coefficient prefers to be β to the metal because of better mixing of the π* and filled dxy orbitals in the transition structure. The experimental observations on the regioselectivity of oxidative couplings of CpCo bis alkyne complexes indicate that two identical, unsymmetrical alkynes can coordinate head to head and cyclize such that the large groups are α to the metal. The isomer with both large groups β to the metal is not observed, because of steric repulsion in the transition structure leading to this complex. However, the most favored pathway involves the alkynes coordinating head to tail, which reduces steric repulsion in the bisalkyne intermediate, and cyclization leads to the favored product, metallacycle 12.

Scheme 3

In the case of the homocoupling pathway and diynes with short tethers, the regioselectivity is determined by the diyne, which can cyclize only one way (Scheme 4). 21 , 22 The oxidative coupling step is usually rate determining, and in the case of unsymmetrical diynes, the regioselectivity is dictated by the insertion, in which the heterocumulene or nitrile inserts into the least hindered metal–carbon bond, with the heteroatom bound to the metal. Reductive elimination yields the constitutional isomer with the small R group proximal to the heteroatom in the ring.

Scheme 4

Cycloadditions of Alkenyl Isocyanates and Alkynes

Of all the transition‐metal‐catalyzed [2+2+2] cycloadditions, the rhodium‐catalyzed intramolecular cycloaddition of alkenyl isocyanates and alkynes is one of the best understood mechanistically. The reaction provides indolizidine scaffolds in the form of lactams and vinylogous amides (Scheme 5).26

Scheme 5

The experimental evidence suggests that the mechanism proceeds by an oxidative cyclization of alkyne and isocyanate on Rh–phosphoramidite complex 13 (Scheme 6). 26 X‐ray crystal structures of Rh(I)–phosphoramidite–COD complexes indicate stronger back‐bonding to the π substituent trans to the phosphoramidite. Given that isocyanates are more electron poor than alkynes and can therefore accept more back donation, it is postulated that the isocyanate coordinates trans to the phosphoramidite, whereas the alkyne is trans to the chloride. Because of the size of the phosphoramidite ligand, the isocyanate carbonyl and the terminus of the alkyne are pointed in the same direction. Complex 13