Table Of ContentContents of All Volumes
Volume 1 Additions to C-X Tr-BondsP, art 1
Nonstabilized Carbanion Equivalents
1.1 Carbanions of Alkali and Alkaline Earth Cations: (i) Synthesis and Structural Characterization
1.2 Carbanions of Alkali and Alkaline Earth Cations: (ii) Selectivity of Carbonyl Addition Reactions
1.3 Organoaluminum Reagents
1.4 Organocopper Reagents
1.5 Organotitanium and Organozirconium Reagents
1.6 Organochromium Reagents
1.7 Organozinc, Organocadmium and Organomercury Reagents
1.8 Organocerium Reagents
1.9 Samarium and Ytterbium Reagents
1.10 Lewis Acid Carbonyl Complexation
1.1 1 Lewis Acid Promoted Addition Reactions of Organometallic Compounds
1.12 Nucleophilic Addition to Imines and Imine Derivatives
1.13 Nucleophilic Addition to Carboxylic Acid Derivatives
Heteroatom-stabilized Carbanion Equivalents
2.1 Nitrogen Stabilization
2.2 Boron Stabilization
2.3 Sulfur Stabilization
2.4 The Benzoin and Related Reactions
2.5 Silicon Stabilization
2.6 Selenium Stabilization
Transformation of the Carbonyl Group into Nonhydroxylic Groups
3.1 Alkene Synthesis
3.2 Epoxidation and Related Processes
3.3 Skeletal Reorganizations: Chain Extension and Ring Expansion
Author Index
Subject Index
Volume 2 Additions to C-X m-Bonds, Part 2
Uncatalyzed Additions of Nucleophilic Alkenes to C-X
1.1 Allyl Organometallics
1.2 Heteroatom-stabilized Allylic Anions
1.3 Propargyl and Allenyl Organometallics
1.4 Formation of Enolates
1.5 The Aldol Reaction: Acid and General Base Catalysis
1.6 The Aldol Reaction: Group I and Group I1 Enolates
1.7 The Aldol Reaction: Group I11 Enolates
1.8 Zinc Enolates: the Reformatsky and Blaise Reactions
1.9 The Aldol Reaction: Transition Metal Enolates
1.10 The Henry (Nitroaldol) Reaction
1.11 The Knoevenagel Reaction
1.12 The Perkin Reaction
1.13 Darzens Glycidic Ester Condensation
1.14 Metal Homoenolates
1.15 Use of Enzymatic Aldol Reactions in Synthesis
1.16 Metalloenamines
xv
xvi Contents of All Volumes
1.17 Hydrazone Anions
Catalyzed Additions of Nucleophilic Alkenes to C==X
2.1 The Prins and Carbonyl Ene Reactions
2.2 Allylsilanes, Allylstannanes and Related Systems
2.3 Formation and Addition Reactions of Enol Ethers
2.4 Asymmetric Synthesis with Enol Ethers
2.5 Reactions of Activated Dienes with Aldehydes
Addition-Elimination Reactions (Acylations)
3.1 The Aliphatic Friedel-Crafts Reaction
3.2 The Bimolecular Aromatic Friedel-Crafts Reaction
3.3 The Intramolecular Aromatic Friedel-Crafts Reaction
3.4 The Reimer-Tiemann Reaction
3.5 The Vilsmeier-Haack Reaction
3.6 Acylation of Esters, Ketones and Nitriles
3.7 The Eschenmoser Coupling Reaction
Additions of Nucleophilic Alkenes to C=NR and C=NR2+
4.1 The Bimolecular Aliphatic Mannich and Related Reactions
4.2 The Bimolecular Aromatic Mannich Reaction
4.3 Reactions of Allyl and Propargyl/Allenic Organometallics with Imines and Iminium Ions
4.4 The Intramolecular Mannich and Related Reactions
4.5 Additions to N-Acyliminium Ions
4.6 The Passerini and Ugi Reactions
Author Index
Subject Index
Volume 3 Carbon-Carbon a-Bond Formation
Alkylation of Carbon
1.1 Alkylations of Enols and Enolates
1.2 Alkylations of Nitrogen-stabilized Carbanions
1.3 Alkylations of Sulfur- and Selenium-containing Carbanions
1.4 Alkylations of Other Heteroatom-stabilized Carbanions
1.5 Alkylations of Nonstabilized Carbanions
1.6 Alkylations of Vinyl Carbanions
1.7 Alkylations of Alkynyl Carbanions
1.8 Friedel-Crafts Alkylations
1.9 Polyene Cyclizations
1.10 Transannular Electrophilic Cyclizations
Coupling Reactions
2.1 Coupling Reactions Between sp3 Carbon Centers
2.2 Coupling Reactions Between sp3 and sp2 Carbon Centers
2.3 Coupling Reactions Between sp2 Carbon Centers
2.4 Coupling Reactions Between sp2 and sp Carbon Centers
2.5 Coupling Reactions Between sp Carbon Centers
2.6 Pinacol Coupling Reactions
2.7 Acyloin Coupling Reactions
2.8 Kolbe Reactions
2.9 Oxidative Coupling of Phenols and Phenol Ethers
Rearrangement Reactions
3.1 Wagner-Meerwein Rearrangements
Contents of All Volumes xvii
3.2 The Pinacol Rearrangement
3.3 Acid-catalyzed Rearrangements of Epoxides
3.4 The Semipinacol and Other Rearrangements
3.5 Dienone-Phenol Rearrangements and Related Reactions
3.6 Benzil-Benzilic Acid Rearrangements
3.7 The Favorskii Rearrangement
3.8 The Rarnberg-Backlund Rearrangement
3.9 The Wolff Rearrangement
3.10 The Stevens and Related Rearrangements
3.11 The Wittig Rearrangement
Other Carbon-Carbon Bond Forming Reactions
4.1 Carbonylation and Decarbonylation Reactions
4.2 Carbon-Carbon Bond Formation by C-H Insertion
Author Index
Subject Index
Volume 4 Additions to and Substitutions at C-C s-Bonds
Polar Additions to Activated Alkenes and Alkynes
1.1 Stabilized Nucleophiles with Electron Deficient Alkenes and Alkynes
1.2 Conjugate Additions of Reactive Carbanions to Activated Alkenes and Alkynes
1.3 Conjugate Additions of Carbon Ligands to Activated Alkenes and Alkynes Mediated by
Lewis Acids
1.4 Organocuprates in the Conjugate Addition Reaction
1.5 Asymmetric Nucleophilic Additions to Electron Deficient Alkenes
1.6 Nucleophilic Addition-Electrophilic Coupling with a Carbanion Intermediate
1.7 Addition of H-X Reagents to Alkenes and Alkynes
1.8 Electrophilic Addition of X-Y Reagents to Alkenes and Alkynes
1.9 Electrophilic Heteroatom Cyclizations
Nucleophilic Aromatic Substitutions
2.1 Arene Substitution via Nucleophilic Addition to Electron Deficient Arenes
2.2 Nucleophilic Coupling with Aryl Radicals
2.3 Nucleophilic Coupling with Arynes
2.4 Nucleophilic Addition to Arene-Metal Complexes
Polar Additions to Alkenes and Alkynes
3.1 Heteroatom Nucleophiles with Metal-activated Alkenes and Alkynes
3.2 Carbon Nucleophiles with Alkenes and Alkynes
3.3 Nucleophiles with Allyl-Metal Complexes
3.4 Nucleophiles with Cationic Pentadienyl-Metal Complexes
3.5 Carbon Electrophiles with Dienes and Polyenes Promoted by Transition Metals
Nonpolar Additions to Alkenes and Alkynes
4.1 Radical Addition Reactions
4.2 Radical Cyclizations and Sequential Radical Reactions
4.3 Vinyl Substitutions with Organopalladium Intermediates
4.4 Carbometallation of Alkenes and Alkynes
4.5 Hydroformylation and Related Additions of Carbon Monoxide to Alkenes and Alkynes
4.6 Methylene and Nonfunctionalized Alkylidene Transfer to Form Cyclopropanes
4.7 Formation and Further Transformations of 1,l- Dihalocyclopropanes
4.8 Addition of Ketocarbenes to Alkenes, Alkynes and Aromatic Systems
4.9 Intermolecular 1,3-DipolarC ycloadditions
4.10 Intramolecular 1,3-DipolarC ycloadditions
xviii Contents of All Volumes
Author Index
Subject Index
Volume 5 Combining C-C n-Bonds
Ene Reactions
1.1 Ene Reactions with Alkenes as Enophiles
1.2 Metallo-ene Reactions
+
12 21 Cycloadditions
2.1 Thermal Cyclobutane Ring Formation
2.2 Formation of Four-membered Heterocycles
2.3 Photochemical Cycloadditions
2.4 The Paterno-Buchi Reaction
2.5 Di-.rr-methane Photoisomerizations
2.6 Oxa-di-.rr-methaneP hotoisomerizations
13 + 21 Cycloadditions
3.1 Thermal Cycloadditions
3.2 Transition Metal Mediated Cycloadditions
+
[4 21 Cycloadditions
4.1 Intermolecular Diels-Alder Reactions
4.2 Heterodienophile Additions to Dienes
4.3 Heterodiene Additions
4.4 Intramolecular Diels-Alder Reactions
4.5 Retrograde Diels-Alder Reactions
Higher-order Cycloadditions
5.1 [4 + 31 Cycloadditions
5.2 [4 + 41 and [6 + 41 Cycloadditions
+ +
5.3 [3 21 and [5 21 Arene-Alkene Photocycloadditions
Electrocyclic Processes
6.1 Cyclobutene Ring Opening Reactions
6.2 1,3-CyclohexadieneF ormation Reactions
6.3 Nazarov and Related Cationic Cyclizations
Sigmatropic Processes
7.1 Cope, Oxy-Cope and Anionic Oxy-Cope Rearrangements
7.2 Claisen Rearrangements
7.3 Consecutive Rearrangements
Small Ring Rearrangements
8.1 Rearrangements of Vinylcyclopropanes and Related Systems
8.2 Rearrangements of Divinylcy clopropanes
8.3 Charge-accelerated Rearrangements
Other Transition Metal Associated Reactions
9.1 The Pauson-Khand Reaction
9.2 Metal-Carbene Cycloadditions
9.3 Alkene Metathesis and Related Reactions
9.4 [2 + 2 + 21 Cycloadditions
9.5 Zirconium-promoted Bicyclization of Enynes
9.6 Metal-catalyzed Cycloadditions of Small Ring Compounds
Contents of All Volumes xix
Author Index
Subject Index
Volume 6 Heteroatom Manipulation
Displacement by Substitution Processes
1.1 Synthesis of Alcohols and Ethers
1.2 Synthesis of Glycosides
1.3 Synthesis of Amines and Ammonium Salts
1.4 Synthesis of Nitroso, Nitro and Related Compounds
1.5 Synthesis of Sulfides, Sulfoxides and Sulfones
1.6 Synthesis of Phosphonium Ylides
1.7 Synthesis of Halides
1.8 Synthesis of Pseudohalides, Nitriles and Related Compounds
1.9 Ritter-type Reactions
Acylation-type Reactions
2.1 Synthesis of Acid Halides, Anhydrides and Related Compounds
2.2 Synthesis of Esters, Activated Esters and Lactones
2.3 Synthesis of Amides and Related Compounds
2.4 Synthesis of Thioamides and Thiolactams
2.5 Synthesis of Thioesters and Thiolactones
2.6 Selenoesters of All Oxidation States
2.7 Synthesis of Iminium Salts, Orthoesters and Related Compounds
2.8 Inorganic Acid Derivatives
Protecting Groups
3.1 Protecting Groups
Functional Group Interconversion
4.1 Carbonyl Group Derivatization
4.2 Use of Carbonyl Derivatives for Heterocyclic Synthesis
4.3 Functional Group Transformations via Carbonyl Derivatives
4.4 Degradation Reactions
4.5 Functional Group Transformations via Allyl Rearrangement
4.6 2,3-SigmatropicR earrangements
4.7 Polonovski- and Pummerer-type Reactions and the Nef Reaction
Elimination Reactions
5.1 Eliminations to Form Alkenes, Allenes and Alkynes and Related Reactions
5.2 Reductive Elimination, Vicinal Deoxygenation and Vicinal Desilylation
5.3 The Cope Elimination, Sulfoxide Elimination and Related Thermal Reactions
5.4 Fragmentation Reactions
Author Index
Subject Index
Volume 7 Oxidation
Oxidation of Unactivated C 4Bo nds
1.1 Oxidation by Chemical Methods
1.2 Oxidation by Nitrene Insertion
1.3 Oxidation by Remote Functionalization Methods
1.4 Oxidation by Microbial Methods
xx Contents of All Volumes
Oxidation of Activated C 4Bo nds
2.1 Oxidation Adjacent to C=CB onds
2.2 Oxidation Adjacent to C=X Bonds by Dehydrogenation
2.3 Oxidation Adjacent to C-X Bonds by Hydroxylation Methods
2.4 Oxidation Adjacent to Sulfur
2.5 Oxidation Adjacent to Nitrogen
2.6 Oxidation Adjacent to Oxygen of Ethers
2.7 Oxidation Adjacent to Oxygen of Alcohols by Chromium Reagents
2.8 Oxidation Adjacent to Oxygen of Alcohols by Activated DMSO Methods
2.9 Oxidation Adjacent to Oxygen of Alcohols by Other Methods
2.10 Vinylic and Arylic C-H Oxidation
2.1 1 Synthesis of Quinones
Oxidation of C-C Bonds
3.1 Addition Reactions with Formation of Carbon-Oxygen Bonds: (i) General Methods of
Epoxidation
3.2 Addition Reactions with Formation of Carbon-Oxygen Bonds: (ii) Asymmetric Methods of
Epoxidation
3.3 Addition Reactions with Formation of Carbon-Oxygen Bonds: (iii) Glycol Forming Reactions
3.4 Addition Reactions with Formation of Carbon-Oxygen Bonds: (iv) The Wacker Oxidation and
Related Reactions
3.5 Addition Reactions with Formation of Carbon-Nitrogen Bonds
3.6 Addition Reactions with Formation of CarbonSulfur or CarbonSelenium Bonds
3.7 Addition Reactions with Formation of Carbon-Halogen Bonds
3.8 Cleavage Reactions
Oxidation of C-X Bonds
4.1 Oxidation of Carbon-Boron Bonds
4.2 Oxidation of Carbon-Metal Bonds
4.3 Oxidation of Carbon-Silicon Bonds
4.4 Oxidation of Carbon-Halogen Bonds
Oxidation of C-CB onds
5.1 The Baeyer-Villiger Reaction
5.2 The Beckmann and Related Reactions
5.3 Glycol Cleavage Reactions
5.4 The Hunsdiecker and Related Reactions
Oxidation of Heteroatoms
6.1 Oxidation of Nitrogen and Phosphorus
6.2 Oxidation of Sulfur, Selenium and Tellurium
Special Topics
7.1 Oxidation by Electrochemical Methods
7.2 Oxidative Rearrangement Reactions
7.3 Solid-supported Oxidants
7.4 Electron-transfer Oxidation
Author Index
Subject Index
Volume 8 Reduction
Reduction of C-X Bonds
1.1 Reduction of C=Ot o CHOH by Metal Hydrides
Contents of All Volumes xxi
1.2 Reduction of &=N to CHNH by Metal Hydrides
1.3 Reduction of b Xto CHXH by Hydride Delivery from Carbon
1.4 Reduction of k Xto CHXH by Dissolving Metals and Related Methods
1.5 Reduction of C=X to CHXH Electrolytically
1.6 Reduction of h Xto CHXH by Catalytic Hydrogenation
1.7 Reduction of (3=X to CHXH by Chirally Modified Hydride Reagents
1.8 Reduction of CIXt o CHXH Using Enzymes and Microorganisms
1.9 Reduction of Acetals, Azaacetals and Thioacetals to Ethers
1.10 Reduction of Carboxylic Acid Derivatives to Alcohols, Ethers and Amines
1.11 Reduction of Carboxylic Acids to Aldehydes by Metal Hydrides
1.12 Reduction of Carboxylic Acids to Aldehydes by Other Methods
1.13 Reduction of b Xto CH2 by Dissolving Metals and Related Methods
1.14 Reduction of CLX to CH2 by Wolff-Kishner and Other Hydrazone Methods
Reduction of X=Y Bonds
2.1 Reduction of Nitro and Nitroso Compounds
2.2 Reduction of N-N, N-N, N - Oa nd 0-0 Bonds
2.3 Reduction of s-0 and SO2 to S, of P 4to P , and of S-X to S-H
Reduction of C 4an d C=C Bonds
3.1 Heterogeneous Catalytic Hydrogenation of C=Ca nd C=C
3.2 Homogeneous Catalytic Hydrogenation of C 4and c--C
3.3 Reduction of and C=C by Noncatalytic Chemical Methods
3.4 Partial Reduction of Aromatic Rings by Dissolving Metals and Other Methods
3.5 Partial Reduction of Enones, Styrenes and Related Systems
3.6 Partial and Complete Reduction of Pyridines and their Benzo Analogs
3.7 Partial and Complete Reduction of Pyrroles, Furans, Thiophenes and their Benzo Analogs
3.8 Partial and Complete Reduction of Heterocycles Containing More than One Heteroatom
3.9 Hydrozirconation of G=C and c--C,a nd Hydrometallation by Other Metals
3.10 Hydroboration of C-C and C=C
3.1 1 Hydroalumination of C=€ and CmC
3.12 Hydrosilylation of C-C and c---C
Reduction of C-X to C 4
4.1 Reduction of Saturated Alkyl Halides to Alkanes
4.2 Reduction of Saturated Alcohols and Amines to Alkanes
4.3 Reduction of Heteroatoms Bonded to Tetrahedral Carbon
4.4 Reduction of Epoxides
4.5 Reduction of Vinyl Halides to Alkenes, and of Aryl Halides to Arenes
4.6 Reduction of Ketones to Alkenes
4.7 Hydrogenolysis of Allyl and Benzyl Halides and Related Compounds
4 x 4 0 -
4.8 Reduction of a-Substituted Carbonyl Compounds to Carbonyl Compounds
-CH--C0-
Author Index
Subject Index
Volume 9
Cumulative Author Index
Cumulative Subject Index
COMPREHENSIVE
ORGANIC SYNTHESIS
Selectivity, Strategy & Efficiency
in Modern Organic Chemistry
Edit or-in-Chief
BARRY M. TROST
Stanford University, CA, USA
Deputy Editor-in-Chief
IAN FLEMING
University of Cambridge, UK
Volume 3
CARBON-CARBON a-BOND FORMATION
Volume Editor
GERALD PATTENDEN, FRS
University of Nottingham, UK
PERGAMQN PRESS
OXFORD NEW YORK SEOUL TOKYO
0 0
ELSEVIER Ltd
The Boulevard, Langford Lane
Kidlington, Oxford OX5 IGB, UK
0 1991 Elsevier Ltd. All rights reserved.
All rights reserved. No part of this publication may be
reproduced, stored in a retrieval system or transmitted in any
form or by any means: electronic, electrostatic, magnetic
tape, mechanical, photocopying, recording or otherwise, with-
out permission in writing from the publishers.
First edition 1991
Second impression 1993
Third impression 1999
Fourth impression 2002
Fifth impression 2005
Library of Congress Cataloging in Publication Data
Comprehensive organic synthesis: selectivity, strategy and
efficiency in modern organic chemistry/editor[s] Barry M.
Trost, Ian Fleming.
p. cm.
Includes indexes.
Contents: Vol. 1.-2. Additions to C-X[pi]-Bonds - v. 3.
Carbon-carbon sigma-Bond formation - v. 4. Additions
to and substitutions at C-C[pi]-Bonds - v. 5. Combining
C-C[pi]-Bonds - v. 6. Heteroatom manipulation - v. 7.
Oxidation - v. 8. Reduction - v. 9. Cumulative indexes.
3. Organic Compounds - Synthesis I. Trost, Barry M.
1941-
11. Fleming, Ian, 1935-
QD262.C535 1991
547.24~209 0-26621
British Library Cataloguing in Publication Data
Comprehensive organic synthesis
3. Organic compounds. Synthesis
I. Trost, Barry M. (Barry Martin) 1941-
547.2
ISBN 0-08-040594-0 (Vol. 3)
ISBN 0-08-035929-9 (set)
($3 The paper used in this publicauon meets the mmimum requirements of American
National Standard for Information Sciences - Permanence of Paper for Printed Library
Materials. ANSI 239.48.1984.
Preface
The emergence of organic chemistry as a scientific discipline heralded a new era in human develop-
ment. Applications of organic chemistry contributed significantly to satisfying the basic needs for food,
clothing and shelter. While expanding our ability to cope with our basic needs remained an important
goal, we could, for the first time, worry about the quality of life. Indeed, there appears to be an excellent
correlation between investment in research and applications of organic chemistry and the standard of liv-
ing. Such advances arise from the creation of compounds and materials. Continuation of these contribu-
tions requires a vigorous effort in research and development, for which information such as that provided
by the Comprehensive series of Pergamon Press is a valuable resource.
Since the publication in 1979 of Comprehensive Organic Chemistry, it has become an important first
source of information. However, considering the pace of advancements and the ever-shrinking timeframe
in which initial discoveries are rapidly assimilated into the basic fabric of the science, it is clear that a
new treatment is needed. It was tempting simply to update a series that had been so successful. However,
this new series took a totally different approach. In deciding to embark upon Comprehensive Organic
Synthesis, the Editors and Publisher recognized that synthesis stands at the heart of organic chemistry.
The construction of molecules and molecular systems transcends many fields of science. Needs in
electronics, agriculture, medicine and textiles, to name but a few, provide a powerful driving force for
more effective ways to make known materials and for routes to new materials. Physical and theoretical
studies, extrapolations from current knowledge, and serendipity all help to identify the direction in which
research should be moving. All of these forces help the synthetic chemist in translating vague notions to
specific structures, in executing complex multistep sequences, and in seeking new knowledge to develop
new reactions and reagents. The increasing degree of sophistication of the types of problems that need to
be addressed require increasingly complex molecular architecture to target better the function of the re-
sulting substances. The ability to make such substances available depends upon the sharpening of our
sculptors’ tools: the reactions and reagents of synthesis.
The Volume Editors have spent great time and effort in considering the format of the work. The inten-
tion is to focus on transformations in the way that synthetic chemists think about their problems. In terms
of organic molecules, the work divides into the formation of carbon-carbon bonds, the introduction of
heteroatoms, and heteroatom interconversions. Thus, Volumes 1-5 focus mainly on carbonxarbon bond
formation, but also include many aspects of the introduction of heteroatoms. Volumes 6-8 focus on
interconversion of heteroatoms, but also deal with exchange of carbonxarbon bonds for carbon-
heteroatom bonds.
The Editors recognize that the assignment of subjects to any particular volume may be arbitrary in
part. For example, reactions of enolates can be considered to be additions to C-C wbonds. However,
the vastness of the field leads it to be subdivided into components based upon the nature of the bond-
forming process. Some subjects will undoubtedly appear in more than one place.
In attacking a synthetic target, the critical question about the suitability of any method involves selec-
tivity: chemo-, regio-, diastereo- and enantio-selectivity. Both from an educational point-of-view for the
reader who wants to learn about a new field, and an experimental viewpoint for the practitioner who
seeks a reference source for practical information, an organization of the chapters along the theme of
selectivity becomes most informative.
The Editors believe this organization will help emphasize the common threads that underlie many
seemingly disparate areas of organic chemistry. The relationships among various transformations
becomes clearer and the applicability of transformations across a large number of compound classes
becomes apparent. Thus, it is intended that an integration of many specialized areas such as terpenoid,
heterocyclic, carbohydrate, nucleic acid chemistry, etc. within the more general transformation class will
provide an impetus to the consideration of methods to solve problems outside the traditional ones for any
specialist.
In general, presentation of topics concentrates on work of the last decade. Reference to earlier work,
as necessary and relevant, is made by citing key reviews. All topics in organic synthesis cannot be
treated with equal depth within the constraints of any single series. Decisions as to which aspects of a
vii
