Table Of ContentL. Brandsma
Preparative
Polar Organometallic
Chemistry
Volume 2
Experimental Collaboration:
H. Andringa, Y. A. Heus, R. Rikers
L. Tip, H. D. Verkruijsse
Springer-Verlag
Berlin Heidelberg New York London
Paris Tokyo HongKong Barcelona
Professor Dr. Lambert Brandsma
Rijksuniversiteit Utrecht
Department of Preparative Organic Chemistry,
Debye Institute
Padualaan 8, NL-3584 CH Utrecht
This work was supported by the Netherlands Technology
Foundation (STW)
ISBN-13:978-3-540-52749-7
Library of Congress Cataloging in Publication Data
Brandsma, L. Preparative polar organometallic chemistry.
Bibliography: v. 1, p. Includes index.
1. Organometallic chemistry.
I. Verkruijsse, H. D. II. Title.
QD411.B67 1987 547'.05 86-17896
ISBN-13:978-3-540-52749-7 e-ISBN-13:978-3-642-61517-7
DOl: 10.1007/978-3-642-61517-7
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Preface
This book is a continuation of Vol. 1, which appeared in 1987. It deals with polar
organometallic intermediates that can be derived by replacement of an Sp3 -proton by
an alkali metal atom. A number ofthese intermediates, among which the acyl-anion
equivalents, have shown their usefulness in various organic syntheses published in
the last two decades.
The experimental procedures described in this book (which exemplify generally
applicable methods) are the result of careful checking of concept-procedures
designed by the author: between 1500 and 2000 experiments have been carried out to
provide the basis for writing this volume. Just as in Vol. 1, it is described how polar
organometallic intermediates can be generated and subsequently be functionalized
with a number of "electrophiles". All procedures have been carried out and
described on a preparative (usually 0.1 molar) scale, using "preparative"
concentrations of starting compounds and reagents (of the order of 0.5 to 0.8 mol/I).
Reaction times have been derived from monitoring (in most cases by temperature or
colour observation) and hence are a reasonable reflection of reactivities.
The scope of a book like this involves some limitations. Since it would be an
impossible task to prepare experimental procedures with all kinds of substrates, we
have carried out and described only syntheses with relatively simple and readily
available starting compounds. We believe, however, that the reaction conditions
described are fairly representative so that they will enable the user of this book to
design experimental conditions for many analogous metallation-functionalization
reactions on a preparative scale.
The author is indebted to AKZO-Chemicals (De venter), Andeno (Venlo),
Chemetall (Frankfurt am Main, FRG), DSM (Geleen), Diosynth (Oss), and Shell
(Amsterdam) for financial support and gifts of chemicals.
Utrecht, November 1990 Lambert Brandsma
Contents
Chapter I. Reactivity of Polar Organometallic Intermediates
1 Introduction . . . . . . . . . . . .
2 Alkylation. . . . . . . . . . . . .
2.1 Reactivity-A Qualitative Comparison
of the Polar Organometallics 1
2.2 Scope of the Alkylation Reaction. . . 2
2.3 Dialkylation . . . . . . . . . . 4
2.4 Remarks on the Reaction Conditions of Alkylations 5
3 Hydroxyalkylation with Epoxides. . . . . 6
4 Hydroxyalkylation with Carbonyl Compounds 7
5 Formylation with Dimethylformamide 7
6 Carboxylation. . . . . . . . . . . . 8
7 Reaction of Organoalkali Compounds with Carbon Disulfide . 8
8 Addition of Organoalkali Compounds to Isocyanates
and Isothiocyanates. 9
9 Sulfenylation . . . . . . . . . . . . . . . 9
10 Trimethylsilylation. . . . . . . . . . . . . 10
11 Reactions of Organometallic Compounds with Chloroformates
and Dimethylcarbamoyl Chloride. . . . . . . . . . . 10
12 Reactions of Organoalkali Compounds with Halogenating Agents 11
13 Conjugate Additions . . . . . . . . . . . . . . 11
Chapter II. Metallation of Aromatic and Olefinic Hydrocarbons 15
Introduction . . . . . . . . . . . . . . . 15
2 Metallation of Alkylbenzenes and Alkylnaphthalenes . 15
3 Dimetallation of Aromatic Compounds. 17
4 Metallation of Olefinic Compounds. . 18
5 Stereochemistry of Allylic Metallations . 21
6 Dimetallation of Olefins. . . . . . 22
7 Experiments . . . . . . . . . . 23
7.1 Metallation of Toluene with BuLi· t-BuOK in Hexane. 23
7.2 Metallation of 1- and 2-Methylnaphthalene
with BuLi· t-BuOK.TMEDA in Hexane. 25
7.3 a-Metallation of Ethylbenzene. . . . . 26
7.4 a,a'-Dimetallation of m-Xylene. . . . . 28
7.5 Lithiation of Toluene, Xylene, Mesitylene with BuLi . TMEDA. 30
VIII List of Contents
7.6 Metallation of Propene and Isobutene . . . . . . . . 33
7.7 Metallation of Various Olefins with Strongly Basic Reagents 36
7.8 Metallation of Cyclohexene 40
7.9 Dimetallation of Isobutene . . 41
7.10 Metallation of Isoprene 43
7.11 Metallation of Methylstyrene . 44
(X-
7.12 Metallation of Indene . . . . 45
7.13 Metallation of Cyclopentadiene. 47
7.14 Preparation of 1,4-Cyclohexadiene. 50
7.15 Allylbenzene . . . . . . . 51
8 Selected Procedures from Literature. . 51
Chapter III. Metallation of Saturated Sulfur Compounds 53
1 Introduction . . . . . . . . . . 53
2 Substrates and Metallation Conditions . 53
2.1 S,S-Acetals. . . . . . . . 53
2.2 Methoxymethyl Phenyl Sulfide . 56
2.3 Ethythiomethyl Ethyl Sulfoxide. 56
2.4 Orthothioformates . . . . . 57
2.5 Dialkyl Sulfides and Alkyl Aryl Sulfides 57
2.6 Dialkyl and Alkyl Aryl Sulfoxides and Sulfones 58
3 Experiments . . . . . . . . . . . . . . 59
3.1 Lithiation of Formaldehyde Dimethylthioacetal
with BuLi in THF and Hexane. . . . . . 59
3.2 Lithiation of Formaldehyde Dimethylthioacetal
with BuLi' TMEDA in Hexane. . . . . . 61
3.3 Reaction of Lithiated Bis(methylthio)methane
with Alkyl Halides . . . . . . . . . . 61
3.4 Hydroxyalkylation of Lithiated Bis(methylthio)methane
with Epoxides. . . . . . . . . . . . . . . 63
3.5 Reaction of Lithiated 1,3-Dithiane with I-Bromo-3-chloropropane
and Ring Closure of the Coupling Product Under the Influence
of Butyllithium . . . . . . . . . . . 64
3.6 Hydroxymethylation of Bis(methylthio)methane
with Paraformaldehyde. . . . . . . . . 66
3.7 Reaction of Lithiated Bis(methylthio)methane
with Dimethylformamide and Subsequent Acid Hydrolysis 67
3.8 Reaction of Lithiated Bis(methylthio)methane
with Carbon Dioxide . . . . . . . . . . . 69
3.9 Reaction of Lithiated Bis(methylthio)methane
with Dimethyl Disulfide and Trimethylchlorosilane. 70
3.10 Lithiation of Methoxymethyl Phenyl Sulfide
and Subsequent Reaction with Dimethylformamide. 72
3.11 Reaction of Lithiated Bis(methylthio )methane
with Methyl Isothiocyanate
and N,N-Dimethyl Carbamoyl Chloride. . . . . . . . .. 73
List of Contents IX
3.12 Peterson Olefination Reactions
with Lithiated Trimethylsilyl Bis(methylthio)methane.
Preparation of Ketene Thioacetals. . . . . . . 74
3.13 Conjugate Addition of Lithiated S,S-Acetals
and Corresponding S-Oxides to 2-Cyclohexen-1-one
and Methyl Acrylate . . . . . . . . . . . 76
3.14 Lithiation of Dimethyl Sulfide and Methyl Phenyl Sulfide
and Subsequent Reaction of the Lithium Compounds
with Benzaldehyde and Trimethylchlorosilane 78
3.15 Lithiation of (Trimethylsilylmethyl)Phenyl Sulfide
and Subsequent Reaction with Acetone. 79
3.16 Dilithiation of Methyl Phenyl Sulfide
and Subsequent Trimethylsilylation . . 80
3.17 Reaction of Bis(methylthio )methane with Potassium Amide
in Liquid Ammonia and Subsequent Reaction with Oxirane. 81
3.18 Reaction of Dimethylsulfoxide with Sodamide in Liquid Ammonia
and Subsequent Alkylation with Bromohexane . 82
3.19 Mono-Deuteration of Bis(ethylthio)methane . . 83
3.20 Lithiation of Methyl Phenyl Sulfoxide with LDA
and Subsequent Alkylation with Butyl Bromide 85
3.21 Preparation of Formaldehyde-S,S-Acetals . . 86
3.22 Preparation of Ethylthiomethyl Ethyl Sulfoxide
and Methyl Phenyl Sulfoxide . . . . . . 87
3.23 Preparation of Benzaldehyde Dimethylthioacetal 88
4 Selected Procedures from Literature. . . . . . . 89
Chapter IV. a-Metallation of Derivatives
of Toluene Containing Heterosubstituents . 91
Scope of this Chapter. . . . . . . . . . . 91
2 Experiments . . . . . . . . . . . . . . 93
2.1 Metallation of N,N -Dimethyl-ortho-Toluidine. 93
2.2 Synthesis of ortho-Pentylphenol via Potassiation
of O-Protected ortho-Cresol. . . . . . . . 95
2.3 Dimetallation of ortho-Cresol . . . . . . . 97
2.4 Metallation of 0- and p-Tolunitrile with Alkali Amides
in Liquid Ammonia and Alkali Diisopropylamide
in THF-Hexane Mixtures . . . . . . . . . 99
2.5 a-Lithiation of p-Toluene-N,N-Dimethylsulfonamide 105
Chapter V. Metallation of Heterosubstituted Allylic
and Benzylic Compounds. . . 105
Introduction . . . . . . . . . . 105
2 Substrates and Metallation Conditions . 105
2.1 Allylic Amines and Ethers. . . . 105
2.2 Allylic and Pentadienylic Sulfur, Silicon and Selenium Compounds 107
X List of Contents
2.3 Benzylic Amines, Silanes and Sulfides. . . . . . . . . . . 109
2.4 Regiochemistry of the Reactions of Allylic Alkali Metal Compounds
with Electrophiles . . . . . . . . . . . . . .. 110
3 Experiments . . . . . . . . . . . . . . . . . .. 112
3.1 Metallation of N,N-Dialkyl Allylamines with BuLi·TMEDA
and BuLi· t-BuOK . . . . . . . . . . . . . 112
3.2 Metallation of Allyl t-Butyl Ether with BuLi . t-BuOK. .. 115
3.3 Lithiation of Allyl Trimethylsilane with BuLi· TMEDA .. 116
3.4 Lithiation of Methyl Allyl Sulfide and Phenyl Allyl Sulfide with BuLi 118
3.5 Metallation of Methyl Isopropenyl Ether with BuLi· t-BuOK. 119
3.6 a-Metallation of Benzyl Dimethylamine with BuLi· t-BuOK.. 120
3.7 Lithiation of Methyl Benzyl Sulfide and Benzyl Trimethylsilane 122
3.8 Preparation of N,N-Dimethyl Allylamine
and N,N-Diethyl Allylamine. . . . . . . . . . . .. 123
3.9 Preparation of t-Butyl Allyl Ether. . . . . . . . . .. 124
3.10 Methyl Allyl Sulfide, Methyl Benzyl Sulfide and Phenyl Allyl Sulfide 125
3.11 Preparation of Allyl Trimethylsilane. . . 126
Chapter VI. Metallation of Heterocyclic Compounds 127
1 Introduction . . . . . . . . . . . . . 127
2 Metallation of Alkyl Derivatives of Pyridine and Quinoline. 127
3 Lateral Metallation of 2-Substituted Oxazolines, Thiazolines,
Dihydrooxazines and Thiazoles . . . . . . . . . . 129
4 Experiments . . . . . . . . . . . . . . . . . 131
4.1 General Procedure for the Metallation of Mono-, Di-
and Trimethyl Pyridines and Quinolines in Liquid Ammonia
and the Subsequent Alkylation. . . . . . . .. .. 131
4.2 Conversion of 2-Methylpyridine, 2,4-Dimethylpyridine,
2,6-Dimethylpyridine and 2,4,6-Trimethylpyridine
into the 2-Lithiomethyl Derivatives . . . . . . . 133
4.3 Regiospecific Generation of 4-Metallomethylpyridines
in Organic Solvents. . . . . 136
4.4 Metallation of 3-Methylpyridine . . . . . . . . 138
4.5 Lithiation of 2-Methylthiazoline . . . . . . . . 139
4.6 Lithiation of 2,4,4,6-Tetramethyl-5,6-dihydro-1,3-oxazine . 140
4.7 Dimetallation of 2,6-Dimethylpyridine 142
5 Organic Syntheses Procedures. . . . . . . 143
Chapter VII. Metallation of Aldimines and Ketimines 145
1 Introduction . . . . . . . 145
2 Conditions for the Metallation. . . . . . . 146
3 Experiments . . . . . . . . . . . . . 146
3.1 Lithiation of Aldimines and Ketimines with LDA 147
3.2 Alkylation of Lithiated Imines. . . . . . . 147
3.3 Metallation of Aldimines by Sodamide in Liquid Ammonia. 149
List of Contents XI
3.4 Trimethylsilylation and Methylthiolation of Lithiated Imines 150
3.5 Conversion of Imines into Aldehydes and Ketones. 152
3.6 Synthesis of a,p-Unsaturated Aldehydes
from Trimethylsilylated Aldimines. . . 153
3.7 Preparation of Aldimines and Ketimines 155
4 Organic Syntheses Procedures. . . . . . 157
Chapter VIII. Metallation of Nitriles and Isonitriles . 159
1 Introduction . . . . . 159
2 a-Metallation of Nitriles . 160
3 Metallation of Isonitriles . 160
4 Experiments . . . . . 161
4.1 Metallation of Nitriles with Alkali Amide in Liquid Ammonia. 161
4.2 Lithiation of Nitriles and Isonitriles
in a Mixture of THF and Hexane. . . . . . . . 162
4.3 Alkylation of Metallated Nitriles in Liquid Ammonia
and in Organic Solvents . . . . . . . . . . . 163
4.4 Reaction of Metallated Nitriles with Aldehydes and Ketones 165
4.5 Reaction of Lithioacetonitrile with Epoxides . . . . .. 167
4.6 Reaction of Lithiomethyl Isocyanide with Hexyl Bromide, Oxirane
and Cyclohexanone. . . . . . . . . . . . . . . . . 168
4.7 Conversion of Acetaldehyde into the Cyanohydrine
and Protection of the OH-Group of the Cyanohydrine
with Ethyl Vinyl Ether. . . . . . . . . . . . . . . . 170
Chapter IX. Generation of Lithium Halocarbenoids . 173
Introduction . . . . . . . . . . . . . 173
2 Methods of Generation of Lithium Halocarbenoids 173
3 Experimental Conditions and Techniques in Carbenoid Chemistry 175
4 Experiments . . . . . . . . . 175
4.1 Lithiation of Dichloromethane . 176
4.2 Lithiation of 1,1-Dichloroalkanes 177
4.3 Lithiation of Dibromomethane . 178
4.4 Lithiation of Chloroform. . . 179
4.5 Lithiation of Bromoform. . . 180
4.6 Lithiation of 7,7-Dibromonorcarane 181
4.7 Lithiation of Ethyl Bromoacetate . 183
Chapter X. Metallation of Carbonyl and Thiocarbonyl Compounds. 185
1 Introduction . . . . . . . . . . . . . . . . . . 185
2 Mono-Metallation of Carbonyl and Thiocarbonyl Compounds 186
3 Other Methods for the Generation of Enolates and Enethiolates . 187
4 Dimetallation of Carbonyl and Thiocarbonyl Compounds 188
5 Experiments . . . . . . . . . . . . . . . . . " 189
XII List of Contents
5.1 Conversions of Ketones into Lithium Enolates
and Subsequent Trimethylsilylation (General Procedure) . 190
5.2 Reaction of 1-Trimethylsilyloxy-1-Heptene with Butyllithium 192
5.3 Metallation of Carboxylic Esters with LDA . . . 193
5.4 Metallation of Carboxylic Esters with Alkali Amides
in Liquid Ammonia. . . . . . 196
5.5 Metallation of N -Methylpyrrolidine
and y-Butyrolactone with LDA. . 197
5.6 Lithiation of Methyl Crotonate. . 199
5.7 Lithiation of Thiolesters, Thionesters and Dithioestets
with LDA (General Procedure). . . . . . 200
5.8 Metallation of Dithioesters with Alkali Amides
in Liquid Ammonia. . . . . . . . . . 202
5.9 Dimetallation of Carboxylic Acids . . . . 203
5.10 Dimetallation of Pentane-2,4-dione with Sodamide
in Liquid Ammonia. . . . . . . . . . 204
5.11 Dimetallation of Pentane-2,4-dione with LDA 205
5.12 1-Trimethylsilyloxy-1-heptene . . . . . . 207
Appendix
Metallation-Functionalization Index (Vol. 2) . . . . . . . 209
Syntheses of Reagents and Starting Compounds (Vols. 1 and 2). 217
Complementary Index (Vols. 1 and 2). . . . . . . . 218
Typical Procedures and Special Techniques (Vols. 1 and 2) 222
Purification and Storage and Some Reagents and Solvents
(Vols. I and 2). . . . . . . . . . . . . . . . 225
