Table Of ContentAdvanced Organic Synthesis
METHODS AND TECHNIQUES
RICHARD S. MONSON
DEPARTMENT OF CHEMISTRY
CALIFORNIA STATE COLLEGE, HAYWARD
HAYWARD, CALIFORNIA
ACADEMIC PRESS
New York and London
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Contents
Preface xi
I. FUNCTIONAL GROUP MODIFICATIONS
1. Chemical Oxidations
I. Chromium Trioxide Oxidation 3
II. Periodate-Permanganate Cleavage of Olefins 5
III. Free Radical Oxidation of an Allylic Position 7
IV. Epoxidation of Olefins 8
V. Baeyer-Villiger Oxidation of Ketones 9
VI. Lead Tetraacetate Oxidation of Cycloalkanols 11
VII. Photolytic Conversion of Cyclohexane to Cyclohexanone Oxime 11
VIII. Oxidation of Ethers to Esters 12
IX. Partial Oxidation of an Aliphatic Side Chain 13
X. Bisdecarboxylation with Lead Tetraacetate 14
XI. Oxidation with Selenium Dioxide 15
References 16
2. Hydride and Related Reductions
I. Reduction by Lithium Aluminum Hydride 18
II. Mixed Hydride Reduction 20
III. Reduction with Iridium-Containing Catalysts 22
IV. Reduction of Conjugated Alkenes with Chromium (H) Sulfate 23
References 24
3. Dissolving Metal Reductions
I. Reduction by Lithium-Amine 25
II. Reduction by Lithium-Ethylenediamine 26
III. Reduction of a,/MJnsaturated Ketones by Lithium-Ammonia 27
IV. Reduction of a,/9-Unsaturated Ketones in Hexamethylphosphoric Triamide . . .. 28
V. Reduction of an a,/?-Unsaturated y-Diketone with Zinc 29
References 30
VI CONTENTS
4. Hydroboration
I. Hydroboration of Olefins as a Route to Alcohols 32
II. Selective Hydroborations Using Bis(3-methyl-2-butyl)borane (BMB) 35
III. Purification of a Mixture of J9-10- and J1(9)-Octalins 37
References 38
5. Catalytic Hydrogenation
I. Hydrogenation over Platinum Catalyst 39
II. Low-Pressure Hydrogenation of Phenols over Rhodium Catalysts 40
III. c/j-4-Hydroxycyclohexanecarboxylic Acid from /?-Hydroxybenzoic Acid 41
IV. 3-Isoquinuclidone from/7-Aminobenzoic Acid 42
V. Homogeneous Catalytic Hydrogenation 43
References 44
6. The Introduction of Halogen
I. Halides from Alcohols by Triphenylphosphine—Carbon Tetrahalide 45
II. Halides from Alcohols and Phenols by Triphenylphosphine Dihalide 46
III. Allylic and Benzylic Bromination with W-Bromosuccinimide 48
IV. a-Bromination of Ketones and Dehydrobromination 49
V. Stereospecific Synthesis of /ra/w-4-Halocyclohexanols 51
References 52
7. Miscellaneous Elimination, Substitution, and Addition Reactions
I. Methylenecyclohexane by Pyrolysis of an Amine Oxide 54
II. The Wolff-Kishner Reduction 55
III. Dehydration of 2-Decalol 56
IV. Boron Trifluoride Catalyzed Hydrolysis of Nitriles 56
V. Bridged Sulfides by Addition of Sulfur Dichloride to Dienes 57
VI. Methylation by Diazomethane 58
VII. Oxymercuration: A Convenient Route to Markovnikov Hydration of Olefins . . .. 60
VIII. Esterification of Tertiary Alcohols 62
IX. Ketalization 63
X. Half-EsterificationofaDiol 64
XI. Substitution on Ferrocene 65
XII. Demethylation of Aryl Methyl Ethers by Boron Tribromide 66
References 67
CONTENTS VlI
II. SKELETAL MODIFICATIONS
8. The Diels-Alder Reaction
I. 3,6-Diphenyl-4,5-cyclohexenedicarboxylic Anhydride ........... 71
II. Reactions with Butadiene .................. 72
III. Catalysis by Aluminum Chloride ................ 74
IV. Generation of Dienes from Diones ................ 75
V. Reactions with Cyclopentadiene ................. 77
References ....................... 79
9. Enamines as Intermediates
I. Preparation of the Morpholine Enamine of Cyclohexanone ......... 80
II. Acylation of Enamines ................... 81
III. Enamines as Michael Addition Reagents .............. 82
IV. Reactions of Enamines with j3-Propiolactone ............. 83
V. Reactions of Enamines with Acrolein ............... 84
References ....................... 86
10. Enolate Ions as Intermediates
I. Ketones as Enolates: Car bethoxylation of Cyclic Ketones ......... 87
II. Esters as Enolates: 1,4-Cyclohexanedione and Meerwein's Ester ....... 90
III. Methylsulfinyl Carbanion as a Route to Methyl Ketones .......... 92
IV. Cyclization with Diethyl Malonate ................ 96
V. Carboxylations with Magnesium Methyl Carbonate (MMC) ......... 97
VI. Alkylation of j3-Ketoesters .................. 99
VII. The Robinson Annelation Reaction ................ 101
References ....................... 103
1 1 . The Wittig Reaction
I. Benzyl-Containing Ylides .................. 104
II. Alkyl Ylides Requiring «-Butyl Lithium .............. 105
III. Methylsulfinyl Carbanion in the Generation of Ylides .......... 106
IV. The Wittig Reaction Catalyzed by Ethylene Oxide ........... 107
V. Cyclopropylidene Derivatives via the Wittig Reaction .......... 108
References ....................... 110
1 2 . Reactions of Trialkylbor anes
I. Trialkylcarbinols from Trialkylboranes and Carbon Monoxide ........ Ill
II. Dialkylketones from Trialkylboranes and Carbon Monoxide- Water ...... 112
III. The Reaction of Trialkylboranes with Methyl Vinyl Ketone and Acrolein ..... 114
IV. The Reaction of Trialkylboranes with Ethyl Bromoacetate ......... 115
References ....................... 115
Viil CONTENTS
13. Carbenes as Intermediates
I. Carbene Addition by the Zinc-Copper Couple 116
II. Dibromocarbenes 117
III. Dihalocarbenes from Phenyl(trihalomethyl)mercury Compounds 119
References 120
14. Ethynylation
I. Generation of Sodium Acetylide in Liquid Ammonia 121
II. The Generation of Sodium Acetylide in Tetrahydrofuran 123
III. The Generation of Sodium Acetylide via Dimsylsodium 124
References 125
15. Structural Isomerizations
I. Acid Catalyzed Rearrangement of Saturated Hydrocarbons 126
II. Photolytic Ring Contraction 127
III. Isomerization of 1-Ethynylcylohexanol: Three Methods 129
IV. Photolytic Isomerization of 1,5-Cyclooctadiene 130
V. Oxidative Rearrangement of /3-Diketones 130
VI. Base Catalyzed Rearrangement of 4-Benzoyloxycyclohexanone 131
VII. Allenes from 1,1-Dihalocyclopropanes by Methyllithium 132
References 133
16. Elimination, Substitution, and Addition Reactions Resulting in
Carbon-Carbon Bond Formation
I. Carboxylation of Carbonium Ions 134
II. Paracyclophane via a 1,6-Hofmann Elimination 136
III. Diphenylcyclopropenone from Commercial Dibenzyl Ketone 137
IV. Phenylcyclopropane from Cinnamaldehyde 139
V. Conversion of Alkyl Chlorides to Nitriles in DMSO 140
VI. Photolytic Addition of Formamide to Olefins 141
VII. Intermolecular Dehydrohalogenation 142
VIII. Ring Enlargement with Diazomethane 143
IX. Conjugate Addition of Grignard Reagents 144
X. Dimethyloxosulfonium Methylide in Methylene Insertions 145
Xl. Acylation of a Cycloalkane: Remote Functionalization 147
XII. The Modified Hunsdiecker Reaction 149
References 150
CONTENTS IX
17. Miscellaneous Preparations
I. Derivatives of Adamantane 151
II. Percarboxylic Acids 153
III. Diazomethane 155
IV. Trichloroisocyanuric Acid 156
References 157
Appendix 1. Examples of Multistep Syntheses 158
Appendix 2. Sources of Organic Reagents 161
Appendix 3. Introduction to the Techniques of Synthesis
I. The Reaction 166
II. TheWorkup 175
III. Purification of the Product 178
References 188
Subject Index 189
Preface
The developments in organic synthesis in recent years have been as dramatic as any
that have occurred in laboratory sciences. One need only mention a few terms to under-
stand that chemical systems that did not exist twenty years ago have become as much a
part of the repertoire of the synthetic organic chemist as borosilicate glassware. The list
of such terms would include the Wittig reaction, enamines, carbenes, hydride
reductions, the Birch reduction, hydroboration, and so on. Surprisingly, an introduc-
tion to the manipulations of these reaction techniques for the undergraduate or grad-
uate student has failed to materialize, and it is often necessary for students interested in
organic synthesis to approach modern synthetic reactions in a haphazard manner.
The purpose of this text is to provide a survey, and systematic introduction to, the
modern techniques of organic synthesis for the advanced undergraduate student or the
beginning graduate student. An attempt has been made to acquaint the student with a
variety of laboratory techniques as well as to introduce him to chemical reagents that
require deftness and care in handling. Experiments have been drawn from the standard
literature of organic synthesis including suitable modifications of several of the reliable
and useful preparations that have appeared in "Organic Synthesis." Other examples
have been drawn from the original literature. Where ever possible, the experiments have
been adapted to the locker complement commonly found in the advanced synthesis
course employing intermediate scale standard taper glassware. Special equipment for
the performance of some of the syntheses would include low-pressure hydrogenation
apparatus, ultraviolet lamps and reaction vessels, Dry Ice (cold finger) condensers,
vacuum sublimation and distillation apparatus, and spectroscopic and chromato-
graphic instruments. In general, an attempt has been made to employ as substrates
materials that are available commercially at reasonable cost, although several of the
experiments require precursor materials whose preparation is detailed in the text. Some
of the reagents are hazardous to handle, but I believe that, under reasonable supervision,
advanced students will be able to perform the experiments with safety.
Introductory discussion of the scope and mechanism of each reaction has been kept
to a minimum. Many excellent texts and reviews exist that provide thorough and ac-
curate discussion of the more theoretical aspects of organic synthesis, and the student is
referred to these sources and to the original literature frequently. Since it is the purpose
XIl PREFACE
of this volume to provide technical procedures, no useful purpose would be served in
merely duplicating previously explicated theoretical material.
The number of experiments that can be done satisfactorily in a one-semester course
varies widely with the physical situation and the individual skills of the student.
Therefore, no attempt is made to suggest a schedule. I recommend, however, that a
common core of about five experiments be assigned. The remainder of the preparations
can then be chosen by individual students as dictated by their interests as well as by the
availability of chemicals and special equipment. The common experiments, representing
frequently used and important techniques, might be chosen from Chapter 1, Sections I
and IV; Chapter 2, Section I; Chapter 3, Section I; Chapter 4, Section I; Chapter 5,
Section I; Chapter 6, Sections III and IV; Chapter 7, Sections II and VI; Chapter 8,
Section II; Chapter 9, Sections I and II; Chapter 11, Sections I and III; or Chapter 13,
Section II. Since many of the other experiments draw on the products of this suggested
list, the possibility of multistep syntheses also presents itself, and several such sequences
are outlined in Appendix 1. Also included, in Appendix 2, are the commercial suppliers
of the chemicals required when these chemicals are not routinely available.
Finally, a brief introduction to the techniques of synthesis is given in Appendix 3.
Students with no synthetic experience beyond the first-year organic chemistry course
are advised to skim through this section in order to acquaint themselves with some of
the apparatus and terminology used in the description of synthetic procedures.
RICHARD S. MONSON
I
FUNCTIONAL GROUP
MODIFICATIONS
