Organolithiums: Selectivity for Synthesis (eBook)

Jonathan Clayden (Autor)

eBook Download: EPUB

2002 | 1. Auflage
400 Seiten
Elsevier Science (Verlag)
978-0-08-053816-7 (ISBN)

Infos

Organolithiums: Selectivity for Synthesis

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This volume, number 23 in the "e;Tetrahedron Organic Chemistry"e; series, presents organolithium chemistry from the perspective of a synthetic organic chemist, drawing from the synthetic literature to present a unified overview of how organolithiums can be used to make molecules. The development of methods for the regioselective synthesis of organolithiums has replaced their image of indiscriminate high reactivity with one of controllable and subtle selectivity. Organolithium chemistry has a central role in the selective construction of C-C bonds in both simple and complex molecules, and for example has arguably overtaken aromatic electrophilic substitution as the most powerful method for regioselective functionalisation of aromatic rings. The twin themes of reactivity and selectivity run through the book, which reviews the ways by which organolithiums may be formed and the ways in which they react. Topics include advances in directed metallation, reductive lithiation and organolithium cyclisation reactions, along with a discussion of organolithium stereochemistry and the role played by ligands such as (-)-sparteine.

Inhalt

Front Cover 1
Organolithiums: Selectivity for Synthesis 4
Copyright Page 5
Table of Contents 6
Foreword 12
Acknowledgements 14
Abbreviations 16
CHAPTER 1. Introduction 18
1.1 Scope and overview 18
1.2 Organolithiums in solution 19
References 24
CHAPTER 2. Regioselective Synthesis of Organolithiums by Deprotonation 26
2.1 General points 26
2.2 Lithiation a a to heteroatoms 27
2.3 Ortholithiation 45
2.4 Lateral lithiation 90
2.5 Remote lithiation, and ß-1ithiation of non-aromatic compounds 103
2.6 Superbases 104
2.7 Cooperation, competition and regioselectivity 107
References 113
CHAPTER 3. Regioselective Synthesis of Organolithiums by X-Li Exchange 128
3.1 Halogen-lithium exchange 128
3.2 Tin-lithium exchange 153
3.3 Chalcogen-lithium exchange 156
3.4 Phosphorus-lithium exchange 159
References 159
CHAPTER 4. Regioselective Synthesis of Organolithiums by C-X Reduction 166
4.1 Reductive lithiation of alkyl and aryl halides 166
4.2 Reductive lithiation of C–O bonds 171
4.3 Reductive lithiation of C–N bonds 175
4.4 Reductive lithiation of C–S bonds 176
4.5 Reductive lithiation of C–C bonds and n-bonds 182
References 182
CHAPTER 5. Stereoselective and Stereospecific Synthesis of Organolithiums 186
5.1 Configurational stability of organolithiums 186
5.2 Stereospecific synthesis of organolithiums by X–Li exchange 231
5.3 Diastereoselective deprotonation 241
5.4 Enantioselective deprotonation 243
References 252
CHAPTER 6. Stereospecific and Stereoselective Substitution Reactions of Organolithiums 258
6.1 Stereospecific reactions of organolithium compounds 258
6.2 Stereoselective substitution in the presence of chiral ligands 275
References 286
CHAPTER 7. Regio- and Stereoselective Addition Reactions of Organolithiums 290
7.1 Intermolecular addition to p bonds: Carbolithiation 290
7.2 Intramolecular addition and substitution reactions: anionic cyclisation 299
References 346
CHAPTER 8. Organolithium Rearrangements 354
8.1 Shapiro Reaction 354
8.2 Brook Rearrangements 357
8.3 [ 1,2]-Wittig Rearrangements 363
8.4 [2,3]-Wittig Rearrangements 368
References 377
CHAPTER 9. Organolithiums in Synthesis 382
9.1 Ochratoxin: ortholithiation and anionic Fries rearrangement 382
9.2 Corydalic acid methyl ester: lateral lithiation 383
9.3 Fredericamycin A: ortho, lateral and a-lithiation 384
9.4 (+)-Atpenin B: metallation of an aromatic heterocycle 386
9.5 Flurbiprofen: metallation with LiCKOR superbases 387
9.6 California Red Scale Pheromone: a- and reductive lithiation 388
9.7 C1-C9 of the Bryostatins: diastereoselective bromine-lithium exchange 389
9.8 (S)-1-Methyldodecyl acetate, a Drosophila pheromone: (-)-sparteine assisted enantioselective lithiation 390
9.9 (–)-Paroxetine: (–)-sparteine-promoted asymmetric lithiation and substitution 391
References 392
INDEX 394

Textauszug

Chapter 1

Introduction

Jonathan Clayden    Department of Chemistry, University of Manchester, Manchester, UK

1.1 Scope and Overview

Organolithiums are central to so many aspects of synthetic organic chemistry that a book on organolithium chemistry must be a book on synthesis. Hardly a molecule is made without a bottle of BuLi: evaporation as butane is the destiny of at least one proton of the starting material in almost any synthetic sequence.

A book on organolithiums is also a book on mechanism. The observation of selectivity in an organolithium reaction has often led to mechanistic insights that later turn out to be general mechanistic features of organic reactions. Directed metallation, for example, started with the ortholithiation of anisole, and led to directed reactions of zinc and palladium. A decade of close investigation of configurational stability in the organolithium series preceded similar studies on organozincs and other organometallics. “Dynamic thermodynamic resolution” is a mechanistic feature first identified in the reactions of organolithiums in the presence of sparteine, and later exploited right outside of the organometallic sphere, in the synthesis of atropisomers.

Given their ubiquity, this book concentrates on one feature of the reactions of organolithiums (pushed to a wider sense in some areas thari others) selectivity. This feature is the result of the civilisation of organolithiums from the savage beasts of 40 years ago (BuLi, benzene, reflux) to the tamed, well-trained species we use to coax out one proton at a time or to nudge a starting material over the energetic barrier of a spectacular cascade reaction.

To explain selectivity I have discussed mechanism in detail but not depth – the mechanistic discussions are intended not as a full account of current understanding of organolithium structure and reactivity, but as a tool for use in predicting likely outcomes of reactions and in accounting for unlikely ones. Similarly, structure is dealt with where necessary to explain a point, but detailed discussions of organolithium structure is outside the scope of a book primarily about organolithium reactions. I have also limited the definition of “organolithium” to those compounds in which there is a clear C–Li bond: compounds with any degree of enolate structure, and lithiated sulfones, sulfoxides, phosphonates, phosphine oxides etc. have been excluded. Inclusion or exclusion of a compound should not be taken to imply anything about its structure – a limit had to be drawn somewhere, and in some discussions the limit is stretched further tan in others.

General points about organolithiums in solution are considered briefly first, followed by chapters addressing the synthesis of functionalised organolithiums, and in particular the various methods for achieving regioselectivity. Some organolithiums have stereochemistry, and an account of the stereoselective synthesis of organolithiums follows an explanation of which and why. Discussions of reactions follow, but rather than give a thin account of a wide range of well-known additions and substitutions, I have limited the coverage to some important and developing areas: stereospecific and selective reactions, particularly those involving (–)-sparteine and other chiral additives, inter- and intramolecular additions to π systems, and rearrangements.

1.2 Organolithiums in solution

Organolithiums (with the exceptions of methyllithium and phenyllithium) are remarkably soluble even in hydrocarbon solvents,1,2 and simple organolithium starting materials are available as stable hydrocarbon solutions (Table 1.2.1). Methyllithium and phenyllithium are indefinitely stable at ambient temperatures in the presence of ethers, and are solubilised by the addition of ether or THF.

Table 1.2.1

Commercially available organolithiums in solution

methyllithium

MeLi

Et2O

1.4 M

cumene/THF

1.0 M

n-butyllithium

BuLi

cyclohexane

2.0 M

hexanes

1.6, 2.5, 10 M

pentane

2.0 M

sec-butyllithium

s-BuLi

cyclohexane

1.3 M

(or cyclohexane/hexane)

tert-butyllithium

t-BuLi

pentane

1.5, 1.7 M

phenyllithium

PhLi

cyclohexane/Et2O

1.8 M

a Abbreviation used in this book

Hydrocarbon solutions of n-, s- and t-BuLi are the ultimate source of most organolithiums, but a number of other bases are widely used to generate organolithiums from more acidic substrates. Among these are LDA, LiTMP and other more hindered lithium amide bases, and hindered aryllithiums such as mesityllithium and triisopropylphenyllithium.

The electron-deficient lithium atom of an organolithium compound requires greater stabilisation than can be provided by a single carbanionic ligand, and freezing-point measurements indicate that in hydrocarbon solution organolithiums are invariably aggregated as hexamers, tetramers or dimers.3 The structure of these aggregates in solution can be deduced to a certain extent from the organolithiums’ crystal structures4 or by calculation:5 the tetramers approximate to tetrahedra of lithium atoms bridged by the organic ligands; the hexamers approximate to octahedra of lithium atoms unsymmetrically bridged by the organic ligands.6,7 The aggregation state of simple, unfunctionalised organolithiums depends primarily on steric hindrance. Primary organolithiums are hexamers in hydrocarbons, except when they are branched β to the lithium atom, when they are tetramers. Secondary and tertiary organolithiums are tetramers, while benzyllithium and very bulky alkyllithiums (menthyllithium) are dimers.1,3

Table 1.2.2

Typical aggregation state in hydrocarbon solution

EtLi

i-PrCH2Li

PhCH2Li

–

BuLi

i-PrLi

t-BuLi

Coordinating ligands – such as ethers or amines, or even metal alkoxides (see section 2.6) – can provide an alternative source of electron density for the electron-deficient lithium atoms. These ligands can first of all stabilise the aggregates by coordinating to the lithium atoms at their vertices, and then allow the organolithiums to shift to an entropically favoured lower degree of aggregation. As shown in Table 1.2.3, the presence of ether or THF typically causes a shift down in aggregation state, but only occasionally results in complete deaggregation to the monomer.1 Methyllithium, ethyllithium and butyllithium remain tetramers in Et2O, THF,8 or dimethoxyethane (DME),9 with some dimer forming at low temperatures;10 t-BuLi becomes dimeric in Et2O and monomeric in THF at low temperatures.11 In the presence of TMEDA alone, however, s-BuLi remains a tetramer.12

Table 1.2.3

Typical aggregation state in the presence of Et2O or THF

–

MeLi

i-PrLi

PhCH2Li

EtLi

s-BuLi

(ArLi)a

BuLi

t-BuLi

(t-BuLi)a

(s-BuLi) b

ArLi

a In THF  < –100  °C or in TMEDA

b In cyclohexane–TMEDA

Table 1.2.4

Stabilities of organolithiums in common...

Produkt-Details

• Erscheint lt. Verlag: 12.7.2002
• Sprache: englisch
• Themenwelt: Naturwissenschaften ► Chemie ► Analytische Chemie
• Themenwelt: Naturwissenschaften ► Chemie ► Anorganische Chemie
• Themenwelt: Naturwissenschaften ► Chemie ► Organische Chemie
• Themenwelt: Naturwissenschaften ► Chemie ► Physikalische Chemie
• Themenwelt: Naturwissenschaften ► Chemie ► Technische Chemie
• Themenwelt: Technik
• ISBN-10: 0-08-053816-9 / 0080538169
• ISBN-13: 978-0-08-053816-7 / 9780080538167