Organic Synthesis E-Book

Stuart Warren

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

Seitenzahl: 420

Veröffentlichungsjahr: 2011

Beschreibung

One approach to organic synthesis is retrosynthetic analysis. With this approach a chemist will start with the structure of their target molecule and progressively cut bonds to create simpler molecules. Reversing this process gives a synthetic route to the target molecule from simpler starting materials. This "disconnection" approach to synthesis is now a fundamental part of every organic synthesis course. Organic Synthesis: The Disconnection Approach, 2nd Edition introduces this important technique, to help students to design their own organic syntheses. There are forty chapters: those on the synthesis of given types of molecules alternate with strategy chapters in which the methods just learnt are placed in a wider context. The synthesis chapters cover many ways of making each type of molecule starting with simple aromatic and aliphatic compounds with one functional group and progressing to molecules with many functional groups. The strategy chapters cover questions of selectivity, protection, stereochemistry, and develop more advanced thinking via reagents specifically designed for difficult problems. Examples are drawn from pharmaceuticals, agrochemicals, natural products, pheromones, perfumery and flavouring compounds, dyestuffs, monomers, and intermediates used in more advanced synthetic work. Reasons for wishing to synthesise each compound are given. This second edition has been fully revised and updated with a modern look. Recent examples and techniques are included and illustrated additional material has been added to take the student to the level required by the sequel, "Organic Synthesis: Strategy and Control". Several chapters contain extensive new material based on courses that the authors give to chemists in the pharmaceutical industry. Organic Synthesis: The Disconnection Approach, 2nd edition provides a full course in retrosynthetic analysis for chemistry and biochemistry students and a refresher for organic chemists working in industry and academia.

Leseprobe

Contents

Preface

General References

1 The Disconnection Approach

The Synthesis of Multistriatin

Summary: Routine for Designing a Synthesis

What the Rest of the Book Contains

References

2 Basic Principles: Synthons and Reagents Synthesis of Aromatic Compounds

Synthesis of Aromatic Compounds

Disconnection and FGI

Synthons Illustrated by Friedel-Crafts Acylation

Synthons Illustrated by Friedel-Crafts Alkylation

Functional Group Addition Illustrated by Friedel-Crafts Alkylation

Reliable Reagents for Electrophilic Substitution

Changing the Polarity: Nucleophilic Aromatic Substitution

Thinking Mechanistically

Changing the Polarity: Nucleophilic Aromatic Substitution by the SN1 Mechanism

References

3 Strategy I: The Order of Events

References

4 One-Group C–X Disconnections

Carbonyl Derivatives RCO.X

The Synthesis of Ethers

The Synthesis of Sulfides

Summary of Compounds Made from Alcohols

References

5 Strategy II: Chemoselectivity

A Warning

References

6 Two-Group C–X Disconnections

One-Group and Two-Group C–X Disconnections

Recognising a Two-Group C–X Disconnection

The 1,3-diX Relationship

The 1,2-diX Relationship

The 1,1-diX Relationship

Two-Group C–X Disconnections as a Preliminary to a Full Analysis

References

7 Strategy III: Reversal of Polarity, Cyclisations, Summary of Strategy

Reversal of Polarity Synthesis of Epoxides and α-Halo-Carbonyl Compounds

The Halogenation of Ketones

Halogenation of Acids

Cyclisation Reactions

Summary of Strategy

Example: Salbutamol

References

8 Amine Synthesis

Reductive Amination

Other Ways to Make Amines

The Synthesis of Monomorine I

References

9 Strategy IV: Protecting Groups

Qualities Needed in a Protecting Group

Ethers and Amides as Protecting Groups

The Achilles Heel Strategy

Protection of Alcohols

The Literature on Protecting Groups

Protecting Group Summary

References

10 One Group C–C Disconnections I: Alcohols

Reagents for Nucleophilic Carbon

‘1,1C–C’ Disconnections: The Synthesis of Alcohols

Aldehydes and Ketones

Oxidising Agents for the Conversion of Alcohols to Aldehydes

Carboxylic Acids

‘1,2C–C’ Disconnections: The Synthesis of Alcohols

Example of the Synthesis of Alcohols and Related Compounds

Other One-Group C–C Disconnections

Carbon–Carbon Disconnections to Avoid

References

11 General Strategy A: Choosing a Disconnection

Greatest Simplification

Symmetry

Recognisable Starting Materials

Available Compounds

Summary of Guidelines for Good Disconnections

References

12 Strategy V: Stereoselectivity A

Enantiomerically Pure Compounds

Stereospecific and Stereoselective Reactions

References

13 One Group C–C Disconnections II: Carbonyl Compounds

Synthesis of Aldehydes and Ketones by Acylation at Carbon

Carbonyl Compounds by Alkylation of Enols

Carbonyl Compounds by Conjugate Addition

References

14 Strategy VI: Regioselectivity

The Regioselective Alkylation of Ketones

Regioselectivity in Nucleophilic Addition to Enones

References

15 Alkene Synthesis

Synthesis of Alkenes by Elimination Reactions

Alkene Synthesis by the Wittig Reaction

References

16 Strategy VII: Use of Acetylenes (Alkynes)

The Reduction of Alkynes to Alkenes

Ketones by Hydration of Acetylenes

An Alkyne-Containing Anti-AIDS Drug

References

17 Two-Group C–C Disconnections I: Diels-Alder Reactions

Stereospecificity

Endo-Selectivity

Regioselectivity

FGI on Diels-Alder Products

Intramolecular Diels-Alder Reactions

Diels-Alder Reactions in Water

References

18 Strategy VIII: Introduction to Carbonyl Condensations

Carbon Acids and the Bases Used to Deprotonate Them

Reference

19 Two-Group C–C Disconnections II: 1,3-Difunctionalised Compounds

β-Hydroxy Carbonyl Compounds: The Aldol Reaction

The Synthesis of α,β-Unsaturated Carbonyl Compounds

1,3-diCarbonyl Compounds

Looking Forward

References

20 Strategy IX: Control in Carbonyl Condensations

The Three Key Questions for Successful Cross-Condensations

Intramolecular Reactions

Cross-Conjugations I: Compounds that Cannot Enolise

Cross-Conjugation II: Specific Enolates

Cross-Condensation III: Removal of a Product from Equilibrium

References

21 Two-Group C–C Disconnections III: 1,5-Difunctionalised Compounds Conjugate (Michael) Addition and Robinson Annelation

Specific Enol Equivalents Good at Michael Addition

Michael Acceptors Good at Conjugate Addition

The Robinson Annelation

Heterocycles Made from 1,5-diCarbonyl Compounds

References

22 Strategy X: Aliphatic Nitro Compounds in Synthesis

Reduction of Nitro Compounds

Diels-Alder Reactions

Summary of Nitro Groups in Synthesis

References

23 Two-Group Disconnections IV:

Acyl Anion Equivalents

Methods from Alkenes

α-Functionalisation of Carbonyl Compounds

Strategy of Available Starting Materials

The Benzoin Condensation

References

24 Strategy XI: Radical Reactions in Synthesis

Functionalisation of Allylic and Benzylic Carbons2

Carbon–Carbon Bond-Forming Reactions

Making 1,2-Difunctionalised Compounds

25 Two-Group Disconnections V:1,4-Difunctionalised Compounds

Reactions of Enol(ate)s with Reagents for a2 Synthons

Conjugate Addition of Acyl Anion Equivalents

Direct Addition of Homoenolates (d3 Reagents)

Strategy of Available Starting Materials with a 1,4-diCO Relationship

The FGA Strategy

References

26 Strategy XII: Reconnection

Synthesis of 1,2- and 1,4-diCO Compounds by Oxidative C=C Cleavage

A Dramatic Example of FGA

References

27 Two-Group C–C Disconnections VI: 1,6-diCarbonyl Compounds

The Diels-Alder Route to 1,6-diCarbonyl Compounds

Cyclohexenes from Other Sources

Oxidative Cleavage by the Baeyer–Villiger Reaction

Other Approaches

References

28 General Strategy B: Strategy of Carbonyl Disconnections

The Synthesis of a Lactone

Synthesis of a Symmetrical Cyclic Acetal

Synthesis of a Spiro Enone

The Synthesis of Piquindone

Summary of General Approach to the Design of Syntheses

References

29 Strategy XIII: Introduction to Ring Synthesis: Saturated Heterocycles

Cyclisation Reactions

Three-Membered Rings

Four-Membered Rings

Five-Membered Rings

Six-Membered Rings

Seven-Membered Rings

References

30 Three-Membered Rings

Cyclopropanes by Alkylation of Enolates

Carbene Insertion into Alkenes

Sulfonium Ylid Chemistry

References

31 Strategy XIV: Rearrangements in Synthesis

Diazoalkanes

Diazoalkanes in Ring Expansion and Contraction

The Pinacol Rearrangement

The Favorskii Rearrangement

References

32 Four-Membered Rings: Photochemistry in Synthesis

Photochemical Cycloadditions

Four-Membered Rings by Ionic Reactions

References

33 Strategy XV: The Use of Ketenes in Synthesis

[2 + 2] Thermal Cycloadditions of Ketenes

References

34 Five-Membered Rings

Five-Membered Rings from 1,4-diCarbonyl Compounds

Cyclopentyl Ketones from 1,6-diCarbonyl Compounds

Cyclopentanes from 1,5-diCarbonyl Compounds

Synthesis of Cyclopentanes by Double Sequential Conjugate Addition

References

35 Strategy XVI: Pericyclic Reaction sin Synthesis: Special Methods for Five-Membered Rings

Electrocyclic Reactions

Sigmatropic Rearrangements

36 Six-Membered Rings

Carbonyl Condensations: The Robinson Annelation

The Diels-Alder Reaction

Reduction of Aromatic Compounds

References

37 General Strategy C: Strategy of Ring Synthesis

Cyclisation to Control Selectivity

Early Disconnection of Small Rings

Alternative Disconnections

References

38 Strategy XVII: Stereoselectivity B

Synthesis of Molecules with Many Chiral Centres

Stereochemical Control in Folded Molecules

A Synthesis of Copaene

Summary of Stereoselectivity on Folded Molecules

The Synthesis of Juvabione

References

39 Aromatic Heterocycles

Carbon–Heteroatom Disconnections

Thiazoles

Six-Membered Rings: Pyridines

Pyrimidines

Benzene-Fused Heterocycles: Indoles

Example: The Synthesis of Indomethacin

Making Bonds to pre-Formed Heterocycles

References

40 General Strategy D: Advanced Strategy

A Synthesis of Pyrazoles

Convergence

Convergence in a Commercial Synthesis

Key Reaction Strategy

References

Index

This edition first published 2008

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Library of Congress Cataloging-in-Publication Data

Warren, Stuart G.

Organic synthesis: the disconnection approach/Stuart Warren and Paul Wyatt.—2nd ed.

p. cm.

Includes bibliographical references and index.

ISBN 978-0-470-71237-5 (cloth)—ISBN 978-0-470-71236-8 (pbk.: alk. paper)

1. Organic compounds-Synthesis. I. Wyatt, Paul. II. Title.

QD262.W284 2008

547’.2-dc22

2008033269

A catalogue record for this book is available from the British Library.

ISBN 978-0-470-7-12375 (HBK) 978-0-470-7-12368 (PBK)

Typeset in 10/12 Times-Roman by Laserwords Private Limited, Chennai, India Printed and bound in Great Britain by Antony Rowe Ltd, Chippenham, Wiltshire

The first edition was written with the active participation of Denis Marrian who died in 2007. We dedicate this second edition to Denis Haigh Marrian, 1920–2007, a great teacher and friend.

Preface

In the 26 years since Wiley published Organic Synthesis: The Disconnection Approach by Stuart Warren, this approach to the learning of synthesis has become widespread while the book itself is now dated in content and appearance. In 2007, Wiley published Organic Synthesis: Strategy and Control by Paul Wyatt and Stuart Warren. This much bigger book is designed as a sequel for fourth year undergraduates and research workers in universities and industry. The accompanying workbook was published in 2008. This new book made the old one look very dated in style and content and exposed gaps between what students were expected to understand in the 1980s and what they are expected to understand now. This second edition is intended to fill some of those gaps.

The plan of the original book is the same in the second edition. It alternates chapters presenting new concepts with strategy chapters that put the new work in the context of overall planning. The 40 chapters have the same titles: some chapters have hardly been changed while others have undergone a thorough revision with considerable amounts of new material. In most cases examples from recent years are included.

One source of new material is the courses that the authors give in the pharmaceutical industry. Our basic course is ‘The Disconnection Approach’ and the material we have gathered for this course has reinforced our attempts to give reasons for the synthesis of the various compounds which we believe enlivens the book and makes it more interesting for students. We hope to complete a second edition of the workbook shortly after the publication of the main text.

The first edition of the textbook was in fact the third in a series of books on organic chemistry published by Wiley. The first: The Carbonyl Group: an Introduction to Organic Mechanisms, published in 1974, is a programmed book asking for a degree of interaction with the reader who was expected to solve problems while reading. People rarely use programmed learning now as the method has been superseded by interactive programmes on computers. Paul Wyatt is writing an electronic book to replace The Carbonyl Group which will complete a package of an electronic book and books with associated workbooks in a uniform format that we hope will prove of progressive value as students of organic chemistry develop their careers.

Stuart Warren and Paul Wyatt

March 2008.

General References

Full details of important books referred to by abbreviated titles in the chapters to avoid repetition.

Clayden, Lithium: J. Clayden, Organolithiums: Selectivity for Synthesis, Pergamon, 2002.

Clayden, Organic Chemistry: J. Clayden, N. Greeves, S. Warren and P. Wothers, Organic Chemistry, Oxford University Press, Oxford, 2000.

Comp. Org. Synth.: eds. Ian Fleming and B. M. Trost, Comprehensive Organic Synthesis, Pergamon, Oxford, 1991, six volumes.

Corey, Logic: E. J. Corey and X.-M. Cheng, The Logic of Chemical Synthesis, Wiley, New York, 1989.

Fieser, Reagents: L. Fieser and M. Fieser, Reagents for Organic Synthesis, Wiley, New York, 20 volumes, 1967-2000, later volumes by T.-L. Ho.

Fleming, Orbitals: Ian Fleming, Frontier Orbitals and Organic Chemical Reactions, Wiley, London, 1976.

Fleming, Syntheses: Ian Fleming, Selected Organic Syntheses, Wiley, London, 1973.

Houben-Weyl; Methoden der Organischen Chemie, ed. E. Müller, and Methods of Organic Chemistry, ed. H.-G. Padeken, Thieme, Stuttgart, many volumes 1909–2004.

House: H. O. House, Modern Synthetic Reactions, Benjamin, Menlo Park, Second Edition, 1972.

Nicolaou and Sorensen: K. C. Nicolaou and E. Sorensen, Classics in Total Synthesis: Targets, Strategies,Methods. VCH, Weinheim, 1996. Second volume now published.

Saunders, Top Drugs: J. Saunders, Top Drugs: Top Synthetic Routes, Oxford University Press, Oxford, 2000.

Strategy and Control; P. Wyatt and S. Warren, Organic Synthesis: Strategy and Control, Wiley, Chichester, 2007 and Workbook, 2008.

Vogel: B. S. Furniss, A. J. Hannaford, P. W. G. Smith, and A. R. Tatchell, Vogel’s Textbook of PracticalOrganic Chemistry, Fifth Edition, Longman, Harlow, 1989.

2

Basic Principles: Synthons and Reagents Synthesis of Aromatic Compounds

Background Needed for this Chapter References to Clayden, Organic Chemistry:

Electrophilic aromatic substitution; chapter 22. (Electrophilic Aromatic Substitution)

Nucleophilic aromatic substitution: chapter 23 (Electrophilic Alkenes).

Reduction: chapter 24 (Chemoselectivity: Selective Reactions and Protection).

Synthesis of Aromatic Compounds

The benzene ring is a very stable structural unit. Making aromatic compounds usually means adding something(s) to a benzene ring. The disconnection is therefore almost always of a bond joining a side chain to the benzene ring. All we have to decide is when to make the disconnection and which reagents to use. You will meet the terms and (FGI) in this chapter.