Workbook for Organic Synthesis:

The Disconnection Approach

Workbook for Organic Synthesis:
The Disconnection Approach
Second Edition

Stuart Warren
Reader in Organic Chemistry, Department of Chemistry,
University of Cambridge, UK

and

Paul Wyatt
Reader and Director of Undergraduate Studies, School of Chemistry,
University of Bristol, UK

A John Wiley and Sons, Ltd., Publication

This edition first published 2009
© 2009 John Wiley & Sons Ltd

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Library of Congress Cataloging-in-Publication Data

Warren, Stuart.
Workbook for organic synthesis : the disconnection approach / Stuart Warren and Paul Wyatt. – 2nd ed.
p. cm.
Includes bibliographical references and index.
ISBN 978-0-470-71227-6 – ISBN 978-0-470-71226-9
1. Organic compounds – Synthesis – Textbooks. I. Wyatt, Paul. II. Title.

QD262.W93 2009
547 .2 – dc22
2009030810

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

ISBN 978-0-470-7-12276 (h/b) 978-0-470-7-12269 (p/b)

Contents

Preface vii

General References ix

1. The Disconnection Approach 1

2. Basic Principles: Synthons and Reagents: Synthesis of Aromatic Compounds 5
3. Strategy I: The Order of Events 11
4. One-Group C–X Disconnections 15
5. Strategy II: Chemoselectivity 21
6. Two-Group C–X Disconnections 29
7. Strategy III: Reversal of Polarity, Cyclisations, Summary of Strategy 35
8. Amine Synthesis 41
9. Strategy IV: Protecting Groups 49
10. One-Group C–C Disconnections I: Alcohols 55
11. General Strategy A: Choosing a Disconnection 61
12. Strategy V: Stereoselectivity A 67
13. One-Group C–C Disconnections II: Carbonyl Compounds 75
14. Strategy VI: Regioselectivity 81
15. Alkene Synthesis 87
16. Strategy VII: Use of Acetylenes (Alkynes) 93
17. Two-Group C–C Disconnections I: Diels-Alder Reactions 99
18. Strategy VIII: Introduction to Carbonyl Condensations 105
19. Two-Group C–C Disconnections II: 1,3-Difunctionalised Compounds 111
20. Strategy IX: Control in Carbonyl Condensations 115
21. Two-Group C–C Disconnections III: 1,5-Difunctionalised Compounds Conjugate
(Michael) Addition and Robinson Annelation 123
22. Strategy X: Aliphatic Nitro Compounds in Synthesis 129
23. Two-Group Disconnections IV: 1,2-Difunctionalised Compounds 133
24. Strategy XI: Radical Reactions in Synthesis 139
25. Two-Group Disconnections V: 1,4-Difunctionalised Compounds 147
26. Strategy XII: Reconnection 153
27. Two-Group C–C Disconnections VI: 1,6-diCarbonyl Compounds 159
28. General Strategy B: Strategy of Carbonyl Disconnections 165
29. Strategy XIII: Introduction to Ring Synthesis: Saturated Heterocycles 173
30. Three-Membered Rings 181
31. Strategy XIV: Rearrangements in Synthesis 189
32. Four-Membered Rings: Photochemistry in Synthesis 195
vi Contents

33. Strategy XV: The Use of Ketenes in Synthesis 201

34. Five-Membered Rings 207
35. Strategy XVI: Pericyclic Reactions in Synthesis: Special Methods
for Five-Membered Rings 213
36. Six-Membered Rings 221
37. General Strategy C: Strategy of Ring Synthesis 227
38. Strategy XVII: Stereoselectivity B 235
39. Aromatic Heterocycles 245
40. General Strategy D: Advanced Strategy 255

Index 263
Preface

In the 26 years since Wiley published Organic Synthesis: The Disconnection Approach and the
accompanying Workbook, this approach to the learning of synthesis has become widespread
while the books themselves are now dated in content and appearance. In 2008, Wiley published
the second edition of Organic Synthesis: The Disconnection Approach by Stuart Warren and Paul
Wyatt for which this is the accompanying Workbook .
This workbook contains further examples, problems (and answers) to help you understand the
material in each chapter of the textbook. The structure of this second edition of the workbook is the
same as that of the textbook. The 40 chapters have the same titles as before but all chapters have
undergone a thorough revision with some new material. The emphasis is on helpful examples and
problems rather than novelty. Many of the problems are drawn from the courses we have given
in industry on ‘The Disconnection Approach’ where they have stimulated discussion leading
to deeper understanding. It makes sense for you to have the relevant chapter of the textbook
available while you are working on the problems. We have usually devised new problems but
some of the problems in the first edition seemed to do such a good job that we have kept them.
Usually, the answers are presented in a different and, we hope, more helpful style.
It is not possible to learn how to design organic syntheses just from lectures or from reading a
textbook. Only by tackling problems and checking your answers against published material can
you develop this skill. We should warn you that there is no single ‘right answer’ to a synthesis
problem. Successful published syntheses give some answers that work, but you may well be able
to design others that have a good chance of success. The style of this second edition is to give
more discussion of alternative routes.

Stuart Warren and Paul Wyatt

2009
General References

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

Clayden Organic Chemistry: J. Clayden, N. Greeves, S. Warren and P. Wothers, Organic Chemistry,
Oxford University Press, Oxford, 2000.
Disconnection Textbook : S. Warren and P. Wyatt, Organic Synthesis: The Disconnection Approach,
Second Edition, Wiley, Chichester, 2008.
Drug Synthesis: D. Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, Wiley,
New York, seven volumes, from 1977.
Fieser, Reagents: L. Fieser and M. Fieser, Reagents for Organic Synthesis, Wiley, New York, 20 vol-
umes, 1967–2000, later volumes by T.-L. Ho.
Fleming, Orbitals: Ian Fleming, Frontier Orbitals and Organic Chemical Reactions, Wiley, London,
1976.
Vogel : B. S. Furniss, A. J. Hannaford, P. W. G. Smith, and A. R. Tatchell, Vogel’s Textbook of Practical
Organic Chemistry, Fifth Edition, Longman, Harlow, 1989.
1 The Disconnection Approach
We start with a few simple problems to set you at ease with disconnections. Problem 1.1: Here
is a two-step synthesis of the benzofuran 3. Draw out the retrosynthetic analysis for the synthesis
of 2 from 1 showing the disconnections and the synthons.
Ph
O O Ph
Br
Ph H
OH O O
base
Br Br Br
1 2 3

Answer 1.1: As this is a simple SN 2 reaction, the disconnection is of the C–O bond 2a and the
synthons are nucleophilic phenolate anion 4, which happens to be an intermediate in the reaction,
and the cation 5, which happens not be an intermediate in the reaction but is represented by the
α-bromoketone 6.
O Ph O Ph O Ph
+
O O Br
Br Br
2a 4 5 6

Problem 1.2: Draw the mechanism of the cyclisation of 2 to 3. This is an unusual reaction and
it helps to know what is going on before we analyse the synthesis. Answer 1.2: The first step is
an acid-catalysed cyclisation of the aromatic ring onto the protonated ketone 7. Loss of a proton
8 completes the electrophilic aromatic substitution giving the alcohol 9.

H Ph Ph
O Ph HO Ph OH OH
H
O O O O

Br Br Br Br
2 7 8 9

Workbook for Organic Synthesis: The Disconnection Approach, Second Edition Stuart Warren and Paul Wyatt
© 2009 John Wiley & Sons, Ltd
2 1 The Disconnection Approach

Now protonation of the alcohol leads to loss of water 10 to give a stabilised cation that loses
a proton 11 to give the new aromatic system 3. Problem 1.3: Now you should be in a position
to draw the disconnections for this step.
Ph Ph Ph
OH2
H
H
9 H
O O O
Br Br Br
10 11 3

Answer 1.3: We hope you might have drawn the intermediate alcohol 9. Changing 3 into 9 is not
a disconnection but a Functional Group Interconversion (FGI) – changing one functional group
into another. Now we can draw the disconnection revealing the synthons 12 represented in real
life by 2.
Ph Ph
Ph
OH OH O Ph
FGI

O O O O
Br Br Br Br
3 9 12 2

A Synthesis of Multistriatin
In the textbook we gave one synthesis of multistriatin 17 and here is a shorter but inferior
synthesis as the yields are lower and there is little control over stereochemistry.1 Problem 1.4:
Which atoms in the final product 17 come from which starting material and which bonds are
made in the synthesis? Hint: Arbitrarily number the atoms in multistriatin and try to trace each
atom back through the intermediates. Do not be concerned over mechanistic details, especially
of the step at 290 ◦ C.

1. CH2O
Me2NH, HCl 290 °C H O
+
O 2. K2CO3 O O
O
3. MeI HO OH
4. KOH 17; multistriatin
13 14 15 16

Answer 1.4: However you numbered multistriatin, the ethyl group (7 and 8 in 17a) finds the
same atoms in the last intermediate 16a and the rest falls into place. It then follows which atoms
come from 14 and which from 15. Finally, you might have said that C-4 in our diagrams comes
from formaldehyde.
4 4
5 3 5 3 5 3
4
O +
8 7 6 2 1
7 6 O 2 1 7 6 O 2
O
1 HO
8 OH 8
17a 16a 14a 15a
 1 References 3

So the disconnections also fall into place. Just one C–O bond was disconnected at first 17b
then one C–O and one C–C 16b and finally the alkene was disconnected 14b in what you may
recognise as an aldol reaction with formaldehyde. If you practise analysing published syntheses
like this, you will increase your understanding of good bonds to disconnect.

4 4
5 3 5 3 5 5
4 + CH 2O
O
8 7 6 2
7 6 O 2 1 7 6 O 7 6 O
O
1
8 OH 8 8
17b 16b 14b 13b

References
1. W. E. Gore, G. T. Pearce and R. M. Silverstein, J. Org. Chem., 1975, 40, 1705.