Workbook for organic synthesis: the disconnection approach

260 Pages·2010·5.13 MB·English

by  Stuart Warren

Workbook for Organic Synthesis:
The Disconnection Approach
Second Edition
Stuart Warren
I{eader jn ()rganic C'henlistry, Departlnenl of Chenlistf)\
University of (~~unbridge. U·K
and
llaul \Vvatt
."
Reader and l)irector of l Indcrgraduate Studies, School of (~henlis1xy,
lJ ni versity of BristoL lJ K
(~WILEY
A John \Nilcy ;1nd Sons, L.td.,. Pubbcatiol1
This edition first published 2009
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Warrcll. Stuan.
WorlbUllk I"nr tlIg;\I1ic synthe:-.is : the disconnection arproach ! Stuart Warren and Paul \-Vyall. - 2nd cd.
p. CIll.
Inclllllc~ bibliogl'Jphical rekrt'nces :lnd index.
ISHN <.J7X-O-470·71227-() - ISBN 97X-O-..J70-7122()-9
1. Organic cOl1lpollmls -- Synthesis - TcxthooKs. !. Wv:1tt. Paul. II. Title.
<)0262. \\'9.1 200()
."47'.2 - del2
2009mox I ()
A cat;tingue record fOt" this hook is :tnil:lhle from the British Library
[.'lBi\: 97X-O-470-71227-h (Hl8) 97K-O--J.70-71226-l) (P/H)
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Contents
Preface vii
General References ix
1. The Djsconnection Approach
2. Basic Principles: Synthons and Reagen~s: Synthesis of Aronlatic Compounds 5
3. Strategy 1: The Order of Events 1 ]
4. One-Group C-X Disconnections 15
5. Strategy II: Chelnoselecti vi ty 21
6. T\vo-Group C-X Disconnections 29
7. Strategy III: Reversal of Polarity, Cyclisations~ Sumn1ary of Strategy 35
8. Anlinc Synthesis 41
9. Strategy IV: Protecting Groups 49
10. One-Group C-C Disconnections I: Alcohols 55
1 1. General Strategy A: Choosing a Disconnection 61
12. Strategy V: Stereoselectivity A 67
j 3. One-Group' C-C Disconnections II: Carbonyl Compounds 75
14. Strategy VI: RegioseJectivity 81
IS. Alkene Synthesj s 87
16.' Strategy VII: Use of Acetylenes CAlkynes) 93
] 7. Two-Group C-C Disconnections 1: Diels-Alder Reactions 99
18. Strategy VIII: Introduction to Carbonyl Condensations _ 105
19. Two-Group C-C Disconnections II: 1,3-Difunctionalised COlnpollnds 111
20. Strategy IX: Control in Carbonyl Condensations '} ) 5
21. Two-Group C-C Disconnections III: 1~ 5-Difunctionalised CC?lnpollnds Conjugate
(Michael) Addi.tion and Robinson Annelation. 123
22. Strategy X: Aliphatic Nitro COlnpounds in Synthesis 129
23. Two-Group Disconnections IV: 1,2-Djfunctionalised COlnpounds 133
24. Strategy XI: Radical Reactions in Synthesis 139
25. Two-Group Disconnections V: ] ~4-Difunctiona]ised Compounds 147
26. Strategy XII: Reconnection 153
27. Two-Group C-C Disconnections VI: 1,6-diCarbonyl Compounds J59
28. General Strategy B: Strategy of Carbonyl Disconnections 165
29. Strategy XIII: Introduction to Ring Synthesis: Saturated Heterocycles 173
30. Three-Membered Rings ] 81
31. Strategy XIV: Rearrangelnents in Synthesis 189
32. Four-Men1bered Rings: Photochenlistry in Synthesis 195
vi
COli/elliS
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: AdwlIlced 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 Disconnectiun 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 ill 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 01 the problems are drawn trom 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 whi Ie you are working on the problems. We have usually devised new problems but
some of lhe problems in the first edition seemed to do such a goud 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 0 .. from reading a
textbook. Only oy 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 discussioJl 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, Oxfonl, 2000.
Discollnection Texthook: S. Warren nnd P. Wy'ntt, Organic Swuhesis: The Disconnectioll Approach,
Second Edition, Wiley, Chichester, 200S.
Drug Synthesis: D. Lcdniccr and L. A. Mitschcr, The OIRanie CheJl1istJ}' of DllIg SYllthesis, Wiley.
New York, seven volumes. from 1977.
Fieser, Reagellfs: L. Fieser and M. Fieser, Reagellts for OIRallic SYllthesis, Wiley, New York, 20 vol
umes. 1967-2000. later volumes by T-L. Ho.
Fleming. Orhiruls: Ian Fleming. Frolllier Orbitals and Orgilllie Chemical ReactioJls, Wiley, London,
1976.
Vogel: B. S. Furniss, A. J. Hannaford, P. W. G. Smith, and A. R. Tntchell, Vogel's Textbollk II/Practical
Organic ChellliSIJ'Y. Fifth Edition. Longman, Harlow, J 989.
1
The Disconnection Approach
We start with a few simple problems to set YOll at ease with disconnections. Problem1.!: Here
is a two-step synthesis of the benzofuran 3. Draw Ollt the retrosynthetic analysis for the synthesis
of 2 from 1 showing the disconnections <!nd the syntholls.
Ph
Ph
yj.
0
rQl:r
rQl
~Br --
::::--..1 Ph .. H0
OH
base
Br Br Br
2 3
Answer 1.1: As this is a simple S,,2 reaction, [he disconnection is of the C-O 90nd 2a and the
synthon" are llucleophilic plH.:nolate <lIlion 4, which llappens to be an intermediate in the reaction,
and the cation 5, which happells not he an intermediate in the reaction but is represented by the
O'-bromokctone 6.
Br ' Br
2a 4 5 6
Problem 1.2: Draw the mechanism of the eyclisation 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 ~Icid-catalysed cyclisation 01: [he aromatic ring onto the protonated ketone 7. Loss of a proton
8 completes the electrophilic aromatic substitution giving the alcohol 9.
rQl Dr Ph yOD"
Ph
:
~tPh- -- ~D"-
?' .
::::--.. I ~~~ -- I
0 ::::--.. .(? (;JG ::::--.. 0
Br Br Br Br
2 7 8 9
_
------_._._._ .. .. _------- -- ---.
WtJrkho()h {(lr Organic Srwli('si"c TIJ(' /)i\"("OI/I/(Tlioll Apl/ruuch. Sf("(IIU/ bli,ioll Slu;nl \~;arrcJ) and Paul ~'y.11I
.~" 20()t) John \VilL':,>' & Son;.;. lid
2 1 JIIC Oiscollllecrioll Afll)roocil
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
~H' q)
--- ---
He.
9
~ C:0. ~ 0
Sr Sr Sr
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 lnterconversion (FGI) - changing one functional group
intll another. Now we can draw the disconnection revealing the synthons 12 represented in real
life by 2.
Ph
v~OH
==FG=I= > ====>
~I~.)
. 0
Sr Sr
3 9 12 2
A Synthesis of Multistriatin
In the textbook we gave one synthesis of lTIultistriatin 17 and here is a shorter but inferior
synthesis as the yields are lower and there is little control over stereochemistry. i Problem 1.4:
Which atoms in the final product 17 come from which starting material and which bonds are
made in the synthesis') Him: Arbitrarily number the atoills in Illultistriatin and try to trace each
atom back through the intermediates. Do not be concerned over mechanistic details, especially
cc.
of the step at 290
fa
)
1. CHzO ..
~o Me NH, HCI 290°C M~
2 + ~
~
2. K C0
2 3
3. Mel
HO OH
4. KOH
13 14 15 16 17; multistriatin
Answer 1.4: However you numbered lJ1ultistriatin. the ethyl group (7 and g in 17a) tinds the
same atoms in the last intermediate 16a and the rest falls into place. It then follows \X!hich atoms·
come from 14 and which from 15. Finally, you might have said that C-4 in our diagrams comes
from formaldehyde.
,t· ):
M4·
5 4 3
8~ ===> , ,I , , ===>
8~C
o
1 HO
8 OH
17a 16a 14a 15a
1 Rlit'rt'JI(,I!.I' 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 16h and finally the alkene was disconnected 14h in what you may
recognise as an aldol reaction with formaldehyde. If you practise analysing published syntheses
Ii ke this. you wi II increase your llnderstandi ngof good bonds to disconnect. '
'I
. 5 4 3
~'3 :::::;.
8~
7 6 0 2 1
o
1
8 OH
17b 1Gb 14b 13b
References
1. W. E. Gore. G. T. Pearce and R. M. Sil\"crslcin. 1. OIR- Cheill., 1975. 40. 1705.