Table Of ContentINTERNATIONAL UNION OF
PURE AND APPLIED CHEMISTRY
ORGANIC CHEMISTRY DIVISION
in conjunction with the
ORGANIC CHEMISTRY DEPARTMENT OF
THE CATHOLIC UNIVERSITY OF LOUVAIN
ORGANIC
SYNTHESIS
Plenary lectures presented at the
FIRST INTERNATIONAL CONFERENCE ON
ORGANIC SYNTHESIS
held in Louvain-la-Neuve, Belgium
26-30 August 1974
Symposium Editors
A. BRUYLANTS,
L. GHOSEZ and H. G. VIEHE
University of Louvain
LONDON
BUTTERWORTHS
ENGLAND: BUTTERWORTH & CO. (PUBLISHERS) LTD.
LONDON: 88 Kingsway, WC2B 6AB
AUSTRALIA: BUTTERWORTHS PTY. LTD.
SYDNEY: 586 Pacific Highway, NSW 2067
Also at Melbourne, Brisbane, Adelaide and Perth
CANADA: BUTTERWORTH & CO. (CANADA) LTD.
TORONTO: 2265 Midland Avenue, Scarborough, Ontario, M1P 4SI
NEW ZEALAND: BUTTERWORTHS OF NEW ZEALAND LTD.
WELLINGTON: 26-28 Waring Taylor Street, 1
SOUTH AFRICA: BUTTERWORTH & CO. (SOUTH AFRICA) (PTY.) LTD.
DURBAN: 152-154 Gale Street
The contents of this book appear in
Pure and Applied Chemistry, Vol. 43 Nos. ^4 (1975)
All rights reserved. No part of this publication may be reproduced or transmitted in any form
or by any means, including photocopying and recording, without the written permission of the
copyright holder, application for which should be addressed to the publisher. Such written
permission must also be obtained before any part of this publication is stored in a retrieval
system of any nature.
International Union of Pure and Applied Chemistry
1975
ISBN 0408 70725 9
Printed in Great Britain by Page Bros (Norwich) Ltd, Norwich
ORGANIZING COMMITTEE
A. BRUYLANTS
L. GHOSEZ
L. VAN SlMAEYS
H. G. VlEHE
SCIENTIFIC COMMITTEE
J. F. ARENS E. JONES
A. BRUYLANTS M. LORA TAMAYO
E. BERGMANN R. H. MARTIN
L. GHOSEZ H. NORMANT
K. HEUSLER M. VANDEWALLE
R. HUISGEN A. VAN DORMAEL
H. G. VlEHE
vi
ORGANIZING COMMITTEE
A. BRUYLANTS
L. GHOSEZ
L. VAN SlMAEYS
H. G. VlEHE
SCIENTIFIC COMMITTEE
J. F. ARENS E. JONES
A. BRUYLANTS M. LORA TAMAYO
E. BERGMANN R. H. MARTIN
L. GHOSEZ H. NORMANT
K. HEUSLER M. VANDEWALLE
R. HUISGEN A. VAN DORMAEL
H. G. VlEHE
vi
OPENING REMARKS
A. BRUYLANTS
Universite de Louvain
Chemistry, which was defined at its beginning as a science of the analysis
of matter is also that of synthesis. Instead of science, perhaps, it may be
better to call it the art of analysis, when we think about the extraordinary
skill of the pioneers and their wonderful intuition, which very often made
up for their ignorance! With the aid of their art, chemists have learnt not
only to analyse but also to reproduce a certain number of natural bodies, to
recompose them and likewise to rediscover all their properties. It is mainly
in the field of organic compounds—these compounds which touch our life
so closely—that their successes have so far been the most numerous and the
most impressive.
In a well known book, published in 1860, La Chimie Organique Fondee
sur la Synthese [Organic Chemistry Founded on Synthesis], Berthelot under-
lined the extraordinary potential of synthetic processes and their fundamental
scientific interest: by utilizing them cleverly one could reach at the absolute
knowledge of the constitution of compounds formed at the expense of their
elements.
At that time, many scientists did still believe in the 'vital force', this
mysterious force which determines exclusively the chemical phenomena
observed in living beings. Having succeeded in preparing lipids by the re-
action of aliphatic acids with glycerin, and in fixing it as his distant and
ultimate aim to reproduce carbohydrates and proteins, Berthelot wrote:
'Synthesis presents an immense and new field which is just opening to us and
it is for us to go through'.
In going through and cultivating this immense field in a systematic
manner, chemists have discovered that synthetic processes lead not only
to reproducing existing bodies but also to creating entirely new ones unknown
in nature. This double possibility of reproduction and creation rapidly
found another immense field, that of industrial applications. Natural and
artificial dyes, essential oils and perfumes extracted from plants and animals
or fabricated by synthesis, numerous pharmaceutical products, and many
other substances unlimited in number were poured into the economic
stream and have grown up into dimensions without precedent in all markets.
By the end of the last century, organic chemistry had become a source of
wealth and constituted a capital factor of the economic flight and demo-
cratization of a country. Now, more than ever, the habitat of man, his
clothing, his nourishment and his health—in a word, his mode of life—
are to a great extent controlled by organic chemistry. The layman is not
always aware of this fact, so much so that it may seem trivial to him. We,
the chemists, dedicated to the obscure and patient work of the laboratory,
know the sum total of intellectual effort, the intensity of thought and con-
centration of mind indispensable for the discovery of a new synthetic process
315
PAC-^3-3/4-B
A. BRUYLANTS
as well as of the wonderful machinery necessary for the elaboration of a
manufactured chemical product.
In the course of these past years, the progress of organic synthesis has
been many-sided and important. New reactions have been discovered, the
possibilities of the classic reactions have been improved; in this respect,
the choice of a wide range of solvents, the employment of physical procedures
of activation, like that of light and pressure, and the utilization of various
types of catalysts have often played a decisive role. Simultaneously, the
mastery of the problems of stereo- and directio-selectivity has been con-
siderably improved.
Reaction mechanisms, the grasp of which is so necessary for the success
of a synthesis, have benefited from a better understanding of the electronic
and quantum factors and of a more judicious application than in the past of
thermodynamic and chemical kinetics. In this regard it is appropriate to
read again the following text written by Hammett in 1940: There is no branch
of physical chemistry of greater importance to the organic chemist than that
of reaction rates. The selection of proper conditions for a synthetic operation
is usually a problem in reaction rates and the study of the rates of reaction
is the most useful tool for the investigation of reaction mechanism1.
The researches in applied organic chemistry have been equally extensive
and the syntheses formerly considered long and difficult have been made easy
in the stage of industrial fabrication.
Moreover the techniques of chemical analysis have been completely
renewed by the use of chromatography and spectrometry, and also by
automation of the apparatus.
In these conditions, organic chemistry has reached new summits in the
course of the last two decades. It is to translate this new spring, to make it
more sensitive, and to make the international chemical community profit
from it that the Division of Organic Chemistry of the I UP AC has decided
to launch a series of biennial conferences on organic synthesis. The Organic
Chemistry Department of our University has had the honour of being
responsible for the organization of the first of these events, and I can assure
you that it has done its best to make it a success as perfect as possible. The
programme of subjects for discussion at the conference has been set up by an
international scientific committee. This committee had at its disposition the
results of a large inquiry conducted by our Department during the first semester
of 1973. Nearly a hundred specialists had agreed to answer the questions
concerning the themes to be treated and the lecturers to be invited; this pro-
cedure allowed us to present a programme on fundamental problems which
responds to the present needs of new general methods, stereochemical control,
the effect of the medium, physical activation and industrial organic synthesis.
These are the themes for fourteen plenary sessions; each one of these
presentations was submitted to discussion by the participants. The abstracts
were published in the special issue of the Bulletin des Societes Chimiques
Beiges (Bulletin of the Belgian Chemical Societies) and distributed to each
and every participant.
316
THE CYCLOPROPANATION OF SILYL ENOL
ETHERS. A POWERFUL SYNTHETIC TOOL
J. M. CONTA
Laboratoire des Carbocycles, Universite de Paris-Sud, 91405 Orsay, France
ABSTRACT
Trimethylsilyl enol ethers of both saturated and unsaturated aliphatic or
alicyclic carbonyl compounds, when submitted to cyclopropanation by an
improved Simmons-Smith reaction (Zn/Ag couple is used and hydrolysis of the
product is replaced by pyridine work-up), lead to siloxycyclopropane deriva-
tives, which are useful synthetic intermediates.
Thus, depending on the starting material and the reactions subsequently
applied, the following may be carried out: the a-monomethylation of saturated
aldehydes and ketones and often, in the case of unsymmetrical ketones, their
specific a- or a'-methylation, as required; the specific a- or a'-monomethylation
of cycloalkenones; the simple preparation of cyclobutanones and cyclopentan-
ones starting from cisoid or labile enones; the synthesis of cyclopropylcyclo-
propanols and cyclopropylketones.
Siloxycyclopropanes, e.g. by methanolysis, are the best intermediates to
cyclopropanols.
Silyl enol ethers
The study of silyl enol ethers and their use as synthetic intermediates
really began with the works of Stork and Hudrlik1 and House et al.2, the
purpose of these authors being to prepare specific enolate anions from such
enol ethers and then to carry out specific alkylation reactions. Trimethylsilyl
enol ethers were employed in these studies; these are now easily preparable,
even in large amounts, using the commercially available, cheap chloro-
trimethylsilane, and form the subject of this lecture.
Two main procedures are used for the preparation of trimethylsilyl enol
ethers from saturated aldehydes and ketones2. (1) With chlorotrimethylsilane
and triethylamine in dimethylformamide solution, an aldehyde or a sym-
metrical ketone leads to the trimethylsilyl enol ether, whereas from an un-
symmetrical ketone an equilibrium mixture of both of the enol ethers is
obtained, the components being sometimes rather difficult to separate by
distillation: (2) Successive reaction of an unsymmetrical ketone with lithium
diisopropylamide and with ClSiMe3 in 1,2-dimethoxyethane solution
normally produces (via kinetically controlled enolate formation) only, or
almost only, the less highly substituted enol ether.
From unsaturated aldehydes and ketones, the preparation of well-
defined trimethylsilyl enol ethers seems more difficult and has been less well
317
J. M. CONIA
investigated. Later on it will be seen that such enol ethers can in fact be pre-
pared easily and are also interesting intermediates in synthesis.
Improved Simmons-Smith reactions
It is well known that the Simmons-Smith reaction3, a powerful method for
the preparation of cyclopropane derivatives from olefins, seems to be not
always reproducible, the yields depending markedly on the procedure
employed and on the structure of the starting olefin; in particular, for ketone-
derived olefins, such as enamines, enol ethers or enol esters, the yields are
generally rather low.
We recently reported two modifications of the reaction4 which give im-
proved yields, particularly with functionally substituted olefins: (1) with
methylene iodide a zinc-silver couple is used in place of the classical zinc-
copper couple; (2) the usual final hydrolysis of the reaction mixture is
replaced by the addition of an amine, e.g. pyridine, in order to remove zinc
salts.
The first modification of the reaction is not essential in the case of the
cyclopropanation of silyl enol ethers; however, the use of zinc-silver couple
is advantageous since it is more reactive towards diiodomethane, it gives
slightly better yields of siloxycyclopropane, a large excess of the reagent
CH I , Zn/Ag is not necessary to complete the reaction and the reaction
2 2
time is reduced
On the other hand, the usual work-up of the reaction mixture by acid
hydrolysis is not convenient in the cyclopropanation of silyl enol ethers,
because the readily formed cyclopropanols can undergo ring opening and
because the coordination complexes formed from siloxycyclopropanes and
ICH ZnI and/or Znl (strong Lewis acid) can be somewhat difficult to
2 2
hydrolyse and furthermore, when present only in traces, may polymerize the
cyclopropane products, e.g. in distillation.
A good preparation of zinc-silver couple is as follows: to a stirred hot
solution of silver acetate in acetic acid (e.g. not more than 100 mg in 100 ml,
for the solution must be clear, and its temperature between ~50 and 60°)
granular zinc (e.g. 17 g, 0.25 g-atom) is added at once. The mixture is stirred
for 30 s; the zinc-silver couple formed is isolated by decantation, washed with
ether (5 x 100 ml) and finally stored under anhydrous ether (150 ml).
The reaction with methylene iodide and with the silyl enol ether is then
carried out: to the stirred, ethereal suspension of the zinc-silver couple,
methylene iodide (34 g 0.13 mol) is added dropwise at such a rate as to main-
tain gentle reflux, and stirring is continued for 1 h at room temperature; then
the silyl enol ether (e.g. 0.10 mol) is added dropwise over a period of 15 min
and the mixture is refluxed for the necessary time.
The pyridine work-up is as follows: after cooling the reaction mixture,
pyridine (2 equiv. with respect to CH I ) is added dropwise with vigorous
2 2
stirring over a 1 h period; the resultant precipitate, Znl , 2C H N, is filtered
2 5 5
off, the ether evaporated in vacuo, the residual solution refiltered and the
filtrate distilled in vacuo.
Cyclopropanation of silyl enol ethers of saturated aldehydes and ketones.
318
THE CYCLOPROPANATION OF SILYL ENOL ETHERS
Synthesis of secondary and tertiary cyclopropanols. a-Monomethylation of
aldehydes and ketones. a- or ix'-Monomethylation of unsymmetrical ketones5
OH
Rf^R 4
3
CH3OH
R
^°
R./OSiMe R^OSiMe _
3 3 QH
R R3 H R^R3 R2 "R3 R3 CH,
1 3 5
The reaction of CH I + Zn/Ag with pyridine work-up carried out on
2 2
silyl enol ether (2) derived from carbonyl compound (1) leads to siloxy-
cyclopropane (3). By methanolysis the latter gives the corresponding cyclo-
propanol (4) (~ 90 per cent), the three-reaction sequence thus providing an
exceedingly simple preparation of these alcohols. By alkaline hydrolysis,
treatment for 8-9 h in boiling ethanolic NaOH (ca.: 1 g/1 with aldehydes,
10 g/1 with most of the ketones) the siloxycyclopropane (3) gives the product
of monomethylation (5) (^90 per cent) (see Table 1).
From unsymmetrical ketones the methylation can be oriented in the oc-
or oe'-position as required. In favourable cases the desired silyl enol ether is
easily available, either because it is the sole isomer formed or because its
separation from the unwanted isomer is possible, e.g. by distillation.
From methylisopropylketone (6), for instance, it is easy to carry out the
direct preparation of 'kinetic7 enol ether (7), practically pure, and thence
methylation at the methyl group. The preparation of isomer enol ether (8),
and thence the methylation on the other side of the carbonyl group, is easily
accomplished by the distillation of the thermodynamic mixture.
OSiMe
3
o
CH2I2. Zn/Ag ~O~H" ^ r\
pyridine
y\
H OSiMe3 \ °
distillation id.
319
Table 1. a-Monomethylation of saturated aldehydes and ketones
Carbonyl compounds Silyl enol ethers (Y) Siloxy-cyclopropanes (Y) a -Methylation
carbonyl com-
pound Y^ 90%
CH3—CH=CHOSiMe A
3
CH —CH —CHO -*trans-cis:5/95 —► CH —/ \ QSiMe —► (CH) CH—CHO
3 2 3 3 3 2
(51%) (61%)
CH
3
(CH ) CH—CHO -(CH ) C=CHOSiMe —► >^—^-OSiMe —► (CH) C—CHO
3 2 3 2 3 3 3 3
(54%) CH (63%)
3
C5HnCH=CHOSi]N .H..-A. J.
CH —(CH ) —CHO ->trans-cis : 27/73 C H —' } OSiMe —► CsH^CH—CHO M
& 3 2 5 (65%) 55 n n (ff8i1l <->> \ 3 | .
C
O CH3 O
N
I
A
/"~^C=0 /^"^COSiMe, ^-COSiMe3 / ^ c =0
(CH )„_ | ► (CH ) _ || — (CH Uh> —* (C[U- |
V2^C2H2 V2 M^2CH V_2 6H V_C2HCH
3
w = 5 60% 65%
6 70 67
7 90 76
8 87 84
