Asymmetric synthesis of 2-substituted 5-, 6- and 7-membered nitrogen
heterocycles by oxime addition ring-closing metathesis
James C. A. Hunt, Pierre Laurent and Christopher J. Moody*
School of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD
Received (in Liverpool, UK) 30th June 2000, Accepted 24th July 2000
First published as an Advance Article on the web 30th August 2000
Ring closing metathesis reactions of the dienes 6 and 9 leads
to the nitrogen heterocycles 7 and 10, respectively, one of
which 10c was converted into (R)-(2)-coniine.
of Grubbs’ catalyst, and gave the required 5- and 6-membered
rings 7 in modest to excellent yield (Table 1).
Although the above results indicate that basic or nucleophilic
nitrogen atoms are tolerated in the RCM reaction of the
hydroxylamine derived substrates, we also investigated the
diene substrates 9 in which the nitrogen is rendered non-basic
by protection as its benzyloxycarbonyl (Z) derivative. Thus a
range of carbamates 8, prepared as previously described,16,17 or
as indicated in Table 2, was converted into the corresponding N-
allyl derivatives 9 by reaction with allyl bromide in the presence
of sodium hydride. In the case of 8b, these conditions caused
migration of the double bond, and therefore the allyl group was
introduced using the palladium catalysed reaction of allyl
methyl carbonate.18 Again the RCM reaction proceeded
smoothly and gave the 5- and 6-membered nitrogen hetero-
cycles 10a–10d in good to excellent yield, with the yield of the
7-membered ring 10e being slightly lower (Table 2).
The development of methods for the asymmetric synthesis of
pyrrolidines and piperidines remains an area of current interest
due to the presence of such saturated heterocyclic rings in a
large number of biologically important compounds.1 One
possible approach to the synthesis of nitrogen heterocycles
involves the ring-closing olefin metathesis (RCM) reaction. The
RCM reaction is a powerful synthetic method and, with the
development of practical and reliable catalysts by Grubbs and
others,2,3 has been widely used in a number of syntheses in the
recent past,4,5 including examples of nitrogen heterocycles.6–14
In continuation of our interest in the asymmetric synthesis of
saturated nitrogen heterocycles,15 we decided to investigate the
combination of the highly diastereoselective addition reactions
of O-(1-phenylbutyl) aldoximes with the RCM reaction as a
new route to this class of heterocycle. This combination of
oxime addition–RCM is shown in outline in Scheme 1, and our
preliminary results are described herein.
As outlined in Scheme 1, the substrates for the RCM
reactions are the dienes 3, accessible either by the addition of an
alkene containing organometallic reagent to the aldoxime ether
1, or by organometallic addition to an aldoxime 2 derived from
an unsaturated aldehyde, followed in both cases by N-allylation
of the resulting hydroxylamine. Both approaches were success-
ful and a number of dienes 6 were prepared by the highly
diastereoselective addition of organolithium reagents to the O-
(1-phenylbutyl) oximes of cinnamaldehyde or allylmagnesium
bromide to the oximes of butyraldehyde or benzaldehyde,16,17
followed by reaction with allyl bromide in the presence of
potassium carbonate (Table 1). The RCM reaction was carried
out by heating the dienes 6 in dichloromethane in the presence
Scheme 1 (R* = 1-phenylbutyl).
Table 1
DOI: 10.1039/b005353h
Chem. Commun., 2000, 1771–1772
This journal is © The Royal Society of Chemistry 2000
1771
Hunt
