Steric acceleration of an uncatalysed ene reaction at room temperature

Article abstract of DOI:10.1039/b106669m

The bulky trityl steric buttress is used to effect an intramolecular, uncatalysed ene reaction that operates at room temperature, whilst smaller buttresses require heat.

Full text of DOI:10.1039/b106669m

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Steric acceleration of an uncatalysed ene reaction at room
temperature
Nandeo Choony,a Peter G. Sammes,*a Graham Smitha and Robert W. Wardb
a Department of Chemistry, School of Physics and Chemistry, UniS, Guildford, Surrey, UK GU2 7XH.
E-mail: p.sammes@surrey.ac.uk
b GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex, UK
CM19 5AW
Received (in Cambridge, UK) 24th July 2001, Accepted 7th September 2001
First published as an Advance Article on the web 27th September 2001
The bulky trityl steric buttress is used to effect an
intramolecular, uncatalysed ene reaction that operates at
room temperature, whilst smaller buttresses require heat.
reactions.2 That a buttressing effect is operating was supported
by the observation that no sign of any cyclisation product was
obtained upon heating the parent amine 5 under the same
conditions. The ease of the buttressed cyclisation, compared
with the harsh conditions normally reported for unactivated ene
reactions,3 led us to seek other examples of the sterically
assisted ene process.
In earlier work we had shown that, on heating, the trityl
protected N-allylfurfurylamine 7 undergoes an intramolecular
Diels–Alder cycloaddition to the corresponding cycloadduct 8
in almost quantitative yield. At rt a competing intermolecular
cycloaddition, with dimethyl butynedioate, is possible to give
the cycloadduct 9 but, on heating, this loses the acetylenic ester
by a retro-cycloaddition reaction and again forms the thermo-
dynamically favoured cycloadduct 8 (Scheme 2).
The ene1 reaction and its intramolecular counterpart2 are
synthetically useful processes that have been exploited in a wide
range of chemistry. Normally the ene reaction requires the use
of heat at temperatures greater than 140 °C to proceed and, for
systems where the enophile is not activated by an electron
withdrawing group, much higher temperatures are often re-
quired.3 For systems with electron deficient enophiles, the
process may be catalysed with Lewis acids, whereby the
reaction has been observed to proceed at ambient temperatures4
but such catalysis is not generally effective for non-activated
enophiles.
The stereochemistry of the intramolecular ene process2 has
also been examined and, under vigorous thermal conditions,
stereocontrol is often lost. Thus, heating the simple N-
trifluoroacetyl-N-allyl-N-dimethylallylamide compound 1 at
220 °C for 30 min effects an intramolecular ene reaction and
converts it into the mixture of cis and trans-pyrrolidines 2 and
3.5 The latter compounds are of interest as members of the
kainic acid family of neuroactive agents,6 the kainic acid series
having the cis-stereochemistry 2 and the allo series the trans-
stereochemistry 3.7 Thus any means of controlling the stereo-
chemistry of the intramolecular ene process would be of
synthetic value.
As part of our interest in the use of steric buttressing as an aid
to reactions,8 herein we describe examples of use of a steric
buttress that assists ene reactions to occur under uncatalysed
and low temperature conditions.
Upon heating in xylene, under argon at 140 °C, for 100 h, the
trityl-protected N-allyl-N-dimethylallylamine 4, prepared by
standard methods,† smoothly produced the ene product 6 in
almost quantitative yield (Scheme 1). Only one isomer could be
detected by 1H NMR spectroscopy ( > 95%), assigned from 1H
NOE experiments, as the cis-isomer. The cis-isomer is known to
be the preferred stereoisomer in analogous carbocyclic ene
Scheme 2 i, 120 °C, 24 h; ii, MeO2C–C·C–CO2Me, rt; iii, 120 °C.
The intramolecular process, e.g. 7 to 8, is sensitive to
substituents on the allyl group and the dimethylallyl derivative
10, only undergoes partial cycloaddition to 11 on heating, to
form an 80+20 equilibrium ratio of the cyclised to uncyclised
components at 140 °C. A similar competing, intermolecular
cycloaddition was attempted with 10 as a parallel reaction to
that performed on the unsubstituted allyl compound 7.
When the tritylated amine 10 was allowed to react with
dimethyl butynedioate at rt over 5 d, a new product formed in
high yield. However, the compound was not the expected
Diels–Alder product 12 but, instead, the ene product 13, isolated
1
as a crystalline solid, mp 164–166 °C (Scheme 3). In its H
NMR spectrum 13 showed loss of the isopropylidene group and
the furan ring protons and formation of the isopropenyl group.
The ring protons, Ha to Hd, showed as a tightly coupled ABXY
system. NOE experiments indicated the geometry shown,
resulting from an approach, via the transition state 12a, from the
least hindered, exo-face of the oxabicycloheptadiene system. It
should be noted that this ene reaction involves a type 1 process
Scheme 1 i, 220 °C, 30 min; ii, 140 °C, 4 days.
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Chem. Commun., 2001, 2062–2063
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106669m

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Scheme 3 i, 140 °C, xylene; ii, MeO2C–C·C–CO2Me, rt.
Scheme 4 i, MeO2C–C·C–CO2Me, rt, 7 days; ii, heat, 70 °C, 3 days.
leaving the equilibrium firmly in favour of the closed form
13.
of a 1,7-diene system, that normally proceed in only modest
yields at very high temperatures.2,9
We thank GlaxoSmithKline Pharmaceutical Research and
the EPSRC for a research studentship (to G. S.)
The striking buttressing effect of the trityl group was further
illustrated by repeating the reaction using the ‘smaller’ buttress,
the 4-toluenesulfonamide 14.10 In this case the dimethyl
butynedioate adduct 15 could be isolated but showed no sign of
ene products after leaving at rt for several weeks. However, on
heating to 70 °C, compound 15 slowly reacted further, an ene
reaction being observed, as indicated by the appearance of the
compound 16 as a transient intermediate but which was unstable
to the reaction conditions and underwent a subsequent retro-
Diels–Alder reaction to form the furfuryl derivative 17 (Scheme
4). That this sequence of ene reaction followed by the retro-
Diels–Alder process occurred, rather than an initial retro-Diels–
Alder reaction, followed by an intermolecular ene process was
supported by the absence of any of the starting material 14 either
as a reaction product or as a transient intermediate. In contrast
to the behaviour of the tosylated intermediate 16, heating the N-
tritylated ene product 13 at 70 °C gave no indication of the
competing retro-Diels–Alder reaction, none of the open form
corresponding to 17 being formed. Thus, not only does the trityl
buttress assist in lowering the activation energy for the ene
process but it also helps prevent the subsequent retro-Diels–
Alder process from occurring. Presumably the open form (cf.
17) would occupy more conformational space than is available
in the presence of the sterically demanding trityl group, hence
Notes and references
† Satisfactory microanalytical and spectroscopic data were recorded for all
new compounds described in this communication.
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