Studies on the [2,3]-Stevens rearrangement of aziridinium ions

Article abstract of DOI:10.1016/j.tetlet.2004.05.087

The aziridinium ylide generated by the intramolecular reaction of a metal carbenoid tethered to a vinylaziridine undergoes [2,3]-Stevens rearrangement to furnish the indolizidine skeleton. It is essential that the correct nitrogen invertomer is used or a competing [1,5]-hydrogen shift predominates. During the preparation of a second system a 'one-pot' acylation-[3,3]-Claisen rearrangement was observed, delivering a seven-membered lactam.

Full text of DOI:10.1016/j.tetlet.2004.05.087

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5347–5350
Studies on the [2,3]-Stevens rearrangement of aziridinium ions
Gareth J. Rowlands* and William Kentish Barnes
Department of Chemistry, University of Sussex, Falmer, Brighton BN1 9QJ, UK
Received 15 April 2004; revised 13May 2004; accepted 18 May 2004
Abstract—The aziridinium ylide generated by the intramolecular reaction of a metal carbenoid tethered to a vinylaziridine
undergoes [2,3]-Stevens rearrangement to furnish the indolizidine skeleton. It is essential that the correct nitrogen invertomer is used
or a competing [1,5]-hydrogen shift predominates. During the preparation of a second system a ‘one-pot’ acylation-[3,3]-Claisen
rearrangement was observed, delivering a seven-membered lactam.
Ó 2004 Published by Elsevier Ltd.
Saturated nitrogen heterocycles, including piperidines,
occur in a wide variety of natural and biologically rel-
evant compounds.1 Thus development of novel routes to
this structural motif is an important area of research. In
recent years the aziridinium ion has become a significant
and versatile synthetic intermediate, as it readily
undergoes ring-opening with a variety of nucleophiles.2
Surprisingly there have been few reports of intramolec-
ular attack upon aziridinium ions.3
The [2,3]-Stevens rearrangement is a synthetically useful
C–C bond forming reaction of N-allyl quaternary
ammonium ylides 3.4 Conventionally the desired ylides
Scheme 1.
are formed via quaternisation of an amine 1 followed by
treatment with a base (Scheme 1).5 The ammonium salt
We were interested in utilising an aziridinium ion in the
2 can be isolated or the sequence performed in ‘one
[2,3]-Stevens rearrangement as an approach to tetrahy-
pot’.6 Alternatively ammonium ylides can be formed
dropyridines 6 (Scheme 2), versatile synthetic building
under essentially neutral conditions via tertiary amine
blocks for the preparation of substituted piperidines. At
insertion into a metal carbenoid. Several groups have
the outset of this work10 there had been no reports of
studied the synthesis of reduced cyclic amines via the
this reaction, and even now there is only one simple
intramolecular generation and rearrangement of
example.9c Our initial approach is outlined in Scheme 2.
ammonium ylides.7–9 West and co-workers8 has pre-
It was believed that the aziridinium ion might decom-
pared quinolizidine alkaloids via a [1,2]-Stevens rear-
pose via a [1,5]-hydrogen shift11;12 so we wanted to avoid
rangement. In a series of elegant papers Clark et al.9 has
its isolation. Therefore ylide 5 was to be prepared from
utilised the [2,3]-Stevens rearrangement to form a vari-
vinylaziridine 4 via the reaction of a metal carbenoid.
ety of heterocycles via tandem intramolecular cyclisa-
tion-rearrangement or intramolecular cyclisation-ring
expansion.
Keywords: Vinylaziridine; Aziridinium; Ylide; Carbene; [2,3]-Stevens
rearrangement.
* Corresponding author. Tel.: +44-1273-678-242; fax: +44-1273-677-
Scheme 2.
196; e-mail: g.rowlands@sussex.ac.uk
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.05.087

5348
G. J. Rowlands, W. Kentish Barnes / Tetrahedron Letters 45 (2004) 5347–5350
There have been two previous reports on the generation
of aziridinium ylides via the interaction of an N-alkyl
aziridine with a carbene.13 Hata and Watanabe found
that treatment of N-phenethylaziridine with ethyl dia-
zoacetate (EDA) in the presence of Cu(acac)2 led to
fragmentation of the aziridine to give ethylene and
an imine via syn-elimination instead of the antici-
pated [1,2]-Stevens rearrangement. We reasoned that a
vinylaziridine would undergo the desired [2,3]-Stevens
rearrangement instead of decomposition. The [1,2]-
rearrangement is symmetry forbidden and there is little
thermodynamic driving force for the ring expansion of
an aziridine to an azetidine. Alternatively, a vinylazir-
idine would allow the ring expansion to proceed via a
symmetry allowed process with considerable release of
ring-strain during the expansion from a 3-ring to a 6-
ring. The anionic variant, the [2,3]-aza-Wittig reaction
proceeds smoothly on account of this driving force.11;14
As a result we decided to reinvestigate the reaction of N-
alkyl aziridines with metal carbenoids and here report
the factors that effect the efficiency of this reaction.
With the vinylaziridine 4 in hand we turned our atten-
tion to the proposed intermolecular ylide generation-
rearrangement reaction (Scheme 2). Treatment of 4 with
EDA in the presence of either Cu(acac)2 or Rh2(OAc)4
in a variety of solvents at room temperature led to no
reaction other than dimerisation of EDA to give diethyl
fumarate and recovery of unreacted 4 (>80%). On
heating, a reaction did occur, but not as desired. The
highly substituted pyrrolidine 9 was isolated in moderate
yield (Scheme 3). Presumably thermal ring-opening of
the vinylaziridine gives the azomethine ylide 8, in which
the vinyl moiety acts as an anion stabilising group. 1,3-
Dipolar cycloaddition with the fumarate formed via the
dimerisation of EDA then furnishes the pyrrolidine 9.
The generation of an azomethine ylide from an aziridine
is well known16 when the ylide is stabilised by a carbonyl
moiety but is rare with other functionality.
Failure of the desired reaction could be attributed to
two possibilities; firstly catalyst deactivation via coor-
dination of the amine and metal centre.17 This argument
might explain the surprising stability of the vinylazir-
idine under the reaction conditions compared to normal
storage! Coordination would prevent nitrogen inversion
and thus inhibit the [1,5]-hydrogen shift. Normally
deactivation is overcome by heating, a possibility not
open to us due to the thermal instability of 4. Alterna-
tively, steric hindrance might prevent interaction of the
amine and the metal carbenoid; the necessicity for three
eclipsing substituents on the same face of an aziridine
combined with the required endo orientation of the
alkene group may be too energetically unfavourable.
The desired N-benzyl vinylaziridine 4 was readily pre-
pared from imine 7 in four steps (Scheme 3). The aza-
Darzens-like reaction of EDA and 7 under Lewis acid
catalysis gave the cis-aziridine ester in good yield.15 The
ester was converted to the desired vinyl substituent in
three steps. The poor yield is due to the instability of
both the aldehyde intermediate and the vinylaziridine 4.
NOE analysis indicated that the vinylaziridine exists as
one nitrogen invertomer with the benzyl group residing
on the opposite face of the aziridine to the two substit-
uents. This is the ideal conformation for the interaction
of the amine with the metal carbenoid as the resultant
ylide would form on the same face as the alkene.
With the failure of the intermolecular variant we decided
to turn our attention to the intramolecular variant.9c It
was hoped that by tethering the diazo moiety to the
amine, quaternisation would be more favourable. The
methodology would also allow an elegant, direct entry
into the indolizidine skeleton via a tandem cyclisation-
ylide generation-rearrangement reaction. This would
offer a considerable advantage over the analogous aza-
Wittig reaction, which required an additional five steps
to create the second ring of the indolizidine skeleton.14b
The N-unsubstituted vinylaziridines 10 and 11 were
prepared in good yield (Scheme 4).14d N-alkylation
proved more problematic. Extensive optimisation al-
lowed the synthesis of 13 and 14 via Lewis acid activated
conjugate addition with copper(I) bromide. Interest-
ingly, the two vinylaziridines behaved very differently.
Compound 13 could be isolated in 56% after 7 days at
Scheme 3.
Scheme 4.

G. J. Rowlands, W. Kentish Barnes / Tetrahedron Letters 45 (2004) 5347–5350
5349
Scheme 5.
room temperature. NOE analysis revealed that the N-
alkyl aziridine existed as a 3:4 13a:13b mixture of
nitrogen invertomers favouring the undesired inver-
tomer 13b in which the N-alkyl substitutent and the
vinyl moiety are cis. Surprisingly no [1,5]-hydrogen shift
was observed. Alkylation of 11 proceeded in a mere
30 min to give 14b as a single nitrogen invertomer in 82%
yield. If the reaction was left longer the only product
isolated was that resulting from a [1,5]-hydrogen shift.
Clearly, in 14b the isopropyl group forces the N-alkyl
substituent cis to the vinyl group thus encouraging ring-
opening. At present we have no explanation for the
incredible difference in reactivity. Addition of the diazo
moiety to 13 via reaction with tosyl azide proceeded in
good yield to give 15. Once again compound 14 was
more problematic due to decomposition via the [1,5]-
hydrogen shift.
The importance of having the correct invertomer is
borne out by the reaction of 16, which exists as only the
undesired invertomer. At reflux 16 rapidly undergoes a
[1,5]-hydrogen shift to give an imine that tautomerises to
the enamine 19 and enol 20 that can be isolated in good
yield (Scheme 6). The presence of the diazo moiety
indicates that the shift is more favourable than ylide
formation.
Introduction of an alternative tether was investigated.
Attempted conjugate addition of vinylaziridine 10 to
diazomethylvinyl ketone under our standard conditions
did not yield the desired cyclisation precursor but the
lactam 22 was obtained as a single diastereoisomer in
moderate yield (Scheme 7). Presumably reaction of the
vinylaziridine with the ketene formed from the Wolff
rearrangement of the diazo ketone generates enolate 21
that undergoes a [3,3]-Claisen rearrangement to give the
lactam 22. The relative stereochemistry can be under-
stood if the reaction is assumed to proceed via a boat-
like transition state 21 as described by Somfai18 for the
base-promoted cyclisation of N-acyl vinylaziridines.
This reaction offers a ‘one-pot’ variant of Somfai’s
work.18 Further studies are required to evaluate the
scope of this ‘one-pot’ reaction of ketenes and vinyl-
aziridines and will be reported in due course.
The tandem cyclisation-ring expansion reaction was
then investigated. Compound 15 did not react with any
catalyst at room temperature but we were pleased to
isolate the desired bicyclic amine 18 in 21% upon heating
the reaction to reflux in acetonitrile (Scheme 5). The
relative stereochemistry was confirmed by NOE and can
be understood if the reaction is assumed to proceed via
formation of ylide 17. [2,3]-Stevens rearrangement then
occurs with the ester functionality orientated away from
the aziridine substituents, placing it on the opposite face
to the phenyl group.
In conclusion, we have shown that the aziridinium ion
can be used in the rapid preparation of the indolizidine
skeleton. In order to prevent a competitive [1,5]-hydro-
gen shift it is crucial that the correct nitrogen invertomer
is formed. This places a structural limitation on this
methodology. The failure of the intermolecular variant
and difficulty in handling vinylaziridines has led us to
investigate a method for producing these species in situ.
This work will be reported in due course.
Whilst the yield appears low it is easily rationalised. The
starting material exists as a 3:4 mixture of nitrogen in-
vertomers. Only the ylide 17 formed cis to the alkene
moiety can undergo the rearrangement, which means
only invertomer 15a can proceed profitably. As this in-
vertomer only accounts for 43% of the material the yield
is restricted. Nitrogen inversion in aziridines is very slow
due to the increased s character of the lone pair whilst
the [1,5]-hydrogen shift is greatly accelerated at the
higher temperatures employed here.12 Therefore we be-
lieve invertomer 15b undergoes the [1,5]-hydrogen shift
more rapidly than nitrogen inversion. The resulting
imine then decomposes under the reaction conditions.
The overall yield is further compromised by the thermal
instability of both starting material and product.
Scheme 7.
Scheme 6.

5350
G. J. Rowlands, W. Kentish Barnes / Tetrahedron Letters 45 (2004) 5347–5350
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6. (a) Arbore, A. P. A.; Cane-Honeysett, D. J.; Coldham, I.;
Acknowledgements
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We would like to thank Dr. Tony Avent for the NOE
analysis. This work was supported by the EPSRC (GR/
N38329/01).
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