1596
LETTER
Synthesis of Functionalised Piperidines Through a [3+3] Cycloaddition
Strategy
Synthesis of
F
i
unction
m
a
lise
d
Piperidine
s
T
o
hrough
a
[3+
n
3] Cycloaddition
SJ
trategy . Hedley,a Wesley J. Moran,a Alexander H. G. P. Prenzel,a David A. Price,b Joseph P. A. Harrity*a
a
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
b
Discovery Chemistry, Pfizer Central Research, Sandwich, Kent, UK
Fax +44(114)2738673; E-mail: j.harrity@sheffield.ac.uk
Received 9 July 2001
Abstract: A novel approach to functionalised piperidines is de-
scribed through a [3+3] cycloaddition reaction of aziridines with
Pd-trimethylenemethane complexes. Importantly, the employment
of enantiomerically pure aziridines (prepared in three steps from the
appropriate amino acids) allows the corresponding piperidines to be
furnished in enantiomerically pure form. Additionally, the applica-
tion of this technique in the total synthesis of (–)-pseudoconhydrine
is described.
Figure [3+3] Cycloaddition strategy to 6-membered heterocycles
Key Words: cycloadditions, aziridines, piperidines, palladium-tri-
methylenemethane
in a short enantioselective synthesis of (–)-pseudoconhy-
drine.
Enantiomerically pure aziridines were prepared in 3 steps
from the appropriate amino acids by the method of Craig.9
We decided to employ the commercially available con-
junctive reagent 2-[(trimethylsilyl)methyl]-2-propen-1-yl
acetate as a convenient source for the in situ generation of
the Pd-TMM complex, since it has been applied success-
fully in the presence of a range of palladium catalysts and
has been shown to be an efficient partner for other cy-
cloaddition processes.10 With the requisite substrates in
hand, we began our studies by investigating the effects of
catalyst system on the efficiency of the [3+3] cycloaddi-
tion reaction. In our hands, the use of Pd(PPh3)4 following
Cycloaddition reactions are amongst the most effective
methods for the rapid synthesis of functionalised cyclic
systems in a stereocontrolled manner.1 Additionally, the
application of transition metal catalysts in these processes
provides added opportunity to exert further control over
the efficiency and selectivity of these reactions. In the
context of six membered ring formation, the Diels–Alder
reaction holds a uniquely prominent position and formally
comprises a [4+2] assembly strategy.2 In contrast, the em-
ployment of a [3+3] cycloaddition approach has been
much less widely studied.3 In this context, the employ-
ment of Pd-catalysis has led to techniques for the assem-
bly of pyran derivatives4 whereas piperidine systems have
been prepared by a formal [3+3] cycloaddition reaction of
1,3-cyclic sulfates with C,N-dianions,5 vinylogous amides
with , -unsaturated iminiums,6 , '-dimethoxylated
amides with allyltrimethylsilane7 and Pd-trimethylen-
emethane (Pd-TMM) complexes with aziridines.8 We an-
ticipated that the latter approach represented a potentially
efficient technique for the synthesis of enantiomerically
pure nitrogen and oxygen containing heterocyclic prod-
ucts through the employment of readily available enantio-
merically pure aziridines and epoxides (Figure). Despite
the attractiveness of this approach, only a single reaction
of this type is known in the literature whereby racemic N-
tosyl and N-acyl 2-methylaziridines have been trans-
formed to the corresponding piperidines.8 We decided to
undertake a study of the generality of this [3+3] cycload-
dition process, particularly with a view to preparing enan-
tiomerically pure piperidines. Accordingly, we report
herein our initial results on the reaction scope and its use
8
the procedure of Kemmitt et al. was ineffective in pro-
moting piperidine formation. Notably, Trost has reported
that the utilisation of non-basic phosphite ligands enhanc-
es the reactivity of Pd-TMM complexes in [3+2] and
[4+3] cycloaddition processes.10 Accordingly, we found
that the use of Pd(OAc)2 and P(OiPr)3 in a 1:6 ratio with
n-BuLi as reductant provided the desired piperidine
smoothly and in high yield (Scheme 1).11
Scheme 1
We subsequently decided to investigate the scope of
the [3+3] cycloaddition process and our results are out-
lined in the Table. As outlined in entries 1, 2, 4 and 7, the
use of tosyl protected 2-substituted aziridines provided
the corresponding piperidines in good to excellent yields.
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
1437-2096,E;2001,0,10,1596,1598,ftx,en;D15901ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214