Novel formation of 6-acyl-5-(2-pyrrolyl)-3H-pyrrolizines by base-catalysed condensation of pyrrole-2-aldehyde with methyl ketones

Article abstract of DOI:10.1016/S0040-4039(01)02284-5

Pyrrole-2-aldehyde undergoes condensation with methyl ketones in aqueous ethanolic alkali in a 2:1 mole ratio yielding 6-acyl-5-(2-pyrrolyl)-3H-pyrrolizines as novel products in moderate yield.

Full text of DOI:10.1016/S0040-4039(01)02284-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1295–1297
Novel formation of 6-acyl-5-(2-pyrrolyl)-3H-pyrrolizines by
base-catalysed condensation of pyrrole-2-aldehyde
with methyl ketones
Asok K. Mallik,a,* Sankar P. Dey,a Falguni Chattopadhyaya and Amarendra Patrab,*
aDepartment of Chemistry, Jadavpur University, Kolkata 700 032, India
bDepartment of Chemistry, University College of Science, Calcutta University, Kolkata 700 009, India
Received 8 June 2001; revised 16 November 2001; accepted 30 November 2001
Abstract—Pyrrole-2-aldehyde undergoes condensation with methyl ketones in aqueous ethanolic alkali in a 2:1 mole ratio yielding
6-acyl-5-(2-pyrrolyl)-3H-pyrrolizines as novel products in moderate yield. © 2002 Published by Elsevier Science Ltd.
Our two recent important findings in the area of base-
catalysed 1:2 condensations of o-hydroxyacetophenones
1 and aromatic aldehydes were: (i) novel formation of
trans-2,3-dimethoxy-3-(p-formylphenylamino)-4%-nitro-
flavanones from 1 and p-nitrobenzaldehyde in aqueous
methanol1 and (ii) successful synthesis of E-3-benzylide-
neflavanones and some of their heterocyclic analogues
from 1 and aromatic aldehydes in a reaction medium
which favours precipitation of the final product.2 Being
encouraged by these findings we undertook a similar
study involving 1 and pyrrole-2-aldehyde (2). The
present communication reports a novel result obtained
in this study.
ture followed by the usual work up and chromato-
graphic separation. The orange compound was the
usual 1:1 condensation product3 3, while the analytical
and spectral data of the red compound definitely indi-
cated that it was formed by condensation of two
molecules of 2 with one molecule of 1 in some unusual
fashion. Detailed NMR spectroscopic analysis includ-
ing COSY, homodecoupling and HETCOR (one bond
as well as long range) studies established the structures
of these compounds as the pyrrolizine derivatives 4a–c.4
The presence of a phenolic OH group in each of 4a–c
indicated that the same group of 1a–c possibly played
no role in the reaction process, and this was substanti-
ated by isolation of 4d starting from acetophenone, and
compounds 5 and 6 starting from acetone in place of
1.5 It is interesting to note that even by starting from 1a
and 2 in a 1:1 mole ratio, 4a could be obtained, which
is contrary to a previous report.6 Again, in the reaction
of the same two starting materials taken in a 1:4 mole
ratio, the yield of 4a was found to increase significantly
but this compound was not the exclusive product.
Similar was the result with 1b, 1c and acetophenone.
All the results are presented in Table 1.
When each of the o-hydroxyacetophenones 1a–c was
allowed to undergo condensation with 2 molar equiva-
lents of 2 in aqueous ethanolic KOH (20%) (4 days, rt),
two products, one orange and the other red, were
obtained after careful acidification of the reaction mix-
The 3H-pyrrolizine derivatives 4 are formed by combi-
nation of 1 molecule of 1 with 2 molecules of 2.
However, the reaction possibly does not proceed fully
through the intermediacy of the 1:1 condensation
product 3 since by subjecting the 1:1 mixtures from
each of 3a–d and 2 to the reaction conditions 4 was
obtained in only poor yield (ca. 10%). So the mechanis-
tic path delineated in Scheme 1 may be suggested for
Keywords: pyrrole-2-aldehyde; methyl ketones; base-catalysed con-
densation; 6-acyl-5-(2-pyrrolyl)-3H-pyrrolizines.
* Corresponding authors. Fax: 91-33-473-1484; e-mail: akmallik@
hotmail.com; amarendra@satyam.net.in
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(01)02284-5

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A. K. Mallik et al. / Tetrahedron Letters 43 (2002) 1295–1297
Table 1. Condensation of methyl ketones with pyrrole-2-
aldehyde (2)
the process. Isomerisation of pyrrolizines similar to that
required for the conversion of the initial dehydration
product of 8 to 4 is not without precedent.7 It may be
pointed out here that the structures of 3a–d suggest that
−OH would preferentially effect deprotonation of the
N–H of these compounds rather than attack at their
b-position leading to 7, thus making the conversion
3“4 a less favourable process.
Ketone
Ketone:2 (mole ratio) Product(s) (yielda, %)
1a
1a
1a
1b
1b
1c
1c
1:2
1:1
1:4
1:2
1:4
1:2
1:4
1:2
1:4
1:4
3a (34)+4a (31)
3a (46)+4a (8)
3a (13)+4a (41)
3b (27)+4b (24)
3b (9)+4b (44)
3c (32)+4c (26)
3c (11)+4c (46)
3d (29)+4d (29)
3d (14)+4d (39)
5 (17)+6 (32)
Thus, we report a novel result from a very simple
condensation reaction. Potential biological activities of
the substituted 3H-pyrrolizines formed and the exis-
tence of ample scope for extension of the reaction to
other substrates are two important aspects which
require mentioning here.
Acetophenone
Acetophenone
Acetone
a Based on the amount of ketone.
Scheme 1.

A. K. Mallik et al. / Tetrahedron Letters 43 (2002) 1295–1297
1297
Acknowledgements
HETCOR [one bond and long range (optimised for J:7
Hz)] done on 4b showed the following correlations:
1H–1H COSY: l 4.67 (br.s) with 6.70, 6.47, 6.34; 6.34 (s)
with 4.67; 6.45 (m) with 7.01, 6.65; 6.47 (dt) with 6.70,
4.67; 6.65 (m) with 7.01, 6.45; 6.70 (dt) with 6.47, 4.67;
6.99 (d) with 7.38; 7.01 (m) with 6.65, 6.45; 7.38 (dd) with
7.82, 6.99 and 7.82 (d) with 7.38.
Financial assistance from the University Grants Com-
mission, New Delhi, and the authorities of Jadavpur
University is gratefully acknowledged.
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4. Selected data for 4: 4a, mp 147–148°C. Anal. found C,
74.11; H, 4.89; N, 9.47%; calcd for C18H14N2O2 C, 74.47;
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1
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