Russian Chemical Bulletin, International Edition, Vol. 57, No. 10, pp. 2175—2179, October, 2008
2175
Threeꢀcomponent condensation
of 2ꢀaminothiopheneꢀ3ꢀcarboxylic acid derivatives
with aldehydes and Meldrum’s acid
B. V. Lichitsky, A. N. Komogortsev, A. A. Dudinov, and M. M. Krayushkin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: mkray@ioc.ac.ru
New approach to the synthesis of 4,7ꢀdihydroꢀ5Hꢀthieno[2,3ꢀb]pyridinꢀ6ꢀones using
2ꢀaminothiophenes unsubstituted at position 3 of the thiophene ring has been developed.
Labile 2ꢀaminothiophenes have been obtained by the in situ decarboxylation of unstable
2ꢀaminoꢀ3ꢀthiophenecarboxylic acids. The threeꢀcomponent condensation of 2ꢀaminothiophenes
with aromatic aldehydes and the Meldrum’s acid is the key step of the process.
Key words: 2ꢀaminothiophenes, the Meldrum’s acid, threeꢀcomponent condensation,
decarboxylation, 4,7ꢀdihydroꢀ5Hꢀthieno[2,3ꢀb]pyridinꢀ6ꢀones.
In the literature, there are data on the reaction of
arylmethylidene derivatives of the Meldrum’s acid 1 with
stable heterocyclic analogs of enamines, viz., aminopyrꢀ
azoles,1,2 aminopyridazinones,3 and aminopyrimidinones,4
resulting in the annulation of the dihydropyridinone ring
with the Meldrum’s acid (2) which plays the role of
C2ꢀsynthon. However, the number of such stable aminoꢀ
heterocycles is limited. In particular, 2ꢀaminothiophenes
unsubstituted at position 3 have not been used in the
condensation described due to their instability,5 though it
is absolutely obvious that transformations, in which
aminothiophenes 3 are used as the 1,3ꢀdinucleophiles,
open access to development of fused heterocyclic system
of the type 4, which contain thiophene fragment and
possess various biological activity.6,7 In the present comꢀ
munication, we suggest to in situ generate these unstable
enamines3 with free position 3 from 2ꢀaminothiopheneꢀ
3ꢀcarboxylic acids 5, which are known to readily undergo
decarboxylation.8—10 Acids 5 were generated from esters
6a—d through sodium salts 7a—d and used without puriꢀ
fication and, as a rule, without isolation (Scheme 1).
The purpose of this research consisted in development
of methods for the synthesis of substituted 4,7ꢀdihydroꢀ
5Hꢀthieno[2,3ꢀb]pyridinꢀ6ꢀones 4 on the basis of the in
situ obtained 2ꢀaminothiophenes 3, aromatic aldehydes
8, and the Meldrum’s acid (2). Such thienopyridinones
have been obtained earlier11 by the Beckmann rearrangeꢀ
ment of 4ꢀarylꢀ4,5ꢀdihydrocyclopenta[b]thiophenꢀ6ꢀone
oximes. However, in this case the target products were
formed as a mixture of two possible isomers in low yield.
In the present work, we suggest a general efficient apꢀ
proach to the synthesis of structures 4 using readily decarꢀ
boxylating acids 5 as the starting compounds. The latter
were obtained by the alkaline hydrolysis of the correꢀ
sponding 2ꢀaminoꢀ3ꢀthiophenecarboxylic acid esters 6,
the products of the Gewald reaction. The hydrolysis was
carried out in aqueous ethanol since in the alkali alcohol
solution, a rearrangement with the formation of sodium
salts of 3ꢀcyanoꢀ2ꢀhydroxythiophenes is possible12,13 and
the presence of electronꢀwithdrawing substituents at poꢀ
sition 5 of the thiophene ring makes the alkaline hydrolyꢀ
sis considerably more difficult.
The procedures for the synthesis of target thieno[2,3ꢀb]ꢀ
pyridinones developed by us differed in the methods of
generation of labile 2ꢀaminothiophenes 3. When esters
6a—c were used, the alkaline hydrolysis resulted in the
corresponding sodium salts 7a—c, which in this case were
not converted to acid 5, rather they were directly introꢀ
duced into the reaction; subsequent addition of acetic
acid to the reaction mixture led to neutralization, decarꢀ
boxylation, and in situ generation of 2ꢀaminothiophenes
3a—c (method A). It should be noted that in the case of
ester 6a, acetic acid can be also used as the solvent, howꢀ
ever, this leads to the insignificant decrease in the yields
of target compounds 4, therefore, excess of acetic acid in
ethanol was used. In the case of esters 6b,c, the use of
acetic acid as the solvent is the optimum for the synthesis
of compounds 4j—s. To obtain products 4k—x on the
basis of ester 6d, the reaction conditions have been modiꢀ
fied since the use of salt 7d led to final compounds in low
yields, apparently, due to the side reactions. In this
case, we isolated acid 5d, the condensation of which
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2133—2137, October, 2008.
1066ꢀ5285/08/5710ꢀ2175 © 2008 Springer Science+Business Media, Inc.
Lichitsky
