Synthesis of hantzsch 1,4-dihydropyridines under microwave irradiation

Article abstract of DOI:10.1081/SCC-120002415

Biologically active substituted 1,4-dihydropyridines have been synthesized in excellent yields by the reaction of aldehydes, ethyl or methyl acetoacetic ester and ammonium acetate under microwave irradiation (MWI) within 0.75-3 min.

Full text of DOI:10.1081/SCC-120002415

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SYNTHESIS OF HANTZSCH 1,4-DIHYDROPYRIDINES
UNDER MICROWAVE IRRADIATION
Marimuthu Anniyappan a , D. Muralidharan a & Paramasivan T. Perumal b
a Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai, 600
020, India
b Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai, 600
020, India
Version of record first published: 16 Aug 2006.
To cite this article: Marimuthu Anniyappan , D. Muralidharan & Paramasivan T. Perumal (2002): SYNTHESIS OF HANTZSCH
1,4-DIHYDROPYRIDINES UNDER MICROWAVE IRRADIATION, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:4, 659-663
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SYNTHETIC COMMUNICATIONS, 32(4), 659–663 (2002)
SYNTHESIS OF HANTZSCH
1,4-DIHYDROPYRIDINES UNDER
MICROWAVE IRRADIATION
Marimuthu Anniyappan, D. Muralidharan, and
Paramasivan T. Perumal*
Organic Chemistry Division, Central Leather
Research Institute, Adyar, Chennai – 600 020, India
ABSTRACT
Biologically active substituted 1,4-dihydropyridines have been
synthesized in excellent yields by the reaction of aldehydes,
ethyl or methyl acetoacetic ester and ammonium acetate under
microwave irradiation (MWI) within 0.75–3 min.
Substantial reduction in reaction times by many fold and minimisation
of thermal decomposition products are the two main advantages offered by
microwave heating in chemical reactions. This has resulted in an increased
number of research articles published during the last decade in the field of
organic synthesis, demonstrating the suitability of microwave heating in
synthesising various compounds of commercial importance.1–7
The conventional methods for the preparation of Hantzsch 1,4-dihy-
dro-pyridines from various aliphatic and aromatic aldehydes, b keto ester
and ammonia reported by earlier workers8–12 involved prolonged reaction
*Corresponding author. Fax: 91-044-491 1589; E-mail: ptperumal@hotmail.com
659
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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ANNIYAPPAN, MURALIDHARAN, AND PERUMAL
times under refluxing conditions and moderate yields. Considering the grow-
ing importance in this class of compounds which possess biological activities
like antihypertensive,13 treatment of benign prostatic hyperplasia,14 over-
coming multidrug resistance encountered in cancer chemotherapy15 etc. and
the advantages offered by microwave irradiation that has been successfully
employed in several organic synthesis, we planned to prepare Hantzsch
1,4-dihydropyridines and their derivatives under microwave irradiation in
good yields.
The reaction of 1 eq. of formaldehyde (1a), 2 eq. of ethyl acetoacetate
(2) with 1 eq. of ammonium acetate (3) in 10 ml of ethanol was subjected
to microwave irradiation for 45 s in a domestic (BPL-SANYO) microwave
oven with a pulse of 15 s each.16 The reaction was carried out at a power level
of 80 which corresponds to an output power of 580 W. The product (4a) was
obtained as a light yellow solid in 96% yield (Scheme 1). The yield obtained
with other substituted aldehydes are given in Table 1.
Scheme 1.
Alajarin et al.17 have reported the synthesis of 1,4-dihydropyridines
under microwave irradiation with moderate yields but much lower com-
pared to our results. Aqueous ammonium hydroxide and ethanol used by
the previous authors have been replaced with ammonium acetate in alcohol
in the present investigation which might have enhanced the yields. The loss
of ammonia during heating could be minimised by using ammonium acetate
thereby improving the yields. Further we have attempted the reaction in an
open glass conical flask (250 ml) in place of teflon vessel and microwave
digestion bomb used by Alajarin et al. for a period of 0.75–3 min with
intermittent cooling. Although we have carried out the experiments at
a higher output power (580 W) no untoward incident occurred during our
investigations indicating that no special precautionary measures are needed
for this experiment. Usage of higher output power during the reactions has
considerably reduced the reaction time and enhanced the yield compared to
earlier studies.

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HANTZSCH 1,4-DIHYDROPYRIDINES
661
Table 1. Synthesis of Hantzsch 1,4-Dihydropyridines Under MWI
In conclusion, this paper describes a simple and convenient method
for the synthesis of substituted Hantzsch 1,4-dihydropyridines under micro-
wave irradiation in excellent yields and shorter reaction times compared
with previous methods which involve longer reaction times under refluxing
conditions with moderate yields.

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ANNIYAPPAN, MURALIDHARAN, AND PERUMAL
GENERAL PROCEDURE
0.5 g (3.3 mmol, 1 eq.) of m-nitrobenzaldehyde, 0.86 g (6.6 mmol, 2 eq.)
of ethyl acetoacetate and 0.26 g (3.3 mmol, 1 eq.) of ammonium acetate
in 10 ml of ethanol taken in a conical flask was subjected to microwave
irradiation for 2 min in a domestic microwave oven with a pulse of 15 s
each and allowed to stand at room temperature. To facilitate crystallization
of the compounds, the reaction mixture was scratched with a glass rod.
Yellow crystals of 2,6-Dimethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-
dihydropyridine (4e) were formed. The solid product obtained was
washed with 20% ethyl acetate pet-ether (bp. 60–80ꢀC) mixture. The yield
was 93%, mp. 163–164ꢀC (lit. 164–165ꢀC). The product was recrystallized
1
from ethanol. H NMR (CDCl3, 300 MHz): d 8.13 (s, 1H), 8.02 (d, 1H,
J ¼ 7.5 Hz), 7.66 (d, 1H, J ¼ 7.5 Hz), 7.40 (d, 1H, J ¼ 8.7 Hz), 6.16 (s, 1H),
5.10 (s, 1H), 4.10 (q, 4H), 2.36 (s, 6H), 1.24 (t, 6H); 13C NMR (CDCl3,
75 MHz): d 167.2, 150.0, 148.1, 145.0, 134.5, 128.6, 123.1, 121.3, 103.2,
60.0, 40.0, 19.5, 14.2; MS m/z: 374 (Mþ); IR (KBr): 3404, 3328, 1674,
1633, 1590, 1529, 1105, 857 cmꢁ1
.
ACKNOWLEDGMENT
One of the authors (M.A.) is grateful to Council of Scientific and
Industrial Research, New Delhi, India for financial support.
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663
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from 155 to 700 W of power output which can be varied by selecting
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Received in the Netherlands April 4, 2001

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