Neat reaction microwave technology for the synthesis of N-substituted-1,4-dihydropyridines Mazaahir Kidwai and Richa Mohan

Article abstract of DOI:10.1139/v03-191

Hantzsch synthesis of N-substituted-1,4-dihydropyridines (1,4-DHP) was carried out using an environmentally benign procedure. Neat reactants were subjected to microwave irradiation (MWI) to give the required products in excellent yield. Appreciable results were not obtained when conventional synthesis using neat reactants was carried out. The good yield and rate enhancement observed in the case of microwave irradiation is attributed to the uniform heating effect of microwaves.

Full text of DOI:10.1139/v03-191

427
Neat reaction microwave technology for the
synthesis of N-substituted-1,4-dihydropyridines
Mazaahir Kidwai and Richa Mohan
Abstract: Hantzsch synthesis of N-substituted-1,4-dihydropyridines (1,4-DHP) was carried out using an environmen-
tally benign procedure. Neat reactants were subjected to microwave irradiation (MWI) to give the required products in
excellent yield. Appreciable results were not obtained when conventional synthesis using neat reactants was carried out.
The good yield and rate enhancement observed in the case of microwave irradiation is attributed to the uniform heating
effect of microwaves.
Key words: 1,4-dihydropyridines (1,4-DHP), microwave irradiation (MWI), neat reaction, solid support.
Résumé : On a réalisé une synthèse de Hantzsch de 1,4-dihydropyridines (1,4-DHP) N-substituées en faisant appel à
une méthode environnementalement bénigne. On a soumis les réactifs sans solvants à une irradiation par des microon-
des (IMO) qui a conduit à la formation des produits requis avec d’excellents rendements. On n’a pas obtenu de bons
résultats lorsqu’on a effectué la synthèse conventionnelle avec des réactifs sans solvant. On attribue les excellents ren-
dements et l’augmentation de la vitesse de la réaction observée avec une irradiation par des microondes à l’effet de
chauffage uniforme des microondes.
Mots clés : 1,4-dihydropyridines (1,4-DHP), irradiation par des microondes (IMO), réaction sans solvant, support solide.
[Traduit par la Rédaction] Kidwai and Mohan 429
Introduction
1 mol of amines 2a–d in acetic acid for several hours
(Scheme 1). The products were obtained in low yield (Ta-
ble 1), while the same reaction over acidic alumina2 using
microwave irradiation gave the desired products in good
yield within a few minutes. The microwave reaction was
also carried out over neutral alumina,3 wherein appreciable
yields were observed within the same reaction time. Al-
though the microwave-assisted solid-support synthesis is a
solventless technique, it requires the use of an appreciable
amount of solvent at the pre- and post-reaction stages.
In our endeavour to develop an environmentally benign
synthesis that eliminates the use of solvent, and in continua-
tion to our earlier work on the neat Hantzsch synthesis (13)
of 1,4-DHP, an attempt was made to synthesize N-substi-
tuted-1,4-DHP under neat reaction conditions. As a test case,
2 mol of ethylacetoacetate and 1 mol each of benzaldehyde
and aniline were subjected to microwave irradiation. On
completion of reaction, as monitored by TLC, the reaction
mixture was cooled at 5 °C for 24 h, and the sticky solid ob-
tained was titurated with a few drops of methanol to give the
required product in excellent yield. The positive results ob-
tained in the above case prompted us to synthesize some
novel N-substituted-1,4-DHP using heterocyclic amines. The
products were obtained in less time than with solid support
and conventional methodology. A slight improvement in
yield was also observed on moving from solid support to
Research on the 1,4-dihydropyridine (1,4-DHP) moiety is
of current interest because of its recognition as a core struc-
ture in calcium antagonists (1). In the case of structure–ac-
tivity relationships, the effect of substitution on the 1,4-DHP
ring has been thoroughly studied (2). However, most of the
studies have been devoted to the Hantzsch synthesis of N-
unsubstituted dihydropyridines (3, 4), since the classical
routes (5), yielding N-alkyl or N-aryl 1,4-DHP products, suf-
fer from negative results (6) or very poor yields (7). Mod-
ified synthetic methodologies (8) for the above compounds
reportedly provide improved yields but use expensive re-
agents and require longer reaction times. The drive for clean
technology in the chemical industry requires a level of inno-
vation. Thus, the eco-friendly goal of making organic com-
pounds without using solvents has come several steps closer
in recent years (9). With the development of microwave-
assisted solid-phase synthesis (10), it has now become easier
to perform reactions without solvents, as these high-yield
protocols offer the benefits of enhanced reaction rates,
greater selectivity, and experimental ease of manipulation
(11).
In this communication, synthesis of N-substituted-1,4-
DHP was carried out under conventional heating by refluxing
1 mol of aldehydes 1a–b, 2 mol of ethylacetoacetate, and
Received 16 January 2003. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 12 December 2003.
M. Kidwai1 and R. Mohan. Department of Chemistry, University of Delhi, Delhi-110007, India.
1Corresponding author (e-mail: mkidwai@mantraonline.com).
2Aluminium oxide, acidic, Brockmann I (~150 mesh; 58 Å; CAMAG 506-C-1; surface area 155 m2/g).
3Aluminium oxide, neutral, Brockmann I (Aldrich Chem. Co., Cat. No., 19997-4; ~150 mesh; 58 Å; surface area 155 m2/g).
Can. J. Chem. 82: 427–429 (2004)
doi: 10.1139/V03-191
© 2003 NRC Canada

428
Can. J. Chem. Vol. 82, 2004
Scheme 1.
Table 1. Comparison of the reaction times and yields for the compounds 3a–h.
Solution phase
(conventional)
Solid support
(microwave)a
Neat
(microwave)a
Yield
(%)
Time
(h)
12
16
24
>48
14
18
Yield
(%)
Time
(min)
Yield
(%)
Time
(min)
Compd
R
R′
mp (°C)
3a
3b
3c
3d
3e
3f
Phenyl
Phenyl
Phenyl
Phenyl
Furyl
Furyl
Furyl
Furyl
Phenyl
2-Pyridyl
2-Furyl
2-Methyl-1,3,4-thiadiazolyl
Phenyl
2-Pyridyl
2-Furyl
2-Methyl-1,3,4-thiadiazolyl
159–160b
142–145
137–139
155–157
150–152
195–198
172–175
240–242
40
38
32
18
34
30
20
15
83
81
79
73
82
80
75
71
4.0
4.5
5.5
6.5
4.5
5.0
7.0
7.0
87
83
80
77
86
81
76
74
3.5
4.0
5.5
6.0
4.0
5.0
6.5
7.0
3g
3h
>48
>48
aMicrowave heating (800 W, 100–110 °C, 1 min).
bLiterature (12) value mp 158 °C.
neat reaction methodology (Table 1). The neat reaction was
also carried out under conventional heating, keeping similar
reaction conditions. Conventional neat synthesis took more
time for completion and gave the products in moderate yield
and, in certain cases, lead to charring.
Thus, we have developed an easier, practically convenient,
and environmentally benign synthesis of bioactive N-substi-
tuted-1,4-DHP that proceeds under much milder reaction
conditions than conventional means. Eliminating organic
solvents in chemical synthesis is an important drive towards
clean chemical technology. Although solventless reactions
are more appropriate for small-scale production, these re-
sults may stimulate interest among researchers involved in
the industrial scale-up of reactions.
silica-gel-coated Al plates (Merck). The reaction tempera-
ture was measured using an AZ minigun type non-contact IR
thermometer (Model No. 8868).
General procedure for the synthesis of N-substituted
diethyl 1,4-dihydro-2,6-dimethyl-4-furyl/phenyl-3,5-
pyridinedicarboxylate (3a–h)
Solution phase (conventional)
A mixture of aldehyde 1a–b (0.01 mol), primary amine
2a–d (0.01 mol), and ethylacetoacetate (0.02 mol) in 30 mL
acetic acid was refluxed for a specified time. On completion
of the reaction, as monitored by TLC examination, the reac-
tion mixture was cooled for 24 h; the solid obtained was fil-
tered, washed with cold MeOH, dried, and recrystallized
from ethanol.
Experimental section
Melting points were determined on a Thomas Hoover
melting point apparatus and are uncorrected. IR spectra were
recorded on a PerkinElmer FT-IR-1710 spectrophotometer.
1H NMR spectra were recorded on an FT-NMR Hitachi
R-600 (60 MHz) instrument using TMS as the internal refer-
ence. Microwave irradiation was carried out in a Kenstar mi-
crowave oven, Model No. OM9925E (2450 MHz, 800 W).
Monitoring of the reaction was done through TLC, using
Solid support (microwave)
To the solution of aldehyde 1a–b (0.01 mol), primary
amine 2a–d (0.01 mol), and ethylacetoacetate (0.02 mol) in
ethanol (15 mL), solid support (20 g) was added. The reac-
tion mixture was dried in air, kept in an alumina bath, and
subjected to MWI for a specified time (Table 1). On comple-
tion of the reaction, as examined by TLC (at an interval of
30 s), the product was extracted in ethanol (3 × 15 mL). Re-
© 2003 NRC Canada

Kidwai and Mohan
429
covering the solvent under reduced pressure gave the re-
quired product, which was recrystallized from ethanol.
CH3), 4.2 (q, 2H, OCH2), 5.4 (s, 1H, 4-H), 6.2–6.4 (m, 3H,
furan), 7.7–8.1 (m, 4H, pyridine). Anal. calcd. for
C22H25N2O5: C 66.66, H 6.06, N 7.07; found: C 66.67, H
6.09, N 7.06.
Neat synthesis (microwave)
A mixture of 0.01 mol of aldehyde 1a–b, 0.01 mol of pri-
mary amine 2a–d, and 0.02 mol of ethyl acetoacetate was
taken in an Erlenmeyer flask and subjected to MWI. The
progress of the reaction was monitored by TLC at an inter-
val of 30 s. On completion of the reaction, the reaction mix-
ture was cooled and titurated with a few drops of methanol,
and the product was recrystallized from aqueous methanol.
Diethyl 1,4-dihydro-2,6-dimethyl-4-furyl-1-(1′-furyl
methyl)-3,5-pyridinedicarboxylate (3g)
IR (cm–1) νmax: 3094.54, 1701.78, 1628.50, 1052.36. H
1
NMR (60 MHz, DMSO-d6) δH: 1.3 (t, 6H, CH3), 2.4 (s, 6H,
CH3), 3.2 (s, 2H, CH2), 4.3 (q, 4H, OCH2), 5.3 (s, 1H, 4-H),
6.4–7.0 (m, 6H, furan). Anal. calcd. for C22H25NO6: C
66.16, H 6.26, N 3.50; found: C 66.14, H 6.23, N 3.52.
Diethyl 1,4-dihydro-2,6-dimethyl-1,4-diphenyl-3,5-
pyridinedicarboxylate (3a)
Diethyl 1,4-dihydro-2,6-dimethyl-4-furyl-1-(5′-methyl
1′,3′,4′-thiadiazolyl)-3,5-pyridinedicarboxylate (3h)
1
IR (cm–1) νmax: 2989.80, 1728.59, 1628.35, 1091.00. H
1
IR (cm–1) νmax: 3093.76, 1692.50, 1639.52, 1065.98. H
NMR (60 MHz, CDCl3) δH: 1.1 (t, 3H, CH3), 2.3 (s, 3H,
CH3), 4.2 (q, 2H, OCH2), 5.0 (s, 1H, 4-H), 7.3–7.6 (m, 10H,
Ar-H). Anal. calcd. for C25H27NO4: C 74.07, H 6.66, N
3.45; found: C 74.09, H 6.70, N 3.42.
NMR (60 MHz, CDCl3) δH: 1.2 (t, 3H, CH3), 2.3 (s, 3H,
CH3), 2.7 (s, 3H, 5′-CH3), 4.1 (q, 2H, OCH2), 5.1 (s, 1H, 4-
H), 6.2–6.4 (m, 3H, furan). Anal. calcd. for C20H23N3O5S: C
57.55, H 5.51, N 10.07; found: C 57.58, H 5.53, N 10.06.
Diethyl 1,4-dihydro-2,6-dimethyl-4-phenyl-1-(2′-pyridyl)-
3,5-pyridinedicarboxylate (3b)
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IR (cm–1) νmax: 3115.56, 2965.64, 1689.18, 1635.22,
1042.22. 1H NMR (60 MHz, DMSO-d6) δH: 1.2 (t, 3H,
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7.2–8.1 (m, 9H, Ar-H & pyridine). Anal. calcd. for
C24H26N2O4: C 70.93, H 6.40, N 6.89; found: C 70.91, H
6.43, N 6.91.
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1
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© 2003 NRC Canada

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