One-pot synthesis of N-substituted 4-aryl-1,4-dihydropyridines under solvent-free conditions and microwave irradiation

Article abstract of DOI:10.1007/s007060170012

The three-component condensation of benzaldehyde derivatives, alkyl propiolates, and primary amines catalyzed by silica gel, zeolite HY, montmorillonite K-10, and acidic alumina under microwave irradiation gave N-substituted 4-aryl-1,4-dihydropyridines in short reaction times and high yields. The best results were obtained with silica gel.

Full text of DOI:10.1007/s007060170012

Monatshefte fuÈr Chemie 132, 1551±1555 (2001)
One-Pot Synthesis of N-Substituted
4-Aryl-1,4-dihydropyridines Under
Solvent-Free Conditions and Microwave
Irradiation
Ã
Saeed Balalaie and Elahe Kowsari
Department of Chemistry, K. N. Toosi University of Technology, Tehran 15875-4416, Iran
Summary. The three-component condensation of benzaldehyde derivatives, alkyl propiolates, and
primary amines catalyzed by silica gel, zeolite HY, montmorillonite K-10, and acidic alumina under
microwave irradiation gave N-substituted 4-aryl-1,4-dihydropyridines in short reaction times and
high yields. The best results were obtained with silica gel.
Keywords. Cyclocondensation; Microwave irradiation; Solvent-free conditions; 1,4-Dihydro-
pyridines.
Introduction
4-Aryl-1,4-dihydropyridines of the nifedipine type are of interest because of their
Ca2 ‡ antagonistic and agonistic activities [1]. N-Substituted 1,4-dihydropyridines
without substituents in positions 2 and 6 exhibit many pharmaceutical activities and
are highly light-sensitive in the solid state. It has been shown that these com-
pounds could be dimerized; the dimers are of interest as novel potential inhibitors
of HIV-1 protease and have anticancer activity [2].
There are many methods for the synthesis of N-substituted 1,4-dihydro-
pyridines [3]. For the preparation of 2,6-unsubstituted 1,4-dihydropyridines,
propiolates are used instead of ꢀ-dicarbonyl compounds. Cyclocondensation of
aldehydes, propiolates, and ammonium acetate in re¯uxing AcOH followed by N-
alkylation and cyclocondensation of propiolates, aromatic aldehydes, and primary
amines under re¯ux resulted in N-substituted 1,4-dihydropyridines [4,5]. N-Methyl
derivatives were produced by methylation of 1,4-dihydropyridine anions in di-
methyl propylene urea (DMPU). Meanwhile it has been found that photochem-
ical addition of alkenes to enaminocarbaldehydes leads to tetahydropyridines
which undergo dehydration to give N-substituted 1,4-dihydropyridines [6, 7, 8].
A combination of supported reagents and microwave irradiation has been
used to carry out a wide range of reactions under solvent-free conditions [9]. In
Ã
Corresponding author. E-mail: balalaie@sc.kntu.ac.ir

1552
S. Balalaie and E. Kowsari
connection with our previous work on solid-state organic synthesis under micro-
wave irradiation [10], we report the three-component condensation of benzalde-
hyde derivatives, alkyl propiolates, and primary amines on the surface of silica gel,
montmorillonite K-10, acidic alumina, and zeolite HY with acidic character under
microwave irradiation as a useful method for the synthesis of N-substituted 4-aryl-
1,4-dihydropyridines.
Results and Discussion
In order to select the best solid support for this reaction we investigated the
condensation of benzaldehyde, ethyl propiolate, and benzylamine on silica gel,
montmorillonite K-10, acidic alumina, and zeolite HY under microwave irradi-
ation. Under all conditions, the reaction product was 4e (62, 44, 41, and 41%).
The best yields were obtained with silica gel as the solid support (Table 1). With
zeolite HY, yields were lower because the Brùnsted acidic sites were partly oc-
cupied by the electron pairs of amine nitrogen atoms. It seems that the reaction
proceeds on the surface of zeolite HY because the size of channels in zeolite HY is
Ê
only around 7 A.
Scheme 1
Table 1. Solvent-free synthesis of N-substituted 4-aryl-1,4-dihydropyridines 4a±h under microwave
irradiation
Ar
R1
R2
Yielda
%
4a
4b
4c
4d
4e
4f
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
C6H5
Me
Et
Benzyl
Benzyl
Me
90
76
90
90
62
94
90
68
Me
Me
Et
Benzyl
Benzyl
Benzyl
n-Bu
C6H5
4-BrC6H4
4-MeOC6H4
4-MeOC6H4
Me
Et
4g
4h
Et
Cyclohexyl
a
In all experiments the optimized time of irradiation was 4 min; silica gel was used as the solid
support

One-Pot Synthesis of 1,4-Dihydropyridines
1553
1
The products were characterized by their IR and H NMR spectroscopic data
and melting points. In the 1H NMR spectra, the peak at 4.80±5.00 ppm is related to
4-H and is indicative of the reaction products. In the IR spectra, the absence of the
carbonyl group and acetylene bands are in accordance with the structure of the
reaction products. Microwave irradiation in the absence of solid support under neat
conditions resulted in low yields, and the reactants and products adhered to the
reaction vessel and led to irreproducible results. The cyclocondensation was also
carried out in HOAc without solid support under microwave irradiation, but yield
and reproducibility were low and work-up was dif®cult. In all experiments, the
optimized time of irradiation was 4 minutes.
We also tried to synthesize the pyrimidine skeleton via a three-component
condensation of N,N0-dimethyl urea, methyl propiolate, and benzaldehyde on silica
gel under microwave irradiation, but we obtained dimethyl-1-methyl-1,4-dihydro-
4-phenylpyridine-3,5-dicarboxylate. Under these conditions, dimethyl urea decom-
posed to methylamine and methyl isocyanate [11], and the resulting methylamine
condensed with methyl propiolate and benzaldehyde to give the above dihydro-
pyridine.
In conclusion, N-substituted 4-aryl-1,4-dihydropyridines are versatile inter-
mediates in the synthesis of pharmacologically active products. Current methods
of preparation lead to relatively large amounts of waste; our method is clean
and environmentally friendly. The advantages of the method are a) reduction
of reaction steps, b) absence of solvents, c) employment of reusable solid cat-
alysts, d) high yields, e) short reaction times and f) easy reaction set-up and
work-up.
Experimental
Melting points were measured on an Electrothermal 9100 melting point apparatus and are
1
uncorrected. IR spectra were recorded on a Shimadzu IR-408 spectrometer in KBr disks. H NMR
spectra were determined in CDCl3 with TMS as internal reference on a Bruker 80 MHz FT-NMR
spectrometer. Elemental analysis was performed using a CHN-O Heraeus instrument; the results
agreed favourably with the calculated values. Mass spectra were recorded on a GC-MS QP 1100
Shimadzu instrument (70 eV). A domestic microwave oven (Moulinex 2735A) at 2450 MHz (100%
power corresponding to 850 W) was used in all experiments.
General procedure
The benzaldehyde derivative (4 mmol), alkyl propiolate (8 mmol), primary amine (4 mmol), and 2 g
silica gel were mixed thoroughly in a mortar. Then the reaction mixture was transferred to a beaker
and irradiated with microwaves for 4 minutes. The progress of reaction was monitored by TLC. The
mixture was extracted with 3 Â 30 cm3 CHCl3, ®ltered, and the solvent was removed by a rotary
evaporator under reduced pressure. Further puri®cation by recrystallization gave the desired pure
products 4a±h.
Dimethyl 1-benzyl-1,4-dihydro-4-(4-methoxyphenyl)-pyridine-3,5-dicarboxylate (4a; C23H23NO5)
Yield: 90%; m.p.: 120±121ꢀC (petroleum ether:diethyl ether ˆ 2:1; [2d]: 120±122ꢀC); IR (KBr):
ꢁ ˆ 1705, 1604 cm 1; 1H NMR (CDCl3, ꢂ, 80 MHz): 3.55 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 4.50
(s, 2H, NCH2), 4.80 (s, 1H, 4-H), 6.60±7.35 (m, 11H, aromatic H, 2,6-H) ppm.

1554
S. Balalaie and E. Kowsari
Diethyl 1-benzyl-1,4-dihydro-4-(4-methoxyphenyl)-pyridine-3,5-dicarboxylate (4b; C25H27NO5)
Yield: 76%; m.p.: 104±106ꢀC (n-hexane: diethyl ether ˆ 2:1; [2d]: 104±106ꢀC); IR (KBr):
1
ꢁ ˆ 1705, 1664, 1605 cm 1; H NMR (CDCl3, ꢂ, 80 MHz): 1.16 (t, J ˆ 7 Hz, 6H, CH2CH3), 3.75
(s, 3H, OCH3), 4.06 (q, J ˆ 7 Hz, 4H, OCH2CH3), 4.57 (s, 2H, NCH2), 4.85 (s, 1H, 4-H), 6.70±7.35
(m, 11H, aromatic H, 2, 6-H) ppm; 13C NMR (CDCl3, ꢂ, 20 MHz): 37.10, 55.20, 58.15, 60.20,
109.10, 113.30, 127.20, 128.10, 129.30, 136.10, 137.25, 158.40, 167.20 ppm.
Dimethyl 1-methyl-1,4-dihydro-4-(4-methoxyphenyl)-pyridine-3,5-dicarboxylate (4c; C17H19NO5)
Yield: 90%; m.p.: 200±202ꢀC (petroleum ether:diethyl ether ˆ 2:1; [2d]: 200±202ꢀC); IR (KBr):
1
ꢁ ˆ 1705, 1608 cm 1; H NMR (CDCl3, ꢂ, 80 MHz): 3.20 (s, 3H, NCH3), 3.60 (s, 6H, CO2CH3),
3.70 (s, 3H, 4-CH3O-C6H4), 4.82 (s, 1H, 4-H), 6.70±7.25 (m, 6H, aromatic H, 2, 6-H) ppm.
Dimethyl 1-benzyl-1,4-dihydro-4-phenylpyridine-3,5-dicarboxylate (4d; C22H21NO4)
Yield: 90%; m.p.: 160±162ꢀC (petroleum ether:diethyl ether ˆ 2:1); IR (KBr): ꢁ ˆ 1695, 1660,
1580 cm 1; 1H NMR (CDCl3, ꢂ, 80 MHz): 3.40 (s, 6H, CO2CH3), 4.40 (s, 2H, NCH2) 4.80 (s, 1H, 4-
H), 6.90±7.40 (m, 12H, aromatic H, 2,6-H) ppm; 13C NMR (CDCl3, ꢂ, 20 MHz): 37.00, 51.00, 59.00,
109.10, 125.10, 126.20, 127.50, 129.30, 136.10, 136.50, 138.20, 147.10, 168.20 ppm.
Diethyl 1-benzyl-1,4-dihydro-4-phenylpyridine-3,5-dicarboxylate (4e; C24H25NO4)
1
Yield: 62%; m.p.: 133±135ꢀC (petroleum ether:diethyl ether ˆ 2:1); IR (KBr) ꢁ ˆ 1695, 1580 cm
;
1H NMR (CDCl3, ꢂ, 80 MHz): 1.10 (t, 6H, J ˆ 7.1 Hz, 2CH3), 3.95 (q, 4H, J ˆ 7.1 Hz, 2CH2) 4.45 (s,
2H, NCH2) 4.80 (s, 1H, 4-H), 6.90±7.70 (m, 12H, aromatic H, 2,6-H) ppm; MS: m/z ˆ 391 [M]Á‡
,
‡
‡
‡
‡
362 [M-C2H5] , 346 [M-OC2H5] , 314 [M-Ph] , 91 [benzyl] .
Dimethyl 1-benzyl-1,4-dihydro-4-(4-bromophenyl)-pyridine-3,5-dicarboxylate (4f; C22H20BrNO4)
Yield: 94%; m.p.: 186±189ꢀC (petroleum ether:diethyl ether ˆ 2:1); IR (KBr): ꢁ ˆ 1710, 1590 cm
1
;
1H NMR (CDCl3, ꢂ, 80 MHz) 3.50 (s, 6H, CO2CH3), 4.40 (s, 2H, NCH2), 4.80 (s, 1H, 4-H), 6.90±
7.60 (m, 11H, aromatic H, 2, 6-H) ppm; MS: m/z ˆ 441 [M]Á‡ , 443 [M ‡ 2]Á‡ , 410 [M-OCH3]Á‡
,
‡
‡
‡
286 [M-C6H4Br] , 91 [benzyl] , 59 [CO2CH3] .
Diethyl 1-butyl-1,4-dihydro-4-(4-methoxyphenyl) pyridine-3,5-dicarboxylate (4g; C22H29NO5)
Yield: 90%; m.p.: 117±119ꢀC (petroleum ether: diethyl ether 2:1); IR (KBr): ꢁ ˆ 1705, 1605,
1
1980 cm 1; H NMR (CDCl3, ꢂ, 80 MHz), 1.10 (t, 3H, J ˆ 7.1 Hz, CH3), 1.20 (t, 6H, J ˆ 7.1 Hz,
2CH3), 1.40±1.80 (m, 4H, 2CH2), 3.50 (t, 2H, J ˆ 7.1 Hz, NCH2), 3.50 (s, 3H, OCH3), 4.15 (q, 4H,
J ˆ 7.1 Hz, 2-OCH2), 4.90 (s, 1H, 4-H), 6.80±7.30 (m, 6H aromatic H, 2,6-H) ppm.
Diethyl 1-cyclohexyl-1,4-dihydro-4-(4-methoxyphenyl) pyridine-3,5-dicarboxylate
(4h; C24H31NO3)
1
Yield: 68%; m.p.: 137.6±138.5ꢀC (n-hexane:diethyl ether ˆ 2:1); IR (KBr): ꢁ ˆ 1700, 1600 cm
;
1H NMR (CDCl3, ꢂ, 80 MHz): 1.0 (t, 6H, J ˆ 7.1 Hz, 2CH2CH3), 1.20±1.90 (m, 10H, 5CH2) 3.10 (m,
1H, N-CH), 3.60 (s, 3H, OCH3), 3.90 (q, 4H, J ˆ 7.1, 2-OCH2CH3) 4.70 (s, 1H, 4-H), 6.60±7.15 (m,
6H aromatic, 2,6-H) ppm; MS: m/z ˆ 413 [M]Á‡ , 384 [M-C2H5] , 368 [M-OC2H5] , 340 [M-
‡
‡
‡
‡
.
CO2C2H5] , 306 [M-C7H7O]

One-Pot Synthesis of 1,4-Dihydropyridines
1555
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