Synthesis of novel hantzsch dihydropyridine derivatives

Article abstract of DOI:10.14233/ajchem.2013.13886

A one-pot synthesis of novel Hantzsch dihydropyridine derivatives via a three-component cyclocondensation reaction of p-nitro acetoacetanilide, aromatic aldehyde and aqueous ammonia solution is presented. The protocol avoids the use of expensive catalyst,

Full text of DOI:10.14233/ajchem.2013.13886

Asian Journal of Chemistry; Vol. 25, No. 6 (2013), 3415-3417
http://dx.doi.org/10.14233/ajchem.2013.13886
Synthesis of Novel Hantzsch Dihydropyridine Derivatives
*
N. MONTAZERI , S. MOMENI, K. POURSHAMSIAN and S. DADO
Department of Chemistry, Faculty of Science, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
*Corresponding author: Fax: +98 192 4274409; Tel: +98 192 4274415; E-mail: montazer50@toniau.ac.ir; montazer1350@gmail.com
(Received: 11 April 2012;
Accepted: 24 December 2012)
AJC-12601
A one-pot synthesis of novel Hantzsch dihydropyridine derivatives via a three-component cyclocondensation reaction of p-nitro
acetoacetanilide, aromatic aldehyde and aqueous ammonia solution is presented. The protocol avoids the use of expensive catalyst, toxic
solvent and chromatographic separation.
Key Words: Hantzsch reaction, Three component, Dihydropyridine derivatives.
practically useful process for synthesis 1,4-dihydropyridine
derivatives is in demand. Prompted by these findings and due
to our interest in the synthesis of heterocyclic compounds29 and
in continuation of our previous works on the applications of
reusable catalyst in organic reactions30-34, herein we wish to report
an efficient synthesis of 2,6-dimethyl -N,N-bis-(4-nitrophenyl)-
4-aryl-1,4-dihydropyridine-3,5-dicarboxamide derivatives (4a-e)
via a three-component cyclocondensation reaction of p-nitro
acetoacetanilide (1), aromatic aldehyde (2a-e) and aqueous
ammonia solution (3) in ambient catalyst (Scheme-I).
INTRODUCTION
The design and development of multi component reactions
for the generation of heterocycles receive growing interest1-5.
Multi component reactions contribute to the requirments of an
environmentally friendly process by reducting the number of
synthetic steps, energy consumption and wast production. One
such reaction is the synthesis of 1,4-dihydropyridine derivatives.
1,4-Dihyrdopyridine derivatives are valuable compounds and
useful in synthetic, therapeutic and bioorganic chemistry6-9. 1,4-
Dihydropyridines are an important class of heterocycles with a
wide range of biological and pharmacological activities such as
antithrombotic10,11, analgesic activity12, antianginal13-15, antitu-
mor16, antiinflammatory activity17,18, antitubercular activity19 and
anticonvulsant20. The 4-substituted hantzsch dihydropyridines,
analogues of NADH coenzymes, are important classes of
drugs21. Amlodipine besylate, nifedipine and related dihydro-
pyridines are Ca2+ channel blockers that are the most important
classes of drugs for the treatment of cardiovascular diseases,
including hypertension. 1, 4-Dihydropyridines are generally
synthesized by classical Hantzsch reaction, which involves the
condensation of an aldehyde, β-ketoester and ammonia or
ammonium acetate in refluxing ethanol or acetic acid for a longer
time22. There are several efficient methods developed for the
synthesis of 1, 4-dihydropyridines which comprise the use of
metal triflates23, TMSCL-NaI24, ionic liquid25,26, high tempe-
rature in refluxing solvents27 and silica sulfuric acid28. However,
many of these methods have some drawbeaks such as use of
expensive catalyst, low yields of the products, tedious proce-
dure, harsh reaction conditions and difficult work-up. Because
of the importance of dihydropyridine derivatives in organic
synthesis, the development of a convenient, efficient and
EXPERIMENTAL
All chemicals were available commercially and used
without additional purification. In all cases the products were
identified by their spectroscopic properties. p-Nitro acetoaceta-
nilide (1) were prepared according to a reported method for
p-chloro acetoacetanilide35. Melting points were recorded on
an electrothermal type 9100 melting points apparatus. The IR
spectra were obtained using a shimadzu IR-470 spectropho-
1
tometer as KBr disks. H NMR and 13C NMR spectra were
recorded with a DRX-500 Avance Bruker spectrophotometer.
Synthesis of 2,6-dimethyl-N,N-bis-(4-nitrophenyl)-4-
aryl-1, 4-dihydropyridine-3,5-dicarboxamide derivatives
4a-e: A mixture of p-nitro acetoacetanilide (10 mmol), aro-
matic aldehyde (5 mmol) and 25 % aqueous ammonia solu-
tion (3 mL) in refluxing ethanol (15 mL) was stirred for 15 h.
One milliliter of 25 % aqueous ammonia solution was added
for every 3 h during the reflux. The reaction was monitored by
TLC. After completion of reaction, the reaction mixture was
cooled to room temperature. The Precipitate was filtered and
washed with cold methanol to afford the pure product 4a-e.

3416 Montazeri et al.
Asian J. Chem.
O2N
NO2
O
Ar
O
O2N
O
O
EtOH
N
H
N
H
ArCHO NH OH
+
4
+
Reflux
15h
N
H
N
H
(1)
(3)
4a-e
2a-e
Scheme-I: Synthesis of 2,6- dimethyl-N,N-bis-(4-nitropenyl)-4-aryl-1,4-dihydropyridine-3,5-dicarboxamide derivatives
2,6-Dimethyl-N,N-bis-(4-nitrophenyl)-4-phenyl-1,4-
dihydropyridine-3, 5-dicarboxamide (4a): Yellow solid, m.p.
268-272 ºC, yield 73 % IR (KBr, νmax, cm-1): 3371 (N-H), 3260
(N-H), 1705 (C=O, amide), 1600 (C=C, Ar), 1545 (N=O),
4-(4-Chlorophenyl)-2,6-dimethyl-N,N-bis-(4-nitro-
phenyl)-1,4-dihydropyridine-3,5-dicarboxamide (4e): Yellow
solid, m.p. 270-274 ºC, yield 76 % IR (KBr, νmax, cm-1): 3442
(N-H), 3371 (N-H), 1673 (C=O, amide), 1592 (C=C,Ar), 1535
1
1
1339 (N=O). H NMR (DMSO-d6) δ: 2.14 [s, 6H, (CH3)2],
(N=O), 1333 (N=O). H NMR (DMSO-d6) δ : 2.14 [s, 6H,
5.17 (s, 1H, CH), 7.09-7.12 (m, 1H, Ar-H), 7.22 (m, 2H, Ar-
H), 7.23 (d, 2H, Ar-H, J = 9.2 Hz), 7.85 (d, 4H, Ar-H, J = 8.8
Hz), 8.18 (d, 4H,Ar-H, J = 8.8Hz), 8.43 (s, 1H, NH), 10.01 [s,
2H, (NH)2]. 13C NMR (DMSO-d6) δ : 18.0 (CH3)2, 41.9 (CH),
106.1 (C), 119.3 (CH)4, 125.2 (CH)4, 126.6 (C2), 127.5 (C2),
128.7 (C2), 139.9 (CH), 142.1 (CH2), 146.4 (CH2), 147.1 (C-
NO2)2, 168.4 (C=O)2.
(CH3)2], 5.17 (s, 1H, CH), 7.23 (d, 2H, Ar-H, J = 8.4 Hz), 7.29
(d, 2H, Ar-H, J = 8.4 Hz), 7.84 (d, 4H, Ar-H, J = 9.2 Hz), 8.18
(d, 4H, Ar-H, J = 9.2 Hz), 8.49 (s, 1H, NH), 10.04 [s, 2H,
(NH)2]. 13C NMR (DMSO-d6) δ: 18.0 (CH3)2, 41.4 (CH), 105.8
(C), 119.3 (CH)4, 125.2 (CH)4, 128.6 (C2), 129.4 (C2), 131.1
(C2), 140.1 (C), 142.2 (CH)2, 146.1 (C-NO2)2, 146.3 (CH)2,
168.2 (C=O)2.
4-(2,4-Dichlorophenyl)-2,6-dimethyl-N,N-bis-(4-
nitrophenyl)-1,4-dihydropyridine -3,5-dicarboxamide (4b):
Yellow solid, m.p. 163-167 ºC, yield 78 % IR (KBr, νmax, cm-1):
3423 (N-H), 3307 (N-H), 1689 (C=O, amide), 1598 (C=C,
Ar), 1535 (N=O), 1333 (N=O). 1H NMR (DMSO-d6) δ : 2.12
[s, 6H, (CH3)2], 5.46 (s, 1H, CH), 7.35 (s, 1H, Ar-H), 7.40-
7.41 (m, 2H, Ar-H), 7.82 (d, 4H, Ar-H, J = 9.2 Hz), 8.19 (d,
4H, Ar-H, J = 9.2 Hz), 8.56 (s, 1H, NH), 10.15 (s, 2H, (NH)2.
13C NMR (DMSO-d6) δ: 17.7 (CH3)2, 40.6 (CH), 105.8 (C),
119.1 (CH)4, 125.3 (CH)4, 128.4 (C), 128.5 (C), 131.3 (C2),
131.8 (C2), 132.5 (C2), 140.0 (CH), 142.2 (CH), 144.4 (C-
NO2)2, 146.3 (CH), 167.9 (C=O)2.
RESULTS AND DISCUSSION
In view of different biological and chemical applications
of 1,4-dihydropyridine derivatives, the development of suitable
synthetic approach for their generation has been a topic of great
interest in recent times.Although many publications have already
reported the synthesis of 1,4-dihydropyridine derivatives22-28
,
very little has been covered regarding the 2,6-dimethyl-N,N-
bis-(4-aryl)-4-aryl-1,4-dihydropyridine-3,5-dicarboxamide
derivatives35. Kumar et al.35 were the first who described the
method of employing the reaction of p-chloro acetoacetanilide,
aromatic aldehyde and excess of aqueous ammonia solution
using ethanol as a solvent under reflux condition. In this commu-
nication, we report a facile and efficient synthesis of 2,6-
dimethyl-N,N- bis-(4-nitrophenyl)-4-aryl-1,4-dihydro-pyridine-
3,5-dicarboxamide derivatives, starting from p-nitro aceto-
acetanilide (1), aromatic aldehyde (2) and aqueous ammonia
solution (3). The reaction between p-nitro acetoacetanilide and
aromatic aldehyde in the presence of NH3 at ambient catalyst
in ethanol led to the corresponding 2,6-dimethyl -N,N-bis-(4-
nitrophenyl)-4-aryl-1,4-dihydropyridine-3,5-dicarboxamide
derivatives in good yield (Table-1). Table-1 contains the results
of study. The structures of compounds 4a-e were deduced from
their IR, 1H NMR and 13C NMR spectral data.
2,6-Dimethyl-4-(4-hydroxyphenyl)-N,N-bis-(4-nitro-
phenyl)-1,4-dihydropyridine-3,5-dicarboxamide (4c): Yellow
solid, m.p. 240-245 ºC, yield 75 % IR (KBr, νmax, cm-1): 3397
(N-H), 3378 (N-H), 1673 (C=O, amide), 1593 (C=C,Ar), 1535
1
(N=O), 1327 (N=O). H NMR (DMSO-d6) δ: 2.12 (s, 6H,
(CH3)2, 5.06 (s, 1H, CH), 6.59 (d, 2H, Ar-H, J = 8.8 Hz), 7.02
(d, 2H, Ar-H, J = 8.8 Hz), 7.84 (d, 4H, Ar-H, J = 9.2 Hz), 8.18
(d, 4H, Ar-H, J = 9.2 Hz), 8.43 (s, 1H, NH), 9.13 (s, 1H, OH),
9.91 (s, 2H, (NH)2. 13C NMR (DMSO-d6) δ : 18.0 (CH3)2, 41.1
(CH), 106.5 (C), 115.4 (C2), 119.2 (CH)4, 125.3 (CH)4, 128.6
(C2), 137.7 (C2), 139.4 (C), 142.1 (CH)2, 146.4 (CH)2, 156.1
(C-NO2)2, 168.5 (C=O)2.
2,6-Dimethyl-N,N-bis-(4-nitrophenyl)-4-(p-tolyl)-1,4-
dihydropyridine-3,5-dicarboxamide (4d): Yellow solid, m.p.
259-263 ºC, yield 81 % IR (KBr, νmax, cm-1): 3423 (N-H), 3378
(N-H), 1667 (C=O, amide), 1596 (C=C, Ar), 1538 (N=O),
Conclusion
In summary, we have described an efficient and simple
method for the preparation of 2,6-dimethyl-N,N-bis-(4-
nitrophenyl)-4-aryl-1, 4-dihydropyridine-3, 5-dicarboxamide
derivatives via a cyclocondensation reaction of p-nitro aceto-
acetanilide, aromatic aldehyde and aqueous ammonia solution
in refluxing ethanol.
1
1330 (N=O). H NMR (DMSO-d6) δ : 2.13 [s, 6H, (CH3)2],
2.19 (s, 3H, CH3), 5.14 (s, 1H, CH), 7.02 (d, 2H, Ar-H, J = 8.0
Hz), 7.11 (d, 2H, Ar-H, J = 8.0 Hz), 7.85 (d, 4H, Ar-H, J = 9.2
Hz), 8.18 (d, 4H, Ar-H, J = 9.2 Hz), 8.39 (s, 1H, NH), 9.97 [s,
2H, (NH)2]. 13C NMR (DMSO-d6) δ : 18.0 (CH3)2, 21.0 (CH3),
41.6 (CH), 106.3 (C), 119.2 (CH)4, 125.3 (CH)4, 127.5 (C2),
129.3 (C2), 135.6 (C2), 139.7 (C), 142.1 (CH)2, 144.2 (C-NO2)2,
146.4 (CH)2, 168.4 (C=O)2.
ACKNOWLEDGEMENTS
The authors are thankful to Islamic Azad University,
Tonekabon Branch for financial support.

Vol. 25, No. 6 (2013)
Synthesis of Novel Hantzsch Dihydropyridine Derivatives 3417
TABLE-1
SYNTHESIS OF 2,6-DIMETHYL-N,N-BIS-(4-NITROPHENYL)-4-ARYL-1,4-DIHYDROPYRIDINE-3,5-DICARBOXAMIDE DERIVATIVESa
Entry
Aromatic aldehyde
Productb
Yield (%)c
73
m.p. (ºC)
268-272
CHO
O2
N
NO2
O
O
1
N
N
H
H
N
H
4a
Cl
78
163-167
Cl
O2
N
Cl
NO2
CHO
O
O
2
N
N
H
H
Cl
N
H
4b
OH
75
240-245
CHO
O2
N
NO2
O
O
3
N
N
H
H
HO
N
H
4c
81
259-263
CHO
O2
N
NO2
O
O
4
N
N
H
H
N
H
4d
Cl
76
270-274
CHO
O2
N
NO2
O
O
5
N
H
N
H
Cl
N
H
4e
a(10 mmol) p-nitro acetoacetanilide, (5 mmol) aromatic aldehyde and (3 mL) 25 % aqueous ammonia solution in ethanol. bAll the products were
characterized by IR, 1H NMR and 13C NMR spectral data. c Isolated yields
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