Synthesis of diethyl 4-(phenyl-substituted)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylates catalyzed by CoCl2/K-10 montmorillonite in water and their antimicrobial activity

Article abstract of DOI:10.1134/S1070363217030264

A simple and efficient method of one pot synthesis of 1,4-dihydropyridine by three components reaction of aromatic aldehydes with 1,3-dicarbonyl compound, ammonium acetate and catalytic amount of CoCl₂ based on the Hantszch reaction is developed. The process is catalysis by an inexpensive catalyst in water medium, gives high yield of products and involves no volatile organic solvents. Some synthesized compounds demonstrated antimicrobial activity.

Full text of DOI:10.1134/S1070363217030264

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 3, pp. 546–549. © Pleiades Publishing, Ltd., 2017.
Synthesis of Diethyl 4-(Phenyl-substituted)-
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylates
Catalyzed by CoCl /K-10 Montmorillonite
2
1
in Water and Their Antimicrobial Activity
S. D. Bajaj, O. A. Mahodaya, P. V. Tekade*, V. B. Patil, and Suraj D. Kukade
Department of Chemistry, Jankidevi Bajaj College of Science,
Jamnalal Bajaj Marg, Civil Lines, Wardha, 442001 India
*
e-mail: jbsciencewardha@yahoo.co.in; pradiptekade@gmail.com
Received July 26, 2016
Abstract—A simple and efficient method of one pot synthesis of 1,4-dihydropyridine by three components
reaction of aromatic aldehydes with 1,3-dicarbonyl compound, ammonium acetate and catalytic amount of
CoCl based on the Hantszch reaction is developed. The process is catalysis by an inexpensive catalyst in water
2
medium, gives high yield of products and involves no volatile organic solvents. Some synthesized compounds
demonstrated antimicrobial activity.
Keywords: antimicrobial activity, CoCl
2
catalyst, 1,4-dihydropyridine, Hantszch reaction, K-10 montmorillonite
DOI: 10.1134/S1070363217030264
INTRODUCTION
water were tested in the process. Water was deter-
mined to be the most efficient media for the reaction.
Dihydropyridyl compounds attract close attention
due to various applications in medicine and specific
properties determined by several reactive centers
combined in their molecules [1, 2]. Dihydropyridine
derivatives, including nifedipine, nitrendipine and
nimodipine [3, 4], are calcium channel blockers. A
number of dihydropyridines are potential drugs for
treatment of congestive heart failure [5, 6] and
demonstrate properties of neuroprotective [7], anti-
hypertensive, antibacterial, and anticancer agents [8, 9].
Aryl aldehydes with electron-donating and electron-
withdrawing substituents at various positions produced
the corresponding products without affecting the
substituents and the substitution pattern. α,β-Unsatu-
rated aryl aldehydes (cinnamaldehyde) underwent rapid
conversion without polymerization and other side
reactions.
Table 1. Physical characteristics of the synthesized compounds
Comp. no.
R
Formula
M, mg Time, min
RESULTS AND DISCUSSION
1
a
C
4
H
3
O
C
17
H
21NO
5
319.35
345.38
65
95
We report herein water-mediated method of
synthesis of Hantzsch dihydropyridines bearing
1b
C H OH C H N0
6
4
19 23
5
1
c
C
6
H
4
NO
2
C
H N O
19 22 2 6
374.38
359.41
343.41
330.37
374.39
319.35
408.29
408.29
60
85
105
70
75
70
65
60
various substituents (Table 1) using CoCl /K-10 Mont-
2
morillonite as the catalyst (Scheme 1). A number of
aryl and heteroaryl aldehydes smoothly underwent
rapid multicomponent condensation to accomplish
several substituted functionally important Hantzsch
dihydropyridines in high yield and purity.
1d
C H O
20 25
C H NO5
7
8
5
7
7
4
1
1
e
f
C
C
H
H
C
H26NO
21 4
N
C
H N O
18 22 2 4
1g
1h
C H NO C H N O
6
4
6
6
4
3
4
4
2
19 22
2
6
Different solvents, including dimethylformamide,
chloroform, tetrahydrofuran, acetonitrile, ethanol, and
C
C
C
H
H
H
O
C
C
C
17
H
19
H
19
H
21NO
5
1
i
Br
Br
22BrNO
4
4
1
22BrNO
The text was submitted by the authors in English.
1j
5
46

SYNTHESIS OF DIETHYL 4-(PHENYL-SUBSTITUTED)-2,6-DIMETHYL-...
547
Scheme 1. Synthesis of 1,4-dihydropyridine derivatives.
O
R1
O
O
O
O
H
3
C
O
O
CH
3
7
0°C, water
+
+ CH COONH4
R1
H
H C
O
CH3
3
.
H
3
C
N
H
CH
3
3
CoCl2 6H O
2
Ammonium acetate
1,4-Dihydropyridine
CoCl in combination with K-10 Montmorillonite
clay acted as efficient catalysts in the synthesis of title
compounds from acid sensitive aldehydes (Table 2).
EXPERIMENTAL
Melting points were determined on a digital melting
point apparatus (EQ-730). H and C NMR spectra
were measured on a BRUKER Avance II 500.1 spec-
2
1
13
Application of CoCl as a catalyst reduced time
2
trometer in CDCl using TMS as the internal standard.
3
required for the reaction to complete and led to high
yields of the process. Influence of concentration of
IR spectra were recorded on a Bruker Alpha FT-IR
spectrophotometer. MS were measured on an Accu
TOF Mass spectrometer. Elemental analysis was
carried out on an Elemental analyser EURO EA 3000.
CoCl catalyst was studied (Table 3). Concentration of
2
2
mol % was determined to be the optimum one.
Antibacterial screening. The compounds 1a–1j
Synthesis of diethyl 4-(phenyl-substituted)-2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylates
were tested for their in vitro antibacterial activity
against Pseudomonas aeruginosa (MTCC-2435),
Streptococcus epidermidis and Staphylococcus aureus
(
1a–1j). A mixture of an aromatic aldehyde (1 mmol),
ethyl acetoacetate (2 mmol), ammonium acetate
1.3 mmol), and cobalt chloride hexahydrate (2 mol %)
(
MTCC-96) by the disc diffusion method using Muller–
(
Hinton agar (Hi-Media) medium and ciprofloxacin
tablet (250 mg) as the standard. The compounds 1a–1j
were tested at concentrations of 50, 100, 200,
and 300 μg/mL in DMSO. The minimum inhibitory
concentration of all compounds was determined to be
was vigorously stirred in water (2 mL) at 70°C for the
stipulated period of time. Upon completion of the
reaction (TLC), 1–2 mL of ethanol were added to
facilitate granulation of a product and poured into
crushed ice. A solid product was filtered off, washed
several times with water and crystallized from aqueous
ethanol. Sometimes the products were isolated as
viscous oils. In such cases those were refluxed with
1
00 μg/mL. The zones of inhibition (mm) were
measured after 24 h incubation at 37°C (Table 4).
Effectivity classified into four zones on the basis of
the diameter of the zone of inhibition: 0–5 mm (poor
activity); 6–10 mm (moderate activity); 11–15 mm
0
.2 g of K-10 Montmorillonite clay as a solid state
catalyst to facilitate formation of a solid product.
Diethyl 4-(furan-2-yl)-2,6-dimethyl-1,4-dihydro-
(
high activity); and above 16 mm (very high activity);
pyridine-3,5-dicarboxylate (1a). Yield 90%, mp 166°C.
–
1
Each value is an average of three independent deter-
R 0.57. IR spectrum, ν cm : 3334 (NH), 2978 (C–H),
f
,
minations.
1686 (C=O), 1639(C=O), 1529 (=C–H and C=C),
Table 2. Optimization of catalysts with respect to yield,
Table 3. Optimization of the catalyst concentration
time, and temperature
Concentration of CoCl
2
, mol %
Yield, %
Catalyst
KF/Alumina
Yield, % Time, min T, °C
71
75
80
70
95
120
500
200
180
65
78
–
6
4
2
1
.0
.0
.0
.0
95
95
95
75
70
Silica gel
Alumina sulphuric acid
70
60
70
3 2
AlCl ·6H O
CoCl
2
0.5
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017

5
48
BAJAJ et al.
Table 4. Zones of inhibition for compounds 1a–1j against bacterial strains
Zone of inhibition, mm (100 μg/mL)
Compound
Pseudomonas aeruginosa
Streptococcus epidermidis
Staphylococcus aureus
1
a
16
0
18
14
10
12
0
17
18
14
12
8
1
b
1
c
8
1
d
10
14
12
14
0
1
e
1
f
7
0
1
g
8
10
9
1
h
10
13
8
1
i
9
15
0
1
j
14
18
Ciprofloxacin
20
20
1
1
487 (C=C in furan), 1371 (CH in O–CH –CH ),
and ring C=C), 1487 (C=C), 1371 (CH in O–CH –CH ),
3
2
3
3
2
3
1
1
325 (C–N in C –N), 1296 (C–O–C). H NMR spec-
1326 (C–N in C –N), 1295 (C–O–C). H NMR
Ar
Ar
trum, δ, ppm: 1.26 s (3H, CH ), 2.33 q (2H, CH ), 4.14
spectrum, δ, ppm: 0.88 s (3H, CH ); 1.23 q (2H, CH ),
3
2
3
2
t (3H, CH ), 5.20 s (1H, CH), 5.81 s (1H, NH), 5.94–
2.33 t (3H, CH ), 3.90 s (1H, CH), 4.07 s (1H, NH).
3
3
+
7
.27 m (3H, Ar-H). LC-MS (m/z): Found: m/z 343.27
LC-MS (m/z): Found: m/z 358.30 [M + H] .
+
+
+
[
M + Na] . Calculated: [M + Na] 343.35.
Calculated: [M + H] 357.
Diethyl 4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-di-
Diethyl-2,6-dimethyl-4-(2-phenylethylene)-1,4-di-
hydropyridine-3,5-dicarboxylate (1b). Yield 93%,
hydropyridine-3,5-dicarboxylate(1e). Yield 85%, mp
–
1
–1
mp 241°C. R 0.60. IR spectrum, ν cm : 3344 (N–H),
224°C. R 0.70. IR spectrum, ν cm : 3334 (N–H), 2978
f
,
f
,
2
986 (C–H), 1792 (C=O), 1716 (C=O), 1540 (=C–H
(C–H), 1686 (C=O), 1639 (C=O), 1487 (C=C), 1214
and ring C=C), 1218 (C–O–C). LC-MS (m/z): Found:
m/z 368.28 [M + Na] . Calculated: [M + Na] 368.
(C–O–C). LC-MS (m/z): Found: m/z 378.31. Cal-
culated: [M + Na] 378.
+
+
+
Diethyl 2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydro-
Diethyl 2',6'-dimethyl-1',4'-dihydro-2,4'-bipyri-
pyridine-3,5-dicarboxylate (1c). Yield 85%, mp 170°C.
dine-3',5'-dicarboxylate (1f). Yield 95%, mp 196°C.
–
1
–1
R 0.54. IR spectrum, ν cm : 3342 (NH), 1703 (C=O),
R 0.65. IR spectrum, ν cm : 3100 (N–H), 2927
f
,
f
,
1
1
643 (C=O), 1523 (=C–H and ring C=C), 1485 (C=C),
369 (sym. CH in O–CH –CH ), 1345 (C–N in
(C–H), 1685 (C=O), 1632 (C=O), 1504 (=C–H and ring
C=C), 1428 (C=C), 1377 (CH in O–CH –CH ), 1300
3
2
3
3
2
3
1
1
C –N). H NMR spectrum, δ, ppm: 1.23 t (3H, CH ),
(C–N in C –N), 1266 (C–O–C). H NMR, δ, ppm: 1.12
Ar
3
Ar
2
5
.40 s (3H, CH ), 4.09 q (2H, CH ), 5.09 s (1H, CH),
s (3H, CH ), 2.32(q, 2H, CH ), 2.48 t (3H, CH ), 4.15 s
3
,
2
3
2
3
1
3
.80 s (1H, NH). C NMR spectrum, δ, ppm: 14.88
(1H, CH), 4.72H s (1H, NH). LC-MS (m/z): Found:
1
3
+
+
(CH ), 18.66 (CH ), 59.35 (CH ), 167.56 (C=O).
C
m/z 368.28 [M + K] . Calculated: [M + K] = 369.
3
3
2
NMR-DEPT spectrum, δ, ppm: 14.07 (CH ), 18.66
3
Diethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-
(
CH ), 40.15 (CH), 61.90 (CH ), 115.61 (CH, Ar),
3
2
pyridine-3,5-dicarboxylate (1g). Yield 75%, mp 173°C.
1
28.74 (CH, Ar). LC-MS (m/z): Found: m/z 397.18
–1
R 0.65. IR spectrum, ν cm : 3343 (N–H), 2888
+
+
f
,
[
M + Na] . Calculated: [M + Na] 397.
(
C–H), 1702 (C=O), 1642 (C=O), 1523 (=C–H and
ring C=C), 1485–1433 (C=C), 1369 (CH in O–CH
CH ), 1346 (C–N in C –N). H NMR spectrum, δ,
Diethyl 4-(4-methoxphenyl)-2,6-dimethyl-1,4-di-
3
–
2
1
hydropyridine-3,5-dicarboxylate (1d). Yield 85%,
3
Ar
–
1
mp 161°C. R 0.65. IR spectrum, ν cm : 3324 (N–H),
ppm: 1.19 t (3H, CH ), 2.42 q (2H, CH ), 2.466 s (3H,
f
,
3 2
2
974 (C–H), 1696 (C=O), 1649 (C=O), 1529 (=C–H
CH ), 5.09 s (1H, CH), 6.46 s (1H, NH).
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017

SYNTHESIS OF DIETHYL 4-(PHENYL-SUBSTITUTED)-2,6-DIMETHYL-...
549
Diethyl 4-(furan-3-yl)-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (1h). Yield 70%, mp 169°C.
ACKNOWLEDGMENTS
–
1
R 0.70. IR spectrum, ν cm : 3344 (N–H), 2960
Authors are thankful to the Department of
Chemistry, Jankidevi Bajaj College of Science,
Wardha for the support to carry out this research work.
f
,
(
C–H), 1697 (C=O), 1644 (C=O), 1539 (=C–H and
ring C=C), 1475 (C=C), 1369 (CH in O–CH –CH ),
3
2
3
1
1
320 (C–N in C –N), 1296 (C–O–C). H NMR
Ar
spectrum, δ, ppm: 1.23 t (3H, CH ), 2.18 q (2H, CH ),
REFERENCES
3
2
2
.32 s (3H, CH ), 4.30 s (1H, NH), 5.19 s (1H, CH).
3
1
. Vijesh, A.M., Isloor, A.M., Peethambar, S.K.,
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Diethyl 4-(3-bromophenyl)-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (1i). Yield 65%, mp 212°C.
R 0.75. H NMR spectrum, δ, ppm: 1.05 t (3H, CH ),
1
f
3
2
5
.12 s (3H, CH ), 2.30 q (2H, CH ), 5.00 s (1H, CH),
.82 s (1H, NH).
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ropyridine-3,5-dicarboxylate (1j). Yield 60%, mp
1
2
2
5
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1
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.19 s (1H, CH).
CONCLUSIONS
6
7
A simple, efficient and green method of synthesis
of substituted 1,4-dihydropyridines via a one-pot three
component coupling of aromatic aldehydes, 1,3-di-
carbonyl compounds and ammonium acetate ca-
talysed by CoCl2 and K-10 montmorillonite is
developed. The advantages of this method include
operational simplicity, short reaction time, use of
relatively inexpensive, commercially available catalysts
and high yields of products. Screening for antibacterial
activity of products was carried out.
8
9
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017