Journal of Saudi Chemical Society (2018) 22, 876–885

King Saud University

Journal of Saudi Chemical Society

www.ksu.edu.sa
www.sciencedirect.com

ORIGINAL ARTICLE

New synthetic method for the synthesis of 1,4-

dihydropyridine using aminated multiwalled carbon
nanotubes as high efficient catalyst and
investigation of their antimicrobial properties
Roya Mahinpour a,*, Leila Moradi b, Zohreh Zahraei a, Nafiseh Pahlevanzadeh b

a
Department of Cell and Molecular Biology, Faculty of Chemistry, University of Kashan, P.O. Box 8731753153, Kashan, Iran
b
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, P.O. Box 8731753153, Kashan, Iran

Received 22 September 2017; revised 25 October 2017; accepted 3 November 2017

Available online 14 November 2017

KEYWORDS
Functionalization of carbon
nanotubes;
1,4-Dihydropyridines;
Aminated carbon nanotubes;
Hantzsch reaction;
Antimicrobial activity;
Multicomponent reaction;
Aminated multiwalled car-
bon nanotubes
Abstract Synthesis of 1,4-dihydropyridines in the presence of aminated multiwalled carbon nan-
otubes and investigation into their antimicrobial properties were carried out.
Amino functionalized carbon nanotubes were prepared through a facile, clean and safe proce-
dure. Obtained modified carbon nanotubes were used as a new efficient solid base catalyst for
the synthesis of 1,4-dihydropyridines. The multicomponent reaction products were obtained in
good to excellent yields. Furthermore, antimicrobial activity of synthesized compounds was evalu-
ated against 12 microorganisms including 3 gram positive bacteria, 5 gram negative bacteria and
fungi strains. The results showed that 3,5-diethoxy carbonyl-4-(4-methyl)phenyl-2,6-dimethyl-1,4-
dihydropyridine was effective against both gram positive bacteria and fungi.
Ó 2018 Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction of known MCRs are important areas of researches in medici-

nal and organic chemistry due to these processes improved
Modeling of the effective processes which allow the rapid syn- atom economy and efficiency [2–5]. Also, MCRs are often
thesis of chemicals, has been attracting much attention of helpful alternatives to reported multistep synthesis. The inter-
organic chemists [1,2]. In recent years, the improvement of action of nanocatalysts and MCRs allow effective synthetic
new multicomponent reactions (MCRs) and the development routes for preparation of diverse nitrogen-containing heterocy-
cles. One of the most eminent methods to prepare these
* Corresponding authors. compounds is the Hantzsch condensation reaction [6]. 1,4-
E-mail address: Mahinpur@kashanu.ac.ir (R. Mahinpour). dihydropyridines (DHPs) are a significant family existing in
Peer review under responsibility of King Saud University. different natural products as well as in combinatorial pharma-
ceuticals [7,8]. The nitrogen containing heterocycles are of
great significance because of their role in biological systems.
DHPs are a prolific source of biological and pharmacological
Production and hosting by Elsevier
actions [9] such as calcium channel blockers [10], antitumor
https://doi.org/10.1016/j.jscs.2017.11.001
1319-6103 Ó 2018 Production and hosting by Elsevier B.V. on behalf of King Saud University.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Synthesis of 1,4-dihydropyridines using aminated multiwalled carbon nanotubes 877

[11], anti-inflammatory [12], antiallergics [13], neurotropic [14], 2. Experimental

antibacterial [15], antimicrobial [16], antioxidant agent [17]
and analgesic activities [18]. The medicinally important drugs 2.1. Chemicals and apparatus
such as Diludine and Felodipine were manufactured and used
worldwide (Fig. 1) [19]. A number of DHPs have been
Multiwalled carbon nanotubes (MWCNTs) were prepared
reported as potential drugs for the treatment of congestive
from Shenzhen Nanotechnology Co., Ltd. (China). The Purity
heart failure and a series of tricyclic dihydropyridine, such as
of CNTs was about 90–95% with diameter and length ranging
Acridinediones were studied to show greater potency to pre-
between 20–40 nm and 5–15 lm, respectively. Chemicals were
vent spontaneous bladder contractions in vitro (Fig. 1) [20].
purchased from Merck Company. The benzaldehydes with
The main structure of DHP was first discovered by
substituents H, pANO2, m-NO2, pACl, pACH3, pAOCH3,
Hantzsch in 1882 [21]. Because of the important biological
pAOH and 2-thienal were used for the synthesis of DHPs.
activity of these compounds, various methods have been
Ethyl acetoacetate and dimedone were used as 1,3-dicarbonyl
reported for the improvement of DHP synthesis. DHP deriva-
compounds and ammonium acetate was used as the ammonia
tives have been synthesized by different catalysts such as cellu-
source. Sulfuric acid, nitric acid, thionyl chloride and methyl
lose sulfuric acid [2], Fe3O4 nanoparticles [22], Iodobenzene
amine were used for the preparation of aminated carbon
diacetate [23], nickel nanoparticles [24,25], aluminum phos-
nanotube.
phate [25,26], bismuth nitrate [26,27], gadolinium triflate
Functionalized MWCNTs were confirmed by FTIR spectra
[27,28], tin dioxide nanoparticles [28,29], MgO nanoparticles
recorded on Bruker ISS-88 instrument, TGA performed in
[29,30], mesoporous vanadium ion doped titania nanoparticles
oxygen atmosphere with a 10 °C/min rate, using a
[30,31], protic pyridinium ionic liquid [31,32], melamine trisul-
METTLER- 810 analyser. ASTRA 3-D. Bath sonicator was
fonic acid [32,33], nanomagnetic-supported sulfonic acid
applied for debundling of MWCNTs. Synthesized DHPs were
[33,34], tetrabutyl ammonium hexatungstate [TBA]2[W6O19]
characterized in detail using 1H NMR and 13C NMR in CDCl3
[34,35], glycine nitrate (GlyNO3) ionic liquid [35,36], magnetic
using Bruker DRX-400 and 100 MHz, respectively.
nanoparticle supported silica sulfuric acid (Fe3O4@SiO2-
SO3H) [36,37], ionic liquid [37,38], and microwave [38,39].
2.2. Preparation of aminated carbon nanotubes as catalyst
In many of these reported methods, expensive reagents and
dangerous solvents were applied together with long reaction
times and boring work up process. Therefore, the research Raw carbon nanotubes are chemically neutral species because
for new catalysts and reaction conditions is still of growing sig- there are no active groups in CNT structure. Functionalization
nificance. Carbon nanotubes (CNTs) can be considered as a of carbon nanotubes enables them to be active in chemical
graphene sheet rolled to obtain a cylinder with a diameter of reactions. In this research, we prepared aminated MWCNTs
nanometers to a few micrometers length, and half fullerene through a three step process (Scheme 1) as follow:
at each end [39,40]. Most of the published studies attributed
the discovery of graphite hollow tubes with diameters in the 2.2.1. Oxidation of MWCNTs
nanometer range to Iijima [40,41]. Carbon nanotubes can be 0.5 g of MWCNTs was added to 200 ml of H2SO4/HNO3 (in
functionalized for further applications [40]. In this research, ratio of 3:2) and sonicated in an ultrasonic bath with a fre-
we reported the synthesis of some DHPs in the presence of quency of 50 Hz for 15 min. The reaction was continued by
aminated multiwalled carbon nanotubes as efficient and reusa- reflux at 80 °C for 3 h. After that, the reaction mixture was fil-
ble nano based catalyst and the study of their antimicrobial tered and washed with distilled water to neutral pH and finally
properties. dried at 95 °C for 24 h.

2.2.2. Chlorination of oxidized MWCNTs

F
Cl 0.5 g of carboxylated carbon nanotubes were added to 100 ml
Br
of thionyl chloride and dry tetrahydrofuran at a ratio of 2:1 in
reflux conditions for 15 h at 70 °C under nitrogen atmosphere.
Cl O O
After that, the reaction mixture was filtered and washed with
EtO2C CO2Et EtO2C CO2Et
tetrahydrofuran and dried at 70 °C.
N N N
H H H 2.2.3. Preparation of aminated carbon nanotubes
Felodipine Diludine Acridinedione 0.3 gr of acylated carbon nanotubes and 6 gr of methyl amine
were added to 15 ml of dimethyl formamide and refluxed for
Fig. 1 Structure of three DHPs as potential drugs. 20 h at 100 °C under nitrogen atmosphere. Then the reaction

Scheme 1 Preparation of aminated carbon nanotubes.

878
R O
O O
O O
OEt (5)
Ethanol, 80oC
N CH3 Cat. (0.001 g)
H H
6a-6h
Scheme 2 Synthetic procedure for the preparation of 1,4-DHPs in the presence of aminated MWCNTs.
mixture was cooled to room temperature, washed with ethanol
and dried at 80 °C.
2.3. General procedure for synthesis of 1,4-dihydropyridines
A mixture of 1 mmol arylaldehyde derivative, 1 mmol ammo-
niume acetoacetate, 2 mmol ethyl acetoacetate and 0.001 gr of
aminated carbon nanotubes as catalyst, (or 1 mmol arylalde-
hyde derivative, 1 mmol ammoniume acetoacetate, 1 mmol
ethyl acetoacetate, 1 mmol dimedone and 0.001 g of catalyst)
in 2 ml EtOH was stirred at 80 °C for appropriate time
(scheme 2). Reaction progress was assessed by thin layer chro-
matography (petroleum ether/ethyl acetate 3:1). After comple-
tion of the reaction, the catalyst was separated with simple
filtration. Finally, the crude product was obtained from filtrate
after evaporation of ethanol. In order to obtain more purifica-
tion, the product was recrystallized in EtOH. Products were
characterized, using FTIR, 1H NMR and 13C NMR
techniques.
2.4. Spectral data of the synthesized compounds
2.4.1. 3,5-Diethoxy carbonyl-4-(4-nitro)phenyl-2,6-dimethyl-
1,4-dihydropyridine (4a)
M.F: C19H22N2O6; M.P(°C): 124–126; IR(KBr) (mmax cm 1):
3321(NAH), 1700(C‚O), 1646(C‚C), 1486(NAH), 1346
(CAH Bending CH3), 1215(CAO), 703(CAH Bending
aromatic).1H NMR(CDCl3,400 MHz): 1.2(t, J = 5.8 Hz, 6H,
2 CH3CH2), 2.35(S, 6H, 2CH3), 4.1(m, 4H, 2CH3CH2), 5.08
(S, 1H, CH), 5.8(S, 1H, NH), 7.45(d, J = 8.8 Hz, 2H, H-Ar),
8.07(d, J = 8.8 Hz, 2H, H-Ar).
2.4.2. 3,5-Diethoxy carbonyl-4-(4-chloro)phenyl-2,6-dimethyl-
1,4-dihydropyridine (4b)
M.F: C19H22NO4Cl; M.P (°C): 149–151 °C; IR(KBr) (mmax
cm 1): 3356 (NAH), 1695 (C‚O), 1651 (C‚C), 1486
(NAH), 1376(CAH Bending CH3), 1214(CAO), 829(CACl),
743(CAH Bending aromatic) .1H NMR(CDCl3,400 MHz):
1.22(t, J = 6.2 Hz, 6H, 2CH2CH3), 2.33(s, 6H, CH3), 4.09
(m, 4H, 2CH2CH3), 4.95(s, 1H, CH), 5.58(s, 1H, NAH), 7.15
(d, J = 10.8 Hz, 2H, H-Ar), 7.3(d, J = 2 Hz, 2H, H-Ar).
2.4.3. 3,5-Diethoxy carbonyl-4-(3-nitro)phenyl-2,6-dimethyl-
1,4-dihydropyridine (4c)
M.F: C19H22N2O6; M.P(°C): 163–165 °C; IR(KBr) (mmax
cm 1): 3344(NAH), 1705(C‚O), 1646(C‚C), 1486(NAH),
1346(CAH Bending CH3), 1212(CAO), 703(CAH Bending
aromatic. 1H NMR(CDCl3,400 MHz): 1.25(t, J = Hz, 6H,
CH2CH3), 2.37(s, 6H, CH3), 4.1(m, 4H,CH2CH3), 5.1(s, 1H,
CH), 5.75(s, 1H, NH), 7.36(t, J = 7.8 Hz, 1H, H-Ar), 7.64(d,
R. Mahinpour et al.
R
EtO
R
OEt O
O O
O
EtO OEt
NH4OAc
O Ethanol, 80oC
H O Cat. (0.001 g) H3C N CH3
(1) (2) (3)
4a-4i
J = 7.6 Hz, 1H, H-Ar), 8.0(d, J = 8 Hz, 1H, H-Ar), 8.12(s,
1H, H-Ar).
2.4.4. 3,5-Diethoxy carbonyl-4-(2,4-dichloro)phenyl-2,6-
dimethyl-1,4-dihydropyridine (4d)
M.F: C19H21NO4Cl2; M.P (°C): 150–152 °C; IR(KBr) (mmax
cm 1): 3377(NAH), 1682(C‚O), 1617(C‚C), 1492(NAH),
1378(CAH Bending CH3), 1201(CAO), 849(CACl), 739
(CAH Bending aromatic) .1H NMR(CDCl3,400 MHz): 1.20
(t, J = 6.2 Hz, 6H, 2CH2CH3), 2.31(s, 6H, 2CH3), 4.10(m,
4H, 2CH2CH3), 5.35(s, 1H, CH), 5.6(s, 1H, NH), 7.1(dd,
1H, H-Ar), 7.25(q, J = 2 Hz, 1H, H-Ar), 7.3(s, 1H, H-Ar).
2.4.5. 3,5-Diethoxy carbonyl-4-phenyl-2,6-dimethyl-1,4-
dihydropyridine (4e)
M.F: C19H23NO4; M.P (°C): 154–156 °C; IR(KBr) (mmax
cm 1): 3342(NAH), 1688(C‚O), 1650(C‚C), 1487(NAH),
1375(CAH Bending CH3), 1247(CAO), 738(CAH Bending
aromatic).
1
H NMR(CDCl3, 400 MHz): 1.25(t, J = 7.2 Hz, 6H,
2CH2CH3), 2.35(s, 6H, CH3), 4.1(m, 4H, CH2CH3),
5.01(s, 1H, CH), 5.65(s, 1H, NH), 7.1(d, J = 6.8 Hz, 1H,
H-Aromatic), 7.2(t, J = 7.6 Hz, 2H, H-Aromatic),
7.3(t, J = 5.8 Hz, 2H, H-Aromatic).
2.4.6. 3,5-Diethoxy carbonyl-4-(4-methyl)phenyl-2,6-dimethyl-
1,4-dihydropyridine (4f)
M.F: C20H25NO4; M.P(°C): 131–133 °C; IR(KBr) (mmax cm 1):
3358(NAH), 1695(C‚O), 1652(C‚C), 1486(NAH), 1375
(CAH Bending CH3), 1298(CAO), 744(CAH Bending aro-
matic). 1H NMR(CDCl3,400 MHz): 1.2(t, J = 7.2 Hz, 6H,
CH2CH3), 2.27(s, 3H, CH3), 2.32(s, 6H,CH3), 4.1(m, 4H, CH2-
CH3), 4.95(s, 1H, CH), 5.65(s, 1H, NH), 7.02(d, J = 8 Hz, 2H,
H-Ar), 7.18(d, J = 8 Hz, 2H, H-Ar).
2.4.7. 3,5-Diethoxy carbonyl-4-(4-methoxy)phenyl-2,6-
dimethyl-1,4-dihydropyridine (4g)
M.F: C20H25NO5; M.P(°C): 150–153 °C; IR(KBr) (mmax cm 1):
3343(NAH), 1690(C‚O), 1650(C‚C), 1488(NAH), 1210
(CAO), 749(CAH Bending aromatic). 1H NMR(CDCl3,400
MHz): 1.23(t, J = 7 Hz, 6H, 2CH2CH3), 2.32(s, 6H, 2CH3),
3.75(s, 3H, OCH3), 4.09(m, 4H, 2CH2CH3), 4.91(s, 1H, CH),
5.56(s, 1H, NH), 6.75(d, J = 8.8 Hz, 2H, H-Ar), 7.2(d, J =
8.4 Hz, 2H, H-Ar).
2.4.8. 3,5-Diethoxy carbonyl-4-(4-hydroxy)phenyl-2,6-
dimethyl-1,4-dihydropyridine (4h)
M.F: C19H23NO5; M.P(°C): 228–230 °C; IR(KBr) (mmax cm 1):
3346(NAH), 1662(C‚O), 1486(NAH), 1370(CAH Bending
Synthesis of 1,4-dihydropyridines using aminated multiwalled carbon nanotubes
CH3), 1229(CAO), 759(CAH Bending aromatic). 1H NMR
(CDCl3,400 MHz): 1.1(t, J = 7 Hz, 6H, 2CH2CH3),2.21(s,
6H, CH3), 3.95(m, 4H, CH2CH3), 4.75(s, 1H, CH), 6.55(d, J
= 8 Hz, 2H, H-Ar), 6.9(d, J = 8 Hz, 2H, H-Ar), 8.7(s, 1H,
NAH), 9.08(s, 1H, OAH).
2.4.9. 3,5-Diethoxy carbonyl-4-(2-thienyl)-2,6-dimethyl-1,4-
dihydropyridine (4i)
M.F: C17H21NO4S; M.P(°C): 165–167 °C; IR(KBr) (mmax
cm 1): 3344(NAH), 1694(C‚O), 1653(C‚C), 1484(NAH),
1371(CAH Bending CH3), 1260(CAO), 742 (CAH Bending
aromatic). 1H NMR(CDCl3,400 MHz): 1.25(t, J = 7.2 Hz,
6H, 2CH2CH3), 2.35 (s, 6H, 2CH3), 4.17(m, 4H, 2CH2CH3),
5.35(s, 1H, CH), 5.85(s, 1H, NH), 6.78(dd, 1H, H-Ar), 6.85
(q, 1H, H-Ar), 7.05(dd, 1H, H-Ar).
2.4.10. 3-Ethoxy carbonyl-4-(4-nitro)phenyl-2,7,7-trimethyl-5-
oxo-1,4-dihydropyridine (6a)
M.F: C21H24N2O5; M.P(°C): 239–241 °C; IR(KBr) (mmax
cm 1): 3276(NAH), 1703(C‚O), 1606(C‚C), 1491(NAH),
1379(CAH Bending CH3), 1216(CAO). 1H NMR(CDCl3,400
MHz): 0.9(s, 3H, CH3), 1.1(s, 3H, CH3), 1.15(t, J = 8.2 Hz,
3H, CH2CH3), 2.2(m, 4H, 2CH2), 2.4(s, 3H, CH3), 4.05(q, J
= 7.2 Hz, 2H, CH2CH3), 5.15(s, 1H, CH), 6.02(s, 1H,
NAH), 7.5(d, J = 8 Hz, 2H, H-Aromatic), 8.1(d, J = 7.6 H
z, 2H, H-Aromatic).
2.4.11. 3-Ethoxy carbonyl-4-(4-chloro)phenyl-2,7,7-trimethyl-
5-oxo-1,4-dihydropyridine (6b)
M.F: C21H24NO3Cl; M.P(°C): 230–235 °C; IR(KBr) (mmax
cm 1): 3275(NAH), 1704(C‚O), 1605(C‚C), 1490(NAH),
1380(CAH Bending CH3), 1216(CAO), 847(CAH Bending
aromatic), 640(CACl). 1H NMR(CDCl3,400 MHz):0.8(s, 3H,
CCH3), 0.95(s, 3H,CCH3), 1.1(t, J = 7 Hz, 3H, CH2-
CH3),2.15–2.23(m, 4H, 2CH2), 2.45(s, 3H, CH3), 3.95(q, J
= 6.8, 2H, CH2CH3), 4.8(s, 1H, CH), 7.12(d, J = 8.4 Hz,
2H, H-Aromatic), 7.22(d, J = 8.4 Hz, 2H, H-Aromatic), 9.1
(s, 1H, NAH).
2.4.12. 3-Ethoxy carbonyl-4-(3-nitro)phenyl-2,7,7-trimethyl-5-
oxo-1,4-dihydropyridine (6c)
M.F: C21H24N2O5; M.P(°C): 176–178 °C; IR(KBr) (vmax
cm 1):): 3283(NAH), 1703(C‚O), 1607(C‚C), 1484(NAH),
1380(CAH Bending CH3), 1212(CAO), 721(CAH Bending
aromatic). 1H NMR(CDCl3,400 MHz): 0.8(s, 3H, CH3), 0.99
(s, 3H,CH3), 1.1(t, J = 7 Hz, 3H, CH2CH3), 1.95–2.3 (m, 4H,
2CH2), 2.46(s, 3H, CH3), 3.96(q, J = 2.4 Hz, 2H, CH2CH3),
4.94(s, 1H, CH), 7.5(t, J = 7.2 Hz, 1H, H-Aromatic),
7.59(d, J = 6.8 1H, H-Ar), 7.95(t, J = 10.6 Hz, 2H,
H-Aromatic), 9.25(s, 1H, NAH).
2.4.13. 3-Ethoxy carbonyl-4-phenyl-2,7,7-trimethyl-5-oxo-1,4-
dihydropyridine (6d)
M.F: C21H25NO3; M.P(°C): 200–203 °C; IR(KBr) (mmax cm 1):
3289(NAH), 1698(C‚O), 1612(C‚C), 1484(NAH), 1379
(CAH Bending CH3), 1213(CAO), 697(CAH Bending
aromatic).
1
H NMR(CDCl3,400 MHz):0.91(s, 3H, CCH3), 1.3(s, 3H,
CCH3), 1.2(t, J = 7.2 Hz, 3H, CH2CH3),2.15–2.23(m, 4H,
2CH2), 2.35(s, 3H, CH3), 4.15(q, J = 7.2 Hz, 2H, CH2CH3),
879
5.02(s, 1H, CH), 6.22(s, 1H, NAH), 7.1(t, J = 7.2 Hz, 1H,
H-Aromatic), 7.2(t, J = 7.6 Hz, 2H, H-Aromatic), 7.3(t, J
= 9.2 Hz, 2H, H-Aromatic).
2.4.14. 3-Ethoxy carbonyl-4-(4-methyl)phenyl-2,7,7-trimethyl-
5-oxo-1,4-dihydropyridine (6e)
M.F: C22H27NO3; M.P(°C): 255–257 °C; IR(KBr) (mmax
cm 1):): 3276(NAH), 1700(C‚O), 1605(C‚C), 1491(NAH),
1380(CAH Bending CH3), 1216(CAO). 1H NMR(CDCl3,400
MHz): 0.92(s, 3H, CH3), 1.01(s, 3H,CH3), 1.2(t, J = 7 Hz, 3H,
CH2CH3), 2.2(m, 4H, 2CH2), 2.38(s, 3H, CH3), 3.7 (s, 3H,
CH3), 4.05(q, J = 6.8 Hz, 2H, CH2CH3), 5.1(s, 1H, CH),
6.01(s, 1H, NAH), 6.75(d, J = 2.4 Hz, 1H, H-Aromatic),
7.25(d, J = 4 Hz, 1H, H-Aromatic), 7.15(d, J = 4.8 Hz, 2H,
H-Aromatic).
2.4.15. 3-Ethoxy carbonyl-4-(4-methoxy)phenyl-2,7,7-
trimethyl-5-oxo-1,4-dihydropyridine (6f)
M.F: C22H27NO4; M.Prep(°C): 258–260 °C; IR(KBr) (mmax
cm 1): 3277(NAH), 1700(C‚O), 1605(C‚C), 1495(NAH),
1380(CAH Bending CH3), 1217(CAO), 848(CAH Bending
aromatic).
1
H NMR(CDCl3,400 MHz):0.91(s, 3H, CH3), 1.17(s, 3H,
CH3), 1.2(t, J = 6.8 Hz, 3H, CH2CH3),2.2–2.35(m, 4H,
2CH2), 2.39(s, 3H, CH3), 3.74(s, 3H, OCH3), 4.05(q, J = 7.2,
2H, CH2CH3), 5.0(s, 1H, CH), 5.85(s, 1H, NAH),
6.73(d, J = 8.8 Hz, 2H, H-Aromatic), 7.2(d, J = 8.4 Hz, 2H,
H-Aromatic).
2.4.16. 3-Ethoxy carbonyl-4-(4-hydroxy)phenyl-2,7,7-
trimethyl-5-oxo-1,4-dihydropyridine (6g)
M.F: C21H25NO4; M.P(°C): 235–237 °C; IR(KBr) (mmax cm 1):
3447(OAH), 3277(NAH), 1681(C‚O), 1605(C‚C), 1485
(NAH), 1380(CAH Bending CH3), 1219(CAO), 768(CAH
Bending aromatic). 1H NMR(CDCl3,400 MHz):0.85(s, 3H,
CCH3), 0.95(s, 3H,CCH3), 1.13(t, J = 7 Hz, 3H,
CH2CH3),3.35(m, 4H, 2CH2), 2.25(s, 3H, CH3),
3.95(q, J = 6.8 Hz, 2H, CH2CH3), 5.75(s, 1H, CH), 6.51(d,
J = 8.4 Hz, 2H, H-Aromatic), 7.9(d, J = 8.4 Hz, 2H,
H-Aromatic), 8.96(s, 1H, NAH), 9.05(s, 1H, OAH).
2.4.17. 3-Ethoxy carbonyl-4-(2-thienyl)-2,7,7-trimethyl-5-oxo-
1,4-dihydropyridine (6h)
M.F: C19H23NO3S; M.P(°C): 226–228 °C; IR(KBr) (mmax
cm 1): 3284(NAH), 1696(C‚O), 1612(C‚C), 1484(NAH),
1382(CAH Bending CH3), 1281(CAO), 698(CAH Bending
aromatic). 1H NMR(CDCl3,400 MHz): 0.92(s, 3H, CH3),
1.01(s, 3H, CH3), 1.2(t, J = 3.6 Hz, 3H, CH2CH3), 2.2(m,
4H, 2CH2), 3.33(s, 3H, CH3), 4.05(q, J = 7.2 Hz, 2H,
CH2CH3), 5.13(s, 1H, CH), 6.62 (d, J = 2.4 Hz, 1H, H-
Aromatic), 6.8(t, J = 4 Hz, 1H, H-Aromatic), 7.15(d, J = 4.
8 Hz, 1H, H-Aromatic), 9.22(s, 1H, NAH).
2.5. Antimicrobial activity
The synthetic compounds were evaluated for antimicrobial
activity against a set of 12 microorganisms by in vitro agar dif-
fusion assay and micro well dilution assay. The microorgan-
isms were provided by Iranian Research Organization for
Science and Technology (IROST). Following microbial strains
880 R. Mahinpour et al.

were used in this research: Pseudomonas aeruginosa (ATCC

27853), Escherichia Coli (ATCC 10536), Klebsiella pneumonia
(ATCC 10031), Shigelladysenteriae (PTCC 1188), Proteus vul-
garis (PTCC 1182) and Salmonella paratyphi-A serotype
(ATCC 5702) as examples of Gram negative bacteria, Bacillus
subtilis (ATCC 6633), Staphylococcus aureus (ATCC 29737)
and Staphylococcus epidermidis (ATCC 12228) as examples
of Gram positive bacteria, Candida albicans (ATCC 10231),
Aspergillus niger (ATCC 16404) and Aspergillus brasiliensis
(ATCC 16404) as examples of fungal strains. Bacterial strains
were cultured in nutrient agar (NA) and fungi were cultured in
sabouraud dextrose agar (SDA).

2.6. Agar diffusion assay

Fig. 2 FT-IR of Raw MWCNTs.
Preliminary antibacterial and antifungal activity of the com-
pounds (4a–4i, 6a–6h) was assayed using the agar diffusion
method with determination of inhibition zones [41]. Uniformly
sized holes (6 mm) were punched in the media plates and filled
with an equal volume (10 ml) of the test compounds dissolved
in DMSO. Tetracycline and Nystatin were used as positive
control for bacteria and fungi, respectively. DMSO was used
as a negative control. Each experiment was repeated twice.

2.7. Micro-well dilution assay

Micro-well dilution assay method was used to evaluate the

bacterio-static activity of the active compounds with inhibition
zone. Each of the compounds was dissolved in 10% DMSO, at
concentrations of 2000 mg/ml. Tetracycline was used as a stan-
dard drug for positive control. Turbidity indicated growth of
microorganism and the MIC were defined as the lowest con- Fig. 3 FT-IR of oxidized carbon nanotubes.
centrations of the compounds that prevented visible growth.

3. Results and discussion that methylamine groups were successfully attached on CNT
surfaces due to increasing the diameter of treated CNTs. Also,
In order to detect the structure characteristic of aminated car- SEM images from aminated CNTs, show that no damage
bon nanotubes, fourier transform infrared spectroscopy (FT- occurred on the morphology of CNT structure after
IR), scanning electron microscopy (SEM), Thermogravimetric functionalization.
(TGA) and elemental analysis were used. FTIR of raw The percentage of functionalization of MWCNTs was
MWCNTs is presented in Fig. 1. As can be seen, weak peaks determined with thermo gravimetric analysis technique
at about 1100 and 1600 cm 1 are from CAO and C‚C (TGA). TGA curves of raw and treated CNTs are shown in
stretching vibrations. Also, the signs at 2890 and 2922 cm 1 Fig. 7. The weight loss of functionalized CNTs between 80
are from stretching vibrations of CAH bonds existing on
MWCNTs defects (Fig. 2). Furthermore, the peak at 3447
cm 1 represented the adsorbed water on KBr or CNT surfaces.
FTIR of oxidized MWCNTs is presented in Fig. 3. A broad
strong peak at 3429 cm 1 is from the OH of carboxylic groups.
Also stretching vibrations at 1712 and 1183 cm 1 are from
C‚O and CAO of carboxylic groups respectively.
In FTIR of chlorinated MWCNT (MWCNT-COCl),
absorption in the region of 1725 and 726 cm 1 proved the exis-
tence of ACOACl groups. Also peaks at 500 and 1024 cm 1
are from CACl and CAO groups on MWCNT surfaces
(Fig. 4).
Fig. 5 show the FTIR of aminated MWCNTs. There is an
absorption peak in the region of 3437 cm 1 which is from
NAH groups and absorption at 1632 cm 1demonstrated the
existence of C‚O amidic groups on CNT surfaces (Fig. 5).
SEM images of raw and functionalized MWCNTs are pre-
sented in Fig. 6. Images from functionalized CNTs indicated Fig. 4 FTIR of chlorinated carbon nanotubes.
Synthesis of 1,4-dihydropyridines using aminated multiwalled carbon nanotubes 881

Fig. 7 TGA of raw (a) and aminated MWCNTs (b).

Fig. 5 FTIR of aminated carbon nanotubes.

and 110 °C is due to the removal of adsorbed H2O on CNT

surfaces (about 2%). Weight loss from 110 to 500 °C is from Table 1 Effect of catalyst amounts on the synthesis of 4a.a
the cleavage of methylamino groups attached on CNT sur- Entry Catalyst (g) Time (h) Yield (%)b
faces. Also, the observed degradation between 600 and 750 1 0.0005 3:00 51
°C corresponds to the thermal oxidation of disordered carbon 2 0.001 3:00 96
nanotubes and graphitized structures [42,43]. As a result, the 3 0.002 3:00 88
prepared catalyst has about 8% of amino groups. 4 0.003 3:00 72
After the preparation of catalyst, we examined the effect of 5 None 10:00 12
catalyst amounts on the yield and time of reaction. In first step, a
1 mmol 4-nitrobenzaldehyde, 2 mmol ethyl acetoacetate, 1
we mentioned a reaction between 4-nitrobenzaldehyde, ethyl mmol ammonium acetate and various amounts of catalyst in
acetoacetate and ammonium acetate as model reaction for ethanol at 85 °C.
the optimization of the reaction conditions in the presence of b
Isolated yields.
the aminated MWCNTs as catalyst. According to results in

Fig. 6 SEM images of raw (a, b) and aminated MWCNTs (c, d).
882 R. Mahinpour et al.

Table 2 optimization of solvent for the synthesis of 4a.a Table 5 Reusability of catalyst.a
Entry Solvent Time (h) Yield (%)b Entry Yield (%)b Time (h) Cycle
1 Ethanol 3:00 96 1 96 3 1
2 Water 3:00 12 2 94 3 2
3 Ethanol:Water (1:1) 3:00 16 3 92 3 3
4 Acetonitrile 3:00 20 4 92 3 4
5 Solvent free 3:00 29 a
1 mmol 4-nitrobenzaldehyde, 2 mmol ethyl acetoacetate,
a
1 mmol 4-nitrobenzaldehyde, 2 mmol ethyl acetoacetate, 1 mmol ammonium acetate and 0.001 gr of catalyst in ethanol at
1 mmol ammonium acetate and 0.001 g of catalyst in various 85 °C.
solvents at 85 °C. b
Isolated yields.
b
Isolated yields.

different temperatures (Table 3). The results showed that 85

Table 3 Effect of temperature on the synthesis of 4a.a
°C can be considered as optimized temperature. At tempera-
Entry Temperature (°C) Time (h) Yield (%)b tures higher than 85 °C, the yield of the product become lower
1 50 3:00 51 because of decomposition of product.
2 75 3:00 79 The synthesis of 1,4-dihydropyridines from aldehyde
3 85 3.00 96 derivatives, 1,3-diketo compounds and ammonium acetate in
4 95 3:00 84 the presence of CNT-CONHCH3 was performed in optimized
5 100 3:00 80 reaction conditions. As shown in Table 4, the yield of products
a
1 mmol 4-nitrobenzaldehyde, 2 mmol ethyl acetoacetate, was high to excellent and in case of aldehyde with electron
1 mmol ammonium acetate and 0.001 g of catalyst in ethanol and withdrawing groups, the yield of reaction was higher than
different temperatures. aldehydes with electron donating groups.
b
Isolated yields. For evaluation the raw MWCNT catalytic activity, the
model reaction was performed in the presence of 0.001 g of
Table 1, the best yield was obtained using 0.001 g of catalyst raw MWCNTs. Yield of product was only 25% after 10 h
and higher amounts lead to lower yields because of the higher (Table 4, entry 1). Also, a control reaction was done in the
amounts of catalysts, catalyzed the decomposition of products presence of 0.001 g of N-methylbenzamide as catalyst (to prove
to starting materials. Also, the yield of reaction in the absence that amid groups are active sites of catalyst). The yield of pro-
of catalyst was only 12% after 10 h. duct was about 87% after 3 h. Obtained results show that
Subsequently, the reaction was carried out in the presence amide groups on CNT surfaces are active sites of prepared
of various solvents. The best yield of reaction was obtained solid base catalyst (Table 4 entry 1).
in ethanol (Table 2) and in solvent free condition only 29% For estimation of catalyst activity in large scale, the
of product was obtained after 3 h. model reaction was done using 2 mmol 4-nitrobenzaldehyde,
The effect of temperature on the time and yield of reaction 2 mmol ammoniume acetoacetate and 4 mmol ethyl
was studied through the running of the model reaction in acetoacetate in the presence of 0.002 gr of aminated carbon

Table 4 Synthesis of 1,4-dihydropyridine derivatives in the presence of MWCNTs-CONHCH3 under thermal condition.
Entry Product R Time (hours) Yield (%)a m.p (°C) [Refs.]
b c b c
1 4a pANO2 3, 12 , 3 96, 25 , 87 124–126 [43,45]
2 4b pACl 3.15 95 149–151 [44,46]
3 4c m-NO2 3.30 91 163–165 [45,47]
4 4d 2,4-di Cl 3.45 87 150–152 [48,50]
5 4e H 4 85 154–156 [46,48]
6 4f p-Me 5 83 131–133 [48,50]
7 4g pAOMe 5.30 81 154–156 [47,49]
8 4h pAOH 5.30 80 228–230 [49,51]
9 4i 2-thienyl 4 93 165–167 [46,48]
10 6a pANO2 1.30 92 239–241 [47,49]
11 6b pACl 2 96 230–232 [28,30]
12 6c m-NO2 3.5 90 176–178 [26,28]
13 6d H 5 86 200–202 [31,33]
14 6e p-Me 5.30 80 255–257 [34,36]
15 6f p-Me 6 81 258–260 [34,36]
16 6g pAOMe 6 80 235–237 [47,49]
17 6h 2-thienyl 3 92 226–228 [50,52]
a
Isolated yields.
b
Time and yield when reaction was performed using 0.001 g of raw MWCNTs as catalyst.
c
Model reaction in the presence of 0.001 g of N-methyl benzamide.
Synthesis of 1,4-dihydropyridines using aminated multiwalled carbon nanotubes 883

Table 6 Antimicrobial activity of compounds (4a–4i, 6a–6h) by agar diffusion assay (mm).
Comp. No. Microorgan
B. S. S. E. coli K. P. S. P. S. A. A. C.
subtilis epidermidis aureus pneumoniae vulgaris dysenteriae aeruginosa paratyphi-A brasiliensis niger albacans
4a 8 16 8 – – – – – – – – –
4b 11 14 11 – – – – – – – – –
4c 12 – – – – – – – – – – –
4d 9 12 9 – – – – – – – – –
4e – 14 8 – – – – – – – – –
4f 8 11 7 – – – – – – – – –
4g 10 13 10 – – – – – – 14 17 –
4h – 10 – – – – – – – – – –
4i 9 12 12 – – – – – – – – –
6a – 14 – – – – – – – – – –
6b 9 14 – – – – – – – – – –
6c – 12 – – – – – – – – – –
6d 9 19 9 – – – – – – – – –
6e – – – – – – – – – – – –
6f 9 – 10 – – – – – – – – –
6g – 15 9 – – – – – – – – –
6h – 10 – – – – – – – – – –
Tetracycline 18 39 24 20 22 20 25 8 20 NT NT NT
Nystatin NT NT NT NT NT NT NT NT NT 33 32 25
A dash (–) indicates no antimicrobial activity.
NT: not tested.

Table 7 Minimum inhibitory concentration (MIC in mg/ml) values of the effective synthesized compounds.
Comp. No. Microorgan
B. subtilis S. epidermidis S. aureus A. niger A. brasiliensis
4a 62.5 31.25> 62.5 – –
4b 250 500 500 – –
4c 250 – – – –
4d 250 125 62.5 – –
4e – 250 31.25> – –
4f 125 31.25> 31.25> – –
4g 62.5 31.25> 31.25> 2000 1000
4h – 250 – – –
4i 250 250 250 – –
6a – 31.25> – – –
6b 500 250 – – –
6c – 500 – – –
6d 250 125 125 – –
6f 250 – 500 – –
6g – 250 500 – –
6h – 31.25> – – –
Tetracycline 7.8 250 250 NT NT
Nystatin NT NT NT 12.5 25
A dash (–) indicates no antimicrobial activity.
NT: not tested.

nanotubes. The yield of product was 92% after 5 h. Conse-
quently, the catalyst has a high performance in the synthesis
of DHPs and can be used in large scale reactions.
The reusability of catalysts is one of the most important
advantages. Presented CNT based catalyst can be reused in
3,4-DHP synthesis easily. After completion of the reaction,
the catalyst was separated, washed with ethanol and dried.
The recovered catalyst was used in the same reaction and
this cycle was repeated four times. Results in Table 5
demonstrate the high efficiency of catalyst even after 4 times
of recycling.
3.1. Antimicrobial activity
The antimicrobial activity of the synthetic compounds (4a–4i,
6a–6h) was evaluated by in vitro agar diffusion and micro well
dilution assay, and results are summarized in Tables 6 and 7.
As can be seen in these Tables, all synthetic compounds were
884
active against all tested gram positive bacteria, Bacillus subtilis,
Staphylococcus epidermidis and Staphylococcus aureus, except
compound 6e. This compound had no antimicrobial activity.
Compound 4g is active against gram positive bacteria as well
as against fungi. Furthermore, All compounds had no antibac-
terial activity against gram negative bacteria.
Compounds 4a and 4g were most effective against B. sub-
tilis with MIC value of 62.5 mg/mL compared with other com-
pounds (Table 6). Compounds 4a, 4f, 4g, 5a and 5 h revealed
the lowest MIC value (<31.25 mg/mL) against S. epidermidis,
while compounds 4e, 4f and 4g were most effective against
S. aureus (MIC value of <31.25 mg/mL). The results indicated
that only compound 4g has antifungal activity against
A. brasiliensis and A. niger with MIC value 1000 and
2000 mg/mL respectively. The results showed that compound
4g in comparison with other compounds has better antimicro-
bial activity.
4. Conclusions
synthesis of 1,4-dihydropyridine was reported in one-pot con-
densation reaction of aldehydes, ammonium acetate, dimedone
or ethyl acetoacetate in the presence of catalytic amounts of
aminated multi-walled carbon nanotubes (0.001 g) under ther-
mal condition. Presented method has some advantages such as
new recyclable catalyst, simple procedure, easy workup and
high yield of products furthermore, the antimicrobial activity
study revealed that all compounds had antibacterial activity
against gram positive bacteria except 3-ethoxy carbonyl -4-
(4-methyl) phenyl-2,7,7-trimethyl-5-oxo-1,4-dihydropyridine
(6e) also 4g is effective against fungi in addition to gram pos-
itive bacteria.
Acknowledgements
We are grateful to the University of Kashan Research Council
for the support of this work.
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