A one-pot four-component reaction providing quinoline-based 1,4-dihydropyridines

Article abstract of DOI:10.1007/s13738-015-0596-x

Abstract In this work, highly functionalized novel quinolinyl 1,4-dihydropyridines were synthesized in a facile and efficient method. A variety of quinoline-based dihydropyridines were obtained via a one-pot four-component condensation of 2-chloroquinoline-3-carbaldehydes, arylamines, acetylenedicarboxylates and malononitrile or ethyl cyanoacetate in moderate to excellent yields. The atom-efficiency, high-yielding, mild reaction conditions, use of simple experimental procedure and prompt isolation of the products are the main advantages of these reactions.

Full text of DOI:10.1007/s13738-015-0596-x

J IRAN CHEM SOC
DOI 10.1007/s13738-015-0596-x
ORIGINAL PAPER
A one‑pot four‑component reaction providing quinoline‑based
1,4‑dihydropyridines
Mehdi Ghandi · Nahid Zarezadeh
Received: 25 October 2014 / Accepted: 12 January 2015
© Iranian Chemical Society 2015
Abstract In this work, highly functionalized novel qui-
nolinyl 1,4-dihydropyridines were synthesized in a facile
and efficient method. A variety of quinoline-based dihy-
dropyridines were obtained via a one-pot four-component
condensation of 2-chloroquinoline-3-carbaldehydes, ary-
lamines, acetylenedicarboxylates and malononitrile or
ethyl cyanoacetate in moderate to excellent yields. The
atom-efficiency, high-yielding, mild reaction conditions,
use of simple experimental procedure and prompt isolation
of the products are the main advantages of these reactions.
1,4-Dihydropyridines (1,4-DHPs) as privileged pharma-
cophores have gained a vital place in the field of pharma-
ceuticals, in view of the abundance of naturally occurring
DHPs and presence in many valuable commercial drugs
such as nifedipine [15–19], cilnidipine [20–23], nicardipine
[24, 25], and nimodipine [26–28], and as calcium channel
blockers with useful effects on cardiovascular disorders
including, hypertension or cardiac arrhythmias [29–38].
In addition to these, functionalized 1,4-DHPs are common
to numerous bioactive compounds, which exhibit a broad
range of considerable biological activities such as antidia-
betic [39, 40], antitumor [41, 42], antitubercular [43, 44],
radioprotective [45], neuroprotective [46, 47], bronchodila-
tor [48], and as anti-ischemic for the treatment of Alzhei-
mer’s disease [49–51], as well as several other potentially
useful activities [52–61]. Replacement of the 4-aryl group
of the DHPs with the bioactive heterocyclic compounds
leads to the formation of scaffolds with variant biologi-
cal properties. For example, isoxazolyldihydropyridine I
exhibits inhibition of the multidrug-resistance transporter
[62]. Moreover, coumarin and pyrazole-based 1,4-DHPs
such as II and III are known as bone anabolic [63] and
potential antitubercular [64] agents, respectively (Fig. 1).
Since quinoline is a core structure present in various
natural products and pharmaceuticals, compounds contain-
ing this scaffold have been extensively used in medicinal
chemistry. Therefore, quinolines and their analogues are
widely utilized as anticancer [65–68], antihypertensive [69,
70], bactericidal [71–75], analgesic [76, 77], antituberculo-
sis [78, 79], and anti-inflammatory [80–82]. The diarylqui-
noline TMC207 (Fig. 1), developed at Johnson & Johnson
Pharmaceutical Research and Development was shown to
possess a new mechanism of action based on the interac-
tion with the enzyme adenosine triphosphate (ATP) syn-
thase, the energy source for the bacterium [83, 84]. This
Keywords 2-Chloroquinoline-3-carbaldehyde ·
1,4-Dihydropyridine · Multicomponent reactions
Introduction
Multicomponent reactions (MCRs) are processes in which
at least three different simple substrates react in one pot
to give the target materials [1–3]. These reactions, which
have gained significant attention during the past years, do
not occur through a single-step procedure, but rather via
several sequential steps involving cascades or domino reac-
tions [4]. Simplicity, greater efficiency, and atom economy
with generation of diverse and complex “drug-like” het-
erocyclic compounds in one-pot transformation are some
of the advantages of these reactions [5–7]. These reactions
are highlighted as diversity-oriented syntheses and can be
extended to combinatorial strategies [8–14].
M. Ghandi (*) · N. Zarezadeh
School of Chemistry, College of Science, University of Tehran,
P.O. Box 14155 6455, Tehran, Iran
e-mail: ghandi@khayam.ut.ac.ir
1 3

J IRAN CHEM SOC
NO2
NO2
NO2
O
O
O
O
NO2
Me O
O
O
O
NH
MeO2C
Me
CO2Me
O
O
MeO
Me
O
Me
OMe
OMe
Me
N
H
Me
N
H
Me
N
H
Me
Me
N
H
Me
Nifedipine
Cilnidipine
Nicardipine
Nimodipin
O
CO2Et
Et
O
N N
O N
Me
Me
Br
Me
CO2Et
Br
EtO2C
Me
CO2Et
HO
N
EtO2C
Me
EtO2C
Me
CO2Et
Me
N
MeO
Me Me
N
Me
Cl
N
H
Me
N
H
Diarylquinoline
TMC207
I
II
III
Fig. 1 Examples of some 1,4-DHPs and quinoline derivative as potential antitubercular agents
drug which is very promising against multidrug-resistant with an Electrothermal model 9100 apparatus and are
tuberculosis (MDR-TB), is currently in phase 2 clinical tri- uncorrected. IR spectra were recorded on a Shimadzu 4300
1
als [78, 79]. It should be emphasized that the preparation spectrophotometer, in cm−1. H and 13C NMR spectra
of quinoline derivatives to be evaluated against TB were were recorded on a Bruker DRX-500-AVANCE spectrom-
malaria drugs, such as quinine [85], chloroquine [86–88], eter at 300 (1H) and 75 MHz (13C) using CDCl3 as solvent
mefloquine [89–91], primaquine [92, 93], and amodiaquine and with the residual solvent signal as internal reference
[94–96], which possessed moderate biological activ- (CDCl3, 7.24 and 77.0 ppm). Mass spectra of the products
ity against TB using the Microplate Alamar Blue Assay were obtained with an HP (Agilent Technologies) 5937
(MABA).
Mass Selective Detector. Elemental analyses were carried
Since substitution of the various functional groups on the out by a CHN-Rapid Heraeus elemental analyzer (Welles-
1,4-DHP ring often results in remarkable changes on phar- ley, MA).
macological properties of these compounds [97–101], it is
not surprising that an increasing interest has always been Representative procedure for the synthesis of 7a–t
on the synthesis of functionalized 1,4-DHPs to organic
chemists because of the biological importance associated To a stirred solution of 2-chloroquinoline-3-carbaldehyde
with these compounds [102–111].
(1 mmol) and malononitrile or ethyl cyanoacetate (1 mmol)
Based on the reported antitubercular activity of some in EtOH (5 mL) was added triethylamine (0.101 g,
4-aryl substituted DHPs and a series of quinoline deriva- 1 mmol), and the solution was stirred at room temperature
tives as mentioned earlier [112], we became interested in for 10 min. A solution of amine (1 mmol) and dialkyla-
the synthesis of new compounds possessing both DHP and cetylenedicarboxylate (1 mmol) in EtOH (2 mL) was then
quinoline scaffolds in their molecular structures in order to added and the mixture stirred for 10 h. After completion of
potentially enhance their biological activities. Herein, we the reaction as indicated by TLC, the resulting solid was
report the one-pot four-component synthesis of some novel filtered and washed with EtOH to afford pure compounds
4-quinoline substituted 1,4-DHP derivatives.
7a–t.
Dimethyl 6‑amino‑4‑(2‑chloroquinoline‑3‑yl)‑5‑cyano‑1‑
Experimental
phenyl‑1,4‑dihydropyridine‑2,3‑dicarboxylate (7a) White
solid, mp 271–273 °C, yield: 0.41 g (86 %). IR (KBr) (νmax
,
General information
cm−1): 3,449 (NH), 3,281 (NH), 2,171 (CN), 1,747 (C=O),
1
1,711 (C=O); H-NMR (300 MHz, CDCl3): δH = 3.33 (s,
All commercially available chemicals and reagents were 3H, OMe), 3.44 (s, 3H, OMe), 5.23 (s, 1H, CH), 5.71 (s,
purchased from Merck Chemical Company and used with- 2H, NH2), 7.42–7.45 (m, 2H, Ar), 7.53–7.55 (m, 3H, Ar),
out further purification. Melting points were determined 7.68 (t, 1H, J = 7.5 Hz, Ar), 7.83 (t, 1H, J = 7.6 Hz, Ar),
1 3

J IRAN CHEM SOC
7.84 (d, 1H, J = 8.4 Hz, Ar), 8.17 (d, 1H, J = 8.0 Hz, Ar),
8.36 (s, 1H, Ar); 13C NMR (75 MHz, CDCl3): δC = 36.7
(CH), 51.9 (OMe), 52.4 (OMe), 58.1 (C-5 of DHP), 102.4
(C-3 of DHP), 120.4 (CN), 127.4, 127.5, 127.5, 128.0,
129.6 (2C), 130.2, 130.5 (2C), 130.9, 134.9, 137.3, 138.5,
143.1, 146.0, 149.1, 151.0 (C–Ar), 162.6 (C=O), 164.7
(C=O); EI-MS: m/z (%): 476 (7, M++2), 474 (21, M+),
415 (43), 355 (7), 312 (100), 288 (13), 176 (15), 162 (7),
139 (47), 127 (10), 111 (20), 101 (14), 77 (77); Anal. Calcd
for C25H19ClN4O4 (474.11): C, 63.23; H, 4.03; N, 11.80 %.
Found: C, 63.12; H, 4.05; N, 11.62 %.
(38 %). Anal. Calcd for C27H23ClN4O4: C, 64.48; H, 4.61;
N, 11.14 %. Found: C, 64.46; H, 4.52; N, 11.17 %.
Dimethyl 6‑amino‑4‑(2‑chloro‑6‑methylquinoline‑3‑yl)‑1‑
(4‑chlorophenyl)‑5‑cyano‑1,4‑dihydropyridine‑2,3‑dicar‑
boxylate (7d) Pale yellow solid, mp 241–243 °C, yield:
0.44 g (84 %). IR (KBr) (νmax, cm−1): 3,454 (NH), 3,282
1
(NH), 2,171 (CN), 1,749 (C=O), 1,703 (C=O); H-NMR
(300 MHZ, CDCl3): δH = 2.52 (s, 3H, Me), 3.49 (s, 3H,
OMe), 3.50 (s, 3H, OMe), 4.31 (s, 2H, NH2), 5.24 (s, 1H,
CH), 7.32 (d, 2H, J = 8.2 Hz, Ar), 7.45 (d, 2H, J = 8.2 Hz,
Ar), 7.52 (d, 1H, J = 8.5 Hz, Ar), 7.60 (s, 1H, Ar), 7.86 (d,
1H, J = 8.5 Hz, Ar), 8.01 (s, 1H, Ar); 13C NMR (75 MHz,
CDCl3): δC = 21.6 (Me), 36.6 (CH), 52.2 (OMe), 52.9
(OMe), 61.0 (C-5 of DHP), 103.8 (C-3 of DHP), 119.8
(CN), 126.4, 127.6, 127.8, 130.3 (2C), 131.7 (2C), 132.8,
133.2, 136.0, 137.0, 137.2, 138.0, 142.6, 145.4, 148.7,
150.1 (C–Ar), 163.2 (C=O), 165.2 (C=O); EI-MS: m/z
(%): 526 (1, M++4), 524 (10, M++2), 522 (14, M+),
487 (9), 463 (25), 421 (9), 369 (11), 346 (100), 304 (13),
247 (12), 176 (18), 140 (16), 111 (24), 75 (21 %). Anal.
Calcd for C26H20Cl2N4O4 (522.09): C, 59.67; H, 3.85; N,
10.71 %. Found: C, 59.69; H, 3.85; N, 10.68 %.
Dimethyl 6‑amino‑4‑(2‑chloroquinoline‑3‑yl)‑5‑cyano‑1‑
p‑tolyl‑1,4‑dihydropyridine‑2,3‑dicarboxylate (7b) White
solid, mp 275–278 °C, yield: 0.46 g (94 %). IR (KBr) (νmax
,
cm−1): 3,453 (NH), 3,279 (NH), 2,169 (CN), 1,743 (C=O),
1
1,709 (C=O); H-NMR (300 MHz, CDCl3): δH = 2.36
(s, 3H, Me), 3.36 (s, 3H, OMe), 3.44 (s, 3H, OMe), 5.23
(s, 1H, CH), 5.68 (s, 2H, NH2), 7.32 (s, 4H, Ar), 7.67 (t,
1H, J = 7.4 Hz, Ar), 7.82 (t, 1H, J = 7.4 Hz, Ar), 7.97 (d,
1H, J = 8.4 Hz, Ar), 8.15 (d, 1H, J = 8.0 Hz, Ar), 8.36
(s, 1H, Ar); 13C NMR (75 MHz, CDCl3): δC = 20.8 (Me),
36.6 (CH), 51.9 (OMe), 52.4 (OMe), 58.0 (C-5 of DHP),
102.2 (C-3 of DHP), 120.4 (CN), 127.4, 127.4, 127.5,
128.0, 130.1 (2C), 130.2 (2C), 130.9, 132.3, 137.4, 138.4,
139.9, 143.3, 146.0, 149.1, 151.1 (C–Ar), 162.7 (C=O),
164.8 (C=O); EI-MS: m/z (%): 490 (10, M++2), 488 (29,
M+), 429 (61), 415 (12), 370 (7), 326 (100), 312 (87), 288
(11), 252 (9), 208 (19), 176 (29), 162 (19), 139 (41), 127
(22), 111 (17), 101 (28), 91 (91), 77 (33 %), Anal. Calcd
for C26H21ClN4O4 (488.13): C, 63.87; H, 4.33; N, 11.46 %.
Found: C, 63.79; H, 4.35; N, 11.42 %.
Dimethyl 6‑amino‑4‑(2‑chloro‑6‑methylquinoline‑3‑yl)‑5‑
cyano‑1‑(3,4‑dimethylphenyl)‑1,4‑dihydropyridine‑2,3‑di‑
carboxylate (7e) Pale yellow solid, mp 257–259 °C,
yield: 0.46 g (89 %). IR (KBr) (νmax, cm−1): 3,450 (NH),
1
3,282 (NH), 2,170 (CN), 1,750 (C=O), 1,707 (C=O); H-
NMR (300 MHz, CDCl3): δH = 2.29 (s, 6H, 2Me), 2.53 (s,
3H, Me), 3.48 (s, 3H, OMe), 3.50 (s, 3H, OMe), 4.32 (s,
2H, NH2), 5.30 (s, 1H, CH), 7.07–7.11 (m, 2H, Ar), 7.23
(d, 1H, J = 7.8 Hz, Ar), 7.52 (d, 1H, J = 8.4 Hz, Ar), 7.61
(s, 1H, Ar), 7.88 (d, 1H, J = 8.5 Hz, Ar), 8.05 (s, 1H, Ar);
13C NMR (75 MHz, CDCl3): δC = 19.6 (Me), 19.8 (Me),
21.6 (Me), 36.4 (CH), 52.0 (OMe), 52.6 (OMe), 60.4 (C-5
of DHP), 103.2 (C-3 of DHP), 120.2 (CN), 126.4, 127.3,
127.7, 127.9, 130.8, 130.9, 132.1, 132.6, 136.6, 137.1,
137.9, 138.8, 139.8, 143.2, 145,4, 148.8, 150.6 (C–Ar),
163.3 (C=O), 165.4 (C=O); EI-MS: m/z (%): 518 (7,
M++2), 516 (21, M+), 457 (38), 340 (100), 310 (22), 282
(23), 222 (9), 176 (20), 160 (70), 140 (18), 123 (36), 105
(29), 91 (13), 77 (49 %). Anal. Calcd for C28H25ClN4O4
(516.16): C, 65.05; H, 4.87; N, 10.84 %. Found: C, 65.11;
H, 4.76; N, 10.87 %.
Dimethyl 6‑amino‑4‑(2‑chloroquinoline‑3‑yl)‑5‑cyano‑1‑
(3,4‑dimethylphenyl)‑1,4‑dihydropyridine‑2,3‑dicarbox‑
ylate (7c) White solid, mp 271–273 °C, yield: 0.46 g,
(92 %). IR (KBr) (νmax, cm−1): 3,469 (NH), 3,423 (NH),
2,196 (CN), 1,728 (C=O), 1,714 (C=O); 1H-NMR
(300 MHz, CDCl3): δH = 2.27 (s. 6H, 2Me), 3.47 (s, 3H,
OMe), 3.50 (s, 3H, OMe), 4.37 (s, 2H, NH2), 5.32 (s, 1H,
CH), 7.06–7.09 (m, 2H, Ar), 7.21 (d, 1H, J = 7.7 Hz, Ar),
7.54 (t, 1H, J = 7.3 Hz, Ar), 7.69 (t, 1H, J = 7.5 Hz, Ar),
7.84 (d, 1H, J = 8.0 Hz, Ar), 7.98 (d, 1H, J = 8.4 Hz, Ar),
8.14 (s, 1H, Ar); 13C NMR (75 MHz, CDCl3): δC = 19.6
(Me), 19.8 (Me), 36.4 (CH), 52.1 (OMe), 52.6 (OMe), 60.2
(C-5 of DHP), 103.1 (C-3 of DHP), 120.2 (CN), 127.0,
127.3, 127.5, 127.6, 128.2, 130.4, 130.8, 130.9, 132.1,
136.7, 138.4, 138.8, 139.8, 143.2, 146.8, 149.8, 150.7 (C–
Ar), 163.3 (C=O), 165.4 (C=O); EI-MS: m/z (%): 504
(7, M++2), 502 (21, M+), 443 (38), 383 (5), 340 (100),
326 (10), 312 (6), 176 (14), 162 (9), 127 (10), 91 (10), 77
Dimethyl 6‑amino‑4‑(2‑chloro‑6‑methoxyquinoline‑3‑yl)‑5‑
cyano‑1‑phenyl‑1,4‑dihydropyridine‑2,3‑dicarboxylate
(7f) White solid, mp 213–215 °C, yield: 0.42 g (83 %).
IR (KBr) (νmax, cm−1): 3,457 (NH), 3,340 (NH), 2,185
1 3

J IRAN CHEM SOC
1
(CN), 1,745 (C=O), 1,693 (C=O); H-NMR (300 MHz,
(C–Ar), 163.2 (C=O), 165.2 (C=O); EI-MS: m/z (%):
542 (1, M++4), 540 (6, M++2), 538 (9, M+), 503 (9), 479
(23), 437 (6), 385 (9), 346 (100), 288 (6), 228 (9), 204 (10),
192 (13), 176 (15), 157 (13), 111 (30 %). Anal. Calcd for
C26H20Cl2N4O5 (538.08): C, 57.90; H, 3.74; N, 10.39 %.
Found: C, 57.88; H, 3.75; N, 10.39 %.
CDCl3): δH = 3.41 (s, 3H, OMe), 3.48 (s, 3H, OMe), 3.90
(s, 3H, OMe), 4.36 (s, 2H, NH2), 5.25 (s, 1H, CH), 7.07
(d, 1H, J = 2.4 Hz, Ar), 7.29-7.45 (m, 6H, Ar), 7.85 (d,
1H, J = 9.2 Hz, Ar), 8.01 (s, 1H, Ar); 13C NMR (75 MHz,
CDCl3): δC = 36.6 (CH), 52.1 (OMe), 52.7 (OMe), 55.7
(OMe), 60.4 (C-5 of DHP), 103.2 (C-3 of DHP), 105.0
(C-5 of quinoline), 120.1 (CN), 123.2, 128.7, 129.5, 130.0
(2C), 130.3 (2C), 130.7, 134.7, 136.6, 137.4, 142.8, 142.9,
147.1, 150.4, 158.1 (C–Ar), 163.3 (C=O), 165.3 (C=O);
EI-MS: m/z (%): 506 (5, M++2), 504 (15, M+), 445 (33),
403 (14), 340 (20), 312 (100), 282 (9), 254 (24), 236 (7),
192 (12), 176 (18), 160 (32), 136 (19), 120 (64), 104 (9), 77
(73 %). Anal. Calcd for C26H21ClN4O5 (504.12): C, 61.85;
H, 4.19; N, 11.10 %. Found: C, 61.93; H, 4.17; N, 11.15 %.
Diethyl
6‑amino‑4‑(2‑chloroquinoline‑3‑yl)‑5‑cyano‑1‑
(4‑methoxyphenyl)‑1,4‑dihydropyridine‑2,3‑dicarbo‑
xylate (7i) Pale yellow solid, mp 220–222 °C, yield:
0.47 g (88 %).IR (KBr) (νmax, cm−1): 3,461 (NH), 3,296
(NH), 2,167 (CN), 1,737 (C=O), 1,696 (C=O); 1H-
NMR (300 MHz, CDCl3): δH = 1.00 (t, 6H, J = 7.1 Hz,
2OCH2Me), 3.82 (s, 3H, OMe), 3.86-4.00 (m, 4H,
2OCH2Me), 4.31 (s, 2H, NH2), 5.33 (s, 1H, CH), 6.95 (d,
2H, J = 8.8 Hz, Ar), 7.30 (d, 2H, J = 8.8 Hz, Ar), 7.54
(t, 1H, J = 7.5 Hz, Ar), 7.69 (t, 1H, J = 7.6 Hz, Ar), 7.84
(d, 1H, J = 8.0 Hz, Ar), 7.99 (d, 1H, J = 8.4 Hz, Ar),
8.14 (s, 1H, Ar); 13C NMR (75 MHz, CDCl3): δC = 13.5
(OCH2Me), 13.8 (OCH2Me), 36.7 (CH), 55.6 (OMe), 60.3
(OCH2Me), 61.0 (OCH2Me), 62.1 (C-5 of DHP), 103.2
(C-3 of DHP), 114.9 (2C), 120.2 (CN), 126.8, 127.0, 127.5,
127.6, 128.2, 130.3, 131.8 (2C), 136.7, 138.7, 143.4, 146.7,
149.9, 150.8, 160.9 (C–Ar), 162.8 (C=O), 164.8 (C=O);
EI-MS: m/z (%): 534 (10, M++2), 532 (27, M+), 459 (57),
431 (9), 395 (9), 370 (100), 342 (14), 296 (9), 270 (67), 255
(8), 227 (13), 209 (6), 181 (8), 162 (9), 127 (9), 92 (14), 77
(16 %). Anal. Calcd for C28H25ClN4O5 (532.15): C, 63.10;
H, 4.73; N, 10.51 %. Found: C, 63.02; H, 4.78; N, 10.49 %.
Dimethyl 6‑amino‑4‑(2‑chloro‑6‑methoxyquinoline‑3‑yl)‑
5‑cyano‑1‑m‑tolyl‑1,4‑dihydropyridine‑2,3‑dicarboxy‑
late (7g) White solid, mp 252–255 °C, 0.41 g (79 %).
IR (KBr) (νmax, cm−1): 3,465 (NH), 3,344 (NH), 2,182
1
(CN), 1,742 (C=O), 1,694 (C=O); H-NMR (300 MHz,
CDCl3): δH = 2.39 (s, 3H, Me), 3.47 (s, 3H, OMe), 3.51 (s,
3H, OMe), 3.93 (s, 3H, OMe), 4.31 (s, 2H, NH2), 5.30 (s,
1H, CH), 7.09 (d, 1H, J = 2.7 Hz, Ar), 7.17 (br s, 2H, Ar),
7.28–7.40 (m, 3H, Ar), 7.88 (d, 1H, J = 9.2 Hz, Ar), 8.01
(s, 1H, Ar); 13C NMR (75 MHz, CDCl3): δC = 21.2 (Me),
36.6 (CH), 52.1 (OMe), 52.6 (OMe), 55.7 (OMe), 60.5
(C-5 of DHP), 103.3 (C-3 of DHP), 105.0 (C-5 of quino-
line), 120.1 (CN), 123.1, 127.2, 128.7, 129.6, 129.7, 130.7,
131.5, 134.6, 136.6, 137.4, 140.4, 142.8, 143.0, 147.2,
150.4, 158.1 (C–Ar), 163.3 (C=O), 165.4 (C=O); EI-MS:
m/z (%): 520 (6, M++2), 518 (18, M+), 459 (33), 417 (10),
365 (9), 346 (14), 326 (100), 268 (9), 236 (7), 208 (11),
192 (8), 176 (14), 157 (10), 133 (9), 91 (62 %). Anal. Calcd
for C27H23ClN4O5 (518.14): C, 62.49; H, 4.47; N, 10.80 %.
Found: C, 62.64; H, 4.37; N, 10.86 %.
Diethyl 6‑amino‑4‑(2‑chloroquinoline‑3‑yl)‑5‑cyano‑1‑p‑
tolyl‑1,4‑dihydropyridine‑2,3‑dicarboxylate (7j) Pale yel-
low solid, mp 208–210 °C, yield: 0.46 g (89 %). IR (KBr)
(νmax, cm−1): 3,462 (NH), 3,295 (NH), 2,169 (CN), 1,740
(C=O), 1,694 (C=O); 1H-NMR (300 MHZ, CDCl3):
δH = 0.96-1.03 (m, 6H, 2OCH2Me), 2.39 (s, 3H, Me), 3.84-
4.00 (m, 4H, 2OCH2Me), 4.29 (s, 2H, NH2), 5.35 (s, 1H,
CH), 7.27 (s, 4H, Ar), 7.55 (t, 1H, J = 7.5 Hz, Ar), 7.70
(t, 1H, J = 7.6 Hz, Ar), 7.84 (d, 1H, d, J = 7.9 Hz, Ar),
8.00 (d, 1H, J = 8.4 Hz, Ar), 8.15 (s,1H, Ar); 13C NMR
(75 MHz, CDCl3): δC = 13.4 (OCH2Me), 13.8 (OCH2Me),
21.3 (Me), 36.7 (CH), 60.4 (OCH2Me), 61.0 (OCH2Me),
62.1 (C-5 of DHP), 103.3 (C-3 of DHP), 120.1 (CN),
127.0, 127.5, 127.6, 128.2, 130.2 (2C), 130.3, 130.5 (2C),
132.0, 136.8, 138.7, 141.1, 143.2, 146.8, 149.9, 150.5 (C–
Ar), 162.8 (C=O), 164.8 (C=O); EI-MS: m/z (%): 518 (4,
M++2), 516 (12, M+), 443 (38), 400 (53), 354 (100), 316
(17), 281 (22), 254 (46), 215 (12), 199 (18), 171 (20), 162
(7), 157 (23), 127 (9), 115 (28), 93 (39), 77 (14 %); Anal.
Calcd for C28H25ClN4O4 (514.14): C, 65.05; H, 4.87; N,
10.84 %. Found: C, 64.81; H, 4.72; N, 10.84 %.
Dimethyl 6‑amino‑4‑(2‑chloro‑6‑methoxyquinoline‑3‑yl)‑
1‑(4‑chlorophenyl)‑5‑cyano‑1,4‑dihydropyridine‑2,3‑di‑
carboxylate (7h) White solid, mp 214–216 °C, yield:
0.43 g (80 %). IR (KBr) (νmax, cm−1): 3,579 (NH), 3,459
1
(NH), 2,184 (CN), 1,732 (C=O), 1,701 (C=O); H-NMR
(300 MHZ, CDCl3): δH = 3.48 (s, 3H, OMe), 3.49 (s, 3H,
OMe), 3.91 (s, 3H, OMe), 4.36 (s, 2H, NH2), 5.23 (s, 1H,
CH), 7.08 (d, 1H, J = 2.6 Hz, Ar), 7.30–7.33 (m, 3H, Ar),
7.43 (d, 2H, J = 8.6 Hz, Ar), 7.85 (d, 1H, J = 9.2 Hz, Ar),
7.99 (s, 1H, Ar); 13C NMR (75 MHz, CDCl3): δC = 36.7
(CH), 52.2 (OMe), 52.9 (OMe), 55.7 (OMe), 60.8 (C-5 of
DHP), 103.6 (C-3 of DHP), 105.0 (C-5 of quinoline), 119.9
(CN), 123.3, 128.7, 129.5, 130.2 (2C), 131.8 (2C), 133.2,
136.2, 136.9, 137.5, 142.6, 142.8, 147.0, 150.1, 158.2
1 3

J IRAN CHEM SOC
1
5‑Ethyl 2,3‑dimethyl 6‑amino‑4‑(2‑chloroquinoline‑3‑yl)‑
1‑p‑tolyl‑1,4‑dihydropyridine‑2,3,5‑tricarboxylate
(7k) White solid, mp 228–230 °C, yield: 0.49 g, (91 %).
IR (KBr) (νmax, cm−1): 3,409 (NH), 3,258 (NH), 1,740
(C=O), 1,685 (C=O), 1,660 (C=O); 1H-NMR (300 MHZ,
CDCl3): δH = 1.12 (t, 3H, J = 7.1 Hz, OCH2Me), 2.40 (s,
3H, Me), 3.42 (s, 3H, OMe), 3.58 (s, 3H, OMe), 3.90-4.08
(m, 2H, OCH2Me), 5.52 (s, 1H, CH), 6.40 (br s, 2H, NH2),
7.31 (s, 4H, Ar), 7.51 (t, 1H, J = 7.5 Hz, Ar), 7.66 (t,1H,
J = 7.6 Hz, Ar), 7.81 (d, 1H, J = 8.1 Hz, Ar), 7.98 (d,
1H, J = 8.4 Hz, Ar), 8.23 (s, 1H, Ar); 13C NMR (75 MHz,
CDCl3): δC = 14.5 (OCH2Me), 21.3 (Me), 36.0 (CH), 52.7
(OMe), 52.5 (OMe), 59.5 (OCH2Me), 78.9 (C-5 of DHP),
105.6 (C-3 of DHP), 126.6, 127.3, 127.6, 128.1, 129.9,
130.3 (2C), 130.5 (2C), 132.1, 139.6, 139.4, 140.8, 142.3,
146.3, 150.7, 151.7 (C–Ar), 163.8 (C=O), 166.1 (C=O),
169.5 (C=O); EI-MS: m/z (%): 537 (3, M++2), 535 (9,
M+), 476 (29), 462 (79), 426 (12), 387 (13), 373 (100),
340 (53), 327 (11), 308 (8), 295 (27), 267 (9), 235 (7), 162
(7), 91 (43 %). Anal. Calcd for C28H26ClN3O6 (535.15): C,
62.75; H, 4.89; N, 7.84 %. Found: C, 62.68; H, 4.89; N,
7.82 %.
(NH), 1,740 (C=O), 1,689 (C=O), 1,662 (C=O); H-
NMR (300 MHz, CDCl3): δH = 1.10 (t, 3H, J = 7.1 Hz,
OCH2Me), 3.45 (s, 3H, OMe), 3.58 (s, 3H, OMe), 3.93–
4.08 (m, 2H, OCH2Me), 5.51 (s, 1H, CH), 6.37 (br s, 2H,
NH2), 7.40 (d, 2H, J = 8.5 Hz, Ar), 7.46-7.54 (m, 3H, Ar),
7.67 (t, 1H, J = 7.3 Hz, Ar), 7.81 (d, 1H, J = 7.8 Hz, Ar),
7.98 (d, 1H, J = 8.4 Hz, Ar), 8.20 (s, 1H, Ar); 13C NMR
(75 MHz, CDCl3): δC = 14.4 (OCH2Me), 36.3 (CH), 51.8
(OMe), 52.6 (OMe), 59.6 (OCH2Me), 79.1 (C-5 of DHP),
106.0 (C-3 of DHP), 126.7, 127.3, 127.5, 128.1, 130.0,
130.2 (2C), 132.0 (2C), 133.4, 136.7, 138.9, 140.0, 141.8,
146.3, 150.6, 151.3 (C–Ar), 163.6 (C=O), 165.9 (C=O),
169.4 (C=O); EI-MS: m/z (%): 559 (0.4, M++4), 557 (2,
M++2), 555 (4, M+), 496 (15), 482 (39), 446 (8), 407
(5), 393 (100), 365 (7), 347 (6), 315 (9), 287 (6), 261 (9),
162 (6), 152 (8), 127 (6), 111 (12 %). Anal. Calcd for
C27H23Cl2N3O6 (555.10): C, 58.28; H, 4.17; N, 7.55 %.
Found: C, 58.48; H, 3.99; N, 7.52 %.
5‑Ethyl 2,3‑dimethyl 6‑amino‑4‑(2‑chloro‑6‑methylquino‑
line‑3‑yl)‑1‑phenyl‑1,4‑dihydropyridine‑2,3,5‑tricarboxy‑
late (7n) Pale yellow solid, mp 188–190 °C, yield: 0.45 g
(86 %). IR (KBr) (νmax, cm−1): 3,337 (NH), 3,257 (NH),
1
5‑Ethyl 2,3‑dimethyl 6‑amino‑4‑(2‑chloroquinoline‑3‑yl)‑
1‑(4‑methoxyphenyl)‑1,4‑dihydropyridine‑2,3,5‑tri‑
carboxylate (7l) White solid, mp 234–237 °C, yield:
0.47 g (85 %). IR (KBr) (νmax, cm−1): 3,417 (NH), 3,259
1,756 (C=O), 1,705 (C=O), 1,656 (C=O); H-NMR (300
MHZ, CDCl3): δH = 1.13 (t, 3H, J = 7.1 Hz, OCH2Me),
2.52 (s, 3H, Me), 3.39 (s, 3H, OMe), 3.58 (s, 3H, OMe),
3.94–4.09 (m, 2H, OCH2Me), 5.51 (s, 1H, CH), 6.38 (br s,
2H, NH2), 7.44-7.57 (m, 7H, Ar), 7.88 (d, 1H, J = 8.5 Hz,
Ar), 8.15 (s, 1H, Ar); 13C NMR (75 MHz, CDCl3):
δC = 14.5 (OCH2Me), 21.5 (Me), 36.1 (CH), 51.7 (OMe),
52.4 (OMe), 59.5 (OCH2Me), 79.1 (C-5 of DHP), 105.9
(C-3 of DHP), 126.1, 127.5, 127.6, 127.8, 129.9 (2C),
130.5, 130.7 (2C), 132.2, 135.0, 136.6, 139.3, 142.1, 144.9,
149.8, 151.1 (C–Ar), 163.7 (C=O), 166.0 (C=O), 169.5
(C=O); EI-MS: m/z (%): 537 (3, M++2), 535 (9, M+),
476 (21), 462 (65), 426 (16), 359 (100), 331 (15), 313 (12),
281 (23), 253 (9), 221 (6), 176 (7), 140 (16), 115 (9), 77
(41 %). Anal. Calcd for C28H26ClN3O6 (535.15): C, 62.75;
H, 4.89; N, 7.84 %. Found: C, 62.75; H, 4.91; N, 7.84 %.
1
(NH), 1,741 (C=O), 1,686 (C=O), 1,657 (C=O); H-
NMR (300 MHz, CDCl3): δH = 1.11 (t, 3H, J = 7.0 Hz,
OCH2Me), 3.43 (s, 3H, OMe), 3.57 (s, 3H, OMe), 3.82
(s, 3H, OMe), 3.90-4.07 (m, 2H, OCH2Me), 5.51 (s, 1H,
CH), 6.41 (br s, 2H, NH2), 6.98 (d, 2H, J = 8.6 Hz, Ar),
7.34 (d, 2H, J = 8.6 Hz, Ar), 7.50 (t, 1H, J = 7.3 Hz, Ar),
7.65 (t, 1H, J = 7.5 Hz, Ar), 7.79 (d, 1H, J = 8.0 Hz, Ar),
7.97 (d, 1H, J = 8.4 Hz, Ar), 8.22 (s, 1H, Ar); 13C NMR
(75 MHz, CDCl3): δC = 14.5 (OCH2Me), 36.1 (CH), 51.7
(OMe), 52.5 (OMe), 55.6 (OMe), 59.5 (OCH2Me), 78.8
(C-5 of DHP), 105.4 (C-3 of DHP), 114.9 (2C), 126.3,
127.0, 127.3, 127.6, 128.1, 129.9, 131.8 (2C), 139.5, 139.9,
142.6, 146.3, 150.7, 151.9, 160.7 (C–Ar), 163.8 (C=O),
166.0 (C=O), 169.4 (C=O); EI-MS: m/z (%): 553 (3,
M++2), 551 (9, M+), 492 (22), 478 (70), 449 (8), 420 (24),
403 (9), 389 (100), 361 (17), 343 (12), 311 (24), 247 (74),
173 (67), 162 (6), 101 (20), 77 (22 %). Anal. Calcd for
C28H26ClN3O7 (551.15): 60.93; H, 4.75; N, 7.61 %. Found:
C, 60.84; H, 4.59; N, 7.67 %.
5‑Ethyl 2,3‑dimethyl 6‑amino‑4‑(2‑chloro‑6‑methylqui‑
noline‑3‑yl)‑1‑p‑tolyl‑1,4‑dihydropyridine‑2,3,5‑tricar‑
boxylate (7o) Pale yellow solid, mp 125–128 °C, yield:
0.49 g (89 %). Rf (33 % EtOAc/hexane) 0.60; IR (KBr)
(νmax, cm−1): 3,402 (NH), 3,261 (NH), 1,741 (C=O),
1,689 (C=O), 1,658 (C=O); 1H-NMR (300 MHZ, CDCl3):
δH = 1.13 (t, 3H, J = 7.1 Hz, OCH2Me), 2.41 (s, 3H, Me),
2.52 (s, 3H, Me), 3.42 (s, 3H, OMe), 3.58 (s, 3H, OMe),
3.91-4.09 (m, 2H, OCH2Me), 5.50 (s, 1H, CH), 6.41 (br s,
2H, NH2), 7.32 (s, 4H, Ar), 7.50 (d, 1H, J = 8.6 Hz, Ar),
7.56 (s, 1H, Ar), 7.87 (d, 1H, J = 8.6 Hz, Ar), 8.14 (s, 1H,
5‑Ethyl 2,3‑dimethyl 6‑amino‑1‑(4‑chlorophenyl)‑4‑(2‑
chloroquinoline‑3‑yl)‑1,4‑dihydropyridine‑2,3,5‑tricar‑
boxylate (7m) White solid, mp 242–243 °C, yield:
0.49 g (88 %). IR (KBr) (νmax, cm−1): 3,403 (NH), 3,226
1 3

J IRAN CHEM SOC
O
R3
R4
R1
N
C
NH2
N
N
C
t
t
H
O
E N E
N
C
,
N
Cl
3
R1
a-c
a
3
4
R5
CO2
RT 1
0 h
+
R5
CO2
,
R4
R3
R5
CO2
N
Cl
R5
O2C
NH2
a-
d
a-
b
a-
5
6
7
j
Scheme 2 Synthesis of quinoline-based DHPs 7a–j
Ar); 13C NMR (75 MHz, CDCl3): δC = 14.5 (OCH2Me),
21.3 (Me), 21.6 (Me), 36.0 (CH), 51.7 (OMe), 52.4 (OMe),
59.5 (OCH2Me), 79.0 (C-5 of DHP), 105.7 (C-3 of DHP),
126.1, 127.6, 127.8, 130.3 (2C), 130.5 (2C), 132.2 (2C),
136.6, 139.3, 139.5, 140.8, 142.3, 144.9, 149.8, 151.7 (C–
Ar), 163.8 (C=O), 166.1 (C=O), 169.5 (C=O); EI-MS:
m/z (%): 551 (2, M++2), 549 (6, M+), 490 (13), 476 (34),
440 (7), 415 (10), 373 (100), 345 (7), 327 (5), 295 (11),
267 (4), 176 (3), 140 (8), 115 (5), 91 (18 %). Anal. Calcd
for C29H28ClN3O6 (549.17): C, 63.33; H, 5.13; N, 7.64 %.
Found: C, 63.31; H, 5.33; N, 7.92 %.
IR (KBr) (νmax, cm−1): 3,398 (NH), 3,255 (NH), 1,734
(C=O), 1,659 (C=O), 1,637 (C=O); H-NMR (300 MHz,
1
CDCl3): δH = 0.93 (t, 3H, J = 7.0 Hz, OCH2Me), 1.12
(t, 6H, J = 7.0 Hz, 2OCH2Me), 2.29 (s, 6H, 2Me), 3.83-
4.06 (m, 6H, 3OCH2Me), 5.51 (s, 1H, CH), 6.43 (b s, 2H,
NH2), 7.14–7.25 (m, 3H, Ar), 7.50 (t, 1H, J = 7.3 Hz, Ar),
7.65 (t, 1H, J = 7.6 Hz, Ar), 7.80 (d, 1H, J = 8.0 Hz, Ar),
7.97 (d, 1H, J = 8.3 Hz, Ar), 8.23 (s, 1H, Ar); 13C NMR
(75 MHz, CDCl3): δC = 13.4 (OCH2Me), 14.0 (OCH2Me),
14.5 (OCH2Me), 19.8 (Me), 19.8 (Me), 36.4 (CH), 59.4
(OCH2Me), 60.7 (OCH2Me), 61.6 (OCH2Me), 78.5 (C-5
of DHP), 105.3 (C-3 of DHP), 126.6, 127.3, 127.5, 127.9,
128.1, 129.8, 130.8, 131.4, 132.4, 138.5, 139.3, 139.4,
140.2, 142.5, 146.3, 150.7, 152.0 (C–Ar), 163.3 (C=O),
165.6 (C=O), 169.5 (C=O); EI-MS: m/z (%): 580 (3,
M++2), 578 (9, M+), 532 (6), 504 (59), 415 (100), 404
(3), 387 (6), 370 (13), 354 (17), 323 (72), 296 (45), 281
(7), 269 (13), 217 (6), 177 (5), 161 (7), 121 (9), 105 (9), 77
(9 %). Anal. Calcd for C31H32ClN3O6 (577.20): C, 64.41;
H, 5.58; N, 7.27 %. Found: C, 64.37; H, 5.55; N, 7.23 %.
Triethyl 6‑amino‑4‑(2‑chloroquinoline‑3‑yl)‑1‑m‑tolyl‑1,4‑
dihydropyridine‑2,3,5‑tricarboxylate (7p) Pale yellow
solid, mp 120–123 °C, yield: 0.48 g (85 %). IR (KBr)
(νmax, cm−1): 3,258 (NH), 3,189 (NH), 1,743 (C=O),
1,703 (C=O), 1,658 (C=O); 1H-NMR (300 MHz, CDCl3):
δH = 0.92 (t, 3H, J = 7.0 Hz, OCH2Me), 1.12 (t, 6H,
J = 7.0 Hz, 2OCH2Me), 2.41 (s, 3H, Me), 3.79-4.07 (m,
6H, 3OCH2Me), 5.52 (s, 1H, CH), 6.41 (br s, 2H, NH2),
7.26–7.31 (m, 3H, Ar), 7.36-7.41 (m, 1H, Ar), 7.52 (t, 1H,
J = 7.4 Hz, Ar), 7.66 (t, 1H, J = 7.6 Hz, Ar), 7.81 (d, 1H,
J = 8.0 Hz, Ar), 7.98 (d, 1H, J = 8.4 Hz, Ar), 8.24 (s, 1H,
Ar); 13C NMR (75 MHz, CDCl3): δC = 13.4 (OCH2Me),
14.0 (OCH2Me), 14.5 (OCH2Me), 21.2 (Me), 36.5 (CH),
59.4 (OCH2Me), 60.8 (OCH2Me), 61.7 (OCH2Me), 78.5
(C-5 of DHP), 105.5 (C-3 of DHP), 126.6, 127.3, 127.5,
127.8, 128.1, 129.6, 129.8, 131.1, 131.3, 134.9, 139.1,
140.1, 140.3, 142.3, 146.3, 150.7, 151.8 (C–Ar), 163.8
(C=O), 166.1 (C=O), 169.5 (C=O); EI-MS: m/z (%):
566 (3, M++2), 564 (9, M+), 518 (6), 490 (56), 444 (3),
418 (5), 401 (100), 373 (5), 354 (6), 308 (4), 255 (10), 209
(5), 162 (3), 152 (4), 127 (4), 91 (14 %). Anal. Calcd for
C30H30ClN3O6 (563.18): C, 63.88; H, 5.36; N, 7.45 %.
Found: C, 63.81; H, 5.38; N, 7.45 %.
Triethyl 6‑amino‑1‑(4‑chlorophenyl)‑4‑(2‑chloroquinoline‑
3‑yl)‑1,4‑dihydropyridine‑2,3,5‑tricarboxylate (7r) Pale
yellow solid, mp 165–167 °C, Yield: 0.51 g (87 %). IR
(KBr) (νmax, cm−1): 3,400 (NH), 3,241 (NH), 1,733
(C=O), 1,663 (C=O), 1,608 (C=O); 1H-NMR (300
MHZ, CDCl3): δH = 0.97 (t, 3H, J = 7.1 Hz, OCH2Me),
1.11 (t, 6H, J = 7.1 Hz, 2OCH2Me), 3.83–4.05 (m, 6H,
3OCH2Me), 5.51 (s, 1H, CH), 6.37 (br s, 2H, NH2), 7.40
(d, 2H, J = 8.7 Hz, Ar), 7.44-7.53 (m, 3H, Ar), 7.66 (t,
1H, J = 7.4 Hz, Ar), 7.79 (d, 1H, J = 8.1 Hz, Ar), 7.98 (d,
1H, J = 8.5 Hz, Ar), 8.20 (s, 1H, Ar); 13C NMR (75 MHz,
CDCl3): δC = 13.4 (OCH2Me), 14.0 (OCH2Me), 14.4
(OCH2Me), 36.7 (CH), 59.5 (OCH2Me), 60.9 (OCH2Me),
61.9 (OCH2Me), 78.7 (C-5 of DHP), 105.8 (C-3 of DHP),
126.7, 127.2, 127.4, 128.1, 129.9, 130.1 (2C), 132.3 (2C),
133.6, 136.7, 138.9, 140.4, 141.9, 146.3, 150.6, 151.5 (C–
Ar), 163.2 (C=O), 165.4 (C=O), 169.4 (C=O); EI-MS:
m/z (%): 587 (0.8, M++4), 585 (5, M++2), 583 (7, M+),
538 (6), 510 (65), 438 (6), 421 (100), 393 (7), 374 (10), 356
Triethyl
6‑amino‑4‑(2‑chloroquinoline‑3‑yl)‑1‑(3,4‑dim
ethylphenyl)‑1,4‑dihydropyridine‑2,3,5‑tricarboxylate
(7q) White solid, mp 153–155 °C, yield: 0.53 g (92 %).
1 3

J IRAN CHEM SOC
Scheme 1 Preparation of
2-chloroquinoline-3-carbalde-
hydes 3a–c
O
CH
CO
3COCl
R1
R1
R1
DMF P
,
acetone
OCl3
K
,
3
O
2
H
NH2
N
H
N
Cl
°
°
80 C
30 C
a-c
a-c
a-c
3
1
2
Table 1 Structure of quinoline-based DHPs 7a–j from reactions of malononitrile
Entry
Product structure
Yield (%)
Entry
Product structure
NH2
Yield (%)a
NH2
N
C
N
N
C
N
e
M
O
1
86
6
83
e
M
CO2
e
e
M
CO2
M
CO2
N
Cl
e
M
CO2
N
Cl
7f
7a
e
M
NH2
N
NH2
N
N
C
N
C
e
M
e
M
O
2
3
4
94
92
84
89
7
8
79
80
88
89
e
M
CO2
e
M
CO2
e
M
CO2
e
M
CO2
N
Cl
7g
N
Cl
7b
e
e
M
Cl
NH2
N
NH2
N
N
N
C
C
M
e
M
O
e
e
M
CO2
M
CO2
e
e
M
M
CO2
Cl
CO2
N
N
C
l
7c
7h
e
M
O
Cl
NH2
N
NH2
N
C
N
C
N
e
M
9
t
E
CO2
e
M
CO2
t
E
e
M
CO2
CO2
N
N
Cl
Cl
7i
7d
e
e
M
M
NH2
N
NH2
N
N
N
C
C
e
M
e
M
5
10
e
M
t
E
CO2
CO2
t
E
e
M
CO2
CO2
Cl
N
N
Cl
7e
7j
a
Isolated yields
(5), 321 (6), 393 (10), 275 (20), 229 (7), 162 (4), 152 (7),
128 (6), 111 (7), 93 (13 %). Anal. Calcd for C29H27Cl2N3O6
(583.13): C, 59.60; H, 4.66; N, 7.19 %. Found: C, 59.56; H,
4.66; N, 7.20 %.
Triethyl 6‑amino‑4‑(2‑chloro‑6‑methylquinoline‑3‑yl)‑1‑
(3,4‑dimethylphenyl)‑1,4‑dihydropyridine‑2,3,5‑tricar‑
boxylate (7s) Pale yellow solid, mp 194–196 °C, yield:
0.54 g (91 %). IR (KBr) (νmax, cm−1) 3,360 (NH), 3,290
1 3

J IRAN CHEM SOC
Scheme 3 Synthesis of
quinoline-based DHPs 7k–t
O
R1
O
R3
NH2
N
C
t
E
t
O2C
O
E
N
Cl
N
R4
t
t
H
O
E N E
,
3
a-
3 b
4b
R1
R5
CO2
+
R5
CO2
R4
R3
RT
10
h
,
R5
CO2
N
Cl
R5
O2C
NH2
a-
5 d
a-
6 b
-t
7k
Table 2 Structure of quinoline-based DHPs 7k–t from reactions of ethyl cyanoacetate
Entry
Product structure
Yield (%)
Entry
Product structure
NH2
Yield (%)a
e
M
NH2
O2C
N
t
E
O2C
e
N
M
t
E
11
91
16
85
t
E
CO2
e
M
CO2
t
E
CO2
Cl
N
e
M
CO2
Cl
N
7p
7k
e
e
M
O
M
NH2
N
NH2
N
t
E
t
E O2C
O2C
N
e
M
12
13
14
85
88
86
17
18
19
20
92
87
91
87
e
t
M
E
CO2
CO2
e
M
t
E
CO2
CO2
Cl
7q
N
Cl
7l
Cl
Cl
NH2
NH2
t
E
t
E
O2C
O2C
N
N
N
e
t
E
M
CO2
CO2
e
M
CO2
t
E
CO2
N
Cl
7m
Cl
7r
e
M
NH2
N
NH2
N
t
E
O2C
N
t
E
O2C
N
e
M
e
M
e
M
e
M
CO2
t
E
CO2
e
M
CO2
Cl
t
E
CO2
Cl
7s
7n
e
M
Cl
NH2
NH2
N
t
E
t
E
O2C
N
C
O2
N
N
e
M
e
M
15
89
e
M
t
E
CO2
CO2
t
e
M
CO2
E
CO2
Cl
Cl
7o
7t
a
Isolated yields
1
(NH), 1,745 (C=O), 1,703 (C=O), 1,656 (C=O); H-
NMR (300 MHz, CDCl3): δH = 0.94 (t, 3H, J = 7.1 Hz,
OCH2Me), 1.12 (t, 6H, J = 7.1 Hz, 2OCH2Me), 2.29 (s,
3H, Me), 2.30 (s, 3H, Me), 2.51 (s, 3H, Me), 3.84-4.06 (m,
6H, 3OCH2Me), 5.50 (s, 1H, CH), 6.40 (br s, 2H, NH2),
7.15-7.19 (m, 2H, Ar), 7.25 (d, 1H, J = 8.5 Hz, Ar), 7.48
1 3

J IRAN CHEM SOC
N
N
C
C
O
N
C
N
C
t
E 3N
H
N
H
+
NC
Michael
addition
N
Knoevenaegl
condensation
Cl
N
C
N
Cl
e
M
CO2
a
3
a
4
I1
e
M
CO2
N
Cl
e
M
CO2
e
e
M
CO2
CO2
I3
+
NH2
N
M
enamine
H2
formation
e
M
CO2
a
5
a
6
I2
NH2
NH
N
N
N
C
C
N
C
N
N
HN
e
M
CO2
e
M
CO2
e
M
CO2
e
M
e
M
CO2
e
M
CO2
CO2
N
N
N
Cl
Cl
I5
Cl
a
7
I4
Scheme 4 Proposed mechanism for the formation of DHP 7a
(d, 1H, J = 8.6 Hz, Ar), 7.55 (s, 1H, Ar), 7.87 (d, 1H,
J = 8.6 Hz, Ar), 8.14 (s, 1H, Ar); 13C NMR (75 MHz,
CDCl3): δC = 13.4 (OCH2Me), 14.1 (OCH2Me), 14.5
(OCH2Me), 19.6 (Me), 19.8 (Me), 21.6 (Me), 36.4 (CH),
59.3 (OCH2Me), 60.7 (OCH2Me), 61.6 (OCH2Me), 78.6
(C-5 of DHP), 105.5 (C-3 of DHP), 126.0, 127.6, 127.8,
127.9, 130.8, 131.5, 132.0, 132.5, 136.5, 138.4, 139.1,
139.3, 139.6, 142.4, 144.9, 149.8, 152.0 (C–Ar), 163.3
(C=O), 165.6 (C=O), 169.5 (C=O); EI-MS: m/z (%):
593 (1, M++2), 591 (3, M+), 518 (37), 415 (100), 400
(2), 387 (3), 341 (3), 315 (2), 297 (3), 269 (12), 251 (3),
223 (6), 140 (6), 105 (9 %). Anal. Calcd for C32H34ClN3O6
(591.21): C, 64.91; H, 5.79; N, 7.10 %. Found: C, 64.87; H,
5.82; N, 7.10 %.
(C-5 of DHP), 105.8 (C-3 of DHP), 126.0, 127.4, 127.7,
130.1 (2C), 132.2, 132.3 (2C), 133.6, 136.6, 136.7, 138.3,
139.8, 141.9, 144.9, 149.7, 151.5 (C–Ar), 163.2 (C=O),
165.4 (C=O), 169.4 (C=O); EI-MS: m/z (%): 602 (0.4,
M++4), 600 (3, M++2), 598 (5, M+), 524 (5), 421 (100),
388 (8), 349 (6), 303 (6), 275 (16), 237 (9), 178 (10), 140
(12), 111 (9 %). Anal. Calcd for C30H29Cl2N3O6 (597.14):
C, 60.21; H, 4.88; N, 7.02 %. Found: C, 60.63; H, 4.85; N,
6.97 %.
Results and discussion
Initially, 2-chloroquinoline-3-carbaldehydes 3a–c were pre-
pared using the traditional Vilsmeier–Haack cyclization of
acetanilides 2a–c (Scheme 1) [113, 114].
Subsequent four-component reactions employing 3a–c,
malononitrile 4a, various aromatic amines 5a–d and dialky-
lacetylenedicarboxylates 6a–b in the presence of triethyl-
amine in ethanol at ambient temperature afforded 7a–j in
moderate to excellent yields (Scheme 2; Table 1).
To demonstrate the versatility of these reactions, we
replaced malononitrile 4a with ethylcyanoacetate 4b in
order to test it in our new one-pot four-component method
(Scheme 3). As illustrated in Table 2, 7k–t were obtained in
moderate to good yields.
Triethyl 6‑amino‑4‑(2‑chloro‑6‑methylquinoline‑3‑yl)‑1‑
(4‑chlorophenyl)‑1,4‑dihydropyridine‑2,3,5‑tricarboxylate
(7t) Pale yellow solid, mp 185–187 °C, yield: 0.52 g
(87 %). IR (KBr) (νmax, cm−1)3,332 (NH), 3,182 (NH),
1
1,751 (C=O), 1,705 (C=O), 1,659 (C=O); H-NMR (300
MHZ, CDCl3): δH = 0.96 (t, 3H, J = 7.1 Hz, OCH2Me),
1.10 (t, 6H, J = 7.1 Hz, 2OCH2Me), 2.50 (s, 3H, Me), 3.85–
4.03 (m, 6H, 3OCH2Me), 5.47 (s, 1H, CH), 6.36 (br s, 2H,
NH2), 7.39 (d, 2H, J = 8.6 Hz, Ar), 7.46-7.49 (m, 3H, Ar),
7.54 (s, 1H, Ar), 7.86 (d, 1H, J = 8.6 Hz, Ar), 8.10 (s, 1H,
Ar); 13C NMR (75 MHz, CDCl3): δC = 13.4 (OCH2Me),
14.0 (OCH2Me), 14.4 (OCH2Me), 21.6 (Me), 36.6 (CH),
59.5 (OCH2Me), 60.9 (OCH2Me), 61.9 (OCH2Me), 78.7
The structure of compounds 7a–t was confirmed by
their analytical and spectral data. The mass spectra of 5a
1 3

J IRAN CHEM SOC
displayed the molecular ion peak at 474 for M+ ([35Cl])
and 476 for M+ ([37Cl]) consistent with the molecular
structure. The IR spectrum of 7a displayed characteristic
absorption bands at 3,449 and 3,281, 2,171, 1,747, and
1,711 cm−1 due to NH2, CN and CO2Me groups stretch-
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1
ing vibrations, respectively. The H NMR spectrum of 7a
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The presence of two C=O groups was further confirmed by
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the appearance of two signals δ 162.6 and 164.7 in the 13
C
NMR spectrum of 7a. The 1H NMR and 13C NMR spectra
of 7b–t were similar to that of 7a.
Although the precise mechanism is not known, a mecha-
nistic postulate as shown in Scheme 4 may be invoked to
rationalize the formation of 7a. It is conceivable that the
zwitterionic intermediate I2, formed by the 1:1 interaction
between the amine 5a and acetylenedicarboxylate (DMAD)
6a attacks the Knoevenagel adduct I1 obtained from con-
densation of the aldehyde 3a with malononitrile 4a, leading
to 1,5-dipolar intermediate I3. The subsequently generated
I4 is transformed into I5 and finally 7a presumably upon
ring closure and tautomerization processes, respectively
(Scheme 4).
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Conclusion
In conclusion, we have developed a novel, basic domino
four-component reactions employing 2-chloroquinoline-
3-carbaldehydes, malononitrile or ethyl cyanoacetate, vari-
ous aromatic amines and dialkylacetylenedicarboxylates
in ethanol at ambient temperature. A variety of quinolinyl
1,4-dihydropyridines were synthesized in a facile and effi-
cient method in moderate to excellent yields. These new
structures broaden the scaffolds that are accessible through
Knoevenagel condensation and enamine formation fol-
lowed by Michael addition and intramolecular cyclization
tandem sequences and many of them may represent inter-
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