Efficient access to pyrido[1,2-a]pyrimidines and imidazo[1,2-a]pyridines through Knoevenagel reaction/aza–ene addition/intramolecular cyclization

Article abstract of DOI:10.1007/s13738-019-01845-6

Abstract: An expeditious metal-free heteroannulation reaction for pyrido[1,2-a]pyrimidines/imidazo[1,2-a]pyridines was developed in green solvent under mild reaction conditions by using three-component reaction of 2-chloroquinoline-3-carbaldehyde, malononitrile and nitroketen aminals, which obtained from the reaction between 1,1-bis(methylthio)-2-nitroethylene and diamines in green solvent under EtOH reflux conditions. This one-pot strategy is very simple and occurs in two steps. The present sequence is visualized as an environmentally benign process with excellent purity and high yields. Graphic abstract: An efficient, useful and general procedure for the synthesis of pyrido[1,2-a]pyrimidines/imidazo[1,2-a]pyridines via a one-pot three-component reaction of 2-chloroquinoline-3-carbaldehyde, malononitrile/ethyl 2-cyanoacetate and nitroketen aminals under mild and catalyst-free conditions in excellent yields is described. The major advantages of this protocol are high yields, mild and catalyst-free conditions, short reaction times and application of green solvent.[Figure not available: see fulltext.].

Full text of DOI:10.1007/s13738-019-01845-6

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-019-01845-6
ORIGINAL PAPER
Efcient access to pyrido[1,2‑a]pyrimidines and imidazo[1,2‑a]
pyridines through Knoevenagel reaction/aza–ene addition/
intramolecular cyclization
Abdolali Alizadeh1 · Atefeh Roosta · Reza Rezaiyehraad
1
1
Received: 20 October 2019 / Accepted: 24 December 2019
©
Iranian Chemical Society 2020
Abstract
An expeditious metal-free heteroannulation reaction for pyrido[1,2-a]pyrimidines/imidazo[1,2-a]pyridines was developed
in green solvent under mild reaction conditions by using three-component reaction of 2-chloroquinoline-3-carbaldehyde,
malononitrile and nitroketen aminals, which obtained from the reaction between 1,1-bis(methylthio)-2-nitroethylene and
diamines in green solvent under EtOH reꢀux conditions. This one-pot strategy is very simple and occurs in two steps. The
present sequence is visualized as an environmentally benign process with excellent purity and high yields.
Graphic abstract
An eꢁcient, useful and general procedure for the synthesis of pyrido[1,2-a]pyrimidines/imidazo[1,2-a]pyridines via a
one-pot three-component reaction of 2-chloroquinoline-3-carbaldehyde, malononitrile/ethyl 2-cyanoacetate and nitroketen
aminals under mild and catalyst-free conditions in excellent yields is described. The major advantages of this protocol are
high yields, mild and catalyst-free conditions, short reaction times and application of green solvent.
Keywords 2-Chloroquinoline-3-carbaldehyde · Malononitrile · 1,1-bis(methylthio)-2-nitroethylene · Imidazo[1,2-a]
pyridines · Pyrido[1,2-a]pyrimidines
Electronic supplementary material The online version of this
Introduction
article (https://doi.org/10.1007/s13738-019-01845-6) contains
supplementary material, which is available to authorized users.
Synthesis of bridgehead nitrogen fused heterocyclic com-
*
Abdolali Alizadeh
pounds [1–3] is important as they have a lead role in medici-
nal chemistry due to their wide range of pharmacological
activities. Among bridgehead nitrogen fused heterocycles,
pyrido[1,2-a]pyrimidines and imidazo[1,2-a]pyridines are
aalizadeh@modares.ac.ir; abdol_alizad@yahoo.com
1
Department of Chemistry, Tarbiat Modares University, P.O.
Box 14115-175, Tehran, Iran
Vol.:(0
1
123456789)
3

Journal of the Iranian Chemical Society
prevalent heterocycles in the medicinal chemistry [4–8].
Imidazo[1,2-a]pyridine scaꢂold exhibits a remarkably wide
range of biological activities, such as antitumoral [5, 6, 9,
containing quinoline ring system through multi-component
reactions [37–40], we carried out the synthesis of these
molecules via MCRs of 2-chloroquinoline-3-carbaldehyde,
malononitrile, 1,1-bis(methylthio)-2-nitroethylene and
diamines in the presence of piperidine and EtOH as solvent
(Scheme 1). The present methodology for the synthesis of
these compounds oꢂered several advantages such as simple
procedure, using EtOH as a green and eco-friendly solvent,
excellent yields, no need to the puriꢃcation of the products
and broad substrate scope.
1
0], anti-inꢀammatory [11, 12], antiviral [13–16], antiul-
cer [4], antiprotozoal [17–19], antifungal [20], inhibitors of
cyclin-dependent kinase [7, 21, 22], inhibitors of gastric acid
secretion [23] and so on.
Also, pyridopyrimidine scaꢂolds are associated with a
broad spectrum of biological properties such as antiallergic,
antipsychotic, analgesic and antiasthmatic [24].
On the other hand, quinoline-based molecules are a sig-
niꢃcant class of N-heterocyclic products which display a
library of bioactivities including bactericidal [25], anti-
inꢀammatory [26], antitumor [27], anti-HIV [28], analgesic
Experimental section
[
29], anticancer [30] and antihypertensive [31]. When these
Melting points measured on an Electrothermal 9100 appa-
ratus. IR spectra were recorded as KBr pellets on a NICO-
LET FT-IR 100 spectrometer. Nuclear magnetic resonance
units are fused into a single molecule, the potential activity
of the created molecule is predicted to be increased. Tra-
ditional syntheses of polycyclic products bearing nitrogen
atoms are time-consuming and expensive. Their syntheses
produce a lot of waste, as well. This is a crucial diꢁculty
for the expansion of this library of biologically active prod-
ucts. Therefore, there is a need to develop new, sustainable
and eꢁcient synthetic routes for the preparation of such
compounds. To address this, polycyclic organic compounds
have been constructed through one-pot multi-component
reactions.
1
13
spectra ( H, C) were recorded on 300 MHz NMR spec-
trometers. All NMR spectra at room temperature were deter-
mined in DMSO-d . Chemical shifts are reported in parts
6
per million (δ) downꢃeld from an internal tetramethylsilane
reference. Coupling constants (J values) are reported in hertz
(Hz), and spin multiplicities are indicated by the following
symbols: s (singlet), bs (broad singlet), d (doublet), t (tri-
plet), q (quartet), m (multiplet). Elemental analyses for C, H
and N performed using a Heraeus CHN–O–Rapid analyzer.
Mass spectra were recorded on a FINNIGAN-MATT 8430
mass spectrometer operating at an ionization potential of
70 eV. All chemicals were purchased from Merck or Aldrich
and were used without further puriꢃcation.
Multi-component reactions (MCRs) [32, 33] are the most
inꢀuential and powerful chemical tools for accessing new
complex products and have been widely used for the drug
discovery process [34–36].
In this context, the goal of the present study includes the
synthesis of highly functionalized pyrido[1,2-a]pyrimidines
and imidazo[1,2-a]pyridines containing quinoline moiety.
Continuing our studies directed toward the eꢁcient and
straightforward synthesis of biologically active molecules
General Procedure for the Synthesis of Compound
4a–g 2-Chloroquinoline-3-carbaldehyde (1 mmol), malo-
nonitrile or ethyl 2-cyanoacetate (1 mmol) and piperidine
(1 drop: 0.0093 g, 0.109 mmol, 11 mol%) were stirred in
Scheme 1 Synthesis of pyrido[1,2-a]pyrimidines and imidazo[1,2-a]pyridines 4
1
3

Journal of the Iranian Chemical Society
3
ethanol at room temperature for 1 h to obtain Knoevenagel
condensation compounds containing quinoline scaꢂold.
Simultaneously, in another pot, nitroketen aminals were pre-
pared through the reaction of aliphatic diamines (1 mmol)
and 1,1-bis(methylthio)-2-nitroethylene (1 mmol) at reꢀux
conditions for 3 h. After completion of the reactions (mon-
itored by TLC), the solutions were mixed and stirred for
NMR (300.13 MHz, DMSO-d ): 1.45 (3H, t, J =6.3 Hz,
6
HH
3
CH ), 2.96 (2H, t, J = 8.1 Hz, CH NH), 3.78 (2H, t,
3
HH
2
3
3
J
=8.4 Hz, CH N), 3.90 (2H, q, J =6.3 Hz, CH O),
HH
2 HH 2
3
6
5.30 (1H, s, CH), 7.55 (1H, t, J = 6.9 Hz, CH of qui-
HH
3
7
noline), 7.71 (1H, t, J = 6.2 Hz, CH of quinoline),
HH
3
5
7.89 (1H, d, J = 7.9 Hz, CH of quinoline), 7.97 (1H,
HH
3
8
4
d, J = 7.2 Hz, CH of quinoline), 8.24 (1H, s, CH of
HH
1
3
2–3 h to achieve pyrido[1,2-a]pyrimidines or imidazo[1,2-a]
quinoline), 8.31 (1H, s, NH), 8.74 (1H, bs, NH ). C NMR
2
pyridines 4 depending on the diamine used for the reaction.
(75.46 MHz, DMSO-d ): 14.3 (CH ), 40.6 (CH), 43.1
6
3
(
CH NH), 43.3 (CH N), 58.4 (CH O), 77.0 (C-CO Et),
2 2 2 2
4
a
6
5
‑Amino‑7‑(2‑chloroquinolin‑3‑yl)‑8‑nitro‑1,2,3,7‑tet‑
105.8 (C–NO ), 126.9 (C of quinoline), 127.3 (C of qui-
2
5
7
rahydroimidazo[1,2‑a]pyridine‑6‑carbonitrile (4a) Yel-
noline), 127.5 (C of quinoline), 127.6 (C of quinoline),
8
4
3
low powder, dec. = 280–282 °C, 0.33 g, yield: 90%. IR
129.9 (C of quinoline), 130.0 (C of quinoline), 137.0 (C
−
1
8a
(
KBr) (ν , cm ): 3338 and 3189(NH ), 2186 (CN),
of quinoline), 145.7 (C–NH ), 150.0 (C of quinoline),
max
2
2
2
1
650 and 1466 (Ar), 1590 and 1336 (NO ). Anal. calcd.
151.7 (C of quinoline), 153.9 (N–C–NH), 160.2 (C=O).
2
for C H ClN O (368.78): C, 55.37; H, 3.55; N, 22.79%.
1
7
13
6
2
Found C, 55.34; H, 3.59; N, 22.77%. MS (EI, 70 eV): m/z
6‑Amino‑8‑(2‑chloroquinolin‑3‑yl)‑9‑nitro‑1,3,4,8‑tet‑
rahydro‑2H‑pyrido[1,2‑a]pyrimidine‑7‑carbonitrile
(4c) Yellow powder, dec.=267 °C, 0.34 g, yield: 88%. IR
+
+
+
(
(
(
%): 367.9 (M -1, 2), 367.1 (M -2, 1), 366 (M -3, 3), 331
31), 330 (11), 260 (21), 230 (12), 218 (10), 204 (15), 203
13), 202 (11), 189 (12), 180 (13), 179 (10), 177.9 (14),
−1
(KBr) (ν , cm ): 3398 and 3350 (NH ), 2178 (CN), 1660,
max
2
1
77.1 (35), 165 (17), 164 (11), 159 (25), 157.8 (13), 153
1629 and 1494 (Ar), 1500 and 1441 (NO ). Anal. calcd.
2
(
18), 152 (18), 150.9 (13), 150 (14), 139.9 (15), 139 (12),
for C H ClN O (382.80): C, 56.48; H, 3.95; N, 21.95%.
1
8
15
6
2
1
1
9
32 (17), 130 (21), 129 (13), 127 (13), 115 (10), 103.9 (16),
03 (15), 102 (19), 101 (12), 97 (16), 96 (100), 95 (15),
1 (15), 89 (11), 85 (12), 83 (12), 81 (12), 77.9 (14), 77
Found C, 56.40; H, 3.99; N, 21.99%. MS (EI, 70 eV): m/z
+
+
+
(%): 382 (M , 3), 381 (M -1, 4), 380 (M -2, 23), 346 (22),
345 (100), 305 (11), 300 (11), 280 (20), 260 (12), 239 (13),
(
25), 71 (15), 70 (18), 69 (48), 68 (26), 67 (14), 66 (17),
235 (11), 220 (14), 204 (18), 177 (21), 110 (10), 66 (25).
1
6
5
3 (15), 60 (12), 57 (30), 56 (15), 55 (36), 54 (20), 53 (13),
H NMR (300.13 MHz, DMSO-d ): 2.05–2.12 (2H, m,
6
1
1.9 (14), 51 (13). H NMR (300.13 MHz, DMSO-d ): 3.86
CH ), 3.63–3.86 (4H, m, CH –N and CH NH), 5.27 (1H,
6
2
2
2
3
3
3
6
(
2H, t, J =8.1 Hz, CH NH), 4.06 (2H, t, J =8.4 Hz,
s, CH), 6.52 (2H, s, NH ), 7.61 (1H, t, J =7.8 Hz, CH
HH
2
HH
2 HH
3
7
CH N), 5.25 (1H, s, CH), 6.62 (2H, s, NH ), 7.61 (1H, t,
of quinoline), 7.76 (1H, t, J =7.0 Hz, CH of quinoline),
HH
2
2
3
6
3
3
5
J
=7.5 Hz, CH of quinoline), 7.76 (1H, t, J =7.2 Hz,
7.92 (1H, d, J =8.4 Hz, CH of quinoline), 8.02 (1H, d,
HH
HH
HH
7
3
5
3
8
4
CH of quinoline), 7.90 (1H, d, J =8.3 Hz, CH of qui-
J
=7.9 Hz, CH of quinoline), 8.25 (1H, s, CH of quino-
HH
HH
3
8
13
noline), 8.01 (1H, d, J =8.0 Hz, CH of quinoline), 8.36
line), 11.71 (1H, s, NH). C NMR (75.46 MHz, DMSO-d ):
HH
6
4
13
(
(
(
(
1H, s, CH of quinoline), 9.62 (1H, s, NH). C NMR
19.5 (CH ), 38.1 (CH), 38.4 (CH NH), 43.2 (CH N), 56.1
2
2
2
4
a
75.46 MHz, DMSO-d ): 40.0 (CH), 43.4 (CH –NH), 44.6
(C–CN), 107.1 (C–NO ), 120.2 (CN), 127.2 (C of quino-
6
2
2
6
5
CH –N), 57.0 (C–CN), 104.9 (C–NO ), 120.4 (CN), 127.2
line), 127.3 (C of quinoline), 127.4 (C of quinoline), 127.8
2
2
4
a
6
5
7
8
4
C
of quinoline and C of quinoline), 127.4 (C of quino-
(C of quinoline), 130.5 (C of quinoline), 135.8 (C of qui-
7
8
3
8a
line), 127.4 (C of quinoline), 127.6 (C of quinoline), 130.4
noline), 137.7 (C of quinoline), 145.9 (C–NH ), 149.3 (C
2
4
3
2
(
C of quinoline), 134.5 (C of quinoline), 145.9 (C–NH ),
of quinoline), 150.7 (C of quinoline), 151.4 (N–C–NH).
2
8
a
2
1
49.4 (C of quinoline), 149.8 (C of quinoline), 151.8
(
NH–C–N).
Ethyl 6‑amino‑8‑(2‑chloroquinolin‑3‑yl)‑9‑ni‑
tro‑1,3,4,8‑tetrahydro‑2H‑pyrido[1,2‑a]pyrimi‑
dine‑7‑carbonitrile (4d) Yellow powder, dec. =288 °C,
Ethyl 5‑amino‑7‑(2‑chloroquinolin‑3‑yl)‑8‑ni‑
tro‑1,2,3,7‑tetrahydroimidazo[1,2‑a]pyridine‑6‑car‑
boxylate (4b) Dark yellow powder, dec. = 198–200 °C,
−
1
0.39 g, yield: 90%. IR (KBr) (ν , cm ): 3356 (NH ),
max
2
1668 (C=O), 1641 and 1481 (Ar), 1562 and 1347 (NO ).
2
−
1
0
1
.37 g, yield: 90%. IR (KBr) (ν , cm ): 3424 (NH ),
Anal. calcd. for C H ClN O (429.86): C, 55.88; H, 4.69;
max
2
20 20
5
4
633 (C=O), 1574 and 1351 (NO ), 1412 (Ar), 1276 (C–N).
N, 16.29%. Found C, 55.89; H, 4.67; N, 16.27%. MS (EI,
2
+
+
+
Anal. calcd. for C H ClN O (415.83): C, 54.88; H, 4.36;
70 eV): m/z (%): 431 (M +2, 19), 430 (M +1, 13), 429 (M ,
53), 412 (10), 401 (16), 400 (11), 399 (46), 385 (28), 384
(50), 383 (81), 382 (83), 381 (14), 376 (22), 347 (12), 340
(16), 339 (33), 338 (45), 337 (74), 320 (8), 319 (22), 311
(11), 310 (17), 309 (13), 304 (23), 302 (15), 301 (45), 291
(26), 275 (26), 274 (14), 273 (28), 267 (37), 247 (13), 245
1
9
18
5
4
N, 16.84%. Found C, 54.81; H, 4.39; N, 16.88%. MS (EI,
+
7
3
0 eV): m/z (%): 413 (M -2, 1), 382 (3), 368 (3), 341 (11),
13 (10), 85 (69), 84.15 (91), 84 (17), 83 (42), 82 (10), 81
(
(
12), 73 (10), 71 (17), 70 (22), 69 (24), 64 (35), 63 (12), 62
1
100), 61 (10), 58 (29), 57 (78), 56 (80), 55 (24), 51 (12). H
1
3

Journal of the Iranian Chemical Society
(
(
(
12), 223 (20), 221 (53), 220 (31), 218 (11), 193 (16), 192
6‑Amino‑8‑(2‑chloro‑6‑methylquinolin‑3‑yl)‑3,3‑di‑
methyl‑9‑nitro‑1,3,4,8‑tetrahydro‑2H‑pyrido[1,2‑a]
pyrimidine‑7‑carbonitrile (4f ) Yellow. powder,
11), 185 (100), 179 (18), 178 (11), 177 (17), 166 (17), 152
1
13), 151 (12), 120 (11). H NMR (300.13 MHz, DMSO-d ):
6
3
−1
1
2
3
.02 (3H, t, J =7.0 Hz, CH ), 1.90–2.00 (1H, m, CH ),
dec. = 258 °C, 0.37 g, yield: 88%. IR (KBr) (ν , cm ):
HH
3
2
max
.12–2.23 (1H, m, CH ), 3.33–3.40 (1H, m, CH NH), 3.50–
3398 and 3328 (NH ), 3203 (NH), 2184 (CN), 1659 and
2
2
2
.70 (1H, m, CH NH), 3.70–3.90 (2H, m, CH –N), 3.91 (2H,
1627 (Ar), 1492 and 1344 (NO ), 1111 (C–N). Anal. calcd.
2
2
2
3
q, J =7.0 Hz, OCH CH ), 5.44 (1H, s, CH), 7.59 (1H, t,
for C H ClN O (424.88): C, 59.36; H, 4.98; N, 19.78%.
HH
2
3
21 21
6
2
3
6
3
J
=7.1 Hz, CH of quinoline), 7.72 (1H, t, J =7.8 Hz,
Found C, 59.39; H, 4.97; N, 19.76%. MS (EI, 70 eV): m/z
HH
HH
7
3
5
+
+
CH of quinoline), 7.90 (1H, d, J =8.5 Hz, CH of qui-
(%): 424 (M , 8), 422 (M -2, 7), 389 (13), 388 (27), 387
(100), 380 (12), 379 (17), 378 (41), 377 (39), 373 (12), 372
(41), 371 (24), 364 (19), 363 (13), 362 (60), 361 (38), 357
(18), 356 (21), 343 (12), 342 (22), 334 (15), 332 (8), 331
(31), 326 (12), 321 (26), 319 (12), 303 (12), 302 (27), 301
(14), 300 (21), 286 (17), 276 (6), 274 (34), 273 (29), 259
(26), 258 (19), 257 (16), 248 (26), 244 (15), 232 (14), 231
(18), 230 (29), 229 (11), 228 (12), 217 (14), 204 (12), 203
HH
3
8
noline), 7.94 (2H, s, NH ), 8.04 (1H, d, J =7.6 Hz, CH
2
HH
4
of quinoline), 8.30 (1H, s, CH of quinoline), 11.78 (1H, s,
1
3
NH). C NMR (75.46 MHz, DMSO-d ): 14.3 (CH ), 19.7
6
3
(
(
CH ), 37.9 (CH), 38.1 (CH –NH), 42.9 (CH –N), 58.8
2 2 2
4
a
OCH -CH ), 77.0 (C–C=O), 108.0 (C–NO ), 126.7 (C of
2
3
2
6
5
quinoline), 126.9 (C of quinoline), 127.2 (C of quinoline),
7
8
4
1
27.7 (C of quinoline), 130.1 (C of quinoline), 135.3 (C
3
of quinoline), 141.2 (C of quinoline), 145.5 (C–NH ), 149.4
(16), 202 (24), 201 (13), 191 (19), 189 (14), 176 (15), 164
2
8
a
2
1
(
C
of quinoline), 150.6 (C of quinoline), 152.8 (N–C–
(21), 146 (19), 138 (35). H NMR (300.13 MHz, DMSO-d ):
6
NH), 168.2 (C=O).
1.07 (3H, s, Me), 1.11 (3H, s, Me), 2.47 (3H, s, Me), 3.30
2
(
2H, AB quartet, J = 12.7 Hz, CH NH), 3.57 (2H, AB
HH
2
2
6
‑Amino‑8‑(2‑chloroquinolin‑3‑yl)‑3,3‑dimethyl‑9‑ni‑
quartet, J =11.8 Hz, CH N), 5.23 (1H, s, CH), 6.52 (2H,
HH 2
3
7
tro‑1,3,4,8‑tetrahydro‑2H‑pyrido[1,2‑a]pyrimi‑
dine‑7‑carbonitrile (4e) Yellow powder, dec. = 234 °C,
s, NH ), 7.60 (1H, d, J =8.0 Hz, CH of quinoline), 7.70
2 HH
5
3
8
(1H, s, CH of quinoline), 7.80 (1H, d, J =8.2 Hz, CH
HH
−
1
4
0
.36 g, yield: 89%. IR (KBr) (ν , cm ): 3422 and 3347
of quinoline), 8.06 (1H, s, CH of quinoline), 11.70 (1H, s,
max
1
3
(
NH ), 2180 (CN), 1661, 1626 and 1499 (Ar), 1590 and
NH). C NMR (75.46 MHz, DMSO-d ): 21.0 (Me), 23.1
2
6
1
5
2
2
1
1
1
341 (NO ). Anal. calcd. for C H ClN O (410.86): C,
(Me), 23.7 (Me), 27.1 (CMe ), 38.4 (CH), 49.1 (CH N),
2
20 19
6
2
2
2
8.47; H, 4.66; N, 20.45%. Found C, 58.45; H, 4.63; N,
52.8 (CH NH), 59.0 (C–CN), 106.9 (C–NO ), 120.2 (CN),
2
2
+
+
5
4a
7
0.49%. MS (EI, 70 eV): m/z (%): 410 (M , 2), 409 (M -1,
126.2 (C of quinoline), 127.1 (C of quinoline and C of
+
8
4
), 408 (M -2, 5), 373 (20), 204 (14), 200 (14), 189 (16),
quinoline), 132.6 (C of quinoline), 135.3 (C of quinoline),
6
3
79 (10), 178 (11), 177 (26), 176 (11), 165 (12), 153 (12),
52 (16), 151 (11), 150 (14), 140 (14), 139 (10), 138 (20),
27 (10), 105 (13), 102 (13), 101 (13), 99 (10), 97 (12), 95
136.9 (C of quinoline), 137.1 (C of quinoline), 144.5 (C–
8
a
2
NH ), 148.2 (C of quinoline), 149.8 (C of quinoline),
2
151.3 (N–C–NH).
(
(
(
11), 89 (11), 85 (11), 84 (30), 83 (14), 82 (12), 81 (13), 77
33), 76 (18), 75 (18), 74 (10), 71 (15), 70 (17), 69 (50), 68
19), 67 (22), 66 (68), 65 (16), 64 (14), 63 (21), 62 (12), 57
42), 56 (50), 55 (100), 54 (18), 53 (32), 52 (16), 51 (27).
H NMR (300.13 MHz, DMSO-d ): 1.07 (3H, s, CH ), 1.11
Ethyl 6‑amino‑8‑(2‑chloroquinolin‑3‑yl)‑3,3‑dime‑
thyl‑9‑nitro‑1,3,4,8‑tetrahydro‑2H‑pyrido[1,2‑a]pyrim‑
idine‑7‑carboxylate (4g) Yellow powder, dec.=268 °C,
(
1
−1
0.41 g, yield: 90%. IR (KBr) (ν , cm ): 3366 (NH ),
6
3
max
2
2
(
3H, s, CH ), 3.30 (2H, AB quartet, J =12.7 Hz, CH –
1646 (C=O), 1600 and 1478 (Ar), 1559 and 1342 (NO ).
3
HH
2
2
2
NH), 3.57 (2H, AB quartet, J = 12.2 Hz, CH N), 5.26
Anal. calcd. for C H ClN O (457.91): C, 57.70; H, 5.28;
HH
2
22 24
5
4
3
(
1H, s, CH), 6.53 (2H, s, NH ), 7.62 (1H, t, J =7.4 Hz,
N, 15.29%. Found C, 57.78; H, 5.24; N, 15.25%. MS (EI,
2
HH
6
3
7
+
CH of quinoline), 7.77 (1H, t, J =7.1 Hz, CH of qui-
70 eV): m/z (%): 457 (M , 8), 411 (15), 374 (13), 366 (10),
HH
3
5
noline), 7.92 (1H, d, J =8.5 Hz, CH of quinoline), 7.95
365 (12), 319 (19), 309 (10), 308 (13), 291 (12), 286 (9),
280 (12), 263 (12), 249 (11), 248 (17), 247 (11), 224 (17),
223 (100), 195 (17), 194 (6), 193 (12), 180 (11), 179 (16),
HH
3
8
4
(
1H, d, J =8.0 Hz, CH of quinoline), 8.19 (1H, s, CH
HH
1
3
of quinoline), 11.72 (1H, s, NH). C NMR (75.46 MHz,
DMSO-d ): 23.1 (CH ), 23.7 (CH ), 27.1 (CMe ), 38.5
177 (24), 166 (11), 152 (22), 151 (10), 125 (14), 68 (13),
6
3
3
2
1
(
(
CH), 49.1 (CH NH), 52.9 (CH N), 58.9 (C–CN), 106.9
55 (12). H NMR (300.13 MHz, DMSO-d ): 1.00 (3H, t,
2
2
6
4
a
6
3
C–NO ), 120.2 (CN), 127.1 (C of quinoline), 127.3 (C
J
=6.3 Hz, CH CH ), 1.12 (6H, s, 2Me), 3.30 (2H, AB
2
HH
3
2
5
7
2
of quinoline), 127.4 (C of quinoline), 127.6 (C of quino-
quartet, J = 12.7 Hz, CH –NH), 3.62 (2H, AB quartet,
HH 2
8
4
2
3
line), 130.5 (C of quinoline), 135.4 (C of quinoline), 137.9
J
=11.8 Hz, CH N), 3.90 (2H, q, J =6.3 Hz, CH O),
HH 2 HH 2
3
8a
3
6
(
C of quinoline), 145.9 (C–NH ), 149.1 (C of quinoline),
5.47 (1H, s, CH), 7.59 (1H, t, J =6.9 Hz, CH of quino-
2
HH
2
3
7
1
49.8 (C of quinoline), 151.3 (N–C–NH).
line), 7.72 (1H, t, J = 6.2 Hz, CH of quinoline), 7.86
HH
3
5
(
1H, d, J = 7.9 Hz, CH of quinoline), 7.96 (1H, d,
HH
3
8
J
= 7.2 Hz, CH of quinoline), 7.97 (2H, s, NH ), 8.24
HH
2
1
3

Journal of the Iranian Chemical Society
Table 1 Diversity of the
products of the reaction
1
2
a
Entry
1, R
2, R
nitro ketene aminal 3
Product 4
Yield (%)
1
1a, H
1a, H
1a, H
1a, H
1a, H
1b, Me
1a, H
2a, CN
3a
90
2
3
4
5
6
7
2
2b, CO Et
3a
3b
3b
3c
3c
3c
90
88
90
89
88
90
2a, CN
2
2b, CO Et
2a, CN
2a, CN
2
2b, CO Et
2
-Chloroquinoline-3-carbaldehyde (1 mmol), malononitrile or ethyl 2-cyanoacetate (1 mmol) and piperi-
dine (1 drop: 0.0093 g, 0.109 mmol, 11 mol%) were stirred in ethanol at room temperature for 1 h to
obtain Knoevenagel condensation compounds containing quinoline scaꢂold. Nitroketen aminals 3 were
prepared through the reaction of aliphatic diamines (1 mmol) and 1,1-bis(methylthio)-2-nitroethylene
(
1 mmol) at EtOH reꢀux conditions for 3 h. The solutions were mixed and stirred for 2–3 h to achieve
product 4
a
Isolated yield
1
3

Journal of the Iranian Chemical Society
Scheme 2 A plausible mechanism for the synthesis of pyrido[1,2-a]pyrimidines 4c
4
13
(
1H, s, CH of quinoline), 11.75 (1H, s, NH). C NMR
scaꢂold 5. Simultaneously, nitroketen aminals 3 were pre-
pared through the reaction of aliphatic diamines 6 and
1,1-bis(methylthio)-2-nitroethylene at reꢀux conditions for
3 h. After completion of the reactions (monitored by TLC),
the solutions were mixed and stirred for 2–3 h to achieve
pyrido[1,2-a]pyrimidines or imidazo[1,2-a]pyridines 4
depending on the diamine used for the reaction (Scheme 1).
Then, the precipitated products were separated by simple
ꢃltration and washed with ethanol. The pure products were
achieved as yellow solids in excellent yields.
(
75.46 MHz, DMSO-d ): 14.2 (CH CH O), 22.9 (Me), 24.1
6
3
2
(
Me), 27.3 (CMe ), 37.7 (CH), 48.7 (CH NH), 52.7 (CH N),
2
2
2
6
5
8.8 (CH O), 77.4 (C-CO Et), 108.3 (C–NO ), 126.7 (CH
2 2 2
4
a
5
of quinoline), 127.0 (C of quinoline), 127.2 (CH of qui-
7
8
noline), 127.5 (CH of quinoline), 130.1 (CH of quinoline),
4
3
1
35.7 (C of quinoline), 140.7 (C of quinoline), 145.5 (C–
8
a
2
NH ), 149.4 (C of quinoline), 149.6 (C of quinoline),
2
1
52.9 (N–C–NH), 168.2 (C=O).
A variety of starting materials including 2-chloroquin-
oline-3-carbaldehydes, malononitrile/ethyl 2-cyanoacetate
and three kinds of diamines were tested (Table 1). Notably,
all the reactions proceeded cleanly under mild conditions to
produce the corresponding products in excellent yields and
no undesirable side products were detected. All the products
were easily isolated simply by ꢃltration and washing with
ethanol.
Results and discussion
Initially, Knoevenagel condensation compounds contain-
ing quinoline scaꢂold 5 and nitroketen aminals 3 were pre-
pared according to the literature [41, 42]. Brieꢀy, 2-chloro-
quinoline-3-carbaldehyde 1 and malononitrile 2a or ethyl
2
-cyanoacetate 2b in the presence of one drop piperidine
were stirred in ethanol at room temperature for 1 h to obtain
Knoevenagel condensation compounds containing quinoline
The chemical structures of the products 4a–g were
1
13
deduced from their IR, mass, H NMR, C NMR and
1
3

Journal of the Iranian Chemical Society
1
elemental analyses. For example, the H NMR spectrum
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