An efficient synthesis of new imidazo[1,2-: A] pyridine-6-carbohydrazide and pyrido[1,2- a] pyrimidine-7-carbohydrazide derivatives via a five-component cascade reaction

Article abstract of DOI:10.1039/c9ra00350a

A highly efficient and straightforward synthesis of N-fused heterocyclic compounds including N′-(1-(4-nitrophenyl)ethylidene)imidazo[1,2-a]pyridine-6-carbohydrazide and N′-(1-(4-nitrophenyl)ethylidene)pyrido[1,2-a]pyrimidine-7-carbohydrazide derivatives is successfully achieved via a five-component cascade reaction utilizing cyanoacetohydrazide, 4-nitroacetophenone, 1,1-bis(methylthio)-2-nitroethylene and various diamines in a mixture of water and ethanol. The new efficient domino protocol involving a sequence of N,N-acetal formation, Knoevenagel condensation, Michael reaction, imine-enamine tautomerization and N-cyclization as key steps. The merit of this catalyst free approach is highlighted by its easily available starting materials, operational simplicity, clean reaction profile, the use of environmentally benign solvents and tolerance of a wide variety of functional groups.

Full text of DOI:10.1039/c9ra00350a

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An efficient synthesis of new imidazo[1,2-a]
pyridine-6-carbohydrazide and pyrido[1,2-a]
pyrimidine-7-carbohydrazide derivatives via a five-
component cascade reaction†
Cite this: RSC Adv., 2019, 9, 7218
*
Hajar Hosseini
and Mohammad Bayat
A highly efficient and straightforward synthesis of N-fused heterocyclic compounds including N0-(1-(4-
nitrophenyl)ethylidene)imidazo[1,2-a]pyridine-6-carbohydrazide and N0-(1-(4-nitrophenyl)ethylidene)
pyrido[1,2-a]pyrimidine-7-carbohydrazide derivatives is successfully achieved via
a five-component
cascade reaction utilizing cyanoacetohydrazide, 4-nitroacetophenone, 1,1-bis(methylthio)-2-
nitroethylene and various diamines in a mixture of water and ethanol. The new efficient domino protocol
involving a sequence of N,N-acetal formation, Knoevenagel condensation, Michael reaction, imine–
enamine tautomerization and N-cyclization as key steps. The merit of this catalyst free approach is
highlighted by its easily available starting materials, operational simplicity, clean reaction profile, the use
of environmentally benign solvents and tolerance of a wide variety of functional groups.
Received 15th January 2019
Accepted 26th February 2019
DOI: 10.1039/c9ra00350a
rsc.li/rsc-advances
benets are highlights for multicomponent cascade reactions,
which involve in situ production of an intermediate with
a reactive site for subsequent transformations.26
Introduction
Imidazopyridines have displayed a broad spectrum of phar-
macological and biological activities.1 Among the diverse
derivatives of imidazopyridine, the imidazo[1,2-a]pyridine
skeleton is probably the most important structure due to its
vital role as a key construction in drugs and biologically active
compounds with properties such as anti-inammatory,2,3 anti-
viral,4–6 antifungal,7–9 anticancer,10 anxiolytic,11 anti-ulcer,12 and
antiprotozoal.13 They can be found in marketed drugs such as
the clinical anti-ulcer compound zolpidem and alpidem,14
olprinone,15 zolimidine,16 necopidem and saripidem17 (Fig. 1).
Pyridopyrimidine derivatives are also known as antidepres-
sant,18 gastrointestinal protective,19 neurotropic and stress-
protecting,20 and anticancer agents.21 pyrido[1,2-a]pyrimidine
constitutes the core structure of some marketed drugs,
including the antiasthmatic agent pemirolast,22 the tranquilizer
pirenperone,23 and the antiallergic agent ramastine24 (Fig. 1).
The design of reactions with minimized number of steps is
one of the purpose of modern synthesis. One approach to
achieve this goal includes the development of multicomponent
methods. Multicomponent reactions (MCRs) offer a wide range
of probabilities for the fast generation of functionalized mole-
cules in a single step with high atom economy, minimum time
and cost and straight forward experimental procedures.25 These
By now, various synthetic approaches have been reported to
synthesize imidazo[1,2-a]pyridines. The common reactions
were the cyclocondensations of 2-aminopyridines with a-hal-
ocarbonyl
compounds,27
1,3-dicarbonyl
compounds,28
Department of Chemistry, Faculty of Science, Imam Khomeini International University,
Qazvin, Iran. E-mail: bayat_mo@yahoo.com; m.bayat@sci.ikiu.ac.ir; Tel: +98 28
33780040
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra00350a
Fig. 1 Drugs containing the imidazo[1,2-a]pyridine and pyrido[1,2-a]
pyrimidine cores.
7218 | RSC Adv., 2019, 9, 7218–7227
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nitroolens or alkynes.29 Condensation of 2-aminopyridines,
aldehydes and isonitriles or alkynes in a one-pot process, was
also a convenient method for the synthesis of imidazo[1,2-a]
pyridines.30 Furthermore, over the past decade, a number of
methods have been described to synthesize pyrido[1,2-a]
pyrimidines by focusing on traditional two-component
condensation of 2-aminopyridines with a variety of bifunc-
tional electrophiles.31–33
In recent years some other new synthetic approaches have
been developed for the synthesis of tetrahydroimidazo[1,2-a]
pyridines and tetrahydro-1H-pyrido[1,2-a]pyrimidine using
heterocyclic ketene aminals (HKAs).34–38 Heterocyclic ketene
aminals (HKAs) are efficient synthons for the synthesis of
heterocyclic compounds. Reactions of cyclic ketene aminals
with a variety of bis-electrophilic compounds have so far been
applied to construct ve- and six-membered fused heterocyclic
structures.39
Optimization of the conditions
Initially, cyanoacetohydrazide 1, 4-nitroacetophenone 2, 4-
chlorobenzaldehyde 3, 1,1-bis(methylthio)-2-nitroethene 4 and
ethylenediamine 5 were used as model substrates to optimize
the reaction conditions.
The experimental results showed when ethanol was used as
solvent without any catalyst at reux conditions, the yield of
desired product was 60% (Table 1, entry 1). With piperidine as
catalyst, the reaction efficiency did not change signicantly
(entry 2). With p-TSA and acetic acid, the product did not form
(entry 3, 4). The use of water or acetonitrile instead of ethanol
did not result in the desired product (entry 5, 8), but when the
mixture of water and ethanol was used (overall 1 : 2, v/v), the
efficiency increased slightly (entry 6). By changing the ratio of
solvents (1 : 3, v/v) at reux conditions the ve-component
product 6c was obtained in a yield of 87% within 5 hours
(entry 7).
In the process of our efforts to synthesize the new hetero-
cyclic compounds using cyanoacetohydrazide, we report herein
an efficient one-pot ve-component synthesis of novel imidazo
With information obtained from optimization conditions
table, we used cyanoacetohydrazide 1, 4-nitroacetophenone 2,
various aromatic aldehydes 3, 1,1-bis(methylthio)-2-nitroethene
4 and diamines (ethylenediamine, 1,3-diaminopropane, 2,2-
[1,2-a]pyridine-6-carbohydrazides
and
1H-pyrido[1,2-a]
pyrimidine-7-carbohydrazides via in situ preparation of nitro-
ketene aminals. To the best of our knowledge, there is no report
on the synthesis of these structures.
dimethyl-1,3-diaminopropane)
5 as starting materials to
synthesize the target compounds 6a–q (Scheme 1).
The reactions were completed aer 4–7 h overall to afford
corresponding heterocyclic systems in good to high yields (73–
90%). The results are summarized in Table 2.
Results and discussion
We succeeded in synthesizing two categories of functionalized
N-fused heterocyclic structures containing tetrahydroimidazo
Effect of substituents
[1,2-a]pyridines-6-carbohydrazides and tetrahydro-1H-pyrido From the observation of reaction times in Table 2, it was found
[1,2-a]pyrimidine-7-carbohydrazides by using of cyanoacetohy- that with aldehydes containing an electron-withdrawing group
drazide 1, 4-nitroacetophenone 2, aromatic aldehydes 3, 1,1- on para position of ring (nitro and halogens), the reaction rate is
bis(methylthio)-2-nitroethene 4 and various diamines 5.
the highest and with methoxy group, the rate is the lowest.
Table 1 Optimization conditions for the formation of 6ca
Entry
Solvent
Catalyst (mol%)
Time (h)
Temp (ꢀC)
Yield (%)
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
—
24
24
24
24
24
10
5
78
78
78
78
100
78
60
57
Piperidine
p-TSA
AcOH
—
—
—
No reaction
No reaction
No reaction
65
H2O
H2O/EtOH (1 : 2, v/v)
H2O/EtOH (1 : 3, v/v)
CH3CN
78
82
87
—
24
No reaction
a
Reagents and conditions: cyanoacetohydrazide (1 mmol), 4-nitroacetophenone (1 mmol), 4-chlorobenzaldehyde (1 mmol), 1,1-bis(methylthio)-2-
nitroethene (1 mmol), ethylenediamine (1 mmol), solvent (20 mL), catalyst (0.2 mmol). The bold row represents the best results.
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C]C–CO and C–NO2 respectively. The carbonyl group appeared
at d 165.78 ppm (Fig. 2).
The mass spectrum of 6a displayed the molecular-ion peak at
m/z 497 in agreement with the proposed structure. The IR
spectrum of this compound showed absorption bands at 3486,
3400, 3327 cmꢁ1 due to NH and NH2 groups, stretching vibra-
tion of aliphatic C–H bands at 2909, and strong absorption of
carbonyl group at 1658 and C–N band at 1254 cmꢁ1. Two
absorption bands due to nitro group appeared at 1519 and
Scheme 1 Synthetic scheme for the generation of products 6a–q.
1375 cmꢁ1
.
This reaction was performed with other derivatives of
diamines (1,4-diaminobutane and 1,2-diaminocyclohexane)
under the same conditions, which did not result in the product.
Also the reaction with ortho derivatives of benzaldehyde (2-
chloro and 2-nitro) did not produce the desired product. Other
derivatives of acetophenone (4-chloro, 4-bromo and 4-methox-
yacetophenone) were also used which resulted no product
formation.
Mechanism
A general reasonable mechanism for the formation of imidazo
[1,2-a]pyridines-6-carbohydrazides
pyrimidine-7-carbohydrazides is shown in Scheme 2. On the
basis of well-established chemistry of 1,1-bis(methylthio)-2-
nitroethene, initially, addition of diamine
bis(methylthio)-2-nitroethene 4 leads to the formation of ketene
aminal 9. On the other hand condensation of cyanoacetohy-
drazide 1 with 4-nitroacetophenone 2 leads to hydrazone 7.
Further, with adding aldehyde 3, the Knoevenagel condensation
affords intermediate 8. Then, Michael addition of ketene ami-
nal 9 to adduct 8 leads to the intermediate 10, which undergoes
successive imine–enamine tautomerization followed by an
intramolecular cyclization via nucleophilic addition of –NH to
nitrile group. Finally, imine–enamine tautomerization gives the
titled products 6 (Scheme 2).
and
pyrido[1,2-a]
5
to 1,1-
In addition, the reaction with aliphatic ketones instead of 4-
nitroacetophenone and aliphatic aldehydes instead of aromatic
aldehydes did not lead to the desired products.
It should be noted that these reactions involve two-, three-
and four-component impurities. In fact, the most important
side product was a four-component structure without partici-
pation of 4-nitroacetophenone that was previously synthesized
using two equivalents of aldehyde.34 To achieve the pure
product, it was necessary to complete the reaction of cyanoa-
cetohydrazide and 4-nitroacetophenone in a mixture of water
and ethanol at reux conditions in sufficient time (3 hours),
then ketene aminal solution and aromatic aldehyde were added
at the same time.
Experimental
Materials
All commercially available reagents and other solvents were
purchased from Aldrich and Merck chemical Co. and used
without further purication. The NMR spectra were recorded
Structure determination
1
with a Bruker DRX-300 AVANCE instrument (300 MHz for H
The structures of compounds 6a–q were deduced from their IR,
1H NMR, 13C NMR spectroscopic and Mass spectrometric data
(see the ESI†).
and 75.4 MHz for 13C) with DMSO-d6 as solvent. Chemical shis
are given in ppm (d), and coupling constant (J) are reported in
Hertz (Hz). Melting points were measured with an electro-
thermal 9100 apparatus. Mass spectra were recorded with an
Agilent 5975C VL MSD with Triple-Axis detector operating at an
ionization potential of 70 eV. IR spectra were measured with
Bruker Tensor 27 spectrometer. Elemental analyses for C, H
and N were performed using a PerkinElmer 2004 series [II] CHN
elemental analyzer.
The formation of suggested products 6a–q is clearly veried
by the 1H and 13C NMR spectra of the crude products. As
a representative case the key signals of 1H and 13C NMR
chemical shis of 5-amino-7-(3-chlorophenyl)-8-nitro-N0-(1-(4-
nitrophenyl)ethylidene)-1,2,3,7-tetrahydroimidazo[1,2-a]
pyridine-6-carbohydrazide 6a are presented in Fig. 2.
The 1H NMR spectrum of 6a showed two NH groups at d 9.16
and 9.43 ppm. The protons of 4-nitrobenzene ring were seen at
d 7.96 and 8.20 ppm as two doublet signals and the protons of 3-
chlorobenzene ring were observed at d 6.92–7.31 ppm. The NH2
group appeared at d 8.21 ppm. The proton of CH at pyridine ring
was seen at d 5.49 ppm. Two protons of two methylene groups
General procedure of the synthesis of tetrahydroimidazo[1,2-
a]pyridine-6-carbohydrazide and tetrahydro-1H-pyrido[1,2-a]
pyrimidine-7-carbohydrazide derivatives
A
mixture of diamine (1 mmol), 1,1-bis(methylthio)-2-
appeared at d 3.81 and 4.05 ppm. The signal at d 2.14 ppm was nitroethylene (0.165 g, 1 mmol) and 10 mL EtOH in a 50 mL
related to methyl group. ask was reuxed for 6 hours. In another 50 mL ask the stoi-
The 1H-decoupled 13C NMR spectrum of 6a indicated 20 chiometric mixture of cyanoacetohydrazide (1 mmol, 0.099 g)
distinct resonances in accordance to desired structure. The and 4-nitroacetophenone (1 mmol, 0.165 g) in H2O/EtOH (5 : 5
characteristic signals of four aliphatic carbons (CH3, CH and mL) was stirred at reux conditions for 3 hours. Aer this time,
two CH2 groups) were seen at d 13.9, 38.2, 43.6 and 44.7 ppm TLC shows the consumption of the starting components. Then,
respectively. Two signals at d 80.0 and 107.4 ppm were related to aromatic aldehyde (1 mmol) and the rst solution (HKA), was
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Table 2 Compounds 6a–qa
Entry
Aromatic aldehyde
Diamine
Product
Time (h)
Yield (%)
Mp (ꢀC)
1
6
90
86
231–233
2
5
235–237
3
5
87
89
90
78
239–241
4
5
6
4
5
7
243–245
239–240
267–269
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Table 2 (Contd.)
Entry
Aromatic aldehyde
Diamine
Product
Time (h)
Yield (%)
Mp (ꢀC)
7
5
80
75
86
271–273
8
6
284–286
9
5
264–266
10
4
88
268–270
11
5
85
265–267
12
4
90
298–300
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Table 2 (Contd.)
Entry
Aromatic aldehyde
Diamine
Product
Time (h)
Yield (%)
Mp (ꢀC)
13
7
73
269–271
14
15
16
7
75
315–317
5
85
317–319
5
84
322–324
17
6
75
329–331
a
The reaction was performed using cyanoacetohydrazide (1 mmol), 4-nitroacetophenone (1 mmol), aromatic aldehyde (1 mmol), 1,1-
bis(methylthio)-2-nitroethene (1 mmol), diamine (1 mmol), EtOH (15 mL), H2O (5 mL), reux.
5-Amino-7-(3-chlorophenyl)-8-nitro-N0-(1-(4-nitrophenyl)eth-
ylidene)-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-
carbohydrazide (6a). Dark yellow solid; yield: 0.447 g (90%); mp:
231–233 ꢀC; IR (KBr) (nmax/cmꢁ1): 3486, 3400, 3327, 2909, 1658,
1519, 1458, 1375, 1254, 785; 1H NMR (300 MHz, DMSO-d6):
added to this mixture simultaneously. The progress of the
reaction was monitored by TLC using ethyl acetate/n-hexane
(1 : 1). Aer completion of the reaction, the precipitated
product was collected by ltration and washed with warm
ethanol to give the pure products 6a–q in 73–90% yield.
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(C]C–CO), 107.5 (C]C–NO2), 113.7, 115.2, 123.9, 124.4, 127.3,
130.2, 145.0, 147.5 (Ar), 148.5 (Me–C]N), 148.5 (C]C–NH),
151.4 (CAr–NO2), 151.5 (C]C–NH2), 160.7 (CAr–F), 165.8 (C]O);
MS (EI, 70 eV): m/z (%) ¼ 481 (0.008) [M]+, 438 (6), 392 (2), 326
(57), 311 (100), 276 (62), 230 (87), 179 (54), 117 (71), 76 (39), 50
(5); anal. calcd for C22H20FN7O5: C, 54.88; H, 4.19; N, 20.37.
Found: C, 54.56; H, 4.04; N, 20.53.
5-Amino-7-(4-chlorophenyl)-8-nitro-N0-(1-(4-nitrophenyl)eth-
ylidene)-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-
carbohydrazide (6c). Yellow solid; yield: 0.432 g (87%); mp: 239–
241 ꢀC; IR (KBr) (nmax/cmꢁ1): 3456, 3401, 3339, 2919, 1675, 1522,
1456, 1373, 1255, 761; 1H NMR (300 MHz, DMSO-d6): d 2.15
(3H, s, CH3), 3.77–3.86 (2H, m, CH2), 4.02–4.10 (2H, m, CH2),
5.45 (1H, s, CH), 7.28 (2H, d, J ¼ 8.4 Hz, ArH), 7.36 (2H, d, J ¼
8.4 Hz, ArH), 7.96 (2H, d, J ¼ 8.7 Hz, ArH), 8.20 (2H, d, J ¼
8.7 Hz, ArH), 8.21 (2H, s, NH2), 9.16 (1H, s, NH), 9.43 (1H, s,
NH); 13C{1H} NMR (75.4 MHz, DMSO-d6): d 13.9 (CH3), 37.8
(CH), 43.6 (CH2–NH), 44.7 (CH2–N), 80.2 (C]C–CO), 107.7 (C]
C–NO2), 123.9, 127.3, 128.5, 129.8, 130.2, 131.3, 145.0 (Ar), 147.5
(Me–C]N), 151.3 (C]C–NH), 151.4 (CAr–NO2), 151.8 (C]C–
NH2), 165.7 (C]O); anal. calcd for C22H20ClN7O5: C, 53.07; H,
4.05; N, 19.69. Found: C, 53.28; H, 4.16; N, 19.51.
Fig. 2 1H and 13C NMR chemical shifts of 6a.
5-Amino-7-(4-nitrophenyl)-8-nitro-N0-(1-(4-nitrophenyl)ethyl-
idene)-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-
carbohydrazide (6d). Light Yellow solid; yield: 0.452 g (89%);
1
ꢀ
mp: 243–245 C; H NMR (300 MHz, DMSO-d6): d 2.18 (3H, s,
CH3), 3.79–3.85 (2H, m, CH2), 4.04–4.07 (2H, m, CH2), 5.67
(1H, s, CH), 7.59 (2H, d, J ¼ 9 Hz, ArH), 7.95 (2H, d, J ¼ 9 Hz,
ArH), 8.10 (2H, d, J ¼ 8.7 Hz, ArH), 8.20 (2H, d, J ¼ 8.7 Hz, ArH),
8.27 (2H, s, NH2), 9.34 (1H, s, NH), 9.50 (1H, s, NH); 13C{1H}
NMR (75.4 MHz, DMSO-d6): d 14.1 (CH3), 38.3 (CH), 43.7 (CH2–
NH), 44.7 (CH2–N), 79.7 (C]C–CO), 107.1 (C]C–NO2), 123.6,
123.9, 124.4, 127.3, 129.6, 145.0, 146.4 (Ar), 147.5 (Me–C]N),
147.6 (C]C–NH), 151.4 (CAr–NO2), 151.5 (CAr–NO2), 153.4 (C]
C–NH2), 166.0 (C]O); MS (EI, 70 eV): m/z (%) ¼ 508 (0.01) [M]+,
326 (40), 311 (72), 257 (32), 204 (14), 179 (100), 117 (59), 76 (7), 57
(12); anal. calcd for C22H20N8O7: C, 51.97; H, 3.96; N, 22.04.
Found: C, 52.13; H, 3.89; N, 22.14.
Scheme 2 Proposed mechanism for the formation of products 6.
d 2.14 (3H, s, CH3), 3.78–3.84 (2H, m, CH2), 3.99–4.11 (2H, m,
CH2), 5.49 (1H, s, CH), 6.92–7.31 (4H, m, ArH), 7.96 (2H, d, J ¼
8.7 Hz, ArH), 8.20 (2H, d, J ¼ 8.7 Hz, ArH), 8.21 (2H, br s, NH2),
9.16 (1H, s, NH), 9.43 (1H, s, NH); 13C{1H} NMR (75.4 MHz,
DMSO-d6): d 13.9 (CH3), 38.2 (CH), 43.6 (CH2–NH), 44.7 (CH2–
N), 80.0 (C]C–CO), 107.4 (C]C–NO2), 123.9, 126.8, 127.1,
127.3, 128.3, 130.3, 132.8, 145.0, 147.3 (Ar), 147.5 (Me–C]N),
148.0 (C]C–NH), 151.3 (CAr–NO2), 151.4 (C]C–NH2), 165.7
(C]O); MS (EI, 70 eV): m/z (%) ¼ 497 (0.008) [M]+, 454 (2), 326
(59), 311 (100), 292 (29), 265 (37), 246 (51), 204 (26), 179 (63), 117
(83), 76 (47), 57 (7); anal. calcd for C22H20ClN7O5: C, 53.07; H,
4.05; N, 19.69. Found: C, 53.37; H, 3.84; N, 19.65.
5-Amino-7-(4-bromophenyl)-8-nitro-N0-(1-(4-nitrophenyl)eth-
ylidene)-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-
carbohydrazide (6e). Yellow solid; yield: 0.486 g (90%); mp: 239–
240 ꢀC; IR (KBr) (nmax/cmꢁ1): 3454, 3338, 2919, 1658, 1522, 1462,
1
1377, 1254, 580; H NMR (300 MHz, DMSO-d6): d 2.14 (3H, s,
CH3), 3.79–3.85 (2H, m, CH2), 4.00–4.07 (2H, m, CH2), 5.42
(1H, s, CH), 7.30 (2H, m, ArH), 7.39 (2H, m, ArH), 7.94 (2H, d, J ¼
7.5 Hz, ArH), 8.19 (2H, d, J ¼ 7.5 Hz, ArH), 8.20 (2H, s, NH2), 9.16
(1H, s, NH), 9.43 (1H, s, NH); 13C{1H} NMR (75.4 MHz, DMSO-
d6): d 13.9 (CH3), 37.9 (CH), 43.6 (CH2–NH), 44.7 (CH2–N), 80.1
(C]C–CO), 107.6 (C]C–NO2), 119.8, 123.8, 127.3, 130.2, 130.6,
131.1, 144.9 (Ar) 147.1 (Me–C]N), 147.4 (C]C–NH), 151.4 (CAr–
NO2), 151.4 (C]C–NH2), 165.7 (C]O); anal. calcd for
5-Amino-7-(3-uorophenyl)-8-nitro-N0-(1-(4-nitrophenyl)eth-
ylidene)-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-
carbohydrazide (6b). Orange solid; yield: 0.413 g (86%); mp:
235–237 ꢀC; IR (KBr) (nmax/cmꢁ1): 3477, 3332, 3401, 1660, 1519,
1
1462, 1377, 1331, 1254; H NMR (300 MHz, DMSO-d6): d 2.15
C
22H20BrN7O5: C, 48.72; H, 3.72; N, 18.08. Found: C, 48.64; H,
(3H, s, CH3), 3.37–3.84 (2H, m, CH2), 4.02–4.12 (2H, m, CH2),
5.47 (1H, s, CH), 7.17–7.39 (4H, m, ArH), 7.96 (2H, d, J ¼ 8.7 Hz,
ArH), 8.20 (2H, d, J ¼ 8.7 Hz, ArH), 8.24 (2H, br s, NH2), 9.17
(1H, s, NH), 9.45 (1H, s, NH); 13C{1H} NMR (75.4 MHz, DMSO-
d6): d 13.9 (CH3), 38.1 (CH), 43.6 (CH2–NH), 44.7 (CH2–N), 80.1
3.78; N, 18.19.
5-Amino-7-(4-methoxyphenyl)-8-nitro-N0-(1-(4-nitrophenyl)
ethylidene)-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-
carbohydrazide (6f). Dark yellow solid; yield: 0.342 g (78%); mp:
267–269 ꢀC; IR (KBr) (nmax/cmꢁ1): 3401, 3343, 2919, 2850, 1658,
7224 | RSC Adv., 2019, 9, 7218–7227
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1514, 1451, 1342, 1257, 1167; 1H NMR (300 MHz, DMSO-d6):
d 2.11 (3H, s, CH3), 3.69 (3H, s, OCH3), 3.74–3.83 (2H, m, CH2),
4.02–4.05 (2H, m, CH2), 5.28 (1H, s, CH), 6.79 (2H, d, J ¼ 8.4 Hz,
ArH), 7.27 (2H, d, J ¼ 8.4 Hz, ArH), 7.94 (2H, d, J ¼ 8.7 Hz, ArH),
8.19 (2H, d, J ¼ 8.7 Hz, ArH), 8.20 (2H, br s, NH2), 8.97 (1H, s,
NH), 9.38 (1H, s, NH); 13C{1H} NMR (75.4 MHz, DMSO-d6):
d 13.7 (CH3), 37.7 (CH), 43.5 (CH2–NH), 44.7 (CH2–N), 55.4
(OCH3), 80.6 (C]C–CO), 108.2 (C]C–NO2), 113.8, 123.9, 127.3,
129.4, 137.4, 145.0 (Ar), 146.4 (Me–C]N), 147.4 (C]C–NH),
151.2 (CAr–NO2), 151.4 (C]C–NH2), 158.3 (CAr–OCH3), 165.5
(C]O); anal. calcd for C23H23N7O6: C, 55.98; H, 4.70; N, 19.87.
Found: C, 55.93; H, 4.77; N, 19.75.
6-Amino-9-nitro-8-(4-nitrophenyl)-N0-(1-(4-nitrophenyl)ethyl-
idene)-2,3,4,8-tetrahydro-1H-pyrido[1,2-a]pyrimidine-7-
carbohydrazide (6j). Yellowish orange solid; yield: 0.459 g
(88%); mp: 268–271 ꢀC; IR (KBr) (nmax/cmꢁ1): 3470, 3389, 2929,
1648, 1521, 1458, 1344, 1259; 1H NMR (300 MHz, DMSO-d6):
d 1.85–1.94 (2H, m, CH2), 2.48 (3H, s, CH3), 3.58–3.75 (2H, m,
CH2NH), 3.76–3.95 (2H, m, CH2N), 5.75 (1H, s, CH), 7.55 (2H, d,
J ¼ 8.4 Hz, ArH), 7.97 (2H, d, J ¼ 8.4 Hz, ArH), 8.09 (2H, d, J ¼
8.7 Hz, ArH), 8.19 (2H, d, J ¼ 8.7 Hz, ArH), 8.31 (2H, s, NH2), 9.55
(1H, s, NH), 11.47 (1H, s, NH); 13C{1H} NMR (75.4 MHz, DMSO-
d6): d 14.2 (CH3), 20.1 (CH2), 37.15 (CH), 38.8 (CH2–NH), 43.2
(CH2–N), 81.0 (C]C–CO), 109.3 (C]C–NO2), 123.8, 127.4,
128.4, 129.1, 144.9, 146.4 (Ar), 147.6 (Me–C]N), 148.4 (C]C–
NH), 150.4 (CAr–NO2), 152.5 (CAr–NO2), 152.8 (C]C–NH2), 166.3
(C]O); MS (EI, 70 eV): m/z (%) ¼ 353 (6), 311 (35), 271 (67), 225
(19), 179 (100), 164 (67), 132 (49), 118 (77), 91 (35), 76 (13), 56
(31); anal. calcd for C23H22N8O7: C, 52.87; H, 4.24; N, 21.45.
Found: C, 52.57; H, 4.62; N, 21.18.
5-Amino-7-(4-uorophenyl)-8-nitro-N0-(1-(4-nitrophenyl)eth-
ylidene)-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-
carbohydrazide (6g). Light orange solid; yield: 0.384 g (80%);
1
ꢀ
mp: 271–273 C; H NMR (300 MHz, DMSO-d6): d 2.12 (3H, s,
CH3), 3.80–3.83 (2H, m, CH2), 4.03–4.05 (2H, m, CH2), 5.42
(1H, s, CH), 6.96–7.23 (4H, m, ArH), 7.95 (2H, d, J ¼ 9 Hz, ArH),
8.19 (2H, d, J ¼ 9 Hz, ArH), 8.24 (2H, br s, NH2), 9.10 (1H, s, NH),
9.42 (1H, s, NH); 13C{1H} NMR (75.4 MHz, DMSO-d6): d 13.8
(CH3), 37.6 (CH), 43.5 (CH2–NH), 44.7 (CH2–N), 80.4 (C]C–CO),
107.9 (C]C–NO2), 114.8, 116.0, 123.9, 127.3, 127.9, 128.8, 130.1
(Ar), 141.7 (Me–C]N), 142.4 (C]C–NH), 147.4 (CAr–NO2), 151.4
(C]C–NH2), 165.6 (C]O); anal. calcd for C22H20FN7O5: C,
54.88; H, 4.19; N, 20.37. Found: C, 54.55; H, 3.94; N, 20.15.
5-Amino-8-nitro-N0-(1-(4-nitrophenyl)ethylidene)-7-phenyl-
1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carbohydrazide
(6h). Yellow solid; yield: 0.347 g (75%); mp: 284–286 ꢀC; 1H NMR
(300 MHz, DMSO-d6): d 2.12 (3H, s, CH3), 3.81–3.84 (2H, m,
CH2), 4.05–4.08 (2H, m, CH2), 5.36 (1H, s, CH), 7.12–7.36 (5H,
m, ArH), 7.94 (2H, d, J ¼ 7.8 Hz, ArH), 8.19 (2H, d, J ¼ 7.8 Hz,
6-Amino-8-(4-chlorophenyl)-9-nitro-N0-(1-(4-nitrophenyl)eth-
ylidene)-2,3,4,8-tetrahydro-1H-pyrido[1,2-a]pyrimidine-7-
carbohydrazide (6k). Light brown solid; yield: 0.434 g (85%);
mp: 265–267 ꢀC; 1H NMR (300 MHz, DMSO-d6): d 1.80–1.90 (2H,
m, CH2), 2.17 (3H, s, CH3), 3.38–3.92 (4H, m, 2CH2N), 5.54
(1H, s, CH), 7.27 (2H, d, J ¼ 8.7 Hz, ArH), 7.32 (2H, d, J ¼ 8.7 Hz,
ArH), 7.97 (2H, d, J ¼ 8.7 Hz, ArH), 8.20 (2H, d, J ¼ 8.7 Hz, ArH),
8.25 (2H, s, NH2), 9.37 (1H, s, NH), 11.49 (1H, s, NH); 13C{1H}
NMR (75.4 MHz, DMSO-d6): d 14.0 (CH3), 20.2 (CH2), 36.5 (CH),
38.7 (CH2–NH), 43.1 (CH2–N), 81.5 (C]C–CO), 109.8 (C]C–
NO2), 123.9, 127.4, 128.5, 129.8, 131.4, 143.7, 144.9 (Ar), 147.6
(Me–C]N), 147.9 (C]C–NH), 150.3 (CAr–NO2), 152.6 (C]C–
NH2), 166.1 (C]O); anal. calcd for C23H22ClN7O5: C, 53.96; H,
4.33; N, 19.15. Found: C, 53.61; H, 4.14; N, 19.37.
ArH), 8.19 (2H, br s, NH2), 9.05 (1H, s, NH), 9.40 (1H, s, NH); 13
C
{1H} NMR (75.4 MHz, DMSO-d6): d 13.8 (CH3), 38.4 (CH), 43.6
(CH2–NH), 44.7 (CH2–N), 80.6 (C]C–CO), 107.4 (C]C–NO2),
123.9, 126.9, 127.3, 128.4, 145.5 (Ar), 146.6 (Me–C]N), 147.5
(C]C–NH), 151.3 (CAr–NO2), 151.5 (C]C–NH2), 165.7 (C]O);
anal. calcd for C22H21N7O5: C, 57.02; H, 4.57; N, 21.16. Found: C,
57.37; H, 4.25; N, 21.45.
6-Amino-3,3-dimethyl-9-nitro-8-(4-nitrophenyl)-N0-(1-(4-
nitrophenyl)ethylidene)-2,3,4,8-tetrahydro-1H-pyrido[1,2-a]
pyrimidine-7-carbohydrazide (6l). Creamy yellow solid; yield:
0.495 g (90%); mp: 297–300 ꢀC; IR (KBr) (nmax/cmꢁ1): 3320, 3199,
2959, 1642, 1518, 1350, 1261; 1H NMR (300 MHz, DMSO-d6):
d 0.95 (3H, s, CH3), 1.09 (3H, s, CH3), 2.19 (3H, s, CH3), 3.23–3.32
(2H, m, CH2NH), 3.52–3.56 (2H, m, CH2N), 5.80 (1H, s, CH), 7.52
(2H, d, J ¼ 7.5 Hz, ArH), 7.96 (2H, d, J ¼ 7.5 Hz, ArH), 8.11 (2H, d,
J ¼ 7.8 Hz, ArH), 8.19 (2H, d, J ¼ 7.8 Hz, ArH), 8.33 (2H, s, NH2),
9.54 (1H, s, NH), 11.38 (1H, s, NH); 13C{1H} NMR (75.4 MHz,
DMSO-d6): d 14.2 (CH3), 22.7 (CH3), 24.5 (CH3), 27.7 (CMe2), 37.0
(CH), 49.4 (CH2–NH), 53.4 (CH2–N), 81.0 (C]C–CO), 109.2 (C]
C–NO2), 123.9, 127.5, 128.9, 144.9, 146.5 (Ar), 147.6 (Me–C]N),
148.5 (C]C–NH), 149.6 (CAr–NO2), 152.6 (CAr–NO2), 152.9 (C]
C–NH2), 166.3 (C]O); MS (EI, 70 eV): m/z (%) ¼ 409 (6), 345 (13),
327 (38), 299 (84), 253 (20), 179 (100), 149 (52), 118 (71), 96 (14),
77 (78), 55 (42); anal. calcd for C25H26N8O7: C, 54.54; H, 4.76; N,
20.35. Found: C, 54.68; H, 4.59; N, 20.24.
6-Amino-8-(4-bromophenyl)-9-nitro-N0-(1-(4-nitrophenyl)eth-
ylidene)-2,3,4,8-tetrahydro-1H-pyrido[1,2-a]pyrimidine-7-
carbohydrazide (6i). Light yellow solid; yield: 0.477 g (86%); mp:
264–266 ꢀC; IR (KBr) (nmax/cmꢁ1): 3481, 3403, 3968, 2925, 1645,
1516, 1456, 1340, 1257, 590; 1H NMR (300 MHz, DMSO-d6):
d 1.80–1.92 (2H, m, CH2), 2.48 (3H, s, CH3), 3.58–3.75 (2H, m,
CH2NH), 3.76–3.92 (2H, m, CH2N), 5.53 (1H, s, CH), 7.26 (2H, d,
J ¼ 8.4 Hz, ArH), 7.41 (2H, d, J ¼ 8.4 Hz, ArH), 7.97 (2H, d, J ¼
8.7 Hz, ArH), 8.20 (2H, d, J ¼ 8.7 Hz, ArH), 8.25 (2H, s, NH2), 9.36
(1H, s, NH), 11.49 (1H, s, NH); 13C{1H} NMR (75.4 MHz, DMSO-
d6): d 14.0 (CH3), 20.2 (CH2), 36.6 (CH), 38.7 (CH2–NH), 43.1
(CH2–N), 81.4 (C]C–CO), 109.8 (C]C–NO2), 119.9, 123.9,
127.4, 130.4, 131.4, 144.1, 144.9 (Ar), 147.6 (Me–C]N), 147.9
(C]C–NH), 150.3 (CAr–NO2), 152.6 (C]C–NH2), 166.1 (C]O);
MS (EI, 70 eV): m/z (%) ¼ 343 (58), 311 (53), 265 (20), 243 (8), 204
(13), 183 (40), 156 (27), 133 (10), 117 (100), 97 (25), 76 (8), 57 (55);
anal. calcd for C23H22BrN7O5: C, 49.65; H, 3.99; N, 17.62. Found:
C, 49.87; H, 3.50; N, 17.26.
6-Amino-8-(3-methoxyphenyl)-3,3-dimethyl-9-nitro-N0-(1-(4-
nitrophenyl)ethylidene)-2,3,4,8-tetrahydro-1H-pyrido[1,2-a]
pyrimidine-7-carbohydrazide (6m). Dark yellow solid; yield:
1
ꢀ
0.390 g (73%); mp: 269–271 C; H NMR (300 MHz, DMSO-d6):
d 0.96 (3H, s, CH3), 1.09 (3H, s, CH3), 2.14 (3H, s, CH3), 3.23
(2H, s, CH2NH), 3.56 (2H, s, CH2N), 3.65 (3H, s, OCH3), 5.49
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(1H, s, CH), 6.71–6.89 (3H, m, ArH), 7.15 (1H, t, J ¼ 7.5 Hz, ArH), NH2), 166.1 (C]O); anal. calcd for C25H26BrN7O5: C, 51.38; H,
7.97 (2H, d, J ¼ 9 Hz, ArH), 8.20 (2H, d, J ¼ 9 Hz, ArH), 8.25 4.48; N, 16.78. Found: C, 51.18; H, 4.66; N, 16.47.
(2H, s, NH2), 9.23 (1H, s, NH), 11.44 (1H, s, NH); 13C{1H} NMR
6-Amino-3,3-dimethyl-9-nitro-N0-(1-(4-nitrophenyl)ethyl-
(75.4 MHz, DMSO-d6): d 13.8 (CH3), 22.6 (CH3), 24.6 (CH3), 27.6 idene)-8-phenyl-2,3,4,8-tetrahydro-1H-pyrido[1,2-a]pyrimidine-
(CMe2), 36.2 (CH), 49.4 (CH2–NH), 53.3 (CH2–N), 55.4 (OCH3), 7-carbohydrazide (6q). Light yellow solid; yield: 0.378 g (75%);
1
ꢀ
82.0 (C]C–CO), 110.2 (C]C–NO2), 114.0, 115.3, 123.9, 127.4, mp: 329–331 C; H NMR (300 MHz, DMSO-d6): d 0.95 (3H, s,
128.0, 133.2, 136.5, 144.9 (Ar), 147.3 (Me–C]N), 147.5 (C]C– CH3), 1.09 (3H, s, CH3), 2.14 (3H, s, CH3), 3.19–3.26 (2H, m,
NH), 149.4 (CAr–NO2), 152.6 (C]C–NH2), 158.4 (CAr–OCH3), CH2NH), 3.56 (2H, s, CH2N), 5.50 (1H, s, CH), 7.11–7.32 (5H, m,
165.8 (C]O); anal. calcd for C25H29N7O6: C, 58.31; H, 5.46; N, ArH), 7.96 (2H, d, J ¼ 8.7 Hz, ArH), 8.20 (2H, d, J ¼ 8.7 Hz, ArH),
18.31. Found: C, 58.50; H, 5.34; N, 18.27.
6-Amino-8-(4-methoxyphenyl)-3,3-dimethyl-9-nitro-N0-(1-(4-
nitrophenyl)ethylidene)-2,3,4,8-tetrahydro-1H-pyrido[1,2-a]
8.26 (2H, s, NH2), 9.26 (1H, s, NH), 11.44 (1H, s, NH); 13C{1H}
NMR (75.4 MHz, DMSO-d6): d 13.9 (CH3), 22.6 (CH3), 24.6 (CH3),
27.7 (CMe2), 37.0 (CH), 49.4 (CH2–NH), 53.3 (CH2–N), 81.9 (C]
pyrimidine-7-carbohydrazide (6n). Yellow solid; yield: 0.401 g C–CO), 110.0 (C]C–NO2), 120.0, 123.9, 127.5, 128.0, 130.0,
1
ꢀ
(75%); mp: 315–317 C; H NMR (300 MHz, DMSO-d6): d 0.96 131.4, 132.0 (Ar), 144.1 (Me–C]N), 147.5 (C]C–NH), 150.5
(3H, s, CH3), 1.09 (3H, s, CH3), 2.13 (3H, s, CH3), 3.26–3.33 (2H, (CAr–NO2), 152.8 (C]C–NH2), 166.0 (C]O); MS (EI, 70 eV): m/z
m, CH2NH), 3.55–3.65 (2H, s, CH2N), 3.75 (3H, s, OCH3), 5.41 (%) ¼ 505 (0.03) [M]+, 447 (0.09), 334 (14), 300 (25), 283 (19), 254
(1H, s, CH), 6.79 (2H, d, J ¼ 8.7 Hz, ArH), 7.23 (2H, d, J ¼ 8.7 Hz, (100), 179 (20), 156 (89), 128 (41), 103 (26), 77 (42), 55 (11); anal.
ArH), 7.96 (2H, d, J ¼ 9 Hz, ArH), 8.20 (2H, d, J ¼ 9 Hz, ArH), 8.24 calcd for C25H27N7O5: C, 59.40; H, 5.38; N, 19.40. Found: C,
(2H, s, NH2), 9.62 (1H, s, NH), 11.45 (1H, s, NH); 13C{1H} NMR 59.56; H, 5.25; N, 19.34.
(75.4 MHz, DMSO-d6): d 13.8 (CH3), 22.6 (CH3), 24.1 (CH3), 27.7
(CMe2), 36.3 (CH), 49.2 (CH2–NH), 53.3 (CH2–N), 55.4 (OCH3),
82.0 (C]C–CO), 110.2 (C]C–NO2), 114.0, 115.3, 123.9, 127.4,
Conclusion
128.9, 133.2, 136.5, 144.9 (Ar), 147.3 (Me–C]N), 147.5 (C]C– A green and convenient approach to easy construction of novel
NH), 149.4 (CAr–NO2), 152.6 (C]C–NH2), 158.4 (CAr–OCH3), and highly substituted imidazo[1,2-a]pyridines and pyrido[1,2-
165.8 (C]O); anal. calcd for C25H29N7O6: C, 58.31; H, 5.46; N, a]pyrimidines has been developed by annulation of heterocyclic
18.31. Found: C, 58.68; H, 5.15; N, 18.23.
6-Amino-8-(4-chlorophenyl)-3,3-dimethyl-9-nitro-N0-(1-(4-
nitrophenyl)ethylidene)-2,3,4,8-tetrahydro-1H-pyrido[1,2-a]
ketene aminals (HKAs) and a three-component product of cya-
noacetohydrazide, 4-nitroacetophenone and aromatic alde-
hydes. The reactions are performed in a mixture of EtOH and
pyrimidine-7-carbohydrazide (6o). Brownish yellow solid; yield: H2O at reux conditions in the absence of any catalyst. The
0.458 g (85%); mp: 317–319 ꢀC; IR (KBr) (nmax/cmꢁ1): 3324, 3204, present reaction shows considerable properties such as high
2925, 2861, 1643, 1524, 1480, 1353, 1263, 755; 1H NMR (300 regioselectivity, cascade one-pot methodology, short reaction
MHz, DMSO-d6): d 0.93 (3H, s, CH3), 1.08 (3H, s, CH3), 2.16 times, easy purication of products, high yields, avoiding the
(3H, s, CH3), 3.23 (2H, s, CH2NH), 3.54 (2H, m, CH2N), 5.58 use of catalyst and high atom economy.
(1H, s, CH), 7.29 (4H, s, ArH), 7.96 (2H, d, J ¼ 8.7 Hz, ArH), 8.20
(2H, d, J ¼ 8.7 Hz, ArH), 8.27 (2H, s, NH2), 9.36 (1H, s, NH), 11.40
Conflicts of interest
(1H, s, NH); 13C{1H} NMR (75.4 MHz, DMSO-d6): d 14.0 (CH3),
22.6 (CH3), 24.5 (CH3), 27.7 (CMe2), 37.0 (CH), 50.4 (CH2–NH), The authors declare no competing nancial interest.
51.5 (CH2–N), 81.5 (C]C–CO), 109.7 (C]C–NO2), 123.9, 124.0,
127.5, 128.0, 128.5, 128.8, 129.1, 129.6 (Ar), 143.7 (Me–C]N),
144.6 (C]C–NH), 148.0 (CAr–NO2), 152.9 (C]C–NH2), 166.0
Acknowledgements
(C]O); MS (EI, 70 eV): m/z (%) ¼ 539 (0.007) [M]+, 368 (4), 311 Financial support of this research from Imam Khomeini
(30), 288 (100), 223 (13), 179 (57), 149 (27), 117 (37), 102 (20), 77 International University, Iran is gratefully acknowledged.
(42), 55 (27); anal. calcd for C25H26ClN7O5: C, 55.61; H, 4.85; N,
18.16. Found: C, 55.90; H, 4.68; N, 18.04.
Notes and references
6-Amino-8-(4-bromophenyl)-3,3-dimethyl-9-nitro-N0-(1-(4-
nitrophenyl)ethylidene)-2,3,4,8-tetrahydro-1H-pyrido[1,2-a]
pyrimidine-7-carbohydrazide (6p). Yellow solid; yield: 0.491 g
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1
ꢀ
(84%); mp: 322–324 C; H NMR (300 MHz, DMSO-d6): d 1.03
(3H, s, CH3), 1.08 (3H, s, CH3), 2.16 (3H, s, CH3), 3.22–3.35 (2H,
m, CH2NH), 3.42–3.55 (2H, m, CH2N), 5.56 (1H, s, CH), 7.24 (2H,
d, J ¼ 8.4 Hz, ArH), 7.43 (2H, d, J ¼ 8.4 Hz, ArH), 7.96 (2H, d, J ¼
9 Hz, ArH), 8.20 (2H, d, J ¼ 9 Hz, ArH), 8.29 (2H, s, NH2), 9.38
(1H, s, NH), 11.41 (1H, s, NH); 13C{1H} NMR (75.4 MHz, DMSO-
d6): d 14.0 (CH3), 22.6 (CH3), 24.5 (CH3), 27.6 (CMe2), 36.4 (CH),
49.4 (CH2–NH), 53.4 (CH2–N), 81.4 (C]C–CO), 109.7 (C]C–
NO2), 120.0, 123.9, 127.5, 128.0, 130.0, 131.4, 132.0 (Ar), 144.1
(Me–C]N), 147.6 (C]C–NH), 149.5 (CAr–NO2), 152.8 (C]C–
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