Simple synthesis of new imidazopyridinone, pyridopyrimidinone, and thiazolopyridinone derivatives and optimization of reaction parameters using response surface methodology

Article abstract of DOI:10.1039/c9ra06054e

The reaction between ketene animal/ketene N,S-acetals (derived from diamines/cysteamine hydrochloride and 1,1-bis(methylthio)-2-nitroethene) with aromatic aldehydes, and Meldrum's acid led to the title compounds. The reaction conditions were optimized using response surface methodology (RSM). The two independent variables (temperature and water content of aqueous ethanol), and the responses (yield of product and reaction time) were studied. The range of each parameter selected was: T = 25-100 °C and water = 0-100%. The optimal values were: T = 72 °C and water = 33%. This work offers significant advantages including use of a green solvent, experimental simplicity, absence of catalyst, a simple work-up and purification process, moderate to good yields, and preparation of potentially bioactive compounds.

Full text of DOI:10.1039/c9ra06054e

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Simple synthesis of new imidazopyridinone,
pyridopyrimidinone, and thiazolopyridinone
derivatives and optimization of reaction parameters
using response surface methodology†
Cite this: RSC Adv., 2019, 9, 30479
Fahimeh Sadat Hosseini
and Mohammad Bayat
*
The reaction between ketene animal/ketene N,S-acetals (derived from diamines/cysteamine hydrochloride
and 1,1-bis(methylthio)-2-nitroethene) with aromatic aldehydes, and Meldrum's acid led to the title
compounds. The reaction conditions were optimized using response surface methodology (RSM). The
two independent variables (temperature and water content of aqueous ethanol), and the responses (yield
Received 4th August 2019
Accepted 17th September 2019
ꢀ
of product and reaction time) were studied. The range of each parameter selected was: T ¼ 25–100
C
ꢀ
and water ¼ 0–100%. The optimal values were: T ¼ 72 C and water ¼ 33%. This work offers significant
advantages including use of a green solvent, experimental simplicity, absence of catalyst, a simple work-
up and purification process, moderate to good yields, and preparation of potentially bioactive compounds.
DOI: 10.1039/c9ra06054e
rsc.li/rsc-advances
1
6,17
8,18
analgesic,
tyrosine kinase, calcium channel antagonists,
Introduction
19
tuberculostatic, antileishmanial, antitumor, antifolate, anti-
Response surface methodology (RSM) is the most popular hypertensive, hepatoprotective, anticancer properties; and
optimization method used in recent years. RSM is a powerful thiazolopyridine derivatives are associated with a wide range of
mathematical and statistical technique which has been widely biological activities such as analgesic, antioxidant, anti-
used for designing experiments and empirical building models cancer, anti-inammatory, antihypertensive, antibacterial,
20
21
11
22
23
24
25,26
with minimal experimental number. This method is exclusively and antifungal
properties.
used to examine the surface, or the relationship between the
The numerous attractive features of enamines or dienamines
response and the factors affecting the response. The application derived from the 1,1-bis(methylthio)-2-nitroethene have made
of RSM to design optimization is aimed at reducing the cost of them important intermediates for the construction of a wide
2
7–33
expensive analysis methods and their associated numerical variety of S- and N-heterocyclic systems.
noise.
Hence during
1–6
recent years, they have been used for the synthesis of various
Nitrogen and sulfur containing heterocyclic compounds fused heterocycles and drug-like compounds. For examples in
broadly exist in various natural and synthetic products, and play 2013 Bazgir et al. described a one-pot, four-component
7–10
vital roles in medicinal chemistry. Among these heterocycles, synthesis of a novel class of functionalized imidazo[1,2-a]pyri-
pyridine derivatives, such as imidazopyridine, pyridopyr- dine derivatives starting from readily available inputs including
imidine, and thiazolopyridine derivatives have received diverse diamines, 1,1-bis(methylthio)-2-nitroethene, aldehydes
considerable attention over the past years due to their diverse and activated methylene compounds in EtOH under reux
11,12
34
biological activities and clinical applications.
Imidazopyr- conditions (Scheme 1, Entry a). In 2014 Yildirim et al. reported
idine derivatives have shown a broad range of interesting bio- a base-catalyzed one-pot cyclocondensation reaction of acryloyl
logical activities, such as antifungal, antitumor, antiviral, and cinnamoyl chlorides with b-nitroenamine derivatives under
13
antibacterial, anti-HIV, antipyretic, analgesic, hypnoselective, mild basic conditions, which affords target thiazolopyridinone
35
anxioselective, anti-inammatory, anticonvulsant, antiulcer, or imidazopyridinone derivatives (Scheme 1, Entry b). In 2017
14
immunomodulatory activities; also pyridopyrimidine deriva- and 2018 we developed an efficient, one-pot, multi-component
15
tives are found to exhibit a broad spectrum of potent anti- synthesis of imidazopyridine, pyridopyrimidine, thiazolopyr-
12
bacterial, antiallergic, antimicrobial,
anti-inammatory, idine, and oxazolopyridine fused heterocyclic systems via reac-
tion of various diamines, cysteamine hydrochloride,
ethanolamine, 1,1-bis(methylthio)-2-nitroethene, cyanoaceto-
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 hydrazide and aromatic aldehydes in ethanol at reux (Scheme
3
6,37
3
†
1
3780040
1, Entry c).
Herein we report synthesis of a new class of
pyridopyrimidinone, and
Electronic supplementary information (ESI) available. See DOI:
0.1039/c9ra06054e
imidazopyridinone,
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A reaction condition is optimized using response surface
methodology (RSM). A central composite design with ve
replicates at the center point requiring 13 treatments was used.
The two independent variables (temperature (A) and water
content of aqueous ethanol (B)), levels (Table 1), and the results
obtained aer running the experiments are represented in
Table 2. The following responses were analyzed: yield of product
1 2
(R ) and reaction time (R ).
Optimum conditions with respect to yield, purity of product and
ꢀ
reaction time were as follow: temperature 72 C, water content of
aqueous ethanol 33%. Verication experiments, carried out at the
predicted conditions showed values reasonably close to those pre-
dicted and further conrmed the adequacy of predicted models.
On the basis of the central composite design, the cubic
1
model relationship between the experimental yield (R ) and the
process variables (temperature (A) and water content of aqueous
ethanol (B)) in coded units is obtained from eqn (1).
2
R ¼ 82.60 + 11.31A ꢁ 18.74B ꢁ 0.25AB ꢁ 10.55A
1
2
2
2
ꢁ
9.30B + 11.49A B ꢁ 5.06AB
(1)
1
where R represents the experimental yield of the reaction, then
A (temperature) and B (water content of aqueous ethanol) are
the coded variables in the reaction.
Fig. 1 illustrates the good linear correlation between the actual
and predicted yield and sufficient accuracy of the forecast values.
Therefore, the models can be used to predict the yield of product
successfully.
Scheme
1 Use of enamines derived from 1,1-bis(methylthio)-2-
nitroethene in organic synthesis.
thiazolopyridinone derivatives through a simple one-pot, multi-
The ANOVA for response surface cubic models are reported in
component reaction of diverse diamines or cysteamine hydro- Table 3. The model F-value of 189.50 implies the model is signi-
chloride, 1,1-bis(methylthio)-2-nitroethene, aromatic alde- cant. The “Lack of Fit F-value” is 0.71 then it is not signicant
hydes, and 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) relative to the pure error. Non-signicant lack of t is good and we
ꢀ
in ethanol/water (2 : 1) at 72 C (Scheme 1, Entry d). RSM in want the model to t. The “Pred R-Squared” of 0.9586 is in
conjunction with a central composite design was used for reasonable agreement with the “Adj R-Squared” of 0.9910; i.e., the
modeling and optimizing the synthetic process.
deviation is about 0.3.
The effects of temperature and water content of aqueous ethanol
on the total reaction yield are shown in Fig. 2. The total yield varied
from 37% to 90%. As temperature increased, the yield increased.
The changes in yield versus the water content of aqueous ethanol is
minor compared to that of temperature. The highest yield (90%)
Result and discussion
The one-pot, multi-component reaction of various diamines or
cysteamine hydrochloride
1
with 1,1-bis(methylthio)-2-
ꢀ
was obtained at 62.5 C and at 0% water. The lowest yield (37%) was
nitroethene 2, aromatic aldehydes 3, and 2,2-dimethyl-1,3-
ꢀ
at 62.5 C and at 100% water.
dioxane-4,6-dione (Meldrum's acid) 4, in EtOH/H
2
O (2 : 1) at
The effects of temperature and the water content of aqueous
ethanol on the total reaction time are shown in Fig. 3. The analysis
of total reaction time (R ) showed the signicant Lack of t and it is
2
not good. So the temperature and water content of aqueous ethanol
have no effect on the reaction time and the total reaction time was
almost identical and short in any case.
ꢀ
7
2 C, gave imidazopyridinone, pyridopyrimidinone, and thia-
zolopyridinone derivatives 5 in moderate to good yields
Scheme 2).
(
Table 1 Selected variables and levels used in central composite design
Levels
Variables
Code Units ꢁ1
0
+1
ꢀ
Reaction temperature
Water content of aqueous ethanol
A
B
C
25
0
62.5 100
50 100
%
Scheme 2 Synthetic scheme for the products 5a–o.
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Table 2 Process variables and experimental data for two factors, three pyridinecarboxaldehyde was used the reaction did not work.
a
levels response surface design
The substitutions of the aromatic aldehydes had some inu-
ence on the yields and reaction times. Reaction with aromatic
aldehydes carrying an electron-withdrawing group, such as
chloro and nitro groups, usually resulted in good yields and
short reaction times; those carrying electron-donating groups
such as methoxy group, resulted in relatively poorer yields. The
reaction did not work, when the reaction was performed using
ethanolamine, cyclohexane-1,2-diamine and benzene-1,2-
diamine.
ꢀ
Run
A ( C)
B (%)
R
1
(%)
2
R (min)
1
2
3
4
5
6
7
8
9
62.50
35.98
89.02
62.50
25.00
62.50
100.00
62.50
62.50
89.02
62.50
62.50
35.98
50.00
85.36
14.64
50.00
50.00
50.00
50.00
0.00
50.00
85.36
100.00
50.00
14.64
80
50
77
83
45
84
77
90
84
62
37
82
64
7
5
5
6
11
5
5
5
5
6
The structures of products were fully characterized using
their infrared (IR), mass spectrometry, proton hydrogen-1
1
1
1
1
0
1
2
3
1
nuclear magnetic resonance ( H NMR), carbon-13 nuclear
11
5
5
1
3
magnetic resonance ( C NMR) spectra. For example, the mass
spectrum of 5a displayed the molecular ion peak at m/z 293 with
frequency of 53% which was in accordance with the proposed
structure. The IR spectrum of this structure indicated absorp-
a
ꢀ
A ¼ temperature ( C), B ¼ water content of aqueous ethanol (%), R
1
¼
yield of reaction, R
2
¼ reaction time.
ꢁ1
tion bands due to the NH stretching (3231 cm ) as well as
ꢁ
1
bands at 2922, 1704, 1623, 1486 and 1337 cm due to the CH,
1
C]O, C]C and NO2 groups. The H NMR spectrum of 5a
The scope of the reaction substrate was explored under showed doublet of doublet for the CH group (d 2.55, 3.21 ppm,
2
2
3
optimized conditions. Several kind of aromatic aldehydes, and
JHH ¼ 15.6 Hz, J ¼ 7.8 Hz), multiplets for CH NH and CH N
HH
2
2
various diamines were tolerated. The reaction was completed groups (d 3.69–3.97 ppm), doublet for CH group (d 4.52 ppm,
3
aer 5–180 min to afford corresponding S- and N-heterocyclic
JHH ¼ 7.5 Hz), two doublets for the aromatic region (d 7.16,
3
systems 5a–p, in moderate to good yields (50–89%). As shown 7.32 ppm, J ¼ 8.4 Hz) and one singlet for NH group (d 9.74
HH
1
13
in Table 4, reactions with diamines, usually resulted in good ppm). The H-decoupled C NMR spectrum of 5a showed 11
yields and short reaction times. Reactions with cysteamine distinct resonances. There are three signals for CH and CH2
hydrochloride, resulted in low yields and long reaction times. groups (d 37.0, 43.0, 43.9 ppm), and signals at 106.3 and
Also the structures of the aldehydes had obvious inuence on 167.6 ppm, which were assigned C–NO and C]O groups,
2
1
13
the yield of product and reaction time. Reactions involving respectively. The H and C NMR spectra of 5b–p are similar to
aromatic aldehydes usually went smoothly and resulted in good those of 5a except for the aryl and diamine moieties, which
yields and short reaction times. Reaction involving hetero- exhibited characteristic signals with appropriate chemical
aromatic aldehyde (such as furfural) and aliphatic aldehyde shis (see the ESI†).
(such as butyraldehyde), on the other hand, were normally slow
An acceptable reaction mechanism for this one-pot, multi-
and resulted in low and trace yields, respectively. When the 4- component reaction is designated in Scheme 3. The one-pot
Fig. 1 Linear correlation between the actual and predicted yield.
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Table 3 ANOVA for response surface cubic model
Source
Sum of square
Degree of freedom
Mean square
F value
p-Value, prob > F
Model
A-temperature
B-percentage of water in ethanol
AB
3501.88
512.00
1404.50
0.25
774.28
601.67
263.96
51.28
7
1
1
1
1
1
1
1
0
500.27
512.00
1404.50
0.25
772.28
601.67
263.96
51.28
189.50
193.94
532.01
0.095
293.29
227.91
99.99
<0.0001 signicant
<0.0001
<0.0001
0.7707
<0.0001
<0.0001
0.0002
0.0070
2
A
2
B
2
A B
2
AB
19.43
3
A
0.000
0.000
3
B
0
Residual
Lack of t
Pure error
13.20
2.0
11.20
5
1
4
2.64
2.00
2.80
0.71
0.4456 not signicant
Correlation total
3515.08
12
protocol started with the reaction of various diamines or are expressed in parts per million (ppm), and coupling constant
cysteamine hydrochloride and 1,1-bis(methylthio)-2- (J) are reported in hertz (Hz). Elemental analyses for C, H and N
1
nitroethene 2 to afford enamine 6. Also condensation reaction were performed using a PerkinElmer 2004 series [II] CHN
between 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) elemental analyzer. Mass spectra were recorded with an Agilent
and the aromatic aldehydes gave adduct 7, which then reacted 5975C VL MSD with Triple-Axis Detector operating at an ioni-
with enamine 6 to form intermediate 8. Compound 10 was zation potential of 70 eV.
formed from 8 through imine–enamine tautomerism and
cyclocondensation. Finally, decarboxylation of 10 yielded the
product 5.
General procedure for the synthesis of product 5
Synthesis of imidazopyridinone and pyridopyrimidinone
derivatives. The mixtures of various diamines (1 mmol), 1,1-
Experimental
General
bis(methylthio)-2-nitroethene (0.165 g, 1 mmol) and 10 mL
ꢀ
EtOH/H O (2 : 1) at 72 C in a 50 mL ask was stirred for 6 h.
2
The various diamines, cysteamine hydrochloride, 1,1- Aer completion of the reaction (monitored by thin-layer
bis(methylthio)-2-nitroethene, aldehydes, 2,2-dimethyl-1,3- chromatography, hexane/ethyl acetate 1 : 1), aromatic alde-
dioxane-4,6-dione (Meldrum's acid) and solvents were hyde (1 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's
purchased from Sigma-Aldrich chemical company and were acid) (0.144 g, 1 mmol) were added to the reaction mixture, and
used as received without further purication. Melting points it was stirred under optimized condition for the time given in
were determined with an electrothermal 9100 apparatus. Table 4. Then, the reaction mixture was cooled to room
Infrared (IR) spectra were recorded on a Bruker Tensor 27 temperature and ltered to give the crude product. The solid
spectrometer. Nuclear magnetic resonance (NMR) spectra were was washed with ethanol to give product in good yields.
obtained on a Bruker DRX-300 Avance instrument (300 MHz for
H and 75.4 MHz for C) with DMSO as solvent. Chemical shis cysteamine hydrochloride (0.113 g, 1 mmol), 1,1-bis(methylthio)-2-
Synthesis of thiazolopyridinone derivatives. The mixtures of
1
13
Fig. 2 The effects of temperature and water content of aqueous ethanol on the total reaction yield.
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Table 4 One-pot, multi-component synthesis of imidazopyridinone, pyridopyrimidinone, and thiazolopyridinone derivatives 5a–p
a
a
Entry
Aldehyde
Amine
Product
Time (min)
Yield (%)
1
5
88
2
5
87
3
10
89
4
20
75
5
6
7
5
85
65
53
120
180
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Table 4 (Contd.)
a
a
Entry
Aldehyde
Amine
Product
Time (min)
Yield (%)
8
120
60
9
150
57
1
0
25
76
1
1
15
70
1
2
25
74
1
3
150
57
1
4
180
50
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Table 4 (Contd.)
a
a
Entry
Aldehyde
Amine
Product
Time (min)
Yield (%)
Trace
1
5
180
b
1
6
180
67
1
7
8
—
—
—
—
—
—
1
1
9
0
—
—
—
—
—
—
2
a
Amine (1 mmol), 1,1-bis(methylthio)-2-nitroethene (1 mmol), aromatic aldehyde (1 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's
b
acid) (1 mmol) were used. Ref. 38.
nitroethene (0.165 g, 1 mmol), 10 mL EtOH/H O (2 : 1), and Et N was ltered. The solid was washed with ethanol to give product in
2
3
ꢀ
(
140 mL, 1 mmol) at 72 C in a 50 mL ask was stirred for 5 h. Aer moderate yields.
completion of the reaction (monitored by thin-layer chromatog- 7-(4-Chlorophenyl)-2,3,6,7-tetrahydro-8-nitroimidazo[1,2-a]pyr-
raphy, hexane/ethyl acetate 1 : 1), aromatic aldehyde (1 mmol), 2,2- idin-5(1H)-one (5a). White solid; yield: 0.257 g (88%); mp 299–
ꢀ
1
2
dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) (0.144 g, 1 mmol) 301 C. H NMR (300 MHz, DMSO-d
6
): d 2.55 (d, JHH ¼ 15.6 Hz,
2
3
were added to the reaction mixture, and it was stirred under opti- 1H, CH
2
), 3.21 (dd, JHH ¼ 15.6 Hz, JHH ¼ 7.8 Hz, 1H, CH
2
),
3
mized condition for the time given in Table 4. The reaction mixture 3.69–3.97 (m, 4H, CH
2
NH and CH
2
N), 4.52 (d, JHH ¼ 7.5 Hz, 1H,
3
3
was monitored by thin layer chromatography (hexane/ethyl acetate CH), 7.16 (d, J ¼ 8.4 Hz, 2H, Ar), 7.32 (d, J ¼ 8.4 Hz, 2H,
HH
HH
1
3
1
: 1); aer completion of the reaction, the reaction mixture was Ar), 9.74 (s, 1H, NH). C NMR (75.4 MHz, DMSO-d ): d 37.0,
6
cooled to room temperature and the product (as colorless crystals) 43.0, 43.9, 106.3, 128.8, 129.0, 131.9, 141.9, 153.0, 167.6. IR
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ꢁ1
(
2 12 4 5
KBr) (nmax/cm ): 3231 (NH), 2922 (CH), 1704 (C]O), 1623 (C] C), 1520 and 1345 (NO ), 1219 (C–N). Anal. calc. for C13H N O
C), 1486 and 1337 (NO ), 1214 (C–N). MS (EI, 70 eV): m/z (%) ¼ (304.26): C, 51.32; H, 3.98; N, 18.41. Found: C, 51.56; H, 3.64; N,
2
+
2
93 (M , 53), 276 (42), 240 (100), 218 (23), 182 (59), 151 (35), 136 18.16.
(
45), 70 (18), 42 (14). Anal. calc. for C H ClN O (293.71): C,
7-(3-Fluorophenyl)-2,3,6,7-tetrahydro-8-nitroimidazo[1,2-a]pyr-
1
3
12
3 3
5
3.16; H, 4.12; N, 14.31. Found: C, 53.01; H, 4.51; N, 14.03.
-(4-Bromophenyl)-2,3,6,7-tetrahydro-8-nitroimidazo[1,2-a]pyr-
idin-5(1H)-one (5b). White solid; yield: 0.294 g (87%); mp 305– 1H, CH
idin-5(1H)-one (5d). White solid; yield: 0.207 g (75%); mp 253–
ꢀ
1
2
7
255 C. H NMR (300 MHz, DMSO-d
6
): d 2.59 (d, JHH ¼ 16.6 Hz,
2
3
2
), 3.20 (m, JHH ¼ 16.6 Hz, JHH ¼ 8.1 Hz, 1H, CH
2
),
ꢀ
1
2
3
3
1
3
07 C. H NMR (300 MHz, DMSO-d
6
): d 2.55 (d, JHH ¼ 16.6 Hz, 3.70–3.94 (m, 4H, CH
2
NH and CH
2
N), 4.55 (d, JHH ¼ 7.5 Hz, 1H,
2
3
H, CH
2
), 3.21 (dd, JHH ¼ 16.6 Hz, JHH ¼ 7.8 Hz, 1H, CH
2
), CH), 6.96–7.06 (m, 3H, Ar), 7.28–7.35 (m, 1H, Ar), 9.75 (s, 1H,
3
13
.69–3.97 (m, 4H, CH NH and CH N), 4.51 (d, J ¼ 7.8 Hz, 1H, NH). C NMR (75.4 MHz, DMSO-d ): d 37.4, 43.1, 44.0, 106.2,
2
2
HH
6
3
3
2
2
CH), 7.10 (d, J ¼ 7.2 Hz, 2H, Ar), 7.45 (d, J ¼ 7.2 Hz, 2H, 113.8 (d, J ¼ 21 Hz), 114.2 (d, J ¼ 21 Hz), 122.8, 131.1,
HH
HH
CF
CF
1
3
1
Ar), 9.73 (s, 1H, NH). C NMR (75.4 MHz, DMSO-d ): d 37.1, 145.9, 153.1, 162.8 (d,
J
¼ 244 Hz), 167.6. Anal. calc. for
6
CF
43.1, 44.0, 106.3, 120.3, 129.1, 131.9, 142.3, 153.0, 167.6. IR
13 3 3
C H12FN O (277.25): C, 56.32; H, 4.36; N, 15.16. Found: C,
ꢁ1
(
KBr) (nmax/cm ): 3224 (NH), 2921 (CH), 1699 (C]O), 1623 (C] 56.70; H, 4.06, N, 15.38.
C), 1486 and 1337 (NO 8-(4-Chlorophenyl)-1,2,3,4,7,8-hexahydro-9-nitropyrido[1,2-a]
37 (M -1, 25), 320 (22), 291 (58), 240 (100), 212 (12), 182 (51), pyrimidin-6-one (5e). White solid; yield: 0.260 g (85%); mp 282–
2
), 1215 (C–N). MS (EI, 70 eV): m/z (%) ¼
+
3
1
ꢀ
1
36 (29), 116 (33), 70 (49), 42 (22). Anal. calc. for C13
H
12BrN
3
O
3
284 C. H NMR (300 MHz, DMSO-d ): d 1.89–1.98 (m, 2H, CH ),
6
2
2
2
3
(
1
338.16): C, 46.17; H, 3.58; N, 12.43. Found: C, 46.52; H, 3.21; N, 2.65 (d, J ¼ 15.0 Hz, 1H, CH ), 3.21 (dd, J ¼ 15.0 Hz, J
HH
2
HH
HH
2.12.
¼ 7.5 Hz, 1H, CH ), 3.41–3.89 (m, 4H, CH NH and CH N), 4.59
2
2
2
3
3
2,3,6,7-Tetrahydro-8-nitro-7-(4-nitrophenyl)imidazo[1,2-a]pyr-
(d, J ¼ 6.6 Hz, 1H, CH), 7.15 (d, J ¼ 8.4 Hz, 2H, Ar), 7.31
HH
HH
3
1
3
idin-5(1H)-one (5c). Yellow solid; yield: 0.270 g (89%); mp 264– (d, JHH ¼ 7.2 Hz, 2H, Ar), 11.55 (s, 1H, NH). C NMR (75.4
ꢀ
1
2
2
1
3
66 C. H NMR (300 MHz, DMSO-d
H, CH
.71–3.99 (m, 4H, CH
6
): d 2.59 (d, JHH ¼ 15.6 Hz, MHz, DMSO-d
6
): d 19.5, 36.0, 38.6, 108.6, 128.8, 129.0, 131.9,
2
3
ꢁ1
2
), 3.26 (dd, JHH ¼ 15.6 Hz, JHH ¼ 8.1 Hz, 1H, CH
2
), 140.9, 152.9, 168.6. IR (KBr) (nmax/cm ): 3089 (NH), 2927 (CH),
3
2
NH and CH
2
N), 4.68 (d, JHH ¼ 7.5 Hz, 1H, 1710 (C]O), 1618 (C]C), 1502 and 1330 (NO
2
), 1232 (C–N). MS
3
3
+
CH), 7.44 (d, JHH ¼ 8.7 Hz, 2H, Ar), 8.12 (d, JHH ¼ 8.7 Hz, 2H, (EI, 70 eV): m/z (%) ¼ 307 (M , 23), 290 (17), 261 (100), 196 (20),
1
3
Ar), 9.79 (s, 1H, NH). C NMR (75.4 MHz, DMSO-d ): d 37.6, 178 (13), 151 (37), 115 (19), 84 (31), 56 (29). Anal. calc. for
6
4
3.1, 44.0, 105.8, 124.3, 128.3, 146.9, 150.8, 153.0, 167.2. IR C H ClN O (307.73): C, 54.64; H, 4.59; N, 13.65. Found: C,
14 14 3 3
ꢁ1
(KBr) (nmax/cm ): 3227 (NH), 2923 (CH), 1712 (C]O), 1628 (C] 54.26; H, 4.90; N, 13.49.
Scheme 3 Plausible mechanism for the formation of product 5.
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Fig. 3 The effects of temperature and the water content of aqueous ethanol on the total reaction time.
7-(4-Bromophenyl)-2,3,6,7-tetrahydro-8-nitrothiazolo[3,2-a]
(321.04): C, 48.59; H, 3.45; N, 13.08. Found: C, 48.79; H, 3.82; N,
pyridin-5-one (5f). Yellow solid; yield: 0.230 g (65%); mp 204– 13.50.
ꢀ
1
2
2
1
CH
06 C. H NMR (300 MHz, DMSO-d ): d 2.60 (d, J ¼ 16.5 Hz,
2,3,6,7-Tetrahydro-8-nitro-7-phenylimidazo[1,2-a]pyridin-
6
HH
ꢀ
H, CH ), 3.17–3.39 (m, 3H, CH and CH S), 3.96–4.06 (m, 1H, 5(1H)-one (5j). White solid; yield: 0.196 g (76%); mp 266–268 C.
2
2
2
3
1
2
N), 4.32–4.39 (m, 1H, CH
2
N), 4.64 (d, JHH ¼ 8.4 Hz, 1H,
H NMR (300 MHz, DMSO-d
6
): d 2.55 (d, JHH ¼ 16.2 Hz, 1H,
2
3
3
2
3
CH), 7.14 (d, JHH ¼ 8.4 Hz, 2H, Ar), 7.36 (d, JHH ¼ 8.4 Hz, 2H, CH
), 3.22 (dd, JHH ¼ 16.2 Hz, JHH ¼ 7.5 Hz, 1H, CH
), 3.73–
2
2
1
3
3
Ar). C NMR (75.4 MHz, DMSO-d
6
): d 29.1, 37.7, 49.4, 120.9, 3.96 (m, 4H, CH
2
NH and CH
2
N), 4.51 (d, JHH ¼ 7.2 Hz, 1H, CH),
ꢁ
1
13
1
2
(
24.8, 129.0, 132.3, 140.3, 159.9, 166.6. IR (KBr) (nmax/cm ): 7.02–7.29 (m, 5H, Ar), 9.73 (s, 1H, NH). C NMR (75.4 MHz,
918 (CH), 1699 (C]O), 1573 (C]C), 1420 and 1350 (NO
), 1223 DMSO-d ): d 37.6, 43.0, 43.9, 106.6, 126.8, 127.3, 129.1, 142.9,
C–N). MS (EI, 70 eV): m/z (%) ¼ 355 (M , 58), 339 (100), 309 (40), 153.1, 167.8.
81 (17), 213 (16), 182 (22), 140 (18), 102 (21), 60 (15). Anal. calc.
2,3,6,7-Tetrahydro-7-(4-methoxyphenyl)-8-nitroimidazo[1,2-a]
2
6
+
2
for C H BrN O S (355.21): C, 43.96; H, 3.12; N, 7.89. Found: C, pyridin-5(1H)-one (5k). White solid; yield: 0.202 g (70%); mp
1
3
11
2 3
ꢀ
1
2
4
3.56; H, 3.33; N, 8.26.
,3,6,7-Tetrahydro-8-nitro-7-phenylthiazolo[3,2-a]pyridin-5-one
5g). Yellow solid; yield: 0.146 g (53%); mp 175–177 C. H NMR CH ), 3.68 (s, 1H, OCH
307–309 C. H NMR (300 MHz, DMSO-d
6
): d 2.55 (d, JHH
¼
2
3
2
16.5 Hz, 1H, CH
2
), 3.14 (dd, JHH ¼ 16.5 Hz, JHH ¼ 7.8 Hz, 1H,
ꢀ
1
(
(
3
(
5
1
2
3
), 3.72–3.97 (m, 4H, CH
2
NH and CH
N),
2
2
3
3
300 MHz, DMSO-d
.40 (m, 3H, CH and CH
m, 1H, CH N), 4.63 (d, J
6
): d 2.66 (d, JHH ¼ 16.2 Hz, 1H, CH
S), 3.95–4.05 (m, 1H, CH
N), 4.33–4.41 7.03 (d, JHH ¼ 7.8 Hz, 2H, Ar), 9.69 (s, 1H, NH). C NMR (75.4
¼ 7.5 Hz, 1H, CH), 7.09–7.32 (m, MHz, DMSO-d ): d 36.7, 43.0, 43.9, 55.4, 107.0, 114.4, 127.8,
H, Ar). C NMR (75.4 MHz, DMSO-d ): d 29.0, 38.3, 49.4, 125.3, 134.7, 153.0, 158.6, 167.9.
2
), 3.25– 4.32 (d, JHH ¼ 7.5 Hz, 1H, CH), 6.81 (d, JHH ¼ 7.5 Hz, 2H, Ar),
3
13
2
2
3
2
2
HH
6
1
3
6
26.7, 127.8, 129.5, 140.9, 159.6, 166.8.
-(4-Chlorophenyl)-2,3,6,7-tetrahydro-8-nitrothiazolo[3,2-a]
2,3,6,7-Tetrahydro-7-(3-methoxyphenyl)-8-nitroimidazo[1,2-a]
pyridin-5(1H)-one (5l). White solid; yield: 0.213 g (74%); mp 213–
7
ꢀ
1
2
pyridin-5-one (5h). Yellow solid; yield: 0.186 g (60%); mp 128– 215 C. H NMR (300 MHz, DMSO-d
): d 2.56 (d, JHH ¼ 16.5 Hz,
6
ꢀ
1
2
2
3
1
1
CH
30 C. H NMR (300 MHz, DMSO-d
H, CH ), 3.18–3.40 (m, 3H, CH
N), 4.32–4.40 (m, 1H, CH
6
): d 2.65 (d, JHH ¼ 16.2 Hz, 1H, CH
2
), 3.14 (dd, JHH ¼ 16.5 Hz, JHH ¼ 8.1 Hz, 1H, CH
2
), 3.69
2
2
and CH
2
S), 3.96–4.06 (m, 1H, (s, 1H, OCH
3
), 3.79–3.97 (m, 4H, CH
NH and CH N), 4.49 (d,
2 2
3
3
3
J
HH ¼ 7.5 Hz, 1H, CH), 6.66 (s, 2H, Ar), 6.77 (d, JHH ¼ 7.2 Hz,
2
2
N), 4.65 (d, JHH ¼ 7.5 Hz, 1H,
3
3
3
13
CH), 7.14 (d, J ¼ 8.7 Hz, 2H, Ar), 7.35 (d, J ¼ 8.4 Hz, 2H, 1H, Ar), 7.18 (t, JHH ¼ 8.1 Hz, 1H, Ar), 9.72 (s, 1H, NH). C NMR
HH
HH
1
3
Ar). C NMR (75.4 MHz, DMSO-d ): d 29.1, 37.7, 49.5, 124.9, (75.4 MHz, DMSO-d
6
): d 37.5, 43.0, 43.9, 55.3, 106.5, 112.2,
6
ꢁ
1
1
2
28.7, 129.4, 132.4, 139.9, 159.9, 166.6. IR (KBr) (nmax/cm ): 113.1, 118.6, 130.2, 144.5, 153.1, 159.9, 167.8.
918 (CH), 1703 (C]O), 1573 (C]C), 1507 and 1350 (NO
7-(Furan-2-yl)-2,3,6,7-tetrahydro-8-nitroimidazo[1,2-a]pyridin-
2
), 1246
(
C–N).
,3,6,7-Tetrahydro-8-nitro-7-(4-nitrophenyl)thiazolo[3,2-a]
pyridin-5-one (5i). Yellow solid; yield: 0.182 g (57%); mp 145– 1H, CH
5(1H)-one (5m). White solid; yield: 0.141 g (57%); mp 241–
ꢀ
1
2
2
243 C. H NMR (300 MHz, DMSO-d
6
): d 2.67 (d, JHH ¼ 16.5 Hz,
2
3
), 3.10 (dd, JHH ¼ 16.5 Hz, JHH ¼ 7.5 Hz, 1H, CH
),
2
2
ꢀ
1
2
3
1
2
47 C. H NMR (300 MHz, DMSO-d
6
): d 2.70 (d, JHH ¼ 16.8 Hz, 3.70–3.97 (m, 4H, CH
2
NH and CH
2
N), 4.61 (d, JHH ¼ 6.9 Hz, 1H,
H, CH ), 3.07–3.46 (m, 3H, CH and CH S), 3.99–4.09 (m, 1H, CH), 6.04 (s, 1H, Ar), 6.31 (s, 1H, Ar), 7.50 (s, 1H, Ar), 9.63 (s, 1H,
2
2
2
3
13
CH N), 4.33–4.41 (m, 1H, CH N), 4.81 (d, J
HH
¼ 8.1 Hz, 1H, NH). C NMR (75.4 MHz, DMSO-d
6
): d 32.0, 36.6, 43.0, 43.8,
2
2
3
3
CH), 7.42 (d, J ¼ 8.7 Hz, 2H, Ar), 8.15 (d, J ¼ 8.7 Hz, 2H, 104.9, 105.7, 110.8, 142.6, 152.7, 154.7, 167.7.
HH
HH
1
3
Ar). C NMR (75.4 MHz, DMSO-d
1
2
(
2
6
): d 29.1, 38.2, 49.5, 124.2,
2,3,6,7-Tetrahydro-7-(3-methoxyphenyl)-8-nitrothiazolo[3,2-a]
ꢁ
1
24.6, 128.3, 147.2, 148.7, 160.4, 166.3. IR (KBr) (nmax/cm ): pyridin-5-one (5n). Yellow solid; yield: 0.153 g (50%); mp 130–
ꢀ
1
2
919 (CH), 1709 (C]O), 1573 (C]C), 1522 and 1357 (NO
2
), 1226 132 C. H NMR (300 MHz, DMSO-d
), 3.27–3.40 (m, 3H, CH and CH
3.93–4.03 (m, 1H, CH N), 4.33–4.41 (m, 1H, CH
2
6
): d 2.70 (d, JHH ¼ 16.5 Hz,
S), 3.70 (s, 1H, OCH ),
N), 4.61 (d, JHH
+
C–N). MS (EI, 70 eV): m/z (%) ¼ 321 (M , 36), 304 (100), 274 (45), 1H, CH
2
2
2
3
3
46 (12), 199 (8), 140 (6), 60 (11). Anal. calc. for C13
H
11
N
3
O
5
S
2
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3
¼
7.2 Hz, 1H, CH), 6.61–6.83 (m, 3H, Ar), 7.21 (t, JHH ¼ 7.8 Hz, 11 G. M. Ziarani, N. H. Nasab, M. Rahimifard and A. A. Soorki, J.
1
3
1
H, Ar). C NMR (75.4 MHz, DMSO-d ): d 29.0, 38.2, 49.4, 55.4,
Saudi Chem. Soc., 2015, 19, 676–681.
6
1
12.8, 112.9, 118.3, 125.1, 130.6, 142.5, 159.6, 160.1, 166.8.
12 S. M. Roopan, S. M. Patil and J. Palaniraja, Res. Chem.
Intermed., 2016, 42, 2749–2790.
2
,3,6,7-Tetrahydro-8-nitro-7-propylimidazo[1,2-a]pyridin-5(1H)-
ꢀ
1
one (5o). White solid; mp 174–176 C. H NMR (300 MHz, 13 L. R. Wen, Z. R. Li, M. Li and H. Cao, Green Chem., 2012, 14,
DMSO-d
J
7
9
6
): d 0.83 (t, 3H, CH
HH ¼ 16.8 Hz, 1H, CH ), 2.77 (dd, JHH ¼ 16.8 Hz, JHH
.2 Hz, 1H, CH ), 3.62–3.93 (m, 5H, CH and CH NH and CH N),
.54 (s, 1H, NH).
3
), 1.15–1.45 (m, 4H, 2CH
2
), 2.42 (d,
707–716.
2
2
3
2
¼
14 S. H. Li, Y. H. Shen, N. Gao and J. T. Li, Eur. J. Chem., 2010, 7,
779–784.
15 I. Yavari, M. Nematpour and E. Sodagar, Monatsh. Chem.,
2
2
2
2
015, 146, 2135–2138.
6 M. Mamaghani and R. Hossein Nia, J. Heterocycl. Chem.,
017, 54, 1700–1722.
7 S. Abdolmohammadi and M. Afsharpour, Chin. Chem. Lett.,
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1
1
1
Conclusion
2
We have reported a simple and clean synthesis of imidazopyr-
idinone, pyridopyrimidinone, and thiazolopyridinone deriva-
tives. We were able to optimize the reaction conditions using
RSM in conjunction with a central composite design. Further
experimentation revealed the optimal values of the water
content of aqueous ethanol (33%), and reaction temperature (72
2
1
1
9 A. M. Rad and M. Mokhtary, Int. Nano Lett., 2015, 5, 109–123.
0 A. H. Shamroukh, A. E. Rashad and F. M. E. Abdelmegeid, J.
Chem. Pharm. Res., 2016, 8, 734–772.
2
ꢀ
C). Also good yield of product in mild conditions show that the
2
1 M. Boominathan, M. Nagaraj, C. Maheshwaran,
S. Muthusubramanian and N. Bhuvanesh, J. Heterocycl.
Chem., 2014, 51, 244–248.
experimental results are in good agreement with the predicted
values, and the model successfully can be used to predict the
synthesis of such heterocyclic compounds.
2
2
2 G. A. El-Hiti, Monatsh. Chem., 2003, 134, 837–841.
3 M. E. Azab, G. A. M. El-Hag Ali and A. H. F. Abd El-Wahab,
Acta Pharm., 2003, 53, 213–221.
Conflicts of interest
2
2
4 H. L. Chen and H. Y. Guo, J. Chem. Res., 2012, 36, 162–165.
5 F. Shi, C. Li, M. Xia, K. Miao, Y. Zhao, S. Tu, W. Zheng,
G. Zhang and N. Ma, Bioorg. Med. Chem. Lett., 2009, 19,
The authors declare no competing nancial interest.
Acknowledgements
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565–5568.
2
6 R. A. Mekheimer, N. M. Hilmy, A. A. Hameed, S. Dacrory and
K. U. Sadek, Synth. Commun., 2011, 41, 2511–2516.
7 K. M. Wang, S. J. Yan and J. Lin, Eur. J. Org. Chem., 2014,
We gratefully acknowledge the nancial support of this
research from Imam Khomeini International University. We
thank the Iran National Science Foundation (No. 97021367) for
2
1
129–1145.

nancial support.
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8 P. H. Yang, Res. Chem. Intermed., 2016, 42, 5617–5637.
9 L. Pan, X. Bi and Q. Liu, Chem. Soc. Rev., 2013, 42, 1251–1286.
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