An Efficient One-pot Three-component Method for the Synthesis of 5-Amino-3-(2-oxo-2H-chromen-3-yl)-7-aryl-7H-thiazolo[3,2-a]pyridine-6,8-dicarbonitriles

Article abstract of DOI:10.1002/jhet.3472

A facile, convenient, and adequate method has been developed for the synthesis of novel 5-amino-3-(2-oxo-2H-chromen-3-yl)-7-aryl-7H-thiazolo[3,2-a]pyridine-6,8-dicarbonitriles (6) by employing 2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetonitrile (3) as an important precursor. Initially, we have synthesized the target compounds in a stepwise manner and then approached a tandem method to examine the feasibility of one-pot method. Subsequently, one-pot three-component protocol has been established for the synthesis of title compounds by the reaction of 3 with benzaldehyde and malononitrile in refluxing ethanol engender a new six-membered thiazolo[3,2-a]?pyridine as a hybrid scaffold. Reaction conditions were optimized for this reaction and a broad substrate scope with various aryl and heteroaryl aldehydes make this protocol very practical, attractive, and worthy. Mechanistic aspects for the formation of these compounds were outlined comprehensively. Characterization of these newly synthesized compounds was achieved by means of IR, ¹H NMR, ¹³C NMR, and HRMS.

Full text of DOI:10.1002/jhet.3472

Month 2019
An Efficient One-pot Three-component Method for the Synthesis of 5-
Amino-3-(2-oxo-2H-chromen-3-yl)-7-aryl-7H-thiazolo[3,2-a]pyridine-
6,8-dicarbonitriles
*
Kavitha Kotthireddy,
Srikrishna Devulapally, Pramod Kumar Dubey, and Aparna Pasula
Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad College of Engineering, Kukatpally,
Hyderabad, Telangana 500085, India
*E-mail: kavithakothireddy@gmail.com
Received August 16, 2018
DOI 10.1002/jhet.3472
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A facile, convenient, and adequate method has been developed for the synthesis of novel 5-amino-3-(2-
oxo-2H-chromen-3-yl)-7-aryl-7H-thiazolo[3,2-a]pyridine-6,8-dicarbonitriles (6) by employing 2-(4-(2-oxo-
2H-chromen-3-yl)thiazol-2-yl)acetonitrile (3) as an important precursor. Initially, we have synthesized the
target compounds in a stepwise manner and then approached a tandem method to examine the feasibility
of one-pot method. Subsequently, one-pot three-component protocol has been established for the synthesis
of title compounds by the reaction of 3 with benzaldehyde and malononitrile in refluxing ethanol engender
a new six-membered thiazolo[3,2-a] pyridine as a hybrid scaffold. Reaction conditions were optimized for
this reaction and a broad substrate scope with various aryl and heteroaryl aldehydes make this protocol very
practical, attractive, and worthy. Mechanistic aspects for the formation of these compounds were outlined
comprehensively. Characterization of these newly synthesized compounds was achieved by means of IR,
1H NMR, 13C NMR, and HRMS.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
(antimicrobial), riluzole (anticonvulsant), pramipexole
(anti-Parkinson’s), dasatinib (anti-cancer), melaxicam
(anti-inflammatory), zopolrestat (anti-diabetic), febuxostat
(anti-gout), nitazoxanide (antiparasitic), etc. Various
researchers reported the diverse therapeutic applications
of thiazoles as antihypertensive [15], anti-tubercular [16],
anti-proliferative [17], antioxidant [18], and EP1 receptor
antagonist [19] agents. Literature review has disclosed
that thiazoles in combination with coumarin ring in their
core structure as a hybrid scaffold have unveiled
Heterocyclic compounds occupy central position in
organic chemistry because they play vital role in the
treatment of human ailments. Indeed, 80% of the drugs
are constituted by heterocyclic ring systems. Among all,
the fragrant compound coumarin and its derivatives are
powerful scaffolds that exert remarkable applications in
medicinal, materials chemistry, and agro-chemical fields,
which have been recently reviewed by us [1]. They have
been found to display various therapeutic activities
that include anti-bacterial [2], anti-tumor [3], anti-
inflammatory [4], anti-HIV [5], anticoagulant [6],
anti-virus [7], anti-tubercular [8], anti-diabetic [9], anti-
thrombotic [10], antioxidant [11], activity etc. Apart from
these, coumarin and its related compounds have been
found to exhibit various applications in materials
chemistry, such as light emitting properties [12],
fluorescent sensors [13], and as dyes [14].
significant
pharmacological
activities
such
as
anticonvulsant [20], antimicrobial [21], anti-inflammatory
[22], anti-tumor [23], antioxidant [24], etc. Also,
thiazolo[3,2-a]pyridines with two or more fused
heterocyclic rings in their structure have prominent
diverse bioactivities such as CDK2-cyclin-A inhibitor
[25], α-glucosidase inhibitor [26], uterus stimulant [27],
and antimicrobial activities [28].
These aforementioned considerable biological activities
have stimulated interest in the synthesis of a new class of
coumarin derivatives with several new approaches for
six-membered and five-membered rings, and their fused
On the other hand, 1,3-thiazoles are also prominent
skeletal motif in number of drugs, few of them are
ritonavir (anti-HIV), abafungin (antifungal), sulfathiazole
© 2019 Wiley Periodicals, Inc.

K. Kotthireddy, S. Devulapally, P. K. Dubey, and A. Pasula
Vol 000
hybrid scaffolds have been developed during our research
that has base to frame this article. Although there are
reports for the synthesis of thiazolo[3,2-a]pyridines, there
is still no report for the preparation of coumarin-
thiazolo[3,2-a]pyridines [29–31]. Thus, in continuation of
our research on the synthesis of hybrid scaffolds of
coumarins [32,33], herein, we wish to report efficient and
environmentally benign methods for the synthesis of
novel coumarin-thiazolo[3,2-a]pyridines via a one-pot
three-component method.
A plausible mechanism for the formation of products 6
by the aforementioned transformation via tandem method
has been deliberated and given in Scheme 3. Initially,
piperidine will facilitate the Knoevenagel condensation
between active methylene center of 3 and aryl/heteroaryl
aldehyde (4) to form α,β-unsaturated nitrile compound 5.
As well, piperidine available in the same reaction vessel
will abstract the proton from the active methylene center
of malononitrile and generates the carbanion that will
undergo nucleophilic attack with 5 to give A that
immediately starts the cyclization process to accord an
intermediate B. The latter will abstract the proton from
the protonated piperidine and undergoes tautomerism to
get converted into a stabilized product 6.
RESULTS AND DISCUSSION
Commercially available salicylaldehyde on reaction
with ethyl acetoacetate in methanol containing a catalytic
amount of piperidine afforded 3-acetyl-2H-chromen-2-
one (1), which on bromination with tetrabutylammonium
tribromide in acetic acid for 2 h resulted in the formation
of 3-(2-bromoacetyl)-2H-chromen-2-one (2) [34]. 3-(2-
Bromoacetyl)-2H-chromen-2-one (2) on reaction with 2-
cyanothioacetamide in ethanol under reflux conditions for
2 h afforded the required synthon, 2-(4-(2-oxo-2H-
chromen-3-yl)thiazol-2-yl)acetonitrile (3) (Scheme 1).
In our initial attempts, we have synthesized the title
compounds in a stepwise method by the reaction of 2-(4-
(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetonitrile (3) with
aryl/heteroaryl aldehydes (4) using piperidine as a base in
ethanol to obtain (E)-2-(4-(2-oxo-2H-chromen-3-yl)
thiazol-2-yl)-3-arylacrylonitriles (5), followed by their
reaction with malononitrile in refluxing ethanol using
piperidine as a base. The structure of these compounds
has been confirmed on the basis of their spectral data
In another set of reactions, this stepwise and tandem
method was performed by reacting aryl/heteroaryl
aldehyde (4) and malononitrile initially to acquire an
arylidene-malononitrile followed by their reaction with
2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetonitrile (3).
Thus, equimolar amounts of aryl/heteroaryl aldehyde (4)
and malononitrile reacted together at RT for 2–3 h
employing piperidine as a base to afford arylidene-
malononitrile (7), which further on reaction with 2-(4-(2-
oxo-2H-chromen-3-yl)thiazol-2-yl) acetonitrile (3) under
refluxing ethanol for 3–5 h resulted in the formation of
required product 6. In addition, in a tandem method, we
have successfully synthesized the desired products 6,
where we have avoided the isolation of arylidene-
malononitriles (7) (Scheme 4).
The mechanism for this approach has been proposed and
depicted systematically in Scheme 5. Here, piperidine will
first facilitate the Knoevenagel condensation reaction
between aryl/heteroaryl aldehydes and malononitrile to
give arylidene-malononitriles (7). As well, piperidine
available in the vessel will abstract the proton from the
active methylene center of 3 and generates carbanion; this
will subsequently attack the arylidene-malononitriles by a
nucleophilic approach to give an intermediate A. The
latter undergoes cyclization process and generates
intermediate C, which will further withdraw its proton
from the protonated piperidine to obtain the product 6.
With the aforementioned enthusiastic and optimistic
results, we intended to synthesize the title compounds in a
one-pot method. Thus, in an initial model one-pot reaction,
we have chosen equimolar amounts of 2-(4-(2-oxo-2H-
1
such as IR, H NMR, 13C NMR, and HRMS (please see
Experimental section). In order to synthesize the target
compounds in a one-pot method, we have bring about the
aforementioned sequence of reactions in a tandem
approach, where we have treated 3 with aryl/heteroaryl
aldehyde (4), and after completion of reaction, (as
indicated by the disappearance of starting materials on
TLC) equimolar amount of malononitrile was added in
the same reaction vessel. The mixture was further
refluxed for 3–5 h to afford a product that is identical
with compounds 6 that have been prepared earlier in the
stepwise route (Scheme 2).
Scheme 1. Synthesis of 2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetonitrile (3). [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
An Efficient One-pot Three-component Method
Scheme 2. Stepwise and tandem syntheses of 5-amino-3-(2-oxo-2H-chromen-3-yl)-7-aryl-7H-thiazolo[3,2-a]pyridine-6,8-dicarbonitriles (6). [Color
figure can be viewed at wileyonlinelibrary.com]
chromen-3-yl)thiazol-2-yl)acetonitrile (3), benzaldehyde
(4a), and malononitrile as substrates and were reacted
together in a single reaction vessel using piperidine as a
catalyst and ethanol as a solvent under refluxing conditions.
Fascinatingly, this reaction successfully completed to
produce the desired product 6a in a good yield, and it was
found to be identical with the one that prepared earlier in
the stepwise and tandem routes.
other catalysts, triethylamine was found to impetus this
one-pot three-component reaction with a high yield of
product 6a in a faster reaction time (Table 1).
After having the best reaction condition in hand, that is,
the use of triethylamine in ethanol, we have extended this
method to various other aldehyde derivatives (4) and
generalized the method to achieve the title compounds
(6) in good to excellent yields (Scheme 6).
To find out the best reaction condition in terms of time
and product yield, this one-pot three-component reaction
has been screened for various catalysts in ethanol at
reflux temperature by proceeding equimolar amounts of
3, benzaldehyde (4a), and malononitrile. From this
screening study, it is greatly notable that compared with
Experimental.
Melting points are uncorrected and
were determined in open capillary tubes using hot
sulfuric acid bath. TLC analyses were carried out on
silica gel-G coated sheets supplied by Merck Company,
and visualization was performed using UV lamp and
iodine staining. IR spectra were recorded using Perkin
Scheme 3. Plausible mechanism for the formation of 6 by a stepwise method. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. Kotthireddy, S. Devulapally, P. K. Dubey, and A. Pasula
Vol 000
Scheme 4. Stepwise and tandem syntheses of 5-amino-3-(2-oxo-2H-chromen-3-yl)-7-aryl-7H-thiazolo[3,2-a]pyridine-6,8-dicarbonitriles (6). [Color
figure can be viewed at wileyonlinelibrary.com]
1
Elmer model-446 FTIR in KBr. NMR spectra were
recorded in DMSO-d6 using TMS as an internal standard
using Varian 400-MHz spectrometer instrument. Mass
spectra were recorded on Agilent instrument using ESI
method. Chemicals like salicylaldehydes, malononitrile,
and solvents were purchased from commercial suppliers
and were used as such.
Procedure for the preparation of 3 from 2. A mixture of
2 (10 mmol) and 2-cyanothioacetamide (10 mmol) was
refluxed in ethanol (30 mL) for a period of 2 h. After the
completion of reaction, as indicated by TLC, the reaction
mixture was poured into ice-cold water (100 mL). The
separated solid was filtered, washed with water
(2 × 50 mL) thoroughly, and air-dried at RT. The product
was recrystallized from methanol to obtain a pure white
colored compound 3.
ring), 2206 cmÀ1 (strong, sharp, ─CN group); H NMR
(400 MHz, DMSO-d6/TMS): δ = 4.66 (s, 2H, ─CH2)
7.38–7.98 (complex, m, 4H, Ar─H), 8.43 (s, 1H,
Ar─H), 8.78 (s, 1H, Ar─H); 13C NMR (100 MHz,
DMSO-d6/TMS): 21.5, 115.8, 116.9, 118.9, 119.8, 121.1,
124.7, 129.1, 132.1, 139.5, 147.3, 152.5, 158.6, 158.9;
HRMS calculated for C14H9N2O2S [M + H]+: 269.0384,
found: 269.0321.
General procedure for the synthesis of 5 from 3 and 4.
A
mixture of 3 (10 mmol), various aldehydes (10 mmol), and
a catalytic amount of piperidine and ethanol (30 mL) was
stirred at RT for a period of 2–4 h. Completion of the
reaction was monitored by TLC analysis. After
completion of reaction, the mixture was poured into ice-
cold water (100 mL), and the separated solid was filtered
and washed with water (2 × 50 mL). These crude
compounds were recrystallized from a suitable solvent to
give pure 5.
White solid; yield: 2.35 g (88%); mp 177–179°C; IR
(KBr): 1730 cmÀ1 (strong, sharp, ─CO of coumarin
Scheme 5. Plausible mechanism for the formation of 6 by a stepwise method. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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Month 2019
An Efficient One-pot Three-component Method
Table 1
Optimization for the suitable catalyst in one-pot method to obtain 6a.
S. No.
Catalyst
Solvent
Reaction condition
Reaction time
Yielda (%)
1
2
3
4
5
6
7
8
9
Piperidine
Morpholine
Piperazine
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
5 h
7 h
6 ½ h
7 ½ h
6 h
75
69
65
61
60
55
47
68
82
44
N-methylpiperazine
N-ethylpiperazine
DABCO
8 h
DBU
8 ½ h
7 ½ h
3 ½ h
12 h
Diethylamine
Triethylamine
Imidazole
10
aYield refer to crude product.
Bold text signifies best optimized condition for the reaction to get the product in high yield.
2-(4-(2-Oxo-2H-chromen-3-yl)thiazol-2-yl)-3-
phenylacrylonitrile (5a). Yellow color solid; yield: 2.52 g
3-(4-Chlorophenyl)-2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-
yl)acrylonitrile (5c).
Yellow color solid; yield: 2.84 g
(71%); mp 222–224°C (methanol); IR (KBr): 1718 cmÀ1
(strong, sharp, ─CO of coumarin ring), 2156 cmÀ1
(strong, sharp, ─CN group); 1H NMR (400 MHz,
DMSO-d6/TMS): δ = 7.38–8.07 (complex, m, 9H,
Ar─H), 8.41 (s, 1H, vinylic─H), 8.54 (s, 1H, Ar─H),
8.85 (s, 1H, Ar─H); 13C NMR (100 MHz, DMSO-d6/
TMS): 109.8, 116.5, 117.9, 118.9, 119.4, 119.8, 121.2,
121.8, 122.1, 125.2, 127.2, 129.3, 129.5, 132.7, 137.0,
143.0, 146.7, 151.2, 153.8, 163.0; HRMS calculated for
(73%); mp 202–204°C (methanol); IR (KBr):
1720 cmÀ1 (strong, sharp, ─CO of coumarin ring),
2205 cmÀ1 (strong, sharp, ─CN group); 1H NMR
(400 MHz, DMSO-d6/TMS): δ = 7.42–8.04 (complex,
m, 8H, Ar─H), 8.43 (s, 1H, vinylic─H), 8.57 (s, 1H,
Ar─H), 8.83 (s, 1H, Ar─H); 13C NMR (100 MHz,
DMSO-d6/TMS): 109.1, 116.1, 118.5, 120.7, 125.1,
125.4, 128.0, 128.4, 128.7, 128.9, 129.1, 129.6, 133.0,
133.4, 134.5, 143.6, 146.3, 153.2, 153.4, 163.1; HRMS
calculated for C21H12ClN2O2S [M + H]+: 391.0308,
C21H13N2O2S [M + H]+: 357.0697, found: 357.0621.
3-(4-Hydroxyphenyl)-2-(4-(2-oxo-2H-chromen-3-yl)thiazol-
2-yl)acrylonitrile (5b). Yellow color solid; yield: 2.52 g
found: 391.0323.
3-(4-Nitrophenyl)-2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)
acrylonitrile (5d). Yellow color solid; yield: 3.12 g (78%);
(68%); mp 179–181°C (acetonitrile); IR (KBr):
1712 cmÀ1 (strong, sharp, ─CO of coumarin ring),
2208 cmÀ1 (strong, sharp, ─CN group); 1H NMR
(400 MHz, DMSO-d6/TMS): δ = 7.42–8.04 (complex, m,
8H, Ar─H), 8.43 (s, 1H, vinylic─H), 8.55 (s, 1H,
Ar─H), 8.89 (s, 1H, Ar─H), 9.45 (s, 1H, ─OH); 13C
NMR (100 MHz, DMSO-d6/TMS): 108.7, 115.781,
115.8, 116.3, 118.9, 120.6, 120.9, 121.1, 124.3, 125.7,
127.7, 128.0, 129.4,130.3, 143.4, 146.4, 153.1, 153.1,
157.0, 158.5, 158.0; HRMS calculated for C21H13N2O3S
[M + H]+: 373.0646, found: 373.0662.
mp 196–198°C (acetone); IR (KBr): 1723 cmÀ1 (strong,
sharp, ─CO of coumarin ring), 2198 cmÀ1 (strong, sharp,
─CN group); 1H NMR (400 MHz, DMSO-d6/TMS):
δ = 7.42–8.08 (complex, m, 8H, Ar─H), 8.42 (s, 1H,
vinylic─H), 8.55 (s, 1H, Ar─H), 8.88 (s, 1H, Ar─H);
13C NMR (100 MHz, DMSO-d6/TMS): 108.7, 116.1,
118.3, 120.9, 124.9, 125.4, 127.9, 128.3, 128.7, 128.7,
129.0, 129.4, 133.3, 133.4, 134.4, 143.7, 146.1, 153.0,
153.5, 162.9; HRMS calculated for C21H12N3O4S
[M + H]+: 402.0548, found: 402.0565.
Scheme 6. One-pot three-component synthesis of title compounds using triethylamine. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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K. Kotthireddy, S. Devulapally, P. K. Dubey, and A. Pasula
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3-(4-Bromophenyl)-2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-
yl)acrylonitrile (5e).
vinylic─H), 8.42 (s, 1H, Ar─H), 8.76 (s, 1H, Ar─H);
13C NMR (100 MHz, DMSO-d6/TMS): 109.4, 112.5,
113.7, 116.4, 118.6, 119.5, 120.7, 124.7, 125.7, 127.2,
128.7, 129.8, 131.0, 142.0, 143.3, 146.7, 151.8, 154.3,
162.2; HRMS calculated for C19H11N2O3S [M + H]+:
347.0490, found: 347.0487.
2-(4-(2-Oxo-2H-chromen-3-yl)thiazol-2-yl)-3-(pyridin-3-yl)
acrylonitrile (5j). Yellow color solid; yield: 2.59 g (73%);
Yellow color solid; yield: 3.20 g
(74%); mp 211–213°C (ethyl acetate); IR (KBr):
1731 cmÀ1 (strong, sharp, ─CO of coumarin ring),
2205 cmÀ1 (strong, sharp, ─CN group); 1H NMR
(400 MHz, DMSO-d6/TMS): δ = 7.44–8.04 (complex, m,
8H, Ar─H), 8.44 (s, 1H, vinylic─H), 8.55 (s, 1H,
Ar─H), 8.83 (s, 1H, Ar─H); 13C NMR (100 MHz,
DMSO-d6/TMS): 109.1, 111.5, 111.7, 116.7, 116.8,
118.3, 120.9, 122.6, 124.9, 125.9, 127.3, 128.7, 128.7,
129.0, 143.4, 146.3, 149.6, 149.9, 153.1, 153.8; HRMS
calculated for C21H12BrN2O2S [M + H]+: 434.9802,
mp 196–198°C (methanol); IR (KBr): 1718 cmÀ1 (strong,
sharp, ─CO of coumarin ring), 2179 cmÀ1 (strong, sharp,
─CN group); 1H NMR (400 MHz, DMSO-d6/TMS):
δ = 7.34–7.96 (complex, m, 8H, Ar─H), 8.22 (s, 1H,
vinylic─H), 8.46 (s, 1H, Ar─H), 8.76 (s, 1H, Ar─H);
13C NMR (100 MHz, DMSO-d6/TMS): 109.3, 112.6,
113.7, 116.7, 118.5, 119.7, 120.3, 122.5, 124.6, 125.1,
125.8, 127.2, 128.6, 128.9, 136.0, 143.2, 146.6, 152.7,
154.8, 162.0; HRMS calculated for C20H12N3O2S
[M + H]+: 358.0650, found: 358.0662.
found: 434.9854.
3-(4-Fluorophenyl)-2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-
yl)acrylonitrile (5f).
Yellow color solid; yield: 2.61Àg1
(70%); mp 188–190°C (methanol); IR (KBr): 1714 cm
(strong, sharp, ─CO of coumarin ring), 2190 cmÀ1
(strong, sharp, ─CN group); 1H NMR (400 MHz,
DMSO-d6/TMS): δ = 7.42–8.05 (complex, m, 8H,
Ar─H), 8.43 (s, 1H, vinylic─H), 8.56 (s, 1H, Ar─H),
8.85 (s, 1H, Ar─H); 13C NMR (100 MHz, DMSO-d6/
TMS): 108.4, 115.5, 115.7, 117.4, 118.6, 120.6, 124.7,
125.7, 127.2, 128.8, 129.6, 130.9, 143.9, 146.2, 150.7,
153.6, 153.9, 154.4, 163.3; HRMS calculated for
General procedure for the synthesis of 6 from 5.
A
mixture of 5 (10 mmol), malononitrile (10 mmol), and a
catalytic amount of piperidine and ethanol (30 mL) was
refluxed on a water bath for a period of 3–5 h.
Completion of the reaction was monitored by TLC
analysis. After completion of reaction, the mixture was
poured into ice-cold water (100 mL), and the separated
solid was filtered and washed with water (2 × 50 mL).
These crude compounds were recrystallized from suitable
solvent to give the pure 6.
C21H12FN2O2S [M + H]+: 375.0603, found: 375.0610.
2-(4-(2-Oxo-2H-chromen-3-yl)thiazol-2yl)-3-(1H-pyrrol-2-yl)
acrylonitrile (5g). Yellow color solid; yield: 2.48 g (72%);
mp 198–200°C (methanol); IR (KBr): 1718 cmÀ1 (strong,
sharp, ─CO of coumarin ring), 2336 cmÀ1 (strong, sharp,
─CN group); 1H NMR (400 MHz, DMSO-d6/TMS):
δ = 7.33–7.91 (complex, m, 7H, Ar─H), 8.17 (s, 1H,
vinylic─H), 8.40 (s, 1H, Ar─H), 8.76 (s, 1H, Ar─H),
11.93 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6/
TMS): 109.8, 116.5, 117.9, 118.9, 119.4, 119.8, 121.2,
121.8, 122.1, 125.2, 127.2, 129.3, 129.5, 139.5, 143.0,
146.7, 151.2, 153.8, 161.8; HRMS calculated for
5-Amino-3-(2-oxo-2H-chromen-3-yl)-7-phenyl-7H-
thiazolo[3,2-a]pyridine-6,8-dicarbonitrile (6a). Yellow color
solid; yield: 3.08 g (73%); mp >250°C (ethanol); IR (KBr):
1718 cmÀ1 (strong, sharp, ─CO of coumarin ring),
2205 cmÀ1 (strong, sharp, ─CN group), 3400–3440
(broad medium, ─NH2 group); 1H NMR (400 MHz,
DMSO-d6/TMS): δ = 4.68 (s, 1H, ─CH─), 7.41–8.89
(complex, m, 13H, Ar─H & NH2); 13C NMR (100 MHz,
DMSO-d6/TMS): 37.7, 104.5, 115.9, 116.3, 118.9, 119.7,
121.5, 124.8, 129.1, 129.2, 129.8, 132.0, 132.2, 132.4,
140.1, 146.0, 148.3, 152.6, 158.7, 162.0; HRMS calculated
for C24H15N4O2S [M + H]+: 423.0914, found: 423.0918.
5-Amino-7-(4-hydroxyphenyl)-3-(2-oxo-2H-chromen-3-yl)-
C19H12N3O2S [M + H]+: 346.0650, found: 346.0661.
2-(4-(2-Oxo-2H-chromen-3-yl)thiazol-2yl)-3-(thiophen-2-yl)
acrylonitrile (5h). Yellow color solid; yield: 2.49 g (69%);
mp 187–189°C (methanol); IR (KBr): 1718 cmÀ1 (strong,
sharp, ─CO of coumarin ring), 2185 cmÀ1 (strong, sharp,
─CN group); 1H NMR (400 MHz, DMSO-d6/TMS):
δ = 7.30–7.92 (complex, m, 7H, Ar─H), 8.21 (s, 1H,
vinylic─H), 8.43 (s, 1H, Ar─H), 8.78 (s, 1H, Ar─H);
13C NMR (100 MHz, DMSO-d6/TMS): 109.5, 113.4,
116.5, 118.7, 119.4, 120.6, 124.6, 125.7, 127.7, 128.2,
128.8, 129.6, 130.9, 141.9, 143.2, 146.9, 151.7, 154.1,
162.0; HRMS calculated for C19H11N2O2S2 [M + H]+:
7H-thiazolo[3,2-a]pyridine-6,8-dicarbonitrile (6b).
Yellow
color solid; yield: 3.06
g (70%); mp 235–237°C
(methanol); IR (KBr): 1720 cmÀ1 (strong, sharp, ─CO of
coumarin ring), 2209 cmÀ1 (strong, sharp, ─CN group),
3300–3340 (broad medium, ─NH2 group), 3520–3570
(broad medium, ─OH group); 1H NMR (400 MHz,
DMSO-d6/TMS): δ = 4.65 (s, 1H, ─CH─), 7.40–8.89
363.0261, found: 363.0258.
(complex, m, 12H, Ar─H & NH2), 10.15 (s, 1H, OH); 13
C
3-(Furan-2-yl)-2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)
acrylonitrile (5i). Yellow color solid; yield: 2.50 g (67%);
NMR (100 MHz, DMSO-d6/TMS): 36.9, 104.8, 116.5,
117.9, 118.9, 119.4, 119.8, 121.2, 121.8, 122.1, 125.2,
127.2, 129.3, 129.5, 130.1, 132.7, 137.0, 139.5, 143.0,
146.7, 151.2, 153.8, 159.8, 162.1; HRMS calculated for
C24H15N4O3S [M + H]+: 439.0864, found: 439.0859.
mp 192–194°C (methanol); IR (KBr): 1734 cmÀ1 (strong,
sharp, ─CO of coumarin ring), 2210 cmÀ1 (strong, sharp,
─CN group); 1H NMR (400 MHz, DMSO-d6/TMS):
δ = 7.32–7.93 (complex, m, 7H, Ar─H), 8.18 (s, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
An Efficient One-pot Three-component Method
5-Amino-7-(4-chlorophenyl)-3-(2-oxo-2H-chromen-3-yl)-
(KBr): 1730 cmÀ1 (strong, sharp, ─CO of coumarin
ring), 2206 cmÀ1 (strong, sharp, ─CN group), 3400–
3440 (broad medium, ─NH group); H NMR (400 MHz,
DMSO-d6/TMS): δ = 4.65 (s, 1H, ─CH─), 7.40–7.89
(complex, m, 11H, Ar─H & NH2), 11.62 (s, 1H, NH);
13C NMR (100 MHz, DMSO-d6/TMS): 37.6, 105.3,
116.3, 117.5, 119.7, 120.7, 121.9, 125.1, 129.4, 129.6,
132.1, 139.0, 141.4, 144.0, 152.7, 159.2, 162.9; HRMS
calculated for C22H14N5O2S [M + H]+: 412.0868, found:
7H-thiazolo[3,2-a]pyridine-6,8-dicarbonitrile (6c).
Yellow
1
color solid; yield: 3.05 g (67%); mp 196–198°C
(acetonitrile); IR (KBr): 1715 cmÀ1 (strong, sharp, ─CO
of coumarin ring), 2224 cmÀ1 (strong, sharp, ─CN
group), 3350–3400 (broad medium, ─NH2 group); 1H
NMR (400 MHz, DMSO-d6/TMS): δ = 4.64 (s, 1H,
─CH─), 7.42–8.90 (complex, m, 12H, Ar─H & NH2);
13C NMR (100 MHz, DMSO-d6/TMS): 37.8, 59.3, 72.3,
105.0, 115.9, 116.6, 117.1, 118.5, 118.8, 125.0, 125.7,
127.5, 128.0, 129.2, 130.5, 131.0, 135.5, 138.9, 152.6,
412.0863.
5-Amino-3-(2-oxo-2H-chromen-3-yl)-7-(thiophen-2-yl)-7H-
thiazolo[3,2-a]pyridine-6,8-dicarbonitrile (6h). Yellow color
153.7,
158.7,
163.1;
HRMS
calculated
for
C24H14ClN4O2S [M + H]+: 457.0526, found: 457.0545.
5-Amino-7-(4-nitrophenyl)-3-(2-oxo-2H-chromen-3-yl)-7H-
thiazolo[3,2-a]pyridine-6,8-dicarbonitrile (6d). Yellow color
solid; yield: 2.99 g (70%); mp 223–225°C (acetonitrile); IR
(KBr): 1726 cmÀ1 (strong, sharp, ─CO of coumarin ring),
2190 cmÀ1 (strong, sharp, ─CN group), 3390–3430 (broad
1
solid; yield: 3.31 g (71%); mp >250°C (chloroform); IR
(KBr): 1717 cmÀ1 (strong, sharp, ─CO of coumarin
ring), 2205 cmÀ1 (strong, sharp, ─CN group), 3320–
3410 (broad medium, ─NH2 group); 1H NMR
(400 MHz, DMSO-d6/TMS): δ = 4.65 (s, 1H, ─CH─),
7.42–8.88 (complex, m, 12H, Ar─H & NH2); 13C NMR
(100 MHz, DMSO-d6/TMS): 37.4, 59.4, 72.7, 105.1,
116.2, 117.6, 118.1, 118.5, 123.4, 125.1, 125.6, 127.3,
128.0, 129.4, 130.4, 139.5, 145.6, 149.3, 152.9, 153.5,
medium, ─NH group); H NMR (400 MHz, DMSO-d6/
TMS): δ = 4.66 (s, 1H, ─CH─), 7.38–7.85 (complex, m,
11H, Ar─H & NH2); 13C NMR (100 MHz, DMSO-d6/
TMS): 37.2, 58.4, 71.0, 105.4, 116.5, 117.2, 118.2,
118.7, 123.5, 125.3, 125.6, 125.9, 127.1, 128.2, 128.6,
130.6, 138.7, 139.9, 152.4, 153.2, 159.6, 162.4; HRMS
calculated for C22H13N4O2S2 [M + H]+: 429.0479, found:
429.0460.
5-Amino-7-(furan-2-yl)-3-(2-oxo-2H-chromen-3-yl)-7H-
thiazolo[3,2-a]pyridine-6,8-dicarbonitrile (6i). Yellow color
158.8, 162.8; HRMS calculated for C24H14N5O4S
[M + H]+: 468.0766, found: 468.0755.
solid; yield: 2.76 g (67%); mp >250°C (ethanol); IR
(KBr): 1720 cmÀ1 (strong, sharp, ─CO of coumarin
ring), 2234 cmÀ1 (strong, sharp, ─CN group), 3390–
5-Amino-7-(4-bromophenyl)-3-(2-oxo-2H-chromen-3-yl)-
7H-thiazolo[3,2-a]pyridine-6,8-dicarbonitrile (6e).
Yellow
1
color solid; yield: 3.55 g (71%); mp >250°C (ethanol);
IR (KBr): 1722 cmÀ1 (strong, sharp, ─CO of coumarin
ring), 2214 cmÀ1 (strong, sharp, ─CN group), 3380–
3430 (broad medium, ─NH2 group); 1H NMR
(400 MHz, DMSO-d6/TMS): 4.66 (s, 1H, ─CH─), 7.41–
8.89 (complex, m, 12H, Ar─H & NH2); 13C NMR
(100 MHz, DMSO-d6/TMS): 37.6, 58.9, 71.8, 105.0,
115.5, 116.7, 118.0, 119.4, 121.1, 125.3, 125.8, 127.6,
129.4, 130.6, 131.8, 132.1, 139.6, 142.4, 152.4, 153.8,
159.6, 162.1; HRMS calculated for C24H14BrN4O2S
3430 (broad medium, ─NH group); H NMR (400 MHz,
DMSO-d6/TMS): δ = 4.65 (s, 1H, ─CH─), 7.40–7.90
(complex, m, 11H, Ar─H & NH2); 13C NMR (100 MHz,
DMSO-d6/TMS): 37.3, 58.6, 70.8, 105.6, 116.8, 117.4,
118.0, 118.6, 123.0, 125.5, 126.0, 126.3, 127.6, 128.4,
128.8, 130.0, 138.1, 139.6, 152.3, 153.1, 158.9, 162.1;
HRMS calculated for C22H13N4O3S [M + H]+: 413.0708,
found: 413.0715.
5-Amino-3-(2-oxo-2H-chromen-3-yl)-7-(pyridin-3-yl)-7H-
thiazolo[3,2-a]pyridine-6,8-dicarbonitrile (6j). Yellow color
[M + H]+: 501.0020, found: 501.0034.
5-Amino-7-(4-fluorophenyl)-3-(2-oxo-2H-chromen-3-yl)-7H-
thiazolo[3,2-a]pyridine-6,8-dicarbonitrile (6f). Yellow color
solid; yield: 2.70 g (64%); mp >250°C (methanol); IR
(KBr): 1725 cmÀ1 (strong, sharp, ─CO of coumarin
ring), 2210 cmÀ1 (strong, sharp, ─CN group), 3420–
1
3480 (broad medium, ─NH group); H NMR (400 MHz,
solid; yield: 2.75 g (63%); mp >250°C (methanol); IR
(KBr): 1719 cmÀ1 (strong, sharp, ─CO of coumarin
ring), 2210 cmÀ1 (strong, sharp, ─CN group), 3410–
3460 (broad medium, ─NH2 group); 1H NMR
(400 MHz, DMSO-d6/TMS): δ = 4.65 (s, 1H, ─CH─),
7.38–8.87 (complex, m, 12H, Ar─H & NH2); 13C NMR
(100 MHz, DMSO-d6/TMS): 37.7, 59.4, 72.3, 105.2,
115.6, 116.6, 118.2, 119.6, 120.2, 125.5, 125.9, 127.7,
128.6, 130.7, 131.1, 138.2, 138.9, 152.3, 153.9, 158.9,
159.5, 162.3; HRMS calculated for C24H13FN4O2S
DMSO-d6/TMS): δ = 4.66 (s, 1H, ─CH─), 7.39–7.88
(complex, m, 12H, Ar─H & NH2); 13C NMR (100 MHz,
DMSO-d6/TMS): 37.5, 58.4, 70.6, 105.2, 116.7, 116.9,
117.5, 119.9, 121.5, 121.7, 125.5, 129.7, 130.3, 132.6,
140.1, 141.9, 142.4, 144.4, 148.0, 150.1, 152.2, 158.5,
162.0; HRMS calculated for C23H14N5O2S [M + H]+:
424.0868, found: 424.0855.
General procedure for the tandem synthesis of 6 from 3
and 4.
A mixture of 3 (10 mmol), various aldehydes
[M + H]+: 440.0743, found: 440.0768.
5-Amino-3-(2-oxo-2H-chromen-3-yl)-7-(1H-pyrrol-2-yl)-7H-
thiazolo[3,2-a]pyridine-6,8-dicarbonitrile (6g). Yellow color
solid; yield: 2.58 g (63%); mp 205–207°C (methanol); IR
(10 mmol), and a catalytic amount of piperidine and
ethanol (30 mL) was stirred at RT for a period of 2–4 h.
Completion of the reaction was monitored by TLC
analysis. After completion of reaction, malononitrile
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. Kotthireddy, S. Devulapally, P. K. Dubey, and A. Pasula
Vol 000
(10 mmol) was added into the same reaction vessel and
6b: Yield: 3.50 g (80%);
6c: Yield: 4.01 g (88%);
6d: Yield: 3.64 g (78%);
6e: Yield: 4.15 g (83%);
6f: Yield: 3.38 g (77%);
6g: Yield: 3.24 g (79%);
6h: Yield: 3.59 g (84%);
6i: Yield: 3.05 g (74%);
6j: Yield: 3.34 g (79%).
refluxed on a water bath for a period of 3–5 h.
Completion of the reaction was monitored by TLC
analysis. After completion of reaction, the mixture was
poured into ice-cold water (100 mL), and the separated
solid was filtered and washed with water (2 × 50 mL).
These crude compounds were recrystallized from suitable
solvent to give the pure 6.
6a: Yield: 3.08 g (73%);
6b: Yield: 3.06 g (70%);
6c: Yield: 3.37 g (74%);
6d: Yield: 3.59 g (77%);
6e: Yield: 3.55 g (71%);
CONCLUSIONS
6f: Yield: 3.38 g (77%);
6g: Yield: 3.20 g (78%);
6h: Yield: 3.12 g (73%);
6i: Yield: 2.84 g (69%);
In summary, we have demonstrated efficient stepwise,
tandem, and one-pot three-component approach for the
synthesis of title compounds. Further, we have optimized
the reaction conditions by screening various catalysts to
obtain optimal conditions. Among all the methods
approached for the synthesis, one-pot three-component
method has been regarded as satisfactory and eminent
approach. The methods applied are operationally simple,
environmentally viable, atom economy, easy accessibility
of reactants, simple workup procedures, use of ethanol as
green solvent, and high yielding. The capacity of various
aldehydes including some heteroaryl aldehyde partners
makes this approach very attractive for the construction
of high-value and biologically significant heterocycles.
6j: Yield: 2.87 g (68%).
General procedure for the tandem synthesis of 6 from 4
and malononitrile.
A mixture of 4 (10 mmol),
malononitrile (10 mmol), and a catalytic amount of
piperidine and ethanol (30 mL) was stirred at RT for a
period of 1–4 h. Completion of the reaction was
monitored by TLC analysis. After completion of reaction,
3 (10 mmol) was added into the same reaction vessel and
refluxed on a water bath for a period of 3–5 h.
Completion of the reaction was monitored by TLC
analysis. After completion of reaction, the mixture was
poured into ice-cold water (100 mL), and the separated
solid was filtered and washed with water (2 × 50 mL).
These crude compounds were recrystallized from suitable
solvent to give the pure 6.
6a: Yield: 3.12 g (74%);
6b: Yield: 3.10 g (71%);
6c: Yield: 3.42 g (75%);
6d: Yield: 3.45 g (74%);
6e: Yield: 3.80 g (76%);
6f: Yield: 3.02 g (69%);
6g: Yield: 3.08 g (75%);
6h: Yield: 3.03 g (71%);
REFERENCES AND NOTES
[1] Kavitha, K.; Aparna, P. RJLBPC 2018, 4, 204 https://doi.org/
10.26479/2018.0402.16.
[2] Lafitte, D.; Lamour, V.; Tsvetkov, P. O.; Makarov, A. A.;
Klich, M.; Deprez, P.; Moras, D.; Briand, C.; Gilli, R. Biochemistry
2002, 41, 7217 https://doi.org/10.1021/bi0159837.
[3] Maucher, A.; von Angerer, E. J Cancer Res Clin Oncol 1994,
120, 502 https://doi.org/10.1007/BF01191806.
[4] Fylaktakidou, K.; Hadjipavlou-Litina, D.; Litinas, K.;
Nicolaides, D. Curr Pharm Des 2004, 10, 3813. https://doi.org/10.2174/
1381612043382710.
[5] Spino, C.; Dodier, M.; Sotheeswaran, S. Bioorg Med Chem
Lett 1998, 8, 3475 https://doi.org/10.1016/S0960-894X(98)00628-3.
[6] Manolov, I.; Maichle-Moessmer, C.; Nikolova, I.; Danchev,
N. Archiv der Pharmazie 2006, 339, 319. https://doi.org/10.1002/
ardp.200500149.
[7] Hwu, J. R.; Singha, R.; Hong, S. C.; Chang, Y. H.; Das, A. R.;
Vliegen, I.; De Clercq, E.; Neyts, J. Antiviral Res 2008, 77, 157. https://
doi.org/10.1016/j.antiviral.2007.09.003.
[8] Kawate, T.; Iwase, N.; Shimizu, M.; Stanley, S. A.;
Wellington, S.; Kazyanskaya, E.; Hung, D. T. Bioorg Med Chem Lett
2013, 23, 6052. https://doi.org/10.1016/j.bmcl.2013.09.035.
[9] Ibrar, A.; Tehseen, Y.; Khan, I.; Hameed, A.; Saeed, A.;
Furtmann, N.; Bajorath, J.; Iqbal, J. Bioorg Chem 2016, 68, 177. https://
doi.org/10.1016/j.bioorg.2016.08.005.
[10] Manish, J.; Surin, W. R.; Ankita, M.; Madhu, D.; Prem, P.;
Vivek, K.; Satish, K.; Siddiqui, H. H.; Kanwal, R. Chem Biol Drug Des
2013, 81, 499. https://doi.org/10.1111/cbdd.12000.
6i: Yield: 2.88 g (70%);
6j: Yield: 2.83 g (67%).
General procedure for the one-pot three-component
synthesis of 6. A mixture of 3 (10 mmol), 4 (10 mmol),
malononitrile (10 mmol), and a catalytic amount of
triethylamine and ethanol (30 mL) was refluxed on a
water bath for a period of 3–5 h. Completion of the
reaction was monitored by TLC analysis. After
completion of reaction, the mixture was poured into ice-
cold water (100 mL), and the separated solid was filtered
and washed with water (2 × 50 mL). These crude
compounds were recrystallized from suitable solvent to
give the pure 6.
[11] Kadhum, A. M. H.; Al-Amiery, A. A.; Musa, A. Y.;
Mohamad, A. B. Int J Mol Sci 2011, 12, 5747 https://doi.org/10.3390/
ijms12095747.
6a: Yield: 3.58 g (85%);
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
An Efficient One-pot Three-component Method
[12] Song, T.; Zhang, G.; Cui, Y.; Yang, Y.; Qian, G. Cryst Eng
[25] Vadivelan, S.; Sinha, B. N.; Irudayam, S. J.; Jagarlapudi, S. A.
R. P. J Chem Inf Model 2007, 47, 1526. https://doi.org/10.1021/
ci7000742.
[26] Park, H.; Hwang, K. Y.; Oh, K. H.; Kim, Y. H.; Lee, J. Y.;
Kim, K. Bioorg Med Chem 2008, 16, 284. https://doi.org/10.1016/j.
bmc.2007.09.036.
[27] Manhi, F. M.; Soliman, G. A. Bull Fac Pharm 1993, 31, 265
Chem Abstr 1993, 121, 50029.
[28] El-Hag, A. G.; Khalil, A.; Lamphon, R.; El-Maghraby, A.
Phosphorus, Sulfur Silicon Relat Elem 2005, 180, 1909 https://doi.org/
10.1080/104265090889620.
[29] Elgemeie, G. E. H.; Fatma, A. E.; Maksoud, A. E. A. Hetero-
cycles 1986, 24, 349. https://doi.org/10.3987/R-1986-02-0349.
[30] Fathya, N. M.; Abdel Mottia, F. M.; Elgemeie, G. E. H. Arch
Pharm 1988, 321, 509.
[31] Hassan, A. Y. Phosphorus, Sulfur, and Silicon 2009, 184,
2856 https://doi.org/10.1080/10426500802590244.
[32] Kavitha, K.; Srikrishna, D.; Dubey, P. K.; Aparna, P.
ARKIVOC 2018, 2018, 172. https://doi.org/10.24820/ark.5550190.
p010.655.
[33] Kavitha, K.; Srikrishna, D.; Sridhar, B.; Aparna, P. Mol Divers
2018 (Accepted article) https://doi.org/10.1007/s11030-018-9880-x.
[34] Srikrishna, D.; Dubey, P. K. New J Chem 2017, 41, 5168.
https://doi.org/10.1039/c7nj00504k.
Comm 2016, 18, 8366. https://doi.org/10.1039/C6CE01870J.
[13] Jung, H. S.; Kwon, P. S.; Jeong, W. L.; Jae, I. K.; Hong, C. S.;
Jong, W. K.; Shihai, Y.; Jin, Y. L.; Jung, H. L.; Taiha, J.; Jong, S. K. J Am
Chem Soc 2009, 131, 2008. https://doi.org/10.1021/ja808611d.
[14] Tao, W.; Yuxia, Z.; Mengquan, S.; Feipeng, W. Dyes Pigm
2007, 75, 104 https://doi.org/10.1016/j.dyepig.2006.04.019.
[15] Bagheri, M.; Shekarchi, M.; Jorjani, M.; Ghahremani, M. H.;
Vosooghi, M.; Shafiee, A. Arch Pharm (Weinheim) 2004, 337, 25.
https://doi.org/10.1002/ardp.200300810.
[16] Bairwa, V. K.; Telvekar, V. N. Comb Chem High Throughput
Screen 2013, 16, 244. https://doi.org/10.2174/1386207311316030009.
[17] Khan, M. H.; Hameed, S.; Akhtar, T.; Al-Masoudi, N. A.;
Al-Masoudi, W. A.; Jones, P. G.; Pannecouque, C. Med Chem Res
2016, 25, 2399 http://sci-hub.tw/10.1007/s00044-016-1669-9.
[18] Koppireddi, S.; Komsani, J. R.; Avula, S.; Pombala, S.;
Vasamsetti, S.; Kotamraju, S.; Yadla, R. EurJ Med Chem 2013, 66,
305. https://doi.org/10.1016/j.ejmech.2013.06.005.
[19] Atobe, M.; Naganuma, K.; Kawanishi, M.; Morimoto, A.;
Kasahara, K.; Ohashi, S.; Suzuki, H.; Hayashi, T.; Miyoshi, S. Bioorg
Med Chem Lett 2013, 23, 6064. https://doi.org/10.1016/j.bmcl.2013.09.032.
[20] Siddiqui, N.; Arshad, M. F.; Khan, S. A. Acta Pol Pharm 2009,
66, 161.
[21] Kamal, A.; Adil, S. F.; Jaki, T. R.; Siddardha, B.; Murthy, U.
Lett Drug Des Discov 2009, 6, 201. https://doi.org/10.2174/
157018009787847855.
[22] Kalkhambkar, R. G.; Kulkarni, G. M.; Shivkumar, H.; Rao, R.
SUPPORTING INFORMATION
N. Eur
J Med Chem 2007, 42, 1272. https://doi.org/10.1016/j.
ejmech.2007.01.023.
[23] Gouda, M. A.; Berghot, M. A.; Baz, E. A.; Hamama, W. S. Med
Chem Res 2012, 21, 1062. https://doi.org/10.1007/s00044-011-9610-8.
[24] Osman, H.; Arshad, A.; Lam, C. K.; Bagley, M. C. Chem Cent
J 2012, 6, 32 https://doi.org/10.1186/1752-153X-6-32.
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet