An efficient one-pot four-component Gewald reaction: Synthesis of substituted 2-aminothiophenes with coumarin–thiazole scaffolds under environmentally benign conditions

Article abstract of DOI:10.1080/17415993.2018.1556275

An elegant and efficient method has been outlined for the synthesis of novel 5-amino-4-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]-3-arylthiophene-2-carbonitriles employing a one-pot four-component reaction of various aldehydes, 2-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]acetonitrile, malononitrile and molecular sulfur independently in the presence of L-proline as a catalyst, under green reaction conditions. In an alternative approach, initially, the Knoevenagel condensation of these various aldehydes has been carried out with active methylene compounds malononitrile or 2-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]acetonitrile to obtain the corresponding condensed compounds. These compounds then further subjected to a one-pot three-component Gewald reaction with molecular sulfur using sodium bicarbonate as a simple and inexpensive catalyst to obtain the target compounds. The effect of solvent and catalyst on these reactions has been screened to obtain the optimal conditions. The advantages of this protocol are the use of mild reaction conditions at ambient temperature, environmental friendliness, good yields in faster reaction times, convenient operation procedures, and broad substrate scope.

Full text of DOI:10.1080/17415993.2018.1556275

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
An efficient one-pot four-component
Gewald reaction: Synthesis of substituted 2-
aminothiophenes with coumarin–thiazole
scaffolds under environmentally benign conditions
Kotthireddy Kavitha, Devulapally Srikrishna, Pramod Kumar Dubey & Pasula
Aparna
To cite this article: Kotthireddy Kavitha, Devulapally Srikrishna, Pramod Kumar Dubey & Pasula
Aparna (2018): An efficient one-pot four-component Gewald reaction: Synthesis of substituted
2-aminothiophenes with coumarin–thiazole scaffolds under environmentally benign conditions,
Journal of Sulfur Chemistry, DOI: 10.1080/17415993.2018.1556275
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JOURNAL OF SULFUR CHEMISTRY
https://doi.org/10.1080/17415993.2018.1556275
An efficient one-pot four-component Gewald reaction:
Synthesis of substituted 2-aminothiophenes with
coumarin–thiazole scaffolds under environmentally benign
conditions
Kotthireddy Kavitha , Devulapally Srikrishna, Pramod Kumar Dubey and
Pasula Aparna
Department of Chemistry, College of Engineering, Jawaharlal Nehru Technological University Hyderabad,
Kukatpally, Telangana, India
ABSTRACT
ARTICLE HISTORY
An elegant and efficient method has been outlined for the syn-
thesis of novel 5-amino-4-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]-3-
arylthiophene-2-carbonitriles employing a one-pot four-component
reaction of various aldehydes, 2-[4-(2-oxo-2H-chromen-3-yl)thiazol-
Received 4 September 2018
Accepted 27 November 2018
KEYWORDS
2
-aminothiophenes; one-pot
2
-yl]acetonitrile, malononitrile and molecular sulfur independently
four-component method;
Knoevenagel condensation;
Gewald reaction;
in the presence of L-proline as a catalyst, under green reaction condi-
tions. In an alternative approach, initially, the Knoevenagel conden-
sation of these various aldehydes has been carried out with active
methylene compounds malononitrile or 2-[4-(2-oxo-2H-chromen-3-
yl)thiazol-2-yl]acetonitrile to obtain the corresponding condensed
compounds. These compounds then further subjected to a one-
pot three-component Gewald reaction with molecular sulfur using
sodium bicarbonate as a simple and inexpensive catalyst to obtain
the target compounds. The effect of solvent and catalyst on these
reactions has been screened to obtain the optimal conditions. The
advantages of this protocol are the use of mild reaction conditions
at ambient temperature, environmental friendliness, good yields in
faster reaction times, convenient operation procedures, and broad
substrate scope.
environmentally benign
conditions
CONTACT Pasula Aparna
aparnajntu5@gmail.com
Department of Chemistry, College of Engineering,
Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, Telangana 500 085, India
Supplemental data for this article can be accessed here. https://doi.org/10.1080/17415993.2018.1556275
©
2018 Informa UK Limited, trading as Taylor & Francis Group

2
K. KAVITHA ET AL.
Introduction
Coumarin is a phytochemical that can be extracted from plants and microorganism
natural sources. It was studied extensively due to its distinct applications in the field
of synthetic organic chemistry, pharmacology, materials chemistry, and agrochemistry.
Coumarin and its derivatives are the constituents of commercially available medicines
namely fraxetin and esculetin which are known to exhibit anti-inflammatory and anti-
oxidant activities, respectively [1]. They exhibit diverse pharmacological properties in
particular anti-tumor [2], anti-diabetic [3], anti-microbial [4], and anti-thrombotic activ-
ities [5]. In addition to coumarins, thiazoles and its derivatives also have a significant role
in the field of medicinal chemistry where they found to exhibit a wide variety of activities
such as anti-tumor [6–8], anti-microbial [9], anti-convulsant [10], and anti-inflammatory
activities [11].
Furthermore, sulfur is significant in the medicinal field as sulfa drugs, large number
of sulfur-containing drugs and has various engineering applications. Sulfur is present
in the human body in the form of amino acids specifically in methionine, cysteine,
and substituted cysteines [12]. In addition, sulfur-containing heterocycles have paved a
way for medicinal chemistry research [13]. On the other hand, thiophene derivatives in
combination with other heterocyclic ring systems have wide variety of applications in phar-
maceutical field such as antidepressants [14], analgesics [15], anti-inflammatory [16], and
anti-microbial activities [17].
In particular, among the thiophene derivatives, 2-aminothiophenes are versatile mate-
rials and have wide scope to apply in every branch of the science. Aminothiophenes have
significant roles in exhibiting potent biological activities such as allosteric enhancers of
adenosine receptor [18] and glucagon receptor antagonist [19]. Moreover, they found
applications in the field of materials science, such as dyes [20], conductivity-based sensors
[
21], and biodiagnostics [22,23]. Generally, these substituted 2-aminothiophenes are pre-
pared by Gewald reaction by a base-promoted one-pot three-component reaction between
active methylene compound, sulfur and an aldehyde or a ketone [24,25]. The core structure
is formed in the multicomponent reaction between a ketone or an aldehyde, an activated
nitrile and sulfur. Since 1961 when the Gewald reaction was first reported, it became a uni-
versal method for the synthesis of substituted 2-aminothiophenes. But still, the research
and generation of new compounds with this method is rapidly expanding due to its easy
adaptability in the field of pharmaceutical and material chemistry. Although this one-pot
synthesis is well established, a step-wise procedure which involves the preparation of α,
β-unsaturated nitrile by the condensation of ketone or aldehyde with an activated nitrile,
followed by base-promoted reaction with sulfur will provide the better understanding in
reaction mechanism.
Nowadays, green and sustainable pathways are the ultimate goal, where reactions ideally
include the advantages of fewer steps, faster reaction time, safer methods of synthesis, easy
isolation procedures, viability in the laboratory, and high yield of the product. In continua-
tion of our earlier work [26,27], the importance of this field of heterocyclic chemistry gave
impetus to the present study. The data on synthesis, reactivity, mechanism for the forma-
tion of substituted 2-aminothiophenes containing coumarin and thiazole rings in a single
framework as hybrid scaffolds and their structural characterization has been systematically
studied and discussed in this article.

JOURNAL OF SULFUR CHEMISTRY
3
Results and discussion
Commercially available salicylaldehyde upon reaction with ethyl acetoacetate in methanol
containing a catalytic amount of piperidine at room temperature (RT) afforded 3-acetyl-
2
H-chromen-2-one (1), this on further bromination with tetrabutylammonium tribro-
mide in acetic acid for 2 h at RT resulted in the formation of 3-(2-bromoacetyl)-2H-
chromen-2-one (2) [28]. 3-(2-Bromoacetyl)-2H-chromen-2-one (2) on reaction with
2
-cyanothioacetamide in ethanol under reflux for 2 h emerged in the origination of 2-[4-
(2-oxo-2H-chromen-3-yl)thiazol-2-yl]acetonitrile (3). Reaction of (3) with benzaldehyde
4a) at room temperature for 2 h in the presence of piperidine as catalyst afforded the
(
corresponding condensed product, i.e. (E)-2-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]-3-
phenylacrylonitrile (5a) (Scheme 1).
Further, a one-pot three-component reaction between 5a, malononitrile and molec-
ular sulfur in the presence of piperidine and ethanol at RT for 6 h afforded 5-amino-
4
-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]-3-phenylthiophene-2-carbonitrile (6a) as the
major product along with by-product 5-amino-3-(2-oxo-2H-chromen-3-yl)-7-phenyl-
H-thiazolo[3,2-a]pyridine-6,8-dicarbonitrile (7a) (Scheme 2). Structure of these isolated
7
compounds was confirmed based on their NMR, IR, and HRMS data. It has been observed
from the literature that the formation of 7a and its related compounds is generally possi-
ble under reflux conditions with the same starting materials without the use of elemental
sulfur in the presence of a base catalyst [29,30].
With a view to obtain 6a as a sole product in maximum yield, and to avoid the forma-
tion of unwanted side product 7a, we have optimized this one-pot reaction conditions with
various base catalysts in ethanol at RT. Catalysts such as morpholine, piperazine, and tri-
ethylamine being secondary and tertiary amines act as strong bases and exhibited the same
results with the formation of side compound 7a as an impurity. It was observed from the
above catalyst screening that the use of mild organic bases instead of stronger bases will
do the job for this reaction. L-Proline can act both as acid and base being amphoteric in
nature, facilitates the chemical transformations in a concerted manner, indistinguishable
with enzymatic catalysis. Indeed we have selected L-proline as a mild base catalyst and car-
ried this experiment to achieve the desired product 6a in good yield as a single compound.
Scheme 1. Synthesis of 5a starting from 3-acetyl-2H-chromen-2-one.
Scheme 2. Synthesis of 6a in a one-pot three-component method.

4
K. KAVITHA ET AL.
Furthermore, the literature survey reveals that the use of inorganic bases for the Gewald
reaction instead of organic bases facilitates the formation of ylidene–sulfur intermediate
and the corresponding ring closure reaction [31]. Hence we have screened several inor-
ganic bases for this one-pot reaction and interestingly good-excellent results were obtained
for the formation of desired product 6a in significantly shorter reaction times. From this
screening study, it is clearly observed that all the inorganic bases are selective and specific
for the formation of the desired product 6a. Among all the bases employed for this screen-
ing study, NaHCO was found to be superior to other bases in terms of product yield and
3
reaction times (Table 1).
After having the best optimal conditions in hand, we have generalized this method, i.e.
the use of saturated sodium bicarbonate in ethanol has been extended to various other aryl
and heteroaryl aldehydes. Achieved the synthesis of target compounds 6(a–j) successfully
with fair yields (Scheme 3).
In another approach, we have synthesized the target compounds 6(a–j), initially
by the reaction of aryl/heteroaryl aldehydes 4(a–j) with malononitrile to obtain
arylidene-malononitriles 8(a–j) followed by their reaction with 2-[4-(2-oxo-2H-chromen-
3
-yl)thiazol-2-yl]acetonitrile (3) and molecular sulfur in ethanol using saturated sodium
bicarbonate as a base catalyst (Scheme 4).
With the above encouraging results, we were curious to synthesize these compounds
in a one-pot four-component reaction pathway. Thus, in an initial model one-pot
Table 1. Catalyst screening for the one-pot synthesis of 6a at RT.
a
Yield (%)
S. no.
Catalyst
Piperidine
Morpholine
Piperazine
Triethylamine
L-proline
Sodium bicarbonate
Solvent
Reaction time
6a
7a
1
2
3
4
5
6
7
8
a
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
6 h
61
64
67
56
75
90
86
84
8
5
9
12
0
0
5½ h
7½ h
5½ h
6 h
2 h
3½ h
2½ h
b
b
Sodium carbonate
0
0
Potassium carbonateb
Yield refers to the pure product.
Saturated aqueous solution.
b
Scheme 3. Synthesis of 6(a–j) in one-pot three-component method starting from 3.

JOURNAL OF SULFUR CHEMISTRY
5
Scheme 4. Alternative approach for the synthesis of 6(a–j).
Scheme 5. One-pot four-component synthesis of 6(a–j).
four-component reaction, we have reacted 2-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-
yl]acetonitrile (3), benzaldehyde (4a), molecular sulfur, and malononitrile using saturated
sodium bicarbonate as a base and ethanol as a solvent media. But the reaction did not pro-
ceed even after stirring for 20 h at RT and also at reflux temperature. This reaction has also
carried out by replacing NaHCO base with other inorganic bases such as Na CO and
3
2
3
K CO But product formation was not observed. It has been noted that these inorganic
2
3.
bases were not able to catalyze the Knoevenagel condensation between either 3 and 4a to
give 5a or 4a and malononitrile to give 8a, as described in our earlier communication [32].
Hence to overcome this problem and to synthesize the target compounds in a one-pot four-
component method, we have adopted L-proline, as an efficient catalyst (without the side
product formation) from the screening study (Table 1) and carried out the same experi-
ment. Thus equimolar amounts of 3, 4a, malononitrile, and molecular sulfur were reacted
together in a single reaction vessel usingL-proline as the catalyst. This reaction successfully
completed to accord corresponding product 6a in 73% yield. Further, we have extended
this method to various other aryl/heteroaryl aldehyde derivatives 4(b–j) and generalized
the method to produce the target compounds 6(b–j) in high yield (Scheme 5).

6
K. KAVITHA ET AL.
Scheme 6. Plausible rationale for the formation of ’6’ from 5.
Scheme 7. Plausible rationale for the formation of ’6’ from 8.

JOURNAL OF SULFUR CHEMISTRY
7
The formation of the products 6 (a–j) is assumed to proceed by two parallel mecha-
nisms. The first mechanism involves the initial condensation of aryl/heteroaryl aldehydes
with 2-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]acetonitrile (3) to afford the correspond-
ing 2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)-3-arylacrylonitriles (5). Michael addition
of malononitrile with 5 followed by its reaction with molecular sulfur and subsequent
cyclization gives the desired product 6(a–j) (Scheme 6).
The second mechanism involves initial condensation of aldehyde with malononitrile
to form arylidene-malononitriles (8) followed by their reaction with 3 and molecular
sulfur. L-Proline will abstract the proton form the active methylene center of 2-[4-(2-oxo-
2H-chromen-3-yl)thiazol-2-yl]acetonitrile (3) to generate the carbanion that undergoes
Michael addition with the ylidenic bond of 8, followed by its subsequent reaction with ele-
mental sulfur to form an intermediate A, this further cyclized by nucleophilic attack of the
sulfur atom with nitrile group to generate the intermediate B. The latter loses a molecule
of HCN followed by tautomerization to give the final product 6 (Scheme 7).
Conclusion
In summary, we have reported a mild and efficient protocol for the preparation of various
2
-aminothiophenes containing coumarin–thiazole hybrid scaffolds via a four-component
Gewald reaction. Thus we have successfully demonstrated the one-pot reaction of various
aldehydes with 2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetonitrile (3), malononitrile,
and sulfur at room temperature using L-proline as an efficient green catalyst. The use
of readily available starting materials, inexpensive and nontoxic catalysts like L-proline
and sodium bicarbonate for this Gewald reaction in environmentally friendly reaction
media are supremacy of this method. Furthermore, operational simplicity, good to excel-
lent product yields, and easy work-up procedures are prominent advantages of this method.
Given the large number of commercially available building blocks, this present method is
applicable for the synthesis of libraries with high diversity.
Experimental section
Melting points are uncorrected and were determined in open capillary tubes using hot
sulfuric acid bath. TLC analysis was performed using silica gel-G coated sheets supplied
by Merck Company with visualization using a UV lamp and iodine staining. IR spec-
1
tra were recorded using a Perkin Elmer model-446 FTIR in KBr. H NMR spectra were
recorded in DMSO-d using TMS as an internal standard using a Varian 400-MHz spec-
6
trometer instrument. Mass spectra were recorded on an Agilent instrument using the ESI
method. Chemicals such as salicylaldehydes, malononitrile, and solvents were purchased
from commercial suppliers and were used directly without purification.
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 completion of the reaction as indicated by TLC, the reac-
tion mixture was poured into ice-cold water (100 mL). The separated solid was filtered,

8
K. KAVITHA ET AL.
washed with water (2×50 mL) thoroughly, air dried at RT. The product was recrystallized
from methanol to obtain a pure colorless compound 3.
−
1
White solid. Yield: 2.35 g (88%); M.p. 177–179°C; IR (KBr): 1730 cm (strong, sharp,
−
1
1
–
CO of coumarin ring), 2206 cm (strong, sharp, –CN group); H NMR (400 MHz,
DMSO-d /TMS): δ = 4.66 (s, 2H, –CH ) 7.38–7.98 (multiplet, 4H, Ar-H), 8.43 (s, 1H, Ar-
6
2
1
3
H), 8.78 (s, 1H, Ar-H); C NMR (100 MHz, DMSO-d /TMS): 21.50, 115.8, 116.9, 118.9,
6
1
19.8, 121.1, 124.7, 129.1, 132.1, 139.5, 147.3, 152.5, 158.6, 158.9; HRMS calculated for
+
C H N O S [M+H] : 269.0384, Found: 269.0321.
1
4
9
2
2
General procedure for the synthesis of 5 from 3 and 4
A mixture of 3 (10 mmol), various aldehydes (10 mmol), catalytic amount of piperidine
and ethanol (30 mL) was stirred at RT for a period of 2–4 h. The completion of the reac-
tion was monitored by TLC analysis. After completion of the reaction, the mixture was
poured into ice cold water (100 mL) and the separated solid was filtered, washed with water
(
2×50 mL). These crude compounds were recrystallized from suitable solvent to give the
pure 5.
(
E)-2-[4-(2-Oxo-2H-chromen-3-yl)thiazol-2-yl]-3-phenylacrylonitrile (5a)
−
1
Yellow solid. Yield: 2.52 g (71%); M.p. 222–224°C (methanol); IR (KBr): 1718 cm (strong,
sharp, –CO of coumarin ring), 2156 cm (strong, sharp, –CN group); H NMR (400 MHz,
−
1
1
DMSO-d /TMS): δ = 7.38–8.07 (multiplet, 9H, Ar-H), 8.41 (s, 1H, vinylic-H), 8.54 (s,
6
1
3
1
1
1
H, Ar-H), 8.85 (s, 1H, Ar-H); C NMR (100 MHz, DMSO-d /TMS): 109.8, 117.9, 118.9,
6
19.4, 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,
+
53.8, 163.0; HRMS calculated for C H N O S [M + H] : 357.0697, Found: 357.0621.
2
1
13
2
2
(
E)-3-(4-Hydroxyphenyl)-2-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]acrylonitrile (5b)
−
1
Yellow solid. Yield: 2.52 g (68%); M.p. 179–181°C (acetonitrile); IR (KBr): 1712 cm
(
−
1
1
strong, sharp, –CO of coumarin ring), 2208 cm (strong, sharp, –CN group); H NMR
(
400 MHz, DMSO-d /TMS): δ = 7.42–8.04 (multiplet, 8H, Ar-H), 8.43 (s, 1H, vinylic-
6
1
3
H), 8.55 (s, 1H, Ar-H), 8.89 (s, 1H, Ar-H), 9.45 (s, 1H, -OH); C NMR (100 MHz,
DMSO-d /TMS): 108.7, 115.7, 115.8, 118.9, 120.6, 120.9, 121.1, 124.3, 125.7, 127.7, 128.0,
6
1
29.4, 130.3, 143.4, 146.4, 153.1, 153.5, 157.0, 163.4; HRMS calculated for C H N O S
21 13 2 3
+
[M+H] : 373.0646, Found: 373.0662.
(
E)-3-(4-Chlorophenyl)-2-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]acrylonitrile (5c)
−
1
Yellow solid. Yield: 2.84 g (73%); M.p. 202–204°C (methanol); IR (KBr): 1720 cm (strong,
sharp, –CO of coumarin ring), 2205 cm (strong, sharp, –CN group); H NMR (400 MHz,
−
1
1
DMSO-d /TMS): δ = 7.42–8.04 (multiplet, 8H, Ar-H), 8.43 (s, 1H, vinylic-H), 8.57 (s,
6
1
3
1
1
1
H, Ar-H), 8.83 (s, 1H, Ar-H); C NMR (100 MHz, DMSO-d /TMS): 109.1, 118.5, 120.7,
6
25.1, 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,
+
53.4, 163.1; HRMS calculated for C H ClN O S [M+H] : 391.0308, Found: 391.0323.
2
1
12
2
2
(
E)-3-(4-Nitrophenyl)-2-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]acrylonitrile (5d)
−
1
Yellow solid. Yield: 3.12 g (78%); M.p. 196–198°C (acetone); IR (KBr): 1723 cm (strong,
sharp, –CO of coumarin ring), 2198 cm (strong, sharp, –CN group); H NMR (400 MHz,
−
1
1

JOURNAL OF SULFUR CHEMISTRY
9
DMSO-d /TMS): δ = 7.42–8.08 (multiplet, 8H, Ar-H), 8.42 (s, 1H, vinylic-H), 8.55 (s,
6
1
3
1
1
1
H, Ar-H), 8.88 (s, 1H, Ar-H); C NMR (100 MHz, DMSO-d /TMS): 108.7, 118.3, 120.9,
6
24.9, 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,
+
53.5, 162.9; HRMS calculated for C H N O S [M+H] : 402.0548, Found: 402.0565.
2
1
12
3
4
(
E)-3-(4-Bromophenyl)-2-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]acrylonitrile (5e)
−
1
Yellow solid. Yield: 3.20 g (74%); M.p. 211–213°C (ethyl acetate); IR (KBr): 1731 cm
(
−
1
1
strong, sharp, –CO of coumarin ring), 2205 cm (strong, sharp, –CN group); H NMR
(
400 MHz, DMSO-d /TMS): δ = 7.44–8.04 (multiplet, 8H, Ar-H), 8.44 (s, 1H, vinylic-H),
6
1
3
8
1
1
4
.55 (s, 1H, Ar-H), 8.83 (s, 1H, Ar-H); C NMR (100 MHz, DMSO-d /TMS): 109.1, 111.7,
6
16.8, 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,
+
53.1, 153.8, 162.2; HRMS calculated for C H BrN O S [M+H] : 434.9802, Found:
2
1
12
2
2
34.9854.
(
E)-3-(4-Fluorophenyl)-2-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]acrylonitrile (5f)
−
1
Yellow solid. Yield: 2.61 g (70%); M.p. 188–190°C (methanol); IR (KBr): 1714 cm (strong,
sharp, –CO of coumarin ring), 2190 cm (strong, sharp, –CN group); H NMR (400 MHz,
−
1
1
DMSO-d /TMS): δ = 7.42–8.05 (multiplet, 8H, Ar-H), 8.43 (s, 1H, vinylic-H), 8.56 (s,
6
1
3
1
1
1
H, Ar-H), 8.85 (s, 1H, Ar-H); C NMR (100 MHz, DMSO-d /TMS): 108.4, 115.5, 115.7,
6
17.4, 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,
+
54.4, 163.3; HRMS calculated for C H FN O S [M+H] : 375.0603, Found: 375.0610.
2
1
12
2
2
(
E)-2-[4-(2-Oxo-2H-chromen-3-yl)thiazol-2yl]-3-(1H-pyrrol-2-yl)acrylonitrile (5g)
−
1
Yellow solid. Yield: 2.48 g (72%); M.p. 198–200°C (Methanol); IR (KBr): 1718 cm (strong,
sharp, –CO of coumarin ring), 2336 cm (strong, sharp, –CN group); H NMR (400 MHz,
−
1
1
DMSO-d /TMS): δ = 7.33–7.91 (multiplet, 7H, Ar-H), 8.17 (s, 1H, vinylic-H), 8.40 (s, 1H,
6
1
3
Ar-H), 8.76 (s, 1H, Ar-H), 11.93 (s, 1H, NH); C NMR (100 MHz, DMSO-d /TMS): 109.8,
6
1
1
3
16.5, 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,
+
46.7, 151.2, 153.8, 161.8; HRMS calculated for C H N O S [M+H] : 346.0650, Found:
1
9
12
3
2
46.0661.
(
E)-2-[4-(2-Oxo-2H-chromen-3-yl)thiazol-2yl]-3-(thiophen-2-yl)acrylonitrile (5h)
−
1
Yellow solid. Yield: 2.49 g (69%); M.P. 187–189°C (Methanol); IR (KBr): 1718 cm (strong,
sharp, –CO of coumarin ring), 2185 cm (strong, sharp, –CN group); H NMR (400 MHz,
−
1
1
DMSO-d /TMS): δ = 7.30–7.92 (multiplet, 7H, Ar-H), 8.21 (s, 1H, vinylic-H), 8.43 (s,
6
1
3
1
1
1
H, Ar-H), 8.78 (s, 1H, Ar-H); C NMR (100 MHz, DMSO-d /TMS): 109.5, 113.4, 116.5,
6
18.7, 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,
+
54.1, 162.0; HRMS calculated for C H N O S2 [M+H] : 363.0261, Found: 363.0258.
1
9
11
2
2
(
E)-3-(Furan-2-yl)-2-[4-(2-oxo-2H-chromen-3-yl)thiazol-2yl]acrylonitrile (5i)
−
1
Yellow solid. Yield: 2.50 g (67%); M.P. 192–194°C (Methanol); IR (KBr): 1734 cm (strong,
sharp, –CO of coumarin ring), 2210 cm (strong, sharp, –CN group); H NMR (400 MHz,
−
1
1
DMSO-d /TMS): δ = 7.32–7.93 (multiplet, 7H, Ar-H), 8.18 (s, 1H, vinylic-H), 8.42 (s,
6
1
3
1
1
1
H, Ar-H), 8.76 (s, 1H, Ar-H); C NMR (100 MHz, DMSO-d /TMS): 109.4, 112.5, 113.7,
6
16.4, 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,
+
54.3, 162.2; HRMS calculated for C H N O S [M+H] : 347.0490, Found: 375.0487.
1
9
11
2
3

10
K. KAVITHA ET AL.
(
E)-2-[4-(2-Oxo-2H-chromen-3-yl)thiazol-2yl]-3-(pyridin-3-yl)acrylonitrile (5j)
−
1
Yellow solid. Yield: 2.59 g (73%); M.p. 196–198°C (Methanol); IR (KBr): 1718 cm (strong,
sharp, –CO of coumarin ring), 2179 cm (strong, sharp, –CN group); H NMR (400 MHz,
−
1
1
DMSO-d /TMS): δ = 7.34–7.96 (multiplet, 8H, Ar-H), 8.22 (s, 1H, vinylic-H), 8.46 (s,
6
1
3
1
1
1
3
H, Ar-H), 8.76 (s, 1H, Ar-H); C NMR (100 MHz, DMSO-d /TMS): 109.3, 112.6, 113.7,
6
16.7, 118.5, 119.7, 120.3, 122.5, 124.6, 125.1, 125.8, 127.2, 128.6, 128.9, 136.0, 143.2,
+
46.6, 152.7, 154.8, 162.0; HRMS calculated for C H N O S [M+H] : 358.0650, Found:
2
0
12
3
2
57.0662.
General procedure for the synthesis of 6 from 5
A mixture of 5 (10 mmol), malononitrile (10 mmol), elemental sulfur (10 mmol), saturated
sodium bicarbonate solution in water (10 mL), and ethanol (50 mL) was stirred at RT for a
period of 2–5 h. Progress of the reaction was monitored by TLC analysis. After completion
of the reaction, the mixture was poured into ice cold water (150 mL) and the separated solid
was filtered, washed with water (2×50 mL). These crude products were recrystallized from
a suitable solvent to give the pure 6.
5
-
-Amino-4- [ 4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl ]
3-phenylthiophene-2-carbonitrile (6a)
Yellow solid. Yield: 3.62 g (85%); M.p. 236–238°C (benzene); IR (KBr): 1723 cm (strong,
−
1
−
1
sharp, –CO of coumarin ring), 2227 cm (strong, sharp, –CN group), 3380–3440 (broad
1
medium, –NH group); H NMR (400 MHz, DMSO-d /TMS): δ = 7.40–8.45 (multi-
2
6
1
3
plet, 11H, Ar-H, NH ), 8.57 (s, 1H, Ar-H), 8.89 (s, 1H, Ar-H); C NMR (100 MHz,
2
DMSO-d /TMS): 111.9, 117.9, 118.9, 119.4, 119.8, 121.2, 121.8, 122.1, 125.2, 127.2, 129.3,
6
1
29.5, 130.1, 132.7, 137.0, 139.5, 143.0, 151.2, 153.8, 154.7, 162.1; HRMS calculated for
+
C H N O S [M+H] : 428.0527, Found: 428.0541.
2
3
14
3
2 2
5
-Amino-3-(4-hydroxyphenyl)-4- [ 4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl ]
thiophene-2-carbonitrile (6b)
Yellow solid. Yield: 3.49 g (79%); M.p. >250°C (benzene); IR (KBr): 1715 cm (strong,
−
1
−
1
sharp, –CO of coumarin ring), 2210 cm (strong, sharp, –CN group), 3400–3440 (broad
medium, –NH group), 3530–3580 (broad medium, –OH group); H NMR (400 MHz,
1
2
DMSO-d /TMS): δ = 7.38-8.42 (multiplet, 10H, Ar-H & NH ), 8.54 (s, 1H, Ar-H), 8.82
6
2
1
3
(
1
1
s, 1H, Ar-H), 10.21 (s, 1H, OH); C NMR (100 MHz, DMSO-d /TMS): 112.2, 117.4,
6
19.1, 119.7, 120.1, 121.4, 121.9, 122.7, 124.9, 127.5, 129.6, 129.9, 131.0, 132.5, 137.3, 139.9,
+
43.5, 151.3, 154.5, 154.9, 162.0; HRMS calculated for C H N O S [M+H] : 444.0476,
2
3
14
3
3 2
Found: 444.0459.
5
-Amino-3-(4-chlorophenyl)-4- [ 4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl ]
thiophene-2-carbonitrile (6c)
Yellow solid. Yield: 3.87 g (84%); M.p. >250°C (ethanol); IR (KBr): 1719 cm (strong,
−
1
−
1
sharp, –CO of coumarin ring), 2210 cm (strong, sharp, –CN group), 3380–3420 (broad
1
medium, –NH group); H NMR (400 MHz, DMSO-d /TMS): δ = 7.41–8.47 (multi-
2
6
1
3
plet, 10H, Ar-H & NH ), 8.58 (s, 1H, Ar-H), 8.87 (s, 1H, Ar-H); C NMR (100 MHz,
2

JOURNAL OF SULFUR CHEMISTRY
11
DMSO-d /TMS): 111.7, 117.0, 118.6, 119.3, 119.7, 121.4, 121.9, 122.4, 125.7, 127.7, 129.8,
6
1
30.2, 130.8, 132.6, 137.4, 139.7, 143.2, 151.3, 153.9, 154.8, 162.3; HRMS calculated for
+
C H ClN O S [M+H] : 462.0137, Found: 462.0116.
2
3
13
3
2 2
5
-Amino-3-(4-nitrophenyl)-4- [ 4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl ]
thiophene-2-carbonitrile (6d)
Yellow solid. Yield: 4.10 g (87%); M.p. 245-247°C (benzene); IR (KBr): 1721 cm (strong,
−
1
−
1
sharp, –CO of coumarin ring), 2214 cm (strong, sharp, –CN group), 3400–3450 (broad
1
medium, –NH group); H NMR (400 MHz, DMSO-d /TMS): δ = 7.42-8.48 (multiplet,
2
6
1
3
m, 10H, Ar-H & NH ), 8.59 (s, 1H, Ar-H), 8.90 (s, 1H, Ar-H); C NMR (100 MHz,
2
DMSO-d /TMS): 112.2, 116.8, 118.8, 120.2, 120.8, 121.4, 121.9, 122.5, 125.5, 127.8, 130.6,
6
1
30.8, 131.4, 132.8, 137.2, 139.7, 142.9, 151.4, 153.9, 154.8, 162.4; HRMS calculated for
+
C H N O S [M+H] : 473.0378, Found: 473.0358.
2
3
13
4
4 2
5
-Amino-3-(4-bromophenyl)-4- [ 4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl ]
thiophene-2-carbonitrile (6e)
Yellow solid. Yield: 4.03 g (80%); M.p. >250°C (ethanol); IR (KBr): 1724 cm (strong,
−
1
−
1
sharp, –CO of coumarin ring), 2226 cm (strong, sharp, –CN group), 3420–3480 (broad
1
medium, –NH group); H NMR (400 MHz, DMSO-d /TMS): δ = 7.40-8.46 (multi-
2
6
1
3
plet, 10H, Ar-H & NH ), 8.55(s, 1H, Ar-H), 8.88 (s, 1H, Ar-H); C NMR (100 MHz,
2
DMSO-d /TMS): 112.7, 118.2, 118.8, 119.6, 120.2, 121.5, 121.9, 122.5, 125.5, 127.0, 129.0,
6
1
29.7, 130.5, 132.8, 137.3, 140.2, 143.2, 151.3, 153.9, 154.8, 161.8; HRMS calculated for
+
C H BrN O S [M+H] : 505.9632, Found: 505.9612.
2
3
13
3
2 2
5
-Amino-3-(4-fluorophenyl)-4- [ 4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl ]
thiophene-2-carbonitrile (6f)
Yellow solid. Yield: 3.47 g (78%); M.p. >250°C (benzene); IR (KBr): 1718 cm (strong,
−
1
−
1
sharp, –CO of coumarin ring), 2198 cm (strong, sharp, –CN group), 3400–3450 (broad
1
medium, –NH group); H NMR (400 MHz, DMSO-d /TMS): δ = 7.43–8.49 (multi-
2
6
1
3
plet, 10H, Ar-H & NH ), 8.56 (s, 1H, Ar-H), 8.90 (s, 1H, Ar-H); C NMR (100 MHz,
2
DMSO-d /TMS): 111.8, 118.4, 119.4, 119.9, 120.4, 121.4, 122.2, 122.8, 125.6, 127.2, 129.5,
6
1
29.9, 130.6, 132.9, 137.1, 140.4, 143.5, 151.5, 154.2, 155.7, 162.2; HRMS calculated for
+
C H FN O S [M+H] : 446.0433, Found: 446.0415.
2
3
13
3
2 2
5
-
-Amino-4- [ 4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl ]
3-(1H-pyrrol-2-yl)thiophene-2-carbonitrile (6g)
Yellow solid. Yield: 3.03 g (73%); M.p. >250°C (benzene); IR (KBr): 1728 cm (strong,
−
1
−
1
sharp, –CO of coumarin ring), 2225 cm (strong, sharp, –CN group), 3410–3460 (broad
1
medium, –NH group); H NMR (400 MHz, DMSO-d /TMS): δ = 7.41-8.42 (multi-
6
1
3
plet, 9H, Ar-H & NH ), 8.55 (s, 1H, Ar-H), 8.87 (s, 1H, Ar-H); C NMR (100 MHz,
2
DMSO-d /TMS): 107.9, 117.7, 118.5, 119.6, 119.6, 119.8, 120.6, 125.2, 129.2, 132.1, 138.6,
6
1
38.6, 139.0, 143.9, 145.2, 145.6, 146.3, 151.2, 152.7, 153.6, 162.5; HRMS calculated for
+
C H N O S [M+H] : 417.0479, Found: 417.0455.
2
1
13
4
2 2

12
K. KAVITHA ET AL.
5’-Amino-4’- [ 4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl ]
-
2,3’-bithiophene-2’-carbonitrile (6h)
−
1
Yellow solid. Yield: 3.07 g (71%); M.P. >250°C (benzene); IR (KBr): 1724 cm (strong,
sharp, –CO of coumarin ring), 2204 cm (strong, sharp, –CN group), 3390–3450 (broad
−
1
1
medium, –NH group); H NMR (400 MHz, DMSO-d /TMS): δ = 7.40–8.40 (multi-
6
1
3
plet, 9H, Ar-H & NH ), 8.56 (s, 1H, Ar-H), 8.89 (s, 1H, Ar-H); C NMR (100 MHz,
2
DMSO-d /TMS): 108.2, 117.8, 118.4, 119.7, 119.7, 119.9, 120.9, 125.5, 129.7, 132.3, 138.7,
6
1
38.7, 139.2, 144.3, 145.1, 145.4, 146.2, 151.5, 152.9, 154.1, 161.8; HRMS calculated for
+
C H N O S [M+H] : 434.0091, Found: 434.0105.
2
1
12
3
2 3
5
-Amino-3-(furan-2-yl)-4- [ 4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl ]
thiophene-2-carbonitrile (6i)
Yellow solid. Yield: 3.09 g (75%); M.P. >250°C (methanol); IR (KBr): 1724 cm (strong,
−
1
−
1
sharp, –CO of coumarin ring), 2242 cm (strong, sharp, –CN group), 3410–3460 (broad
1
medium, –NH group); H NMR (400 MHz, DMSO-d /TMS): δ = 7.39–8.42 (multi-
6
1
3
plet, 9H, Ar-H & NH ), 8.57 (s, 1H, Ar-H), 8.91 (s, 1H, Ar-H); C NMR (100 MHz,
2
DMSO-d /TMS): 107.7, 117.5, 118.6, 119.6, 119.6, 119.8, 120.5, 121.3, 125.7, 129.9, 132.4,
6
1
38.8, 139.5, 144.4, 145.3, 145.6, 146.5, 151.6, 153.2, 154.4, 161.7; HRMS calculated for
+
C H N O S [M+H] : 418.0320, Found: 418.0308.
2
1
12
3
3 2
5
-
-Amino-4- [ 4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl ]
3-(pyridin-3-yl)thiophene-2-carbonitrile (6j)
Yellow solid. Yield: 2.99 g (70%); M.p. 228–230°C (ethanol); IR (KBr): 1718 cm (strong,
−
1
−
1
sharp, –CO of coumarin ring), 2223 cm (strong, sharp, –CN group), 3410–3470 (broad
1
medium, –NH group); H NMR (400 MHz, DMSO-d /TMS): δ = 7.38–8.40 (multiplet,
6
1
3
1
0H, Ar-H & NH ), 8.55 (s, 1H, Ar-H), 8.90 (s, 1H, Ar-H); C NMR (100 MHz, DMSO-
2
d6/TMS): 107.9, 118.3, 118.8, 119.2, 119.3, 119.7, 120.6, 120.8, 121.7, 126.2, 130.2, 132.6,
1
39.2, 139.9, 141.7, 145.7, 148.5, 149.6, 151.8, 153.5, 155.5, 161.9; HRMS calculated for
+
C H N O S [M+H] : 429.0479, Found: 429.0468.
2
2
13
4
2 2
General procedure the synthesis of 6 from 8 and 3
A mixture of 8 (10 mmol), 3 (10 mmol), elemental sulfur (10 mmol), saturated sodium
bicarbonate solution in water (10 mL), and ethanol (50 mL) was stirred at RT for a period
of 2–4 h. The progress of the reaction was monitored by TLC analysis. After completion of
the reaction, the mixture was poured into ice cold water (150 mL) and the separated solid
was filtered and washed with water (2×50 mL). These crude products were recrystallized
from a suitable solvent to give the pure 6.
6
a: Yield: 3.50 g (82%); 6b: Yield: 3.01 g (68%); 6c: Yield: 3.82 g (83%); 6d: Yield: 4.01 g
85%); 6e: Yield: 3.88 g (77%); 6f: Yield: 3.29 g (74%); 6g: Yield: 2.91 g (70%); 6h: Yield:
.16 g (73%); 6i: Yield: 3.12 g (75%); 6j: Yield: 2.99 g (70%).
(
3
General procedure for the one-pot four-component synthesis of 6
A mixture of 3 (10 mmol), 4 (10 mmol), malononitrile (10 mmol), elemental sulfur
(
10 mmol), L-proline (10 mol%), and ethanol (50 mL) was stirred at RT for a period of

JOURNAL OF SULFUR CHEMISTRY
13
5–8 h. The completion of the reaction was monitored by TLC analysis. After completion of
the reaction, the mixture was poured into ice-cold water (150 mL) and the separated solid
was filtered and washed with water (2×50 mL). These crude products were recrystallized
from a suitable solvent to give the pure 6.
6
a: Yield: 3.28 g (77%); 6b: Yield: 3.10 g (70%); 6c: Yield: 3.47 g (75%); 6d: Yield: 3.82 g
81%); 6e: Yield: 3.98 g (79%); 6f: Yield: 3.20 g (72%); 6g: Yield: 2.82 g (68%); 6h: Yield:
.03 g (70%); 6i: Yield: 2.75 g (66%); 6j: Yield: 2.95 g (69%).
(
3
Acknowledgments
The authors would like to express their gratitude towards Department of Chemistry, College of
Engineering, and Jawaharlal Nehru Technological University Hyderabad for providing research
facilities.
Disclosure statement
No potential conflict of interest was reported by the authors.
ORCID
Kotthireddy Kavitha http://orcid.org/0000-0002-7810-1296
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