Synthesis and characterisation of some new hybrid molecules containing thiophene, triazole and coumarin rings under microwave conditions

Article abstract of DOI:10.3184/174751918X15314831778603

In this work, a new series of N′-([4-amino-5-oxo-3-(thiophen-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl)-2-oxo-2H-1-benzopyran-3-carbohydrazides (thiophene–triazole–coumarin hybrid molecules) was synthesised from the reaction of 2-[4-amino-5-oxo-3-(thiophen-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetohydrazide and 3-(1H-benzotriazol-1-ylcarbonyl)-2H-chromen-2-ones by using microwave irradiation and conventional heating procedures and their results were compared. The reaction was performed using a very small amount of organic solvent and without using a catalyst.

Full text of DOI:10.3184/174751918X15314831778603

JOURNAL OF CHEMICAL RESEARCH 2018
VOL. 42 JULY, 361–365
RESEARCH PAPER 361
Synthesis and characterisation of some new hybrid molecules containing
thiophene, triazole and coumarin rings under microwave conditions
Fatih Yilmaz*
Recep Tayyip Erdogan University, Vocational School of Technical Studies, Department of Chemistry and Chemical Processing Technology, 53100 Rize, Turkey
In this work, a new series of N′-{[4-amino-5-oxo-3-(thiophen-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}-2-oxo-2H-1-benzopyran-3-
carbohydrazides (thiophene–triazole–coumarin hybrid molecules) was synthesised from the reaction of 2-[4-amino-5-oxo-3-(thiophen-
2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetohydrazide and 3-(1H-benzotriazol-1-ylcarbonyl)-2H-chromen-2-ones by using microwave
irradiation and conventional heating procedures and their results were compared. The reaction was performed using a very small amount
of organic solvent and without using a catalyst.
Keywords: thiophene, triazole, coumarin, hybrid molecule, microwave irradiation, benzotriazole
Results and discussion
Sulfur-containing heterocycles (such as the thiophene ring) have
an important role in medicinal chemistry. Thiophene derivatives
with other bioactive heterocycles have been used extensively
in pharmaceutical applications as they have antiallergic,1 anti-
inflammatory2 and ocular hypotensive3 activities. Raloxifene,
a drug based on thiophene, has been approved by the US Food
and Drug Administration for the prevention and treatment of
osteoporosis associated with the postmenopause.4
In this study, a simple procedure was used for the synthesis
of hybrid compounds that include thiophene, 1,2,4-triazol-
3-one and coumarin moieties. The synthesis of the target
compounds was performed by the reaction of 2-[4-amino-
5-oxo-3-(thiophen-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]
acetohydrazide and 3-(1H-benzotriazol-1-ylcarbonyl)-2H-
chromen-2-one derivatives.
1,2,4-Triazole rings are well-known to show powerful
antimicrobial,5 anticonvulsant,6 antilipase7 and analgesic8
activities. Furthermore, synthesis of 1,2,4-triazoles in
combination with other heterocyclic rings has attracted wide
First, ethyl 2-thiophenecarboximidate hydrochloride (1) was
synthesised according to the literature.17 Then, compound 1
was converted to ethyl(thiophen-2-yl) etoxycarbonylhydrazone
(2). The treatment of compound 2 with hydrazine monohydrate
in water gave 4-amino-5-(thiophen-2-yl)-2,4-dihydro-3H-1,2,4-
triazol-3-one (3). Ethyl[4-amino-5-oxo-3-(thiophen-2-yl)-4,5-
dihydro-1H-1,2,4-triazol-1-yl]acetate 4 was prepared from
the reaction of 4-amino-5-(thiophen-2-yl)-2,4-dihydro-3H-
1,2,4-triazol-3-one (3) and ethyl bromoacetate in the presence
of potassium carbonate in dry acetone. Then, compound 4
was treated with hydrazine hydrate in ethanol to prepare
2-[4-amino-5-oxo-3-(thiophen-2-yl)-4,5-dihydro-1H-1,2,4-
triazol-1-yl]acetohydrazide (5) (Scheme 1).
Coumarin-3-carboxylic acid derivatives (6a–e and 7) were
obtained from the reaction of the respective salicylic aldehydes
and 2,2-dimethyl-1,3-dioxane-4,6-dione in ethanol containing
a catalytic amount of pyridine. Then, these compounds were
reacted with 1H-benzotriazole in the presence of SOCl2 in
dichloromethane to prepare 3-(1H-benzotriazol-1-ylcarbonyl)-
2H-chromen-2-ones (8a–e and 9) (Scheme 2).
attention because of their biological applications6,9–12
.
Coumarins are an important class of oxygen-containing
heterocycles that are obtained from both natural and synthetic
sources. Most coumarin derivatives have been extensively used
as key intermediates in the design of synthetic drug candidates
due to their pharmacological activities such as anti-microbial,13
anti-inflammatory,14 anti-diabatic15 and anti-HIV.16
Molecular hybridisation is a strategy for drug design widely
used in medicinal chemistry and aims to combine two or more
chemical moieties into a single compound, targeting an increase
in biological activity. The presence of prototype heterocyclic
systems is of great interest in the design of new drugs. Features
such as small molecular weight and the presence of heteroatoms
and aromatic structures can mimic endogenous substrates,
which may lead to the development of biological activity.14,16
Thus, this study describes the production of novel thiophene–
triazole–coumarin hybrid molecules through the molecular
hybridisation strategy. These new hybrid molecules might serve
as interesting bioactive templates.
A literature search revealed that benzotriazole is an easy
leaving group and this offers many advantages for synthetic
applications.18,19 Therefore, we used compounds 7a–f and 9 for
O
O
HCl (g)
OC2H5
N
NH.HCl
N
NH
C2H5OH
OC2H5
+
+
0 - 5 °C
-NH4Cl
S
0 - 5 °C
S
S
H2N NH
OC2H5
OC2H5
1
2
NHNH 2
OC2H5
H
N
O
N
N
N
N
N
O
N
O
NH2NH2.H2O
BrCH2COOC2H5
NH2NH2.H2O
OC2H5
N
O
NH
O
O
N
N
Ethanol
Reflux
3 hours
S
K2CO3,Acetone
1 night
reflux
12 hours
S
S
S
NH2
NH2
OC2H5
NH2
5
4
3
2
Scheme 1 Synthetic route for compound 5.
* Correspondent. E-mail: fyilmaz@erdogan.edu.tr

362 JOURNAL OF CHEMICAL RESEARCH 2018
O
O
O
O
O
R1
R2
R1
R2
R1
R2
N
N
N
OH
H
SOCl2
Pyridine
N
O
N
+
CH3
CH3
+
Dichloromethane
12 hours
Ethanol, reflux
6 hours
O
O
N
N
H
O
OH
O
O
R3
R3
R3
6a–f
8a–f
O
OH
N
N
O
O
O
O
O
H
O
N
SOCl2
O
Pyridine
O
N
OH
+
CH3
CH3
+
O
Dichloromethane
12 hours
Ethanol, reflux
6 hours
N
H
O
7
9
a: R1: H, R2:H, R3: H, b: R1: Cl, R2:H, R3: H, c: R1: Br, R2:H, R3: H
d: R1: Cl, R2:H, R3: Cl, e: R1: H, R2:N(et)2, R3: H, f: R1: H, R2:H, R3: OCH3
Scheme 2 Synthetic route for compounds 8a–f and 9.
O
1
R
R
N
N
O
O
N
R1
2
NH
NH
N
O
O
N
3
R
8a–f
O
O
R2
S
N
O
MW, Ethanol, 10-15 min. 120 °C
R3
H2N
or
10a–f
DMSO, Δ, 6-8 hours
NHNH2
N
N
O
O
N
S
O
O
O
NH2
5
N
NH
N
N
N
NH
N
O
S
O
O
9
N
O
O
H2N
11
MW, Ethanol, 15 min. 120 °C
or
DMSO, Δ, 8 hours
a: R1: H, R2:H, R3: H, b: R1: Cl, R2:H, R3: H, c: R1: Br, R2:H, R3: H
d: R1: Cl, R2:H, R3: Cl, e: R1: H, R2:N(et)2, R3: H, f: R1: H, R2:H, R3: OCH3
Scheme 3 Synthetic route for compounds 10a–f and 11.
Table 1 Comparison of microwave and conventional heating procedures
for the synthesis of compounds 10a–f and 11
the preparation of hybrid molecules (10a–f and 11) (Scheme 3).
In some of the literature sources, it can be seen that this reaction
can be directly carried out by using coumarin-3-acyl chloride
and a hydrazide derivative.20 However, this approach is not
suitable for the microwave irradiation technique in a closed
system because of the excess of HCl(g). Therefore, we chose
to convert coumarin-3-carboxylic acids to 1H-benzotriazole
derivatives to allow the use of the microwave irradiation
technique. In addition, these reactions were performed with
conventional heating and it was shown that microwave heating
gives higher yields and faster reaction rates, compared with
conventional heating (Table 1).
Microwave heating
Temperature
Conventional heating
Time (h) Yield (%)
Compound
Time (min) Yield (%)
(°C)
120
120
120
120
120
120
120
10a
10b
10c
10d
10e
10f
11
10
15
15
15
10
15
15
67
52
55
59
65
60
53
6.0
7.5
7.5
7.0
6.0
7.0
8.0
65
48
39
53
57
47
50
The results of spectral investigations of the target compounds
are in agreement with the proposed structures. In the 1H NMR
spectra of these compounds, two NH signals were shown at
about 11.00 and 10.50 ppm and an NH2 signal was shown at about
5.50 ppm. The NCH2 signal was observed at about 4.50 ppm. In
the 13C NMR spectra of these compounds, four C=O signals
were shown at about 165.0 (hydrazide), 160.0 (hydrazide), 159.0
(coumarin C2) and 153.0 (triazole C3) ppm, while the C=N

JOURNAL OF CHEMICAL RESEARCH 2018 363
temperature. After the reaction was completed (monitored by TLC,
eluent EtOAc–hexane, 3:1), the product was precipitated by the
addition of water. The product was filtered off, washed with water
and recrystallised from ethanol/water (1:1) to give compound 4 as a
white solid; yield 2.47 g (92%); m.p. 116–117 °C; 1H NMR (400 MHz,
DMSO-d6): δ 1.91 (t, J = 6.4 Hz, 3H), 4.14 (q, J = 6.4 Hz, 2H), 4.62
(s, 2H), 5.76 (s, 2H), 7.17 (br, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.92 (br,
1H); 13C NMR (100 MHz, DMSO-d6): δ 14.46, 47.26, 61.65, 127.53,
127.95, 128.84, 129.52, 142.15, 142.69, 153.66, 168.24. Anal. calcd for
C10H12N4O3S: C, 44.77; H, 4.51; N, 20.88; S 11.95; found: C, 44.68; H,
4.44; N, 20.76; S, 11.78%.
(triazole C5) signal was observed at about 147.0 ppm. Also, the
number of aromatic carbon atoms in the 13C NMR spectra was
in agreement with their structures. In addition, all compounds
showed the expected elemental analysis results.
Conclusion
We report here the synthesis of thiophene–triazole–coumarin
hybrid molecules using a simple method. This present method
was achieved using microwave irradiation and conventional
heating procedures without using a catalyst. This study could
provide inspiration for further investigation of the potential
bioactivity of these heterocyclic compounds.
Synthesis of 2-[4-amino-5-oxo-3-(thiophen-2-yl)-4,5-dihydro-1H-
1,2,4-triazol-1-yl]acetohydrazide (5)
Experimental
Hydrazine monohydrate (1.25 mL, 0.025 mol) was added to a solution
of ethyl[4-amino-5-oxo-3-(thiophen-2-yl)-4,5-dihydro-1H-1,2,4-triazol-
1-yl]acetate (4) (0.01 mol) in ethanol (25 mL). The mixture was then
refluxed for 3 h. After the mixture was cooled, a white solid formed.
This crude product was filtered off, and recrystallised from EtOH to
give compound 5 as a white solid; yield 2.00 g (80%); m.p. 198–199 °C;
1H NMR (400 MHz, DMSO-d6): δ 4.28 (s, 2H), 4.31 (s, 2H), 5.57 (s,
2H), 7.16 (t, J = 6.4 Hz, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.90 (br, 1H), 9.24
(s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 47.13, 127.83, 127.90, 128.61,
129.80, 141.86, 153.77, 166.21. Anal. calcd for C8H10N6O2S: C, 37.79; H,
3.96; N, 33.05; S, 12.61; found: C, 37.66; H, 3.88; N, 32.89; S, 12.57%.
All the chemicals were supplied from Merck, Sigma-Aldrich and
Fluka. All reaction progress was monitored by TLC on silica gel
plates (Merck 60, F254, 0.2mm). The melting points were determined
on capillary tubes on Stuart SMP30 melting point apparatus and are
uncorrected. 1H and 13C NMR spectra (400 and 100MHz, respectively)
were obtained using a Varian-Mercury (tetra methyl silane as internal
standard): chemical shifts are expressed in δ values (ppm). The
elemental compositions were determined on a Carlo Erba 1106 CHN
analyser; the experimental values were in agreement ( 0.4%) with
the calculated ones. A monomode CEM Discover Microwave was
used in the standard configuration as delivered, including proprietary
software. All experiments were carried out in microwave process vials
(30 mL) with temperature control by an infrared sensor. Temperature
was monitored by a computer and maintained constant by discrete
modulation of the delivered microwave power. After the reaction
completion, the vial was cooled to 60 °C via air-jet cooling.
Synthesis of compounds 6a–f and 7; general procedure
A solution of salicylaldehyde derivatives or 2-hydroxynaphthaldehyde
(0.01 mol) and Meldrum’s acid (1.58 g, 0.011 mol) in ethanol (50 mL)
and pyridine (0.5 mL) was refluxed in a round-bottom flask for 6 h.
After the reaction was completed (monitored by TLC, EtOAc–hexane,
4:1), the solvent was evaporated under reduced pressure. The obtained
solid was washed with H2O and recrystallised from a mixture of
EtOH–H2O, 3:2.
2-Oxo-2H-chromene-3-carboxylic acid (6a): White solid; yield
1.39 g (73%); m.p. 189–190 °C (lit.10 188 °C).
6-Chloro-2-oxo-2H-chromene-3-carboxylic acid (6b): White solid;
yield 2.47 g (76%); m.p. 194–195 °C (lit.21 193 °C).
Synthesis of ethyl(thiophen-2-yl)acetateetoxycarbonylhydrazone (2)
In a round-bottom flask equipped with a magnetic stirrer, ethyl
2-thiophenecarboximidate hydrochloride (1) (0.01 mol) was dissolved
in absolute ethanol (50 mL) with ice-bath cooling. Then ethyl
carbazate (0.01 mol) dissolved in absolute ethanol (20 mL) was then
added to this solution. After stirring for 8 h in an ice bath, the mixture
was filtered to remove the ammonium chloride, which separated from
the solution, and the filtrate was evaporated at 30–35 ºC under reduced
pressure. The solid residue, after drying in a desiccator, was extracted
with petroleum ether to give compound 2 as a white solid; yield 1.76 g
6-Bromo-2-oxo-2H-chromene-3-carboxylic acid (6c): White solid;
yield 1.80 g (67%); m.p. 195–196 °C (lit.10 194–196 °C).
6,8-Dichloro-2-oxo-2H-chromene-3-carboxylic acid (6d): White
solid; yield 1.78 g (69%); m.p. 222–223 °C (lit.22 220–224 °C).
7-Diethylamino-2-oxo-2H-chromene-3-carboxylic acid (6e): Yellow
solid; yield 1.95 g (75%); m.p. 232–233 °C (lit.23 230–232 °C).
8-Methoxy-2-oxo-2H-chromene-3-carboxylic acid (6f): White solid;
yield 1.95 g (75%); m.p. 215–216 °C (lit.24 214–216 °C).
1
(72%), m.p. 78–79 °C; H NMR (400 MHz, DMSO-d6): δ 1.19–1.30
(m, 6H), 4.06–4.13 (m, 4H), 7.13 (br, 1H), 7.63 (d, J = 4.8 Hz, 1H), 7.70
(s, 1H), 10.09 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 14.98, 15.42,
60.97 + 63.22 (CH2), 67.44, 128.04, 128.44, 129.15, 134.41, 153.94,
155.61. Anal. calcd for C10H14N2O3S: C, 49.57; H, 5.82; N, 11.56; S,
13.23; found: C, 49.43; H, 5.71; N, 11.47; S, 13.15%.
3-Oxo-3H-naphtho[2,1-b]pyran-2-carboxylic acid (7): White solid;
yield 1.61 g (67%); m.p. 238–239 °C (lit.25 236–237 °C).
Synthesis of compounds 8a–f and 9; general procedure
Synthesis
of
4-amino-5-(thiophen-2-yl)-2,4-dihydro-3H-1,2,4-
Thionyl chloride (1.78 g, 0.015 mol) was added to a solution of
1H-benzotriazole (5.95 g, 0.05 mol) in CH2Cl2 (75 mL). The mixture
was stirred for 30 min at room temperature. Then the corresponding
coumarin-3-carboxylic acid (6a–f and 7) (0.01 mol) was added and
the reaction mixture was stirred for 12 h at room temperature. The
precipitate was removed by filtration, and the filtrate was evaporated
under reduced pressure. The residue was diluted with CH2Cl2
(100 mL), and the solution was washed with 10 % Na2CO3 solution
(50 mL) and 4 N HCl (50 mL) and dried over MgSO4. Removal of the
solvent under reduced pressure gave compounds 8a–f and 9, which
were recrystallised from CH2Cl2–hexane, 1:1.
3-(1H-Benzotriazol-1-ylcarbonyl)-2H-chromen-2-one (8a): White
solid; yield 2.12 g (73%); m.p. 179–180 °C (lit.10 176–177 °C).
3- (1H-Benzotriazol-1-ylcarbonyl)-6-chloro-2H-chromen-2-
one (8b): White solid; yield 2.20 g (63%); m.p. 248–249 °C (lit.16
248–249 °C). Anal. calcd for C16H8ClN3O3: C, 59.00; H, 2.48; N,
12.90; found: C, 58.87; H, 2.39; N, 12.82%.
triazol-3-one (3)
A solution of ethyl(thiophen-2-yl)acetate etoxycarbonylhydrazone (2)
(0.01 mol) in H2O (75 mL) was refluxed with hydrazine monohydrate
(1.50 mL, 0.03 mol) for 12 h. After the mixture was cooled to room
temperature, a white solid appeared. This was filtered, dried and
recrystallised from water to give compound 3 as a white solid; yield
1
1.52 g (83%); m.p. 195–196 °C; H NMR (400 MHz, DMSO-d6): δ
5.46 (s, 2H), 7.14 (s, 1H), 7.67 (d, J = 4.8 Hz, 1H), 7.80 (br, 1H), 11.79
(s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 127.82, 128.17, 128.44,
128.82, 142.69, 154.95. Anal. calcd for C6H6N4OS: C, 39.55; H, 3.32; N,
30.75; S, 17.60; found: C, 39.47; H, 3.24; N, 30.64; S, 17.53%.
Synthesis of ethyl[4-amino-5-oxo-3-(thiophen-2-yl)-4,5-dihydro-1H-
1,2,4-triazol-1-yl]acetate (4)
4-Amino-5-(thiophen-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one
(3)
(0.01 mol) was dissolved in dry acetone (50 mL). Then, potassium
carbonate (0.025 mol) was added to this solution and it was stirred
for 15 min at room temperature. Then, ethyl bromoacetate (1.84 g,
0.011 mol) was added and the mixture was stirred overnight at room
3-(1H-Benzotriazol-1-ylcarbonyl)-6-bromo-2H-chromen-2-one (8c):
White solid; yield 2.52 g (68%); m.p. 250–251 °C (lit.10 250–251 °C).

364 JOURNAL OF CHEMICAL RESEARCH 2018
3-(1H-Benzotriazol-1-ylcarbonyl)-6,8-dichloro-2H-chromen-
2-one (8d): White solid; yield 2.34 g (65%); m.p. 263–264 °C (lit.12
263–264 °C).
3-(1H-Benzotriazol-1-ylcarbonyl)-7-diethylamino-2H-chromen-
2-one (8e): Yellow solid; yield 2.46 g (68%); m.p. 210–211 °C (lit.12
210–211 °C).
DMSO-d6): δ 46.79, 117.16, 118.97, 119.97, 120.59, 127.71, 127.92,
128.72, 129.41, 132.60, 136.96, 142.05, 146.97, 153.42, 153.85, 158.95,
159.72, 164.53. Anal. calcd for C18H13BrN6O5S: C, 42.78; H, 2.59; N,
16.63; S, 6.35; found: C, 42.67; H, 2.47; N, 16.58; S, 6.26%.
N′-{[4-amino-5-oxo-3-(thiophen-2-yl)-4,5-dihydro-1H-1,2,4-
triazol-1-yl]acetyl}-6,8-dichloro-2-oxo-2H-1-benzopyran-3-
1
carbohydrazide (10d): White solid; m.p. 345–346 °C; H NMR (400
3-(1H-Benzotriazol-1-ylcarbonyl)-8-methoxy-2H-chromen-2-one
1
MHz, DMSO-d6): δ 4.55 (s, 2H), 5.64 (s, 2H), 7.17 (br, 1H), 7.20 (d,
J = 4.0 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 8.13 (s, 1H), 8.80 (s, 1H),
10.63 (s, 1H), 11.06 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 46.79,
117.16, 118.97, 119.77, 120.60, 127.70, 127.92, 128.71, 129.42, 132.59,
136.98, 142.01, 146.96, 153.41, 153.87, 158.96, 159.71, 164.55. Anal.
calcd for C18H12Cl2N6O5S: C, 43.65; H, 2.44; N, 16.97; S, 6.47; found:
C, 43.54; H, 2.32; N, 16.83; S, 6.36%.
(8f): White solid; yield 2.46 g (68%); m.p. 236–237 °C; H NMR
(400 MHz, DMSO-d6): δ 3.96 (s, 3H), 7.57 (d, J=7.2 Hz, 1H). 7.77 (t,
J=7.2Hz, 1H), 7.98 (s, 1H), 7.99–8.11 (m, 3H), 8.29 (s, 1H), 8.74 (s,
1H); 13C NMR (100 MHz, DMSO-d6): δ 62.14, 114.20, 119.11, 119.35,
120.77, 122.62, 127.56, 129.51, 130.92, 131.78, 134.44, 145.91, 146.92,
153.46, 157.29, 162.75. Anal. calcd for C17H11N3O4: C, 63.55; H, 3.45;
N, 13.08; found: C, 63.47; H, 3.40; N, 13.01%.
N′-{[4-amino-5-oxo-3-(thiophen-2-yl)-4,5-dihydro-1H-1,2,4-
triazol-1-yl]acetyl}-7-diethylamino-2-oxo-2H-1-benzopyran-3-
carbohydrazide (10e): White solid; m.p. 327–328 °C; H NMR (400
2-(1H-Benzotriazole-1-carbonyl)-3H-naphtho[2,1-b]pyran-3-one
(9): CAS Registry Number: 886124-23-8; White solid; yield: 2.47 g
(72%); m.p. 267–268 °C; 1H NMR (400 MHz, DMSO-d6): δ 7.64–7.77
(m, 4H), 7.88 (t, J = 7.6 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 8.28–8.35
(m, 3H), 8.85 (d, J = 8.4 Hz, 1H), 9.96 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): δ 112.44, 114.18, 117.09, 119.98, 120.78, 122.64, 127.09,
127.50, 129.51, 131.07, 131.74, 136.67, 144.66, 145.98, 155.25, 157.21,
163.27. Anal. calcd for C20H11N3O3: C, 70.38; H, 3.25; N, 12.31; found:
C, 70.26; H, 3.18; N, 12.20%.
1
MHz, DMSO-d6): δ 1.12 (t, J = 6.4 Hz, 6H), 3.48 (q, J = 6.4 Hz,
4H), 4.71 (s, 2H), 5.48 (s, 2H), 6.62 (s, 1H), 6.80 (d, J = 8.8 Hz, 1H),
7.47–7.58 (m, 3H), 7.71 (d, J = 8.8 Hz, 1H), 7.89–7.93 (m, 1H), 8.70 (s,
1H), 10.34 (s, 1H), 10.85 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ
12.76 (2CH3), 44.85 (2CH2), 46.54, 96.37, 108.04, 110.80, 122.07,
128.36, 130.02, 130.98, 131.90, 132.25, 139.05, 147.00, 148.69, 153.85,
157.85, 160.09, 161.82, 164.28. Anal. calcd for C22H23N7O5S: C, 53.11;
H, 4.66; N, 19.71; S, 6.44; found: C, 53.03; H, 4.53; N, 19.63; S, 6.36%.
N′-{[4-amino-5-oxo-3-(thiophen-2-yl)-4,5-dihydro-1H-1,2,4-
triazol-1-yl]acetyl}-8-methoxy-2-oxo-2H-1-benzopyran-3-
Synthesis of compounds 10a–f and 11; general procedure
Conventional method. A solution of 2-[4-amino-5-oxo-3-(thiophen-
2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetohydrazide (5) (0.01 mol)
and compounds 8a–f and 9 (0.012 mol) in dimethyl sulfoxide (10 mL)
were placed in a round-bottomed flask. The mixture was refluxed for
6–8 h. After the completion of the reaction (monitored by TLC, eluent
EtOAc–hexane, 3:1), the mixture was cooled to room temperature,
and the product was precipitated by addition of water. It was filtered
and washed with hot water and hot ethanol to obtain the pure product.
Microwave method. A mixture of 2-[4-amino-5-oxo-3-(thiophen-2-
yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetohydrazide (5) (0.01 mol) and
compounds 8a–f and 9 (0.012 mol) in ethanol (5 mL) were transferred to
a microwave process vial and irradiated with microwaves at 120 °C for
10–15 min at 300 W maximum power. After the reaction was completed
(monitored by TLC, EtOAc–hexane, 3:1), the mixture was poured into a
beaker with hot ethanol, and a solid was formed. This crude product was
filtered off and washed with hot ethanol to obtain the pure product.
N′-{[4-amino-5-oxo-3-(thiophen-2-yl)-4,5-dihydro-1H-1,2,4-
triazol-1-yl]acetyl}-2-oxo-2H-1-benzopyran-3-carbohydrazide
(10a): White solid; m.p. 325–326 °C; 1H NMR (400 MHz, DMSO-d6):
δ 4.55 (s, 2H), 5.64 (s, 2H), 7.17 (t, J = 4.4 Hz, 1H), 7.44 (t, J = 7.6
Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.71–7.77 (m, 2H), 7.92 (d, J = 4.4
Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 8.82 (s, 1H), 10.64 (s, 1H), 11.07 (s,
1H); 13C NMR (100 MHz, DMSO-d6): δ 46.79, 116.70, 118.50, 118.73,
125.68, 127.71, 127.93, 128.72, 129.41, 130.81, 134.88, 142.01, 148.40,
153.86, 154.38, 159.16, 160.25, 164.46. Anal. calcd for C18H14N6O5S: C,
50.70; H, 3.31; N, 19.71; S, 7.52; found: C, 50.57; H, 3.25; N, 19.63; S,
7.45%.
1
carbohydrazide (10f): White solid; m.p. 335–336 °C; H NMR (400
MHz, DMSO-d6): δ 3.92 (s, 3H), 4.55 (s, 2H), 5.64 (s, 2H), 7.17 (br,
1H), 7.38 (d, J = 6.8 Hz, 1H), 7.44 (d, J = 6.8 Hz, 1H), 7.53 (d, J = 6.0
Hz, 1H), 7.72 (br, 1H), 7.92 (s, 1H), 8.84 (s, 1H), 10.65 (s, 1H), 11.06
(s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 46.78, 56.69, 116.84,
118.62, 119.29, 121.68, 125.63, 127.71, 127.92, 128.72, 129.41, 142.01,
143.71, 146.75, 148.65, 153.85, 159.12, 159.95, 164.46. Anal. calcd for
C19H16N6O6S: C, 50.00; H, 3.53; N, 18.41; S, 7.03; found: C, 49.85; H,
3.41; N, 18.34; S, 6.92%.
N′- {[4-amino-5-oxo-3- (thiophen-2-yl) - 4,5-dihydro-1H-
1,2,4-triazol-1-yl]acetyl}-3-oxo-3H-naphtho[2,1-b]pyran-2-
carbohydrazide (11): White solid; m.p. >350 °C; 1H NMR (400 MHz,
DMSO-d6): δ 4.48 (s, 2H), 5.37 (s, 2H), 7.15 (br, 1H), 7.25 (d, J = 6.4
Hz, 1H), 7.39 (d, J = 6.4 Hz, 1H), 7.44–7.57 (m, 3H), 7.65 (br, 1H),
7.70–7.81 (m, 2H), 7.95 (br, 1H), 8.81 (s, 1H), 10.68 (s, 1H), 11.09 (s,
1H); 13C NMR (100 MHz, DMSO-d6): δ 46.52, 118.72, 119.73, 120.07,
128.74, 128.76, 129.35, 129.57 (2C), 131.11, 131.79 (2C), 134.27, 135.25,
147.05, 147.22, 149.87, 152.78, 153.88, 158.78, 164.59. Anal. calcd for
C22H16N6O5S: C, 55.46; H, 3.38; N, 17.64; S, 6.73; found: C, 55.39; H,
3.27; N, 17.58; S, 6.61%.
Electronic Supplementary Information
The ESI associated with this paper can be found at:
http://ingentaconnect.com/content/stl/jcr/2018/00000042/00000007/art00005
N′- {[4-amino-5-oxo-3- (thiophen-2-yl) - 4,5-dihydro-1H-
1,2,4-triazol-1-yl]acetyl}-6-chloro-2-oxo-2H-1-benzopyran-3-
carbohydrazide (10b): White solid; m.p. 343–344 °C; H NMR (400
MHz, DMSO-d6): δ 4.44 (s, 2H), 5.30 (s, 2H), 7.23 (t, J = 8.0 Hz, 1H),
7.45–7.53 (m, 3H), 7.75 (d, J = 8.8 Hz, 1H), 8.10 (s, 1H), 8.80 (s, 1H),
10.62 (s, 1H), 11.02 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 46.54,
118.70, 119.69, 120.05, 120.27, 129.36, 129.58, 131.50, 131.69, 134.22,
135.66, 147.01, 147.17, 152.97, 153.88, 158.77, 159.78, 164.59. Anal.
calcd for C18H13ClN6O5S: C, 46.91; H, 2.84; N, 18.24; S, 6.96; found:
C, 46.80; H, 2.75; N, 18.18; S, 6.85%.
Received 27 May 2018; accepted 26 June 2018
Paper 1805442
https://doi.org/10.3184/174751918X15314831778603
Published online: 18 July 2018
1
References
1
2
A.M. Isloor, B. Kalluraya and K.S. Pai, Eur. J. Med. Chem., 2010, 45, 825.
K.I. Molvi, V. Sudarsanam, M.M. Patel and N. Haque, J. Enzyme Inhib.
Med. Chem., 2008, 23, 819.
3
S.L. Graham, K.L. Shepard, P.S. Anderson, J.J. Baldwin, D.B. Best, M.E.
Christy, M.B. Freedman, P. Gautheron, C.N. Habecker, J.M. Hoffman,
P.A. Lyle, S.R. Michelson, G.S. Ponticello, C.M. Robb, H. Schwam, A.M.
Smith, R.L. Smith, J.M. Sondey, K.M. Strohmaier, M.F. Sugrue and S.L.
Varga, J. Med. Chem., 1989, 32, 2548.
N′- {[4-amino-5-oxo-3- (thiophen-2-yl) - 4,5-dihydro-1H-
1,2,4-triazol-1-yl]acetyl}-6-bromo-2-oxo-2H-1-benzopyran-3-
1
carbohydrazide (10c): White solid; m.p. 331–332 °C; H NMR (400
MHz, DMSO-d6): δ 4.55 (s, 2H), 5.64 (s, 2H), 7.17 (s, 1H), 7.47 (d,
J = 8.8 Hz, 1H), 7.77 (d, J = 4.4 Hz, 1H), 7.87–7.90 (m, 2H), 8.25 (s,
1H), 8.80 (s, 1H), 10.62 (s, 1H), 11.05 (s, 1H); 13C NMR (100 MHz,
4
5
V.C. Jordan, J. Med. Chem., 2003, 46, 1081.
C. Radhika, A. Venkatesham and M. Sarangapani, Med. Chem. Res., 2012,
21, 3509.

JOURNAL OF CHEMICAL RESEARCH 2018 365
6
B. Kahveci, E. Mentese, E. Akkaya, F. Yilmaz, I.S. Dogan and A. Ozel,
Arch. Pharm., 2014, 347, 449.
16 I. Kostova, Curr. HIV. Res., 2006, 4, 347.
17 B. Kahveci, Molecules, 2005, 10, 376.
7
8
O. Bekircan, E. Mentese, S. Ulker and C. Kucuk, Arch. Pharm., 2014, 347, 387.
B. Tozkoparan, E. Kupeli, E. Yesilada, S. Isik, M. Ozalp and M. Ertan,
Arzneimittelforschung, 2005, 55, 533.
E. Mentese, N. Karaali, F. Yilmaz, S. Ulker and B. Kahveci, Arch. Pharm.,
2013, 346, 556.
18 E. Mentese, N. Karaali, G. Akyuz, F. Yilmaz, S. Ulker and B. Kahveci,
Chem. Heterocycl. Compd, 2016, 52, 1017.
19 F. Yilmaz and E. Mentese, J. Chem. Res., 2017, 41, 4.
20 L.L. Long, Y.J. Wu, L. Wang, A.H. Gong, R.F. Hu and C. Zhang, Anal.
Chim. Acta, 2016, 908, 1.
9
10 B. Kahveci, F. Yilmaz, E. Mentese and S. Ulker, Chem. Heterocycl.
Compd, 2015, 51, 447.
21 G.R. Bardajee, F. Jafarpour and H.S. Afsari, Cent. Eur. J. Chem., 2010,
8, 370.
11 N. Karaali and E. Mentese, Rev. Roum. Chim., 2016, 61, 187.
12 B. Kahveci, F. Yilmaz, E. Mentese and S. Ulker, Arch. Pharm., 2017, 350.
13 S.M. de Souza, F. Delle Monache and A. Smania, Z. Naturforsch. C., 2005,
60, 693.
14 Y. Bansal, P. Sethi and G. Bansal, Med. Chem. Res., 2013, 22, 3049.
15 H.B. Li, Y.F. Yao and L.H. Li, J. Pharm. Pharmacol., 2017, 69, 1253.
22 B.S. Creaven, D.A. Egan, K. Kavanagh, M. McCann, A. Noble, B. Thati
and M. Walsh, Inorg. Chim. Acta, 2006, 359, 3976.
23 M. Danko, E. Szabo and P. Hrdlovic, Dyes Pigm., 2011, 90, 129.
24 E.E. Shults, S.P. Bondarenko, M.M. Shakirov, I.Y. Bagryanskaya and G.A.
Tolstikov, Russ. J. Org. Chem., 2010, 46, 1709.
25 F. Bigi, L. Chesini, R. Maggi and G. Sartori, J. Org. Chem., 1999, 64, 1033.