Synthesis and characterisation of some coumarin-1,2,4-triazol-3-thioether hybrid molecules

Article abstract of DOI:10.3184/174751917X14815427219040

A new series of N′-{[(4-methyl/phenyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio]acetyl}-2-oxo-2H-chromene-3-carbohydrazides was synthesised via the reaction of 2-[(4-methyl/phenyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio]acetohydrazides and 3-(1H-benzotriazol-1-ylcarbonyl)-2H-chromen-2-ones in good yields.

Full text of DOI:10.3184/174751917X14815427219040

4 RESEARCH PAPER
VOL. 41 JANUARY, 4–6
JOURNAL OF CHEMICAL RESEARCH 2016
Synthesis and characterisation of some coumarin-1,2,4-triazol-3-thioether
hybrid molecules
Fatih Yılmaz and Emre Menteşe*
Department of Chemistry, Art and Science Faculty, Recep Tayyip Erdogan University 53100-Rize, Turkey
A new series of N’-{[(4-methyl/phenyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio]acetyl}-2-oxo-2H-chromene-3-carbohydrazides was synthesised
via the reaction of 2-[(4-methyl/phenyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio]acetohydrazides and 3-(1H-benzotriazol-1-ylcarbonyl)-2H-
chromen-2-ones in good yields.
Keywords: coumarin, 1,2,4-triazol-3-thiol, hybrid molecule, acid hydrazide, benzotriazole
Results and discussion
Coumarin and its derivatives are common oxygen-containing
heterocyclic compounds that are the subject of many studies.
The great interest in these compounds comes from their
biological activities against different pathologies, which
has motivated researchers to develop several drugs based
on these compounds, such as warfarin, acenocoumarol and
phenprocoumon. Also, coumarin analogues have shown a broad
spectrum of pharmacological activities, such as anticoagulant,
antibacterial, antifungal, antimycobacterial, antimutagenic and
anti-inflammatory. With these activities, coumarins have been
used for preliminary studies in pharmacology.1–5
1,2,4-Triazoles have great importance in medicinal chemistry
and are known to show diverse biological activities. Ribavirin
(antiviral), rizatriptan (antimigraine), alprazolam (anxiolytic),
letrozole, vorozole and anastrozole (antitumoral) are some
examples of 1,2,4-triazole-containing drugs.6–9
The molecular modification method is considered as an
effective method for developing new drug members. Molecular
hybridisation is included in this method for obtaining new
molecules that have better pharmaceutical activities. Recently,
this method has become a powerful tool for obtaining more
bioactive compounds.10–12 Considering the promising activity of
coumarin and triazole moieties, the use of these heterocycles
in a molecule can result in the formation of more bioactive
compounds. In the literature, studies on coumarin-1,2,4-triazol-
3-thioether derivatives are limited. However, synthesis of these
types of molecules is an important research area today. In our
previous studies, we have synthesised coumarin-triazol-3-on
hybrid molecules as antimicrobial and antilipase agents.11 In
this work, coumarin-1,2,4-triazol-3-thioether hybrid molecules
were synthesised as potential bioactive agents. Hence, we
decided to use coumarin and 1,2,4-triazol-3-thiol moieties in
one molecule to design new potential bioactive compounds
The primary aim of this study was to synthesise coumarin-
1,2,4-triazole hybrid molecules. The synthetic strategy for the
intermediate and target compounds was performed according
to the reactions outlined in Schemes 1–3. The compounds
1a and 1b were obtained by the reaction of phenyl hydrazide
and the corresponding isothiocyanate in ethanol. Treatment
of compounds 1a and 1b with NaOH solution in ethanol gave
1,2,4-triazol-3-thiol derivatives (2a, 2b). The compounds 3a
and 3b were obtained by simple alkylation of compounds 2a
and 2b and ethyl bromoacetate in acetone and these compounds
were reacted with hydrazine monohydrate in ethanol to prepare
compounds 4a and 4b, which are the first intermediate13,14
(Scheme 1).
To synthesise the second intermediate compounds, five
different salicylaldehyde derivatives were reacted with
2,2-dimethyl-1,3-dioxane-4,6-dione15 in ethanol to synthesise
coumarin-3-carboxylic acid (5a–e). Then, the compounds
5a–e were reacted with 1H-benzotriazole in dichloromethane
in the presence of thionyl chloride to obtain compounds 6a–e11
(Scheme 2).
The benzotriazole group is an easy leaving group. This
group offers many advantages to researchers in synthetic
applications.11,12,15 Treatment of compounds 6a–e with 4a and 4b
resulted in the synthesis of the target coumarin-1,2,4-triazol-3-
thioether hybrid molecules (7a–j) (Scheme 3). In this reaction,
we aimed for the use of organic solvent in minimum quantity in
line with principle of environmental chemistry.
Spectral investigations of the hybrid molecules were in
accordance with the proposed structures. In the IR spectra,
NH and C=O signals were shown at about 3150 and 1700 cm−1,
1
respectively. In the H NMR spectra of these compounds, two
NH signals (exchangeable with D2O) were shown at about 10.70
and 11.20 ppm. The SCH2 and coumarin–C3–H signals were
observed at about 4.00 and 8.80 ppm, respectively. In the 13C
O
O
N
N
H
H
NaOH
N
N
+
SH
NHNH2
N
R
N
R
NCS
N
R
Ethanol
H
Ethanol
S
2a,b
1a,b
H
N
N
N
N
N
N
O
O
NH2
K2CO3
NH2NH2
Ethanol
O
SH
S
S
+
Br
N
R
N
R
N
R
O
Acetone
O
2a,b
4a,b
3a,b
R=a:CH3, b:C6H5
Scheme 1 Synthesis of compounds 4a and 4b.
* Correspondent. E-mail: emre.mentese@erdogan.edu.tr

JOURNAL OF CHEMICAL RESEARCH 2016 5
O
O
O
O
R1
R2
O
O
O
R1
R2
N
N
R1
R2
N
SOCl2
H
Pyridine
Ethanol
+
N
OH
+
N
N
Dichloromethane
O
OH
O
O
O
H
R3
R3
R3
5a-e
6a-e
5, 6
R1
R2
R3
a
b
c
d
e
H
H
H
H
H
H
H
H
Cl
H
Cl
Br
Cl
H
N(C2H5)2
Scheme 2 Synthesis of compounds 6a–e.
R1
O
O
H
N
N
N
R1
R2
N
H
N
NH2
R2
N
Ethanol
N
N
N
+
N
S
N
O
O
Reflux, 5 h
S
O
R3
O
H
O
N
R
O
R
R3
7a-j
4a,b
6a-e
Compound
R
R1
R2
R3
Compound
R
R1
R2
R3
7a
7b
7c
7d
7e
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
Cl
H
7f
7g
7h
7i
C6H5
C6H5
C6H5
C6H5
C6H5
H
H
H
H
H
H
H
H
Cl
H
Cl
Br
Cl
H
Cl
Br
Cl
H
N(C2H5)2
7j
N(C2H5)2
Scheme 3 The synthetic route for target compounds.
mixture to room temperature. The product was filtrated off and washed
with ethanol to obtain the pure products.
NMR spectra of these compounds, three C=O signals were
observed at about 165.00, 160.00 and 158.00 ppm. The triazole
C=N signals were shown at about 156.00 and 154.00 ppm. Also,
the numbers of other aromatic carbons in the 13C NMR spectra
were in agreement with the proposed structure. In addition, all
compounds gave suitable elemental analysis results.
N’-{[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio]acetyl}-2-
oxo-2H-chromene-3-carbohydrazide (7a): Yield 3.30 g (76%); m.p.
268–269 °C; IR (KBr) (cm−1): 3168, 3110, 1697, 1680, 1193; 1H NMR:
δ (400 MHz, DMSO-d6): 3.67 (s, 3H), 4.03 (s, 2H), 7.66 (t, J = 8.0,
1H), 7.52–7.98 (m, 4H), 7.70–7.74 (m, 2H), 7.78 (t, J = 8.0, 1H), 8.01
(d, J = 8.0, 1H), 8.89 (s, 1H), 10.72 (s, 1H), 11.15 (s, 1H); 13C NMR
(400 MHz, DMSO-d6): δ 31.80, 34.89, 116.25, 118.00, 118.30, 127.12,
128.38, 128,88, 129.97, 130.35, 134.42, 147.95, 149.99, 153.95, 155.45,
158.42, 159.84, 164.53. Anal. calcd for C21H17N5O4S: C, 57.92; H, 3.93;
N, 16.08; S, 7.36; found; C, 57.87; H, 3.79; N, 15.89; S, 7.28.
6-Chloro-N’-{[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio]
acetyl}-2-oxo-2H-chromene-3-carbohydrazide (7b): Yield 3.20 g
(68%); m.p. 277–278 °C; IR (KBr) (cm−1): 3153, 1702, 1689, 1186;
1H NMR (400 MHz, DMSO-d6): δ 3.65 (s, 3H), 4.02 (s, 2H), 7.56–7.59
(m, 4H), 7.71–7.74 (m, 2H), 7.80 (dd, J = 8.8, J = 2.4, 1H), 8.16 (d,
J = 2.4, 1H), 8.84 (s, 1H), 10.70 (s, 1H), 11.14 (s, 1H); 13C NMR (400
MHz, DMSO-d6): δ 31.75, 35.11, 115.29, 118.03, 118.91, 128.10, 128.25,
128,83, 129.99, 130.81, 135.61, 148.99, 150.99, 154.99, 156.98, 159.92,
160.81, 165.56. Anal. calcd for C21H16ClN5O4S: C, 53.68; H, 3.43; N,
14.90; S, 6.82; found; C, 53.57; H, 3.39; N, 14.81; S, 6.74.
Conclusion
We report here the synthesis of coumarin-1,2,4-triazole hybrid
molecules using a simple and practical method. This present
method was achieved under catalyst-free conditions and using
a low amount of organic solvent (only 10 mL). Therefore,
this method is more important than others in terms of green
chemistry. This study could be the inspiration for further
investigation of potential bioactive heterocyclic compounds.
Experimental
All chemicals were supplied from Merck, Aldrich and Fluka. Melting
points were determined in capillary tubes on a Stuart SMP30 melting
point apparatus and uncorrected. The IR spectra were recorded for
1
KBr pellets on a PerkinElmer 100 FTIR spectrometer. H NMR and
13C NMR spectra were performed on a Bruker 400 MHz spectrometer
in DMSO-d6 using TMS as an internal standard. The elemental
compositions were determined on a Carlo Erba 1106 CHN analyser;
the experimental values were in agreement ( 0.4%) with the calculated
values. All reactions were monitored by TLC using precoated aluminum
sheets (silica gel 60 F 2.54 0.2 mm thickness). Compounds 4a and 4b13,14
and 6a-e11 were synthesised according to published methods.
6-Bromo-N’-{[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio]
acetyl}-2-oxo-2H-chromene-3-carbohydrazide (7c): Yield 3.65 g
(71%); m.p. 273–274 °C; IR (KBr) (cm−1): 3158, 1703, 1688, 1186;
1H NMR (400 MHz, DMSO-d6): δ 3.65 (s, 3H), 4.03 (s, 2H), 7.52 (d,
J = 9.2, 1H), 7.56–7.58 (m, 3H), 7.71–7.74 (m, 2H), 7.92 (dd, J = 8.4,
J = 2.4, 1H), 8.29 (d, J = 2.4, 1H), 8.83 (s, 1H), 10.70 (s, 1H), 11.15
(s, 1H);
13C NMR (400 MHz, DMSO-d6): δ 31.90, 34.88, 116.72,
118.55, 119.28, 120.16, 127.11, 128,37, 128.89, 129.97, 132.16, 136.52,
146.51, 149.98, 152.98, 155.45, 158.21, 159.32, 164.60. Anal. calcd for
C21H16BrN5O4S: C, 49.04; H, 3.14; N, 13.62; S, 6.23; found; C, 49.00;
H, 3.04; N, 13.51; S, 6.11.
6,8-Dichloro-N’-{[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)
sulfanyl]acetyl}-2-oxo-2H-chromene-3-carbohydrazide (7d): Yield
Synthesis of compounds 7a–j; general procedure
A mixture of compounds 4a or 4b (0.01 mol), 6a–e (0.011 mol) and
ethanol (10 mL) were placed in a round-bottomed flask and refluxed
for 5 h. The end of the reaction was determined by TLC (ethyl
acetate:hexane: 4:1) and the product was precipitated by cooling the

6 JOURNAL OF CHEMICAL RESEARCH 2016
3.69 g (73%), m.p. 292–293 °C; IR (KBr) (cm−1): 3206, 1731, 1699,
1204; H NMR (400 MHz, DMSO-d6): δ 3.66 (s, 3H), 4.03 (s, 2H),
1H), 11.21 (s, 1H); 13C NMR (400 MHz, DMSO-d6): δ 33.95, 118.29,
119.27, 119.68, 120.25, 120.91, 127.66, 128.26, 128.56, 128.77,
128.91, 129.15, 129.77, 129.98, 130.11, 133.01, 133.76, 146.20, 146.62,
148.38, 151.17, 152.56, 154.44, 158.05, 159.41, 164.22. Anal. calcd for
C26H17Cl2N5O4S: C, 55.13; H, 3.03; N, 12.36; S, 5.66; found; C, 55.04;
H, 2.91; N, 12.28; S, 5.55.
7-Diethylamino-N’-{[(4-phenyl-5-phenyl-4H-1,2,4-triazol-3-yl)
thio]acetyl}-2-oxo-2H-chromene-3-carbohydrazide (7j): Yield 3.86 g
(68%); m.p. 211–212 °C; IR (KBr) (cm−1): 3150, 1709, 1688, 1187;
1H NMR (400 MHz, DMSO-d6): δ 1.17 (t, J = 6.4, 6H), 3.51 (d, J = 6.4,
6H), 4.09 (s, 2H), 6.67 (d, J = 2.0, 1H), 6.86 (dd, J = 9.2, J = 2.0, 2H),
7.20–7.63 (m, 6H), 7.71–7.94 (m, 5H), 8.87 (s, 1H), 10.61 (s, 1H), 11.11
(s, 1H); 13C NMR (400 MHz, DMSO-d6): δ 12.33, 31.90, 35.93, 44.45,
95.98, 96.34, 106.89, 107.71, 110.27, 110.39, 113.71, 120,04, 126.51,
127.61, 128.56, 129.76, 129.96, 130.10, 131.81, 131.93, 145.38, 148.25,
149.55, 153.87, 153.17, 157.87, 159.48, 163.24, 163.92. Anal. calcd for
C30H28N6O4S: C, 63.36; H, 4.96; N, 14.78; S, 5.64; found; C, 63.29; H,
4.84; N, 14.63; S, 5.51.
1
7.56–7.58 (m, 3H), 7.71–7.73 (m, 2H), 8.11 (d, J = 2.4, 1H), 8.14 (d,
J = 2.4, 1H), 8.82 (s, 1H), 10.63 (s, 1H), 11.11 (s, 1H); 13C NMR (400
MHz, DMSO-d6): δ 31.90, 34.88, 99.51, 118.47, 119.59, 120.75, 128.26,
128.37, 129.81, 130.17, 133.10, 137.59, 147.01, 150.62, 153.70, 156.59,
159.19, 160.97, 165.71. Anal. calcd for C21H15Cl2N5O4S: C, 50.01; H,
3.00; N, 13.89; S, 6.36; found; C, 49.89; H, 2.91; N, 13.78; S, 6.27.
7-Diethylamino-N’-{[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)
thio]acetyl}-2-oxo-2H-chromene-3-carbohydrazide (7e): Yield 3.23 g
(64%), m.p. 259–260 °C; IR (KBr) (cm−1): 3155, 1699, 1685, 1188;
1H NMR (400 MHz, DMSO-d6): δ 1.15 (t, J = 6.8, 6H), 3.50 (q, J = 6.8,
4H), 3.66 (s, 3H), 4.02 (s, 2H), 6.42 (d, J = 2.0, 1H), 6.82 (dd, J = 9.2,
J = 2.4, 2H), 7.56–7.59 (m, 3H), 7.70–7.74 (m, 3H), 8.69 (s, 1H), 10.62
(s, 1H), 11.08 (s, 1H); 13C NMR (400 MHz, DMSO-d6): δ 12.30, 31.92,
34.90, 44.40, 99.46, 107.58, 107.69, 110.37, 127.06, 128,38, 128.88,
129.99, 131.80, 148.22, 150.03, 152.85, 155.42, 157.40, 159.48, 161.38,
164.24. Anal. calcd for C25H26N6O4S: C, 59.27; H, 5.17; N, 16.59; S,
6.33; found; C, 59.18; H, 5.10; N, 16.47; S, 6.25.
N’-{[(4-Phenyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio]acetyl}-2-
oxo-2H-chromene-3-carbohydrazide (7f): Yield 3.53 g (71%), m.p.
Electronic Supplementary Information
1
275–276 °C; IR (KBr) (cm−1): 3161, 1716, 1690, 1194; H NMR (400
The ESI is available through
MHz, DMSO-d6): δ 4.11 (s, 2H), 7.30–7.35 (m, 5H), 7.43–7.48 (m, 4H)
7.57 (t, J = 8.0, 2H), 7.78 (t, J = 8.4, 1H), 8.03 (d, J = 8.4, 1H), 8.91
(s, 1H), 10.73 (s, 1H), 11.21 (s, 1H); 13C NMR (400 MHz, DMSO-d6):
δ 33.95, 116.25, 117.95, 118.31, 125.24, 126.58, 127.66, 127.90, 128.56,
129.77, 129.97, 130.11, 130.36, 133.77, 134.43, 147.98, 151.18, 153.95,
154.44, 158.28, 159.89, 164.17. Anal. calcd for C26H19N5O4S: C, 62.77;
H, 3.85; N, 14.08; S, 6.44; found; C, 62.63; H, 3.78; N, 14.01; S, 6.30.
6-Chloro-N’-{[(4-phenyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio]
acetyl}-2-oxo-2H-chromene-3-carbohydrazide (7g): Yield 3.08 g
(58%); m.p. 283–284 °C; IR (KBr) (cm−1): 3174, 3104, 1715, 1694,
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data
Received 3 October 2016; accepted 7 November 2016
Paper 1604355 doi: 10.3184/174751917X14815427219040
Published online: 16 January 2017
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3
1
1188; H NMR (400 MHz, DMSO-d6): δ 4.11 (s, 2H), 7.34–7.45 (m,
7H), 7.55–7.60 (m, 4H), 7.80 (dd, J = 8.8, J = 2.4, 1H), 8.16 (dd, J = 8.8,
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6-Bromo-N’-{[(4-phenyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio]
acetyl}-2-oxo-2H-chromene-3-carbohydrazide (7h): Yield 3.55 g
(63%); m.p. 277–278 °C; IR (KBr) (cm−1): 3159, 1716, 1690, 1188;
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3H) 7.46–7.58 (m, 4H), 7.62–7.78 (m, 4H), 7.92 (dd, J = 8.8, J = 2.0,
1H), 8.28 (dd, J = 2.0, 1H), 8.84 (s, 1H), 10.71 (s, 1H), 11.20 (s, 1H);
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119.21, 119.42, 120.17, 127.15, 127.77, 128.56, 129.77, 129.98, 130.11,
132.17, 136.52, 146.55, 151.17, 152.97, 154.43, 158.06, 159.37, 164.23.
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found; C, 54.07; H, 3.09; N, 12.04; S, 5.47.
4
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6,8-Dichloro-N’-{[(4-phenyl-5-phenyl-4H-1,2,4-triazol-3-yl)
thio]acetyl}-2-oxo-2H-chromene-3-carbohydrazide
(7i):
Yield
3.51 g (62%); m.p. 285–286 °C; IR (KBr) (cm−1): 3153, 1710, 1682,
1
1196; H NMR (400 MHz, DMSO-d6): δ 4.12 (s, 2H), 7.35–7.45 (m,
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7H), 7.53–7.58 (m, 3H), 8.11–8.16 (m, 2H), 8.85 (s, 1H), 10.72 (s,