Synthesis of some new 3-(5-(Arylamino)-1,3,4-thiadiazol-2-yl)-2H-chromen-2- ones and 3-(4-Aryl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-YL)-2H-chromen-2-ones

Article abstract of DOI:10.1080/10426507.2010.534520

In this study, 2-oxo-2H-chromene-3-carbohydrazide (1) was synthesized by the condensation of ethyl 2-oxo-2H-chromene-3-carboxylate with hydrazine hydrate. Thiosemicarbazide derivatives (3a-g) were afforded by the treatment of carbohydrazide (1) with subst

Full text of DOI:10.1080/10426507.2010.534520

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Phosphorus, Sulfur, and Silicon and the
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Synthesis of Some New 3-(5-
(Arylamino)-1,3,4-thiadiazol-2-yl)-2H-
chromen-2-ones and 3-(4-Aryl-5-
thioxo-4,5-dihydro-1H-1,2,4-triazol-3-
YL)-2H-chromen-2-ones
Aamer Saeed a & Aliya Ibrar a
a Department of Chemistry , Quaid-i-Azam University , Islamabad,
Pakistan
Published online: 11 Aug 2011.
To cite this article: Aamer Saeed & Aliya Ibrar (2011) Synthesis of Some New 3-(5-(Arylamino)-1,3,4-
thiadiazol-2-yl)-2H-chromen-2-ones and 3-(4-Aryl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-YL)-2H-
chromen-2-ones, Phosphorus, Sulfur, and Silicon and the Related Elements, 186:8, 1801-1810, DOI:
10.1080/10426507.2010.534520
To link to this article: http://dx.doi.org/10.1080/10426507.2010.534520
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Phosphorus, Sulfur, and Silicon, 186:1801–1810, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.534520
SYNTHESIS OF SOME NEW 3-(5-(ARYLAMINO)-1,3,4-
THIADIAZOL-2-YL)-2H-CHROMEN-2-ONES AND
3-(4-ARYL-5-THIOXO-4,5-DIHYDRO-1H-1,2,4-TRIAZOL-3-
YL)-2H-CHROMEN-2-ONES
Aamer Saeed and Aliya Ibrar
Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan
GRAPHICAL ABSTRACT
Abstract In this study, 2-oxo-2H-chromene-3-carbohydrazide (1) was synthesized by the con-
densation of ethyl 2-oxo-2H-chromene-3-carboxylate with hydrazine hydrate. Thiosemicar-
bazide derivatives (3a–g) were afforded by the treatment of carbohydrazide (1) with substituted
phenyl isothiocyanates (2a–g). The cyclization of compounds (3a–g) in the presence of aque-
ous sodium hydroxide resulted in the formation of compounds 4a–g containing a 1,2,4-triazole
ring. On the other hand, the treatment of compounds 3a–g with polyphosphoric acid caused
the conversion of side chain of 3a–g into the 1,3,4-thiadiazole ring; thus, compounds 5a–g
were obtained. The structures of the products were established by elemental analyses, IR, 1H,
and 13C NMR spectroscopy.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Coumarin; 1; 3; 4-thiadiazole; thiosemicarbazides; 1; 2; 4-triazole
Received 19 August 2010; accepted 20 October 2010.
A.I. is thankful for a research scholarship from HEC Islamabad under HEC Indigenous PhD Scholarship
5000 Scheme.
Address correspondence to Aamer Saeed, Department of Chemistry, Quaid-i-Azam University, 45320,
Islamabad, Pakistan. E-mail: aamersaeed@yahoo.com
1801

1802
A. SAEED AND A. IBRAR
INTRODUCTION
Coumarins (2H-1-benzopyran-2-ones) are natural lactones and among the best known
oxygen heterocycles, well represented as a structural motif in numerous natural products.1
Various coumarin derivatives are known to possess an array of biological activities, includ-
ing anticancer, anti-HIV, anti-acetylcholinesterase, antifungal, antioxidant, antihelmintic,
anticoagulant, antibacterial, antiviral, and anticlotting activities, and find extensive applica-
tion in pharmaceuticals, fragrances, agrochemicals, and as additives in food, cosmetics, and
insecticides.2–10 Moreover, coumarins find application as dyes in laser technology, fluores-
cent indicators, optical brighteners, and photosensitizers.1,11 Introduction of fluorine at the
4-position in the aryloxy and arylamino moieties of coumarin enhances their antimicrobial
activities.12 Scoparone isolated from the hypolipidaemic Chinese herb Artemisia scoparia
is shown to reduce the proliferative responses of human peripheral mononuclear cells, to
relax smooth muscle, to reduce total cholesterol and triglycerides, and to retard the charac-
teristic pathomorphological changes in hypercholesterolaemic diabetic rabbits.13 Osthole
from Angelica pubescens causes hypotension in vivo and inhibits platelet aggregation and
smooth muscle contraction in vitro.14
Over the last few decades, the biological and pharmaceutical properties of 1,2,4-
triazoles have created considerable interest in their synthesis and characterization. 4,5-
Disubstituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones and their derivatives are of great
importance due to their biological,15 industrial, and agricultural activities. A well-known
example is that of fluconazole, an antifungal agent for the treatment of superficial and
systemic infections.16 Others have diuretic,17 antibacterial,18 hypoglycemic,19 and anti-
tubercular20 activities. Moreover, they are inhibitors of corrosion of copper, brass, alu-
minium, and steel in marine environments21 and inhibitors of fog formation in photographic
emulsions.22
Similarly the substituted-1,3,4-thiadiazoles are found to exhibit a variety of appli-
cations including antibacterial agents,23 radioprotective agents, investigational antitumor
drugs, gastroprotective drugs,24 corrosion inhibitors,25 ulcer inhibitors,26 in photography,27
and as diuretic drugs.28
Keeping in view the biological significance of the aforementioned individual hete-
rocycles, namely triazoles and thiadiazoles on one hand and that of coumarins on other,
the aim of the present work was the synthesis of biheterocyclic compounds by coupling
of these heterocycles with a coumarin nucleus to combine their useful effects in a single
structural unit.
RESULTS AND DISCUSSION
The coumarinyl ester was synthesized by the reaction of salicylaldehyde with diethyl-
malonate according to the reported procedure.29 It was converted into the corresponding
hydrazide (1) by refluxing with hydrazine hydrate (80%) in methanol.30 The IR spectrum of
hydrazide exhibited a characteristic absorption band for primary NH2 along with a shoulder
at 3380 and for the secondary NH at 3287 cm−1. The strong absorptions at 1732 and 1643
1
cm−1 were assigned to the coumarin and amide carbonyls, respectively. In the H NMR
spectrum, the characteristic singlets at 7.88 for H-4 of coumarin nucleus and those for
N H and NH2 protons at 11.11 and 5.45 ppm, respectively, were observed. The 13C NMR
spectrum showed characteristic absorption at 157.7 and 165.1 ppm due to coumarin and
amide carbonyl groups, respectively (Scheme 1).

3-(5-(ARYLAMINO)-1,3,4-THIADIAZOL-2-YL)-2H-CHROMEN-2-ONES
1803
O
O
O
O
4
H
6'
H
6'
5
8
5
8
NH2
S
4
3
N
N
1'
2'
N
3
C
N
H
N
H
CH3OH
1'
R
S
Reflux
12-14 h
2'
O
O
R
(3a-g)
(2a-g)
(1)
PPA
4N NaOH
Reflux
Stirring
6'
NH
N
N
N
R
5
8
4
3
4
5
8
S
3
N
N
1'
2'
H
S
1'
2'
R
O
O
6'
O
O
(4a-g)
(5a-g)
R= 2-Cl, 3-Cl, 4-Cl, 3-CH3, 4-CH3, 2-OCH3, 3-OCH3
Scheme 1 Synthetic pathway of 3-(5-(arylamino)-1,3,4-thiadiazol-2-yl)-2H-chromen-2-ones and 3-(4-Aryl-5-
thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2H-chromen-2-ones.
Aryl isothiocyanates (2a–g) were prepared from the corresponding substituted ani-
lines according to the standard procedure.31 The thiosemicarbazides (3a–g) were synthe-
sized by the condensation of corresponding hydrazide (1) and isothiocyanates (2a–g) in
methanol.32 The formation of thiosemicarbazides (3a–g) was indicated by the IR spectra
where (C O) absorption appeared in the range of 1644–1689 cm−1 and that of (C S)
in the range of 1235–1268 cm−1. The characteristic absorption bands for three secondary
N H groups were observed in the region of 3143–3432 cm−1. In the 1H NMR spectrum,
the NH proton of amide type linkage appeared in the range of 11.23–11.96 ppm and a
signal for two NH protons of thiourea type linkage appeared in the range of 9.99–11.14
ppm. In the 13C NMR spectrum, the appearance of new peaks in aromatic region and
carobonyl intherangeof164.7–167.0andthiocarbonyl intherangeof 176.2–181.7ppmwas
noted.
The 4,5-disubstituted-1,2,4-triazol-3-thiones (4a–g) were synthesized by refluxing
the corresponding thiosemicarbazides (3a–g) in an aqueous sodium hydroxide (4N) solu-
tion.33,34 The products were purified by recrystallization in aqueous ethanol. The formation
of triazoles (4a–g) was indicated by the disappearance of broad peaks of NH groups and
of a (C O) group of thiosemicarbazides and by the appearance of (C N) absorption
in the range 1375–1413 cm−1. In 1H NMR, a signal for N H proton of triazoles appeared
in the range of 11.13–13.94 ppm. The disappearance of signals for N H protons confirmed
the formation of the triazoles. In the 13C NMR spectrum, the disappearance of a peak due
to amidic (C O) group and the appearance of a (C N) peak in the range of 156.3–159.1
ppm was detected.
2,5-Disubstituted-1,3,4-thiadiazoles (5a–g) were synthesized by treating the
thiosemicarbazide intermediates (3a–g) with concentrated polyphosphoric acid at low
temperature.35 The formation of thiadiazoles was indicated by the disappearance of broad
peaks of NH groups and amidic (C O) group of thiosemicarbazides, and appearance of
(C N) absorption in the range 1415–1471 cm−1. In the 1H NMR spectrum, the signal for

1804
A. SAEED AND A. IBRAR
the N-H proton of thiadiazoles appeared in the range of 11.14–11.86 ppm, while in the 13
C
NMR spectrum, the disappearance of a (C O) group peak and the appearance of a (C N)
peak in the range of 157.0–159.2 ppm indicated the desired conversion.
CONCLUSIONS
In conclusion, 2-oxo-2H-chromene-3-carbohydrazide has successfully been used as
a molecular handle to generate 1,2,4-triazole and 1,3,4-thiadiazole rings leading to biolog-
ically potent biheterocyclic compounds containing a coumarin nucleus to combine their
useful effects in a single structural unit.
EXPERIMENTAL
The Rf-values were determined using aluminum precoated silica gel plates Kiesel
60 F254 from Merck (Germany). Melting points of the compounds were measured in open
capillaries using Stuart melting point apparatus (SMP3) and are uncorrected. The IR spectra
were recorded on an FTS 3000 MX, Bio-Rad Merlin (Excalibur Model) spectrophotometer.
1H NMR spectra were determined as CDCl3 solutions at 300 MHz using a Bruker AM-
300 spectrophotometer using TMS as an internal reference, and the 13C NMR spectra
were determined at 75 MHz using a Bruker 75 MHz NMR in DMSO-d6 and CDCl3
solutions using TMS as an internal standard. The elemental analysis was performed on Leco
CHNS-932 Elemental Analyzer (Leco Corporation, USA). Figures S1–S4 (Supplemental
Materials, available online) include the 1H and 13C NMR spectra of 3e and 4f.
Synthesis of 2-Oxo-2H-chromene-3-carbohydrazide (1)
2-Oxo-2H-chromene-3-carboxylate (0.02 mol) was dissolved in methanol (100 mL)
in a round bottom flask fitted with a reflux condenser and a calcium chloride drying tube.
Hydrazine hydrate (80%, 1.94 mL, 0.04 mol) was added slowly, and the reaction was
monitored by thin layer chromatography. After completion of the reaction, the reaction
mixture was concentrated under reduced pressure. The resulting crude solid was filtered,
washed with water, and recrystallized from aqueous ethanol. White solid (87%): mp:
145–148◦C; Rf∗: 0.13, IR (KBr, cm−1): 3380, 3287 (NH), 1732 (C O), 1643 (C O),
1572, 1540 (C C ring). 1H NMR (300MHz, CDCl3): δ 11.11 (s, 1H, NH-C O), 7.88 (s,
1H, C-H, H-4), 7.24 (d, 1H, J = 7.8Hz, H-8), 7.13-7.10 (m, 1H, H-6), 6.98-6.95 (m, 1H,
H-7), 6.88 (d, 1H, J = 7.5Hz, H-5), 5.45 (s, 2H, NH2); 13C NMR (75MHz, CDCl3): δ
165.1 (C O), 157.7 (NH C O), 146.8, 133.5, 130.0, 129.3, 119.8, 119.1, 118.4, 116.5
(Ar-Cs). Anal. Calcd. for C10H8N2O3: C, 58.82; H, 3.95; N, 13.72; Found: C, 58.62; H,
3.81; N, 13.76.
Synthesis of 1,4-Disubstituted Thiosemicarbazides (3a–g):
General procedure
The carbohydrazide (1) (6.8 mmol) was dissolved in methanol (30 mL), and a solution
of substituted isothiocyanate (2a–g) (6.6 mmol) separately dissolved in methanol (10 mL)
was added dropwise with continuous stirring. The reaction mixture was refluxed for 10–12 h
and monitored by TLC. After consumption of the starting materials, the mixture was cooled

3-(5-(ARYLAMINO)-1,3,4-THIADIAZOL-2-YL)-2H-CHROMEN-2-ONES
1805
to room temperature. The methanol was evaporated on a rotary evaporator leaving behind
the crude product as oil that became solidified upon cooling and was recrystallized from a
mixture of ethyl acetate and petroleum ether (4:1) to yield thiosemicarbazides (3a–g).
4-(2-Chlorophenyl)-1-(2-oxo-2H-chromene-3-carbonyl)thiosemicarbazide
(3a). Green solid (54%): mp 215–217◦C; Rf∗ : 0.54; IR (KBr, cm−1): 3296–3163 (NH),
1
1731 (C O), 1673 (C O), 1596, 1512 (C C), 1268 (C S); H NMR (300 MHz,
DMSO-d6): δ 11.96 (s, 1H, NH C O), 10.05 (s, 2H, NH C S), 9.01 (s, 1H, C-H, H-4),
8.03 (d, 1H, J = 7.5 Hz, H-8), 7.71–7.69 (m, 1H, H-6), 7.37–7.09 (m, 3H, H-7, H-3ꢀ,
H-5ꢀ), 6.99 (d, 1H, J = 8.1 Hz, H-5), 6.94–6.76 (m, 2H, H-4ꢀ, H-6ꢀ); 13C NMR (75 MHz,
DMSO-d6): δ 181.2 (C S), 166.9 (NH C O), 159.5 (C O), 150.2, 135.3, 134.6, 132.1,
129.5, 126.6, 125.5, 124.9, 123.4, 122.4, 120.9, 118.6, 116.2 (Ar-Cs). Anal. Calcd. for
C17H12ClN3O3S: C, 54.62; H, 3.24; N, 11.24, S, 8.58; Found: C, 54.54; H, 3.11; N, 11.09;
S, 8.49.
4-(3-Chlorophenyl)-1-(2-oxo-2H-chromene-3-carbonyl)thiosemicarbazide
(3b). Yellow solid (59%): mp 189–191◦C; Rf∗: 0.54; IR (KBr, cm−1): 3295–3163 (NH),
1
1724 (C O), 1670 (C O), 1590, 1508 (C C), 1267 (C S); H NMR (300 MHz,
DMSO-d6): δ 11.35 (s, 1H, NH C O), 10.15 (s, 2H, NH C S), 9.00 (s, 1H, C H,
H-4), 7.68 (d, 1H, J = 7.8 Hz, H-8), 7.42–7.36 (m, 2H, H-6, H-7), 7.20 (d, J = 7.8Hz,
H-5), 6.99–6.89 (m, 2H, H-3ꢀ, H-5ꢀ), 6.84–6.79 (m, 2H, H-4ꢀ, H-6ꢀ); 13C NMR (75MHz,
DMSO-d6): δ 181.4 (C S), 163.1 (NH C O), 159.3 (C O), 156.9, 142.2, 133.6, 131.1,
129.0, 128.6, 125.4, 120.2, 119.8, 119.4, 118.7, 117.1, 116.1 (Ar-Cs). Anal. Calcd. for
C17H12ClN3O3S: C, 54.62; H, 3.24; N, 11.24, S, 8.58; Found: C, 54.71; H, 3.17; N, 11.15;
S, 8.43.
4-(4-Chlorophenyl)-1-(2-oxo-2H-chromene-3-carbonyl)thiosemicarbazide
(3c). Greenish solid (56%): mp 177–179◦C; Rf∗: 0.57; IR (KBr, cm−1): 3341–3223
(NH), 1732 (C O), 1670 (C O), 1558, 1514, 1484 (C C), 1268 (C S); 1H NMR (300
MHz, DMSO-d6): δ 11.23 (s, 1H, NH C O), 11.11 (s, 2H, NH C S), 9.01 (s, 1H,
C H, H-4), 7.70 (d, 1H, J = 7.5 Hz, H-8), 7.50–7.22 (m, 5H, H-5, H-6, H-7, H-3ꢀ, H-5ꢀ),
7.00–6.94 (m, 2H, H-2ꢀ, H-6ꢀ); 13C NMR (75 MHz, DMSO-d6): δ 181.5 (C S), 167.0
(NH C O), 163.2 (C O), 149.3, 133.7, 131.3, 131.2, 129.1, 125.3, 124.3, 123.7, 123.4,
118.7, 117.0 (Ar-Cs). Anal. Calcd. for C17H12ClN3O3S: C, 54.62; H, 3.24; N, 11.24, S,
8.58; Found: C, 54.51; H, 3.32; N, 11.07; S, 8.43.
1-(2-Oxo-2H-chromene-3-carbonyl)-4-m-tolylthiosemicarbazide (3d). Yel-
low solid (61%): mp 150–152◦C; Rf∗: 0.50; IR (KBr, cm−1): 3300–3143 (NH), 1732 (C O),
1674 (C O), 1522, 1497 (C C), 1236 (C S); 1H NMR (300 MHz, DMSO-d6): δ 11.76
(s, 1H, NH C O), 9.99 (s, 2H, NH C S), 8.48 (s, 1H, C H, H-4), 8.10 (d, 1H, J =
7.5 Hz, H-8), 7.41–7.36 (m, 1H, H-6), 7.25–7.20 (m, 2H, H-7, H-5ꢀ), 7.21–7.14 (m, 1H,
H-2ꢀ), 7.01 (d, 1H, J = 7.5 Hz, H-5), 6.89–6.81 (m, 2H, H-4ꢀ, H-6ꢀ), 2.31 (s, 3H, CH3);
13C NMR (75 MHz, DMSO-d6): δ 179.2 (C S), 164.7 (NH C O), 157.0 (C O), 149.4,
138.7, 137.7, 131.7, 128.3, 126.6, 126.2, 124.5, 123.3, 122.4, 120.7, 119.7, 116.4 (Ar-Cs),
21.4 (CH3). Anal. Calcd. for C18H15N3O3S: C, 61.18; H, 4.28; N, 11.89, S, 9.07; Found:
C, 61.11; H, 4.33; N, 11.75; S, 8.97.
1-(2-Oxo-2H-chromene-3-carbonyl)-4-p-tolylthiosemicarbazide (3e). Wh-
ite solid (59%): mp 179–181◦C; Rf∗: 0.51; IR (KBr, cm−1): 3432–3179 (NH), 1718 (C O),
1689 (C O), 1573, 1538, 1513 (C C), 1259 (C S); 1H NMR (300 MHz, DMSO-d6): δ
∗Rf solvent system (petroleum ether:ethyl acetate, 4:1).

1806
A. SAEED AND A. IBRAR
11.73 (s, 1H, NH C O), 11.14 (s, 2H, NH C S), 9.98 (s, 1H, C H, H-4), 7.42 (d, 1H,
J = 7.5 Hz, H-8), 7.26–7.23 (m, 2H, H-7, H-6), 7.21–7.14 (m, 2H, H-2ꢀ, H-6ꢀ), 6.99 (d,
1H, J = 7.5 Hz, H-5), 6.89–6.81 (m, 2H, H-3ꢀ, H-5ꢀ), 2.30 (s, 3H, CH3); 13C NMR (75
MHz, DMSO-d6): δ 176.2 (C S), 165.4 (NH C S), 157.0 (C O), 148.2, 137.0, 134.8,
131.8, 128.9, 126.2, 123.4, 122.7, 120.7, 119.7, 116.5 (Ar-Cs), 21.1 (CH3). Anal. Calcd.
for C18H15N3O3S: C, 61.18; H, 4.28; N, 11.89, S, 9.07; Found: C, 61.02; H, 4.20; N, 11.95;
S, 8.92.
4-(2-Methoxyphenyl)-1-(2-oxo-2H-chromene-3-carbonyl)thiosemicarba
zide (3f). White solid (57%): mp 198–200◦C; Rf∗: 0.56; IR (KBr, cm−1): 3326–3281
(NH), 1726 (C O), 1644 (C O), 1593, 1520 (C C), 1235 (C S); 1H NMR (300 MHz,
DMSO-d6): δ 11.90 (s, 1H, NH C O), 11.14 (s, 2H, NH C S), 9.97 (s, 1H, C-H, H-4),
7.88 (d, 1H, J = 7.8Hz, H-8), 7.28–7.25 (m, 1H, H-6), 7.23–7.14 (m, 1H, H-7), 7.09 (d,
1H, J = 7.2Hz, H-5), 7.00–6.96 (m, 2H, H-3ꢀ, H-6ꢀ), 6.93–6.86 (m, 2H, H-4ꢀ, H-5ꢀ), 3.35
(s, 3H, OCH3); 13C NMR (75MHz, DMSO-d6): δ 181.7 (C S), 166.2 (NH C O), 161.2
(C O), 151.6, 139.1, 136.2, 130.4, 128.2, 126.0, 125.9, 125.7, 124.5, 120.6, 120.3, 119.9,
116.6, 111.6 (Ar-Cs), 55.7 (OCH3). Anal. Calcd. for C18H15N3O4S: C, 58.53; H, 4.09; N,
11.38, S, 8.68; Found: C, 58.67; H, 4.21; N, 11.24; S, 8.53.
4-(3-Methoxyphenyl)-1-(2-oxo-2H-chromene-3-carbonyl)thiosemicarba
zide (3g). Green solid (57%): mp 169–172◦C; Rf∗: 0.56; IR (KBr, cm−1): 3324–3283
(NH), 1721 (C O), 1652 (C O), 1589, 1518 (C C), 1237 (C S); 1H NMR (300 MHz,
DMSO-d6): δ 11.70 (s, 1H, NH C O), 10.00 (s, 2H, NH C S), 9.01 (s, 1H, C-H, H-4),
7.69 (d, 1H, J = 7.8Hz, H-8), 7.40–7.37 (m, 1H, H-6), 7.30–7.17 (m, 2H, H-7, H-5),
7.00–6.91 (m, 2H, H-4ꢀ, H-5ꢀ), 6.90–6.75 (m, 2H, H-2ꢀ, H-6ꢀ), 3.76(s, 3H, OCH3); 13C
NMR (75 MHz, DMSO-d6): δ 180.7 (C S), 163.2 (NH C O), 159.4 (C O), 150.4,
140.7, 133.7, 131.3, 129.9, 129.1, 127.5, 125.7, 124.5, 120.7, 120.0, 119.6, 117.0, 111.5
(Ar-Cs), 55.5 (OCH3). Anal. Calcd. for C18H15N3O4S: C, 58.53; H, 4.09; N, 11.38, S,
8.68; Found: C, 58.45; H, 4.11; N, 11.29; S, 8.51.
Synthesis of 4,5-Disubstituted-1,2,4-triazol-3(4H) thiones (4a–g):
General Procedure
The thiosemicarbazides (3a–g) (1.4 mmol) were refluxed (4–5 h) in aqueous sodium
hydroxide solution (4N, 25 mL). The progress of the reaction was monitored by TLC.
After completion of the reaction, the reaction mixture was cooled to room temperature and
filtered. The filtrate was neutralized with hydrochloric acid (4N) to precipitate the triazoles,
which were filtered and recrystallized from aqueous ethanol.
3-(4-(2-Chlorophenyl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2H-chro
men-2-one (4a). Yellow solid (63%): mp 205–207◦C; Rf∗: 0.61; IR (KBr, cm−1): 3292
(NH), 1730 (C O), 1555, 1477 (C C), 1409 (C N), 1253 (C S); 1H NMR (300 MHz,
DMSO-d6): δ 11.13 (s, 1H, NH), 9.01 (s, 1H, C-H, H-4), 7.63 (d, 1H, J = 7.8 Hz, H-8),
7.42–7.38 (m, 2H, H-6, H-7), 6.93 (d, 1H, J = 7.5Hz, H-5), 7.11–7.08 (m, 2H, H-3ꢀ, H-5ꢀ),
7.03–6.99 (m, 1H, H-6ꢀ), 6.88–6.81 (m, 1H, H-4ꢀ); 13C NMR (75MHz, DMSO-d6): δ 165.2
(C S), 159.5 (C O), 158.5 (C N), 148.7, 133.6, 131.8, 131.1, 128.9, 128.6, 127.6,
126.4, 122.2, 121.4, 119.4, 119.1, 117.3, 116.9 (Ar-Cs). Anal. Calcd. for C17H10ClN3O2S:
C, 57.39; H, 2.83; N, 11.81, S, 9.01; Found: C, 57.23; H, 2.71; N, 11.70; S, 8.87.
3-(4-(3-Chlorophenyl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2H-chro
men-2-one (4b). Yellow solid (61%): mp 207–209◦C; Rf∗: 0.61; IR (KBr, cm−1): 3282
(NH), 1728 (C O), 1553, 1482 (C C), 1383 (C N), 1267 (C S); 1H NMR (300 MHz,

3-(5-(ARYLAMINO)-1,3,4-THIADIAZOL-2-YL)-2H-CHROMEN-2-ONES
1807
DMSO-d6): δ 11.13 (s, 1H, NH), 9.00 (s, 1H, C-H, H-4), 7.68 (d, 1H, J = 7.8Hz, H-8),
7.43–7.41 (m, 2H, H-6, H-7), 7.38–7.37 (m, 2H, H-4ꢀ, H-5ꢀ), 7.00 (d, 1H, J = 7.8 Hz,
H-5), 6.97–6.95 (m, 2H, H-2ꢀ, H-6ꢀ); 13C NMR (75 MHz, DMSO-d6): δ 163.2 (C S),
159.3 (C O), 157.8 (C N), 148.4, 133.7, 131.2, 130.5, 129.1, 128.6, 122.2, 120.1, 119.2,
118.6, 117.3, 117.0 (Ar-Cs). Anal. Calcd. for C17H10ClN3O2S: C, 57.39; H, 2.83; N,
11.81, S, 9.01; Found: C, 57.27; H, 2.69; N, 11.88; S, 8.92.
3-(4-(4-Chlorophenyl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2H-chro
men-2-one (4c). Green solid (66%): mp 204–206◦C; Rf∗: 0.62; IR (KBr, cm−1): 3287
(NH), 1728 (C O), 1571, 1486 (C C), 1381 (C N), 1269 (C S); 1H NMR (300 MHz,
DMSO-d6): δ 11.14 (s, 1H, NH), 9.01 (s, 1H, C-H, H-4), 7.69 (d, 1H, J = 7.8 Hz, H-8),
7.43–7.40 (m, 2H, H-6, H-7), 7.39–7.37 (m, 2H, H-3ꢀ, H-5ꢀ), 6.98 (d, 1H, J = 7.8 Hz,
H-5), 6.96–6.94 (m, 2H, H-2ꢀ, H-6ꢀ); 13C NMR (75MHz, DMSO-d6): δ 163.3 (C S),
159.1 (C O), 157.9 (C N), 148.6, 133.7, 131.3, 130.4, 129.2, 128.7, 122.6, 120.0, 119.3,
118.7, 117.2, 117.0 (Ar-Cs). Anal. Calcd. for C17H10ClN3O2S: C, 57.39; H, 2.83; N,
11.81, S, 9.01; Found: C, 57.26; H, 2.69; N, 11.67; S, 8.92.
3-(5-Thioxo-4-m-tolyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2H-chromen-2-o
ne (4d). Yellow solid (59%): mp 217–219◦C; Rf∗: 0.59; IR (KBr, cm−1): 3281 (NH),
1
1725 (C O), 1576, 1541 (C C), 1413 (C N), 1235 (C S); H NMR (300 MHz,
DMSO-d6): δ 11.15 (s, 1H, NH), 9.00 (s, 1H, C-H, H-4), 7.71–7.68 (m, 2H, H-8, H-6),
7.43–7.37 (m, 2H, H-7, H-5), 6.99–6.95 (m, 4H, H-2ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ), 2.21 (s, 3H, CH3);
13C NMR (75MHz, DMSO-d6): δ 163.3 (C S), 160.1 (C O), 159.1 (C N), 149.3, 133.7,
131.3, 131.1, 129.2, 128.2, 126.1, 124.6, 122.1, 120.1, 119.3, 118.6, 117.4, 117.0 (Ar-Cs),
24.3 (CH3). Anal. Calcd. for C18H13N3O2S: C, 64.46; H, 3.91; N, 12.53, S, 9.56; Found:
C, 64.51; H, 3.79; N, 12.42; S, 9.40.
3-(5-Thioxo-4-p-tolyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2H-chromen-2-one
(4e). Yellow solid (61%): mp 211–213◦C; Rf∗: 0.58; IR (KBr, cm−1): 3297 (NH), 1732
(C O), 1557, 1513 (C C), 1375 (C N), 1288 (C S); 1H NMR (300 MHz, DMSO-d6):
δ 11.14 (s, 1H, NH), 9.01 (s, 1H, C-H, H-4), 7.43–7.25 (m, 4H, H-8, H-7, H-6, H-5), 7.07
(d, 2H, J = 8.1Hz, H-2ꢀ, H-6ꢀ), 6.99 (d, 2H, J = 7.8 Hz, H-3ꢀ, H-5ꢀ), 2.23 (s, 3H, CH3); 13
C
NMR (75 MHz, DMSO-d6): δ 163.5 (C S), 159.4 (C O), 158.6 (C N), 149.1, 137.7,
133.6, 130.9, 129.6, 128.7, 125.5, 121.0, 119.3, 118.6, 117.0, 116.0, 112.7, 116.8 (Ar-Cs),
20.8 (CH3). Anal. Calcd. for C18H13N3O2S: C, 64.46; H, 3.91; N, 12.53, S, 9.56; Found:
C, 64.61; H, 3.82; N, 12.39; S, 9.41.
3-(4-(2-Methoxyphenyl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2H-ch
romen-2-one (4f). Yellow solid (64%): mp 214–216◦C; Rf∗: 0.51; IR (KBr, cm−1):
1
3275 (NH), 1730 (C O), 1552, 1475 (C C), 1410 (C N), 1233 (C S); H NMR (300
MHz, DMSO-d6): δ 13.94 (s, 1H, NH), 9.88 (s, 1H, C-H, H-4), 7.36–7.28 (m, 2H, H-8,
H-6), 7.22–7.14 (m, 2H, H-5, H-7), 7.00–6.95 (m, 2H, H-3ꢀ, H-5ꢀ), 6.77–6.72 (m, 2H, H-4ꢀ,
H-6ꢀ), 3.56 (s, 3H, OCH3); 13C NMR (75 MHz, DMSO-d6): δ 168.5 (C S), 159.1 (C O),
156.3 (C N), 150.9, 139.7, 132.3, 131.4, 130.7, 126.2, 123.1, 120.5, 119.8, 118.8, 117.7,
116.0, 112.7, 113.7 (Ar-Cs), 56.0 (OCH3). Anal. Calcd. for C18H13N3O3S: C, 61.53; H,
3.73; N, 11.96, S, 9.13; Found: C, 61.43; H, 3.56; N, 11.88; S, 9.01.
3-(4-(3-Methoxyphenyl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2H-ch
romen-2-one (4g). Green solid (60%): mp 218–220◦C; Rf∗: 0.51; IR (KBr, cm−1):
1
3273 (NH), 1727 (C O), 1551, 1477 (C C), 1412 (C N), 1237 (C S); H NMR (300
MHz, DMSO-d6): δ 11.13 (s, 1H, NH), 9.01 (s, 1H, C-H, H-4), 7.71–7.68 (m, 2H, H-8,
H-6), 7.43–7.37 (m, 2H, H-5, H-7), 7.01–6.95 (m, 2H, H-4ꢀ, H-5ꢀ), 6.70–6.36 (m, 2H, H-2ꢀ,
H-6ꢀ), 3.53 (s, 3H, OCH3); 13C NMR (75 MHz, DMSO-d6): δ 163.5 (C S), 159.1 (C O),

1808
A. SAEED AND A. IBRAR
156.4 (C N), 150.8, 139.9, 133.7, 131.3, 130.4, 126.6, 123.2, 120.7, 119.7, 118.6, 117.0,
116.1, 113.5, 112.4 (Ar-Cs), 56.7 (OCH3). Anal. Calcd. for C18H13N3O3S: C, 61.53; H,
3.73; N, 11.96, S, 9.13; Found: C, 61.48; H, 3.61; N, 11.81; S, 9.16.
Synthesis of 2,5-Disubstituted-1,3,4-thiadiazoles (5a–g):
General Procedure
1,4-Disubstituted thiosemicarbazides (3a–g) (1.4 mmol) in polyphosphoric acid (0.5
mL, 2.8 mmol) were stirred overnight at 70◦C. After completion of the reaction, the cooled
solution was poured onto the crushed ice. The reaction mixture was extracted with ethyl
acetate (3 × 20 mL), and the combined extracts were washed with sodium bicarbonate (5%)
and water until the washings were neutral. The organic layer was dried with anhydrous
sodium sulfate and concentrated under reduced pressure to yield the 2,5-disubstituted-
1,3,4-thiadiazoles, purified by recrystallization in ethanol.
3-(5-(2-Chlorophenylamino)-1,3,4-thiadiazol-2-yl)-2H-chromen-2-one (5a).
Yellow solid (45%): mp 212–214◦C; Rf∗: 0.40; IR (KBr, cm−1): 3278 (NH), 1725 (C O),
1563, 1529 (C C), 1415 (C N); 1H NMR (300 MHz, DMSO-d6): δ 11.42 (s, 1H, NH),
8.73 (s, 1H, C-H, H-4), 7.44–7.36 (m, 4H, H-6, H-8, H-3ꢀ, H-5ꢀ), 7.04–6.96 (m, 4H, H-5,
H-7, H-4ꢀ, H-6ꢀ); 13C NMR (75 MHz, DMSO-d6): δ 164.7 (C O), 159.8 (C N NH),
159.2 (C N), 149.2, 133.5, 132.6, 131.9, 130.7, 129.1, 128.5, 127.8, 127.6, 120.0, 119.8,
117.8, 117.3, 116.8 (Ar-Cs). Anal. Calcd. for C17H10ClN3O2S: C, 57.39; H, 2.83; N, 11.81,
S, 9.01; Found: C, 57.27; H, 2.76; N, 11.72; S, 8.87.
3-(5-(3-Chlorophenylamino)-1,3,4-thiadiazol-2-yl)-2H-chromen-2-one (5b).
Yellow solid (44%): mp 210–212◦C; Rf∗: 0.40; IR (KBr, cm−1): 3271 (NH), 1728 (C O),
1565, 1527 (C C), 1419 (C N); 1H NMR (300 MHz, DMSO-d6): δ 11.15 (s, 1H, NH),
9.01 (s, 1H, C-H, H-4), 7.70–7.61 (m, 4H, H-6, H-8, H-3ꢀ, H-5ꢀ), 7.50–7.36 (m, 4H, H-5,
H-7, H-2ꢀ, H-6ꢀ); 13C NMR (75MHz, DMSO-d6): δ 163.7 (C O), 159.9 (C N NH),
159.1 (C N), 148.2, 135.5, 133.6, 132.9, 130.5, 129.2, 128.6, 127.7, 126.6, 120.2, 119.1,
117.9, 117.1, 116.3 (Ar-Cs). Anal. Calcd. for C17H10ClN3O2S: C, 57.39; H, 2.83; N, 11.81,
S, 9.01; Found: C, 57.23; H, 2.71; N, 11.67; S, 9.09.
3-(5-(4-Chlorophenylamino)-1,3,4-thiadiazol-2-yl)-2H-chromen-2-one (5c).
Yellow solid (59%): mp 216–218◦C; Rf∗: 0.45; IR (KBr, cm−1): 3256 (NH), 1728 (C O),
1543, 1521 (C C), 1432 (C N); 1H NMR (300 MHz, DMSO-d6): δ 11.15 (s, 1H, NH),
9.01 (s, 1H, C-H, H-4), 7.69 (d, 1H, J = 7.5Hz, H-8), 7.65–7.61 (m, 1H, H-6), 7.48 (d,
2H, J = 8.4Hz, H-3ꢀ, H-5ꢀ), 7.42-7.36 (m, 1H, H-7), 6.98 (d, 1H, J = 8.4Hz, H-5), 6.95
(d, 2H, J = 8.1Hz, H-2ꢀ, H-6ꢀ); 13C NMR (75 MHz, DMSO-d6): δ 163.3 (C O), 159.1
(C N NH), 157.3 (C N), 148.6, 133.7, 131.3, 130.7, 129.3, 129.1, 128.3, 127.9, 120.1,
119.3, 118.6, 116.9 (Ar-Cs). Anal. Calcd. for C17H10ClN3O2S: C, 57.39; H, 2.83; N, 11.81,
S, 9.01; Found: C, 57.26; H, 2.96; N, 11.74; S, 8.89.
3-(5-(m-Toluidino)-1,3,4-thiadiazol-2-yl)-2H-chromen-2-one (5d). Yellow
solid (39%): mp 219–221◦C; Rf∗: 0.47; IR (KBr, cm−1): 3198 (NH), 1730 (C O),
1
1600, 1561, 1501 (C C), 1463 (C N); H NMR (300 MHz, DMSO-d6): δ 11.14 (s,
1H, NH), 9.01 (s, 1H, C-H, H-4), 7.71–7.68 (m, 2H, H-8, H-6), 7.43–7.37 (m, 2H, H-7,
H-5ꢀ), 6.99–6.94 (m, 4H, H-5, H-2ꢀ, H-4ꢀ, H-6ꢀ), 2.08 (s, 3H, CH3); 13C NMR (75 MHz,
DMSO-d6): δ 163.2 (C O), 159.1 (C N NH), 157.4 (C N), 148.8, 133.7, 130.9, 130.2,
128.3, 127.1, 124.3, 121.9, 121.8, 120.1, 119.7, 119.5, 119.1, 118.6, 117.9, 117.3, 117.0,

3-(5-(ARYLAMINO)-1,3,4-THIADIAZOL-2-YL)-2H-CHROMEN-2-ONES
1809
116.7, 116.3, 116.0 (Ar-Cs), 31.1 (CH3). Anal. Calcd. for C18H13N3O2S: C, 64.46; H,
3.91; N, 12.53, S, 9.56; Found: C, 64.34; H, 3.98; N, 12.38; S, 9.41.
3-(5-(p-Toluidino)-1,3,4-thiadiazol-2-yl)-2H-chromen-2-one (5e). Yellow
solid (56%): mp 191–193◦C; Rf∗: 0.44; IR (KBr, cm−1): 3267 (NH), 1725 (C O), 1592,
1554 (C C), 1471 (C N); 1H NMR (300 MHz, DMSO-d6): δ 11.14 (s, 1H, NH), 9.70 (s,
1H, C-H, H-4), 7.72–7.64 (m, 2H, H-8, H-6), 7.45–7.24 (m, 2H, H-7, H-5), 7.17–7.13 (m,
2H, H-2ꢀ, H-6ꢀ), 7.12–7.08 (m, 2H, H-3ꢀ, H-5ꢀ), 2.27 (s, 3H, CH3); 13C NMR (75 MHz,
DMSO-d6): δ 167.4 (C O), 163.0 (C N NH), 157.0 (C N), 145.8, 134.0, 131.6, 130.0,
129.0, 124.3, 121.9, 119.7, 119.5, 117.9, 117.0, 116.3 (Ar-Cs), 20.8 (CH3). Anal. Calcd.
for C18H13N3O2S: C, 64.46; H, 3.91; N, 12.53, S, 9.56; Found: C, 64.32; H, 3.78; N,
12.40; S, 9.45.
3-(5-(2-Methoxyphenylamino)-1,3,4-thiadiazol-2-yl)-2H-chromen-2-one
(5f). Yellow solid (49%): mp 206–208◦C; Rf∗: 0.51; IR (KBr, cm−1): 3287 (NH), 1726
1
(C O), 1594, 1544 (C C), 1466 (C N); H NMR (300 MHz, DMSO-d6): δ 11.86 (s,
1H, NH), 9.96 (s, 1H, C-H, H-4), 7.69 (d, 1H, J = 7.2Hz, H-8), 7.43–7.38 (m, 2H, H-6,
H-7), 7.04–6.85 (m, 5H, H-5, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ), 3.87 (s, 3H, OCH3); 13C NMR (75
MHz, DMSO-d6): δ 163.2 (C O), 159.1 (C N NH), 157.3 (C N), 148.6, 147.0, 133.7,
132.0, 129.5, 128.3, 128.0, 121.7, 121.0, 120.1, 118.6, 116.8, 116.4 (Ar-Cs), 56.5 (OCH3).
Anal. Calcd. for C18H13N3O3S: C, 61.53; H, 3.73; N, 11.96, S, 9.13; Found: C, 61.41; H,
3.60; N, 11.83; S, 9.04.
3-(5-(3-Methoxyphenylamino)-1,3,4-thiadiazol-2-yl)-2H-chromen-2-one
(5g). Yellow solid (46%): mp 202–204◦C; Rf∗: 0.51; IR (KBr, cm−1): 3284 (NH), 1729
1
(C O), 1584, 1545 (C C), 1468 (C N); H NMR (300 MHz, DMSO-d6): δ 11.15 (s,
1H, NH), 9.79 (s, 1H, C-H, H-4), 7.70 (d, 1H, J = 7.2 Hz, H-8), 7.43–7.37 (m, 2H, H-6,
H-7), 7.99–6.85 (m, 5H, H-5, H-2ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ), 3.56 (s, 3H, OCH3); 13C NMR (75
MHz, DMSO-d6): δ 165.2 (C O), 159.9 (C N NH), 157.7 (C N), 147.,8 146.3, 133.6,
131.0, 129.2, 128.4, 127.7, 123.7, 121.9, 120.5, 119.6, 118.8, 116.4 (Ar-Cs), 58.6 (OCH3).
Anal. Calcd. for C18H13N3O3S: C, 61.53; H, 3.73; N, 11.96, S, 9.13; Found: C, 61.46; H,
3.81; N, 11.85; S, 9.02.
Supplementary Material
1H NMR and 13C NMR spectra of representative compounds are available online as
Supplementary Material.
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