Synthetic approaches towards the sulfonamide substituted-4,5-diaryl-4H-1,2, 4-triazole-3-thiones

Article abstract of DOI:10.1002/jhet.5570440614

(Chemical Equation Presented) A new series of 3-alkylthio-4,5-diaryl-4H-1, 2,4-triazoles having a SO₂NH₂ substituent in the para-position on one of the aryl rings (19/25) were prepared starting from the appropriate benzoic acid hydra

Full text of DOI:10.1002/jhet.5570440614

Nov-Dec 2007
1323
Synthetic Approaches Towards the Sulfonamide Substituted-4,5-
diaryl-4H-1,2,4-triazole-3-thiones
Latifeh Navidpour, Mohsen Amini, Abbas Shafiee*
Department of Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center,
Tehran University of Medical Sciences, Tehran, 14174 Iran. E-Mail: ashafiee@ams.ac.ir
Received Nov 12, 2006
Y'
X'
Y''
X''
N
N
X
CONHNH2
NH
N
N
N
S
SR
X= SO2NBn2, H, F, Cl, Br, Me
X' = SO2NBn2, Y' = H, F, OMe
X'' = SO2NH2, Y'' = H, F, OMe
or X' = H, F, Cl, Br, Me, Y' = SO2NBn2
or X'' = H, F, Cl, Br, Me, Y'' = SO2NH2
A new series of 3-alkylthio-4,5-diaryl-4H-1,2,4-triazoles having a SO2NH2 substituent in the para-
position on one of the aryl rings (19/25) were prepared starting from the appropriate benzoic acid
hydrazides (15/21). Reaction of the corresponding hydrazides with the appropriate isothiocyanates yielded
16/22, which were cyclized in basic media to give 4,5-diaryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones
17/23. Alkylation of 17/23 afforded the alkylthio compounds 18/24. Final debenzylation was achieved with
concentrated sulfuric acid to give the target sulfonamides 19/25.
J. Heterocyclic Chem., 44, 1323 (2007).
The selective COX-2 inhibitors celecoxib [1] and
As part of our ongoing program to design novel
selective COX-2 inhibitors [13-18], we describe here the
synthesis of a novel class of 4,5-diaryl-1,2,4-triazoles
possessing a 3-alkylthio substituent on the central five-
membered 1,2,4-triazole ring.
etoricoxib [2,3] have been clinically validated as anti-
inflammatory therapeutics for indications such as
rheumatoid arthritis with less gastrointestinal and renal
toxicity (Figure 1) [4-7]. In addition to its role in
rheumatoid arthritis and osteoarthritis, COX-2 is also
implicated in colon cancer and Alzheimer disease [8-10].
Tricyclic compounds possessing a 1,2-diaryl substitu-
tion on a central heterocyclic or carbocyclic system
constitute a major class of selective COX-2 inhibitors.
Structure-activity relationship (SAR) studies have shown
that a SO2Me or SO2NH2 substituent in the para-position
on one of the aryl rings often provides optimum COX-2
selectivity and inhibitory potency [11]. Whereas a small
lipophilic substituent (Me, CF3) on the central ring
frequently enhances, or is often a requirement for COX-2
selectivity [12], modification of the substituents to
identify new ligands with improved properties is
desirable.
Syntheses of 1,2,4-triazole-3-thiones have been
reported via several pathways [20-22]. In an attempt to
prepare the target 4-(3-alkylthio-5-aryl-4H-1,2,4-triazol-
4-yl)benzenesulfonamides (19), chlorosulfonation of 1
was first investigated (see Scheme 1). This reaction was
unsatisfactory at room temperature and the unchanged
starting material was isolated. On refluxing of 1 with
ClSO3H, the expected chlorosulfonation reaction preceded
by a competitive chlorination reaction that gave 4 (instead
of 2) [23]. The arylation reaction was next investigated
using 3-methylthio-5-phenyl-4H-1,2,4-triazole (5) and
fluorobenzene activated by an electron-withdrawing 4-
N,N-dibenzylaminosulfonyl group 6 (see Scheme 1). In
good agreement with our previous study [24], arylation
occurred predominantly at the N-2 position of the triazole
ring, affording N,N-dibenzyl-4-(3-methylthio-5-phenyl-
2H-1,2,4-triazol-2-yl)benzenesulfonamide (7). However,
N-4 and N-1 arylated compounds (8 and 9) were also
formed in low yield. The differentiation between these
two products 8 and 9 was possible on the basis of
comparison with 18a (see later). 8 was identical to 18a.
Obviously, the most nucleophilic position at the 1,2,4-
triazole should attack most rapidly. Since N-2 is receiving
electron density by the adjacent alkylthio substituent -SR
at the C-3 which acts as a donor substituent, arylation
occurred predominantly at the N-2 position to produce 7.
H3CO2S
H3C
Cl
CF3
N
N
N
H3C
H2NO2S
2 (Etoricoxib)
1 (Celecoxib)
Figure 1. Representative Examples of Selective Tricyclic COX-2
Inhibitors.

1324
L. Navidpour, M. Amini, A. Shafiee
Vol 44
Scheme 1
N
N
N
N
Cl
Cl
X
SR
SR
N
N
a
X
N
N
2
3
Cl
SR
N
SO2NH2
SO2Cl
1
a
N
N
Cl
SR
N
4
Cl
N
N
b
SO2NBn2
F
SCH3
+
N
H
5
6
SO2NBn2
Bn2NO2S
N
N
N
N
N
+
SCH3
N
N
+
N
SCH3
SCH3
N
Bn2NO2S
9
7
8
Reagents and conditions: (a) ClSO3H, reflux, overnight; (b) NaH, DMSO, 120°C, 20 h.
In an another attempt to prepare compound 19, the
reaction of 10 [25] and 4-amino-N,N-dibenzylbenzene-
sulfonamide 11 was investigated. However, because of
the weak nucleophilicity of the amino group in 11, this
reaction was also unsatisfactory (Scheme 2).
Finally, the previously reported reaction of benzoic
acid hydrazide 15 and the appropriate isothiocyanate [26]
was extended for the preparation of compound 19. The
synthetic reactions used for the synthesis of compound 19
are outlined in Scheme 3.
saturated sodium carbonate gave 17. Alkylation of 17
using alkyl iodide in basic media, followed by debenz-
ylation in concentrated H2SO4 afforded the title sulfon-
amides 19 [26, 27].
We were also interested in preparing 4,5-diaryl-1,2,4-
triazole-3-thiones in which the 4-sulfonylphenyl moiety is
attached in a 1,3-relationship relative to thio substituent of
the triazole, namely 4-(3-alkylthio-4-aryl-4H-1,2,4-triazol-
5-yl)benzenesulfonamides 25.
The reaction of 4-(N,N-dibenzylaminosulfonyl)benzoic
acid hydrazide 21 and the corresponding isothiocyanates
was then investigated, which in four steps gave the
desired compounds 25 (Scheme 4) [26,27].
Treatment of the corresponding hydrazides 15 with
N,N-dibenzyl-4-isothiocyanatobenzenesulfonamide 14
and subsequent cyclization of the intermediate 16 in
Scheme 2
X
N
NH
C
S
C
c
NH
X
NHNH
10
NH2
H2N
SO2NBn2
N
+
X
S
11
Bn2NO2S
12
X = H, Cl, CH3
Reagents and conditions: (c) dry DMF, reflux, 24 h.

Nov-Dec 2007
Substituted 4,5-diaryl-4H-1,2,4-triazole-3-thiones
1325
Scheme 3
d
CONHNH2
15
Bn2NO2S
NH2
X
+
NCS
Bn2NO2S
13
14
X
O
C
S
C
N
f
e
NHNH
16
NH
SO2NBn2
X
NH
N
S
Bn2NO2S
17
X
X
g
N
N
N
h
N
N
N
SR
SR
Bn2NO2S
H2NO2S
18
19
X: H, F, OMe
R: Me, Et
Reagents and conditions: (d) CSCl2, H2O/HCl, r.t., overnight; (e) EtOH, r.t., overnight; (f) Na2CO3, reflux, overnight; (g) RI, KOH,
EtOH, r.t., overnight; (h) H2SO4 concentrated, r.t., 20 min.
4-(N,N-Dibenzylaminosulfonyl)benzoic acid hydrazide
21 was prepared by the reaction of methyl 4-(N,N-
dibenzylaminosulfonyl)benzoate 20 with hydrazine
hydrate (5 equiv.). Reaction of the corresponding hydra-
zide 21 with the respective 4-substituted phenyl isothio
cyanates yielded 22, which were cyclized in saturated
sodium carbonate solution to triazole-3-thiones 23 in good
yields. Subsequent alkylation of 23 using alkyl iodide in
basic media afforded the alkylthiotriazoles 24. Final
debenzylation was achieved using concentrated sulfuric
Scheme 4
j
i
COOCH3
Bn2NO2S
CONHNH2
Bn2NO2S
21
20
Bn2NO2S
S
O
N
k
Bn2NO2S
CNHNHCNH
X
NH
N
S
22
X
23
Bn2NO2S
H2NO2S
N
N
m
l
N
N
N
N
SR
SR
X
X
24
25
X: H, F, Cl, Br, Me
R: Me, Et
Reagents and conditions: (i) NH2NH2.H2O, MeOH, 4 h; (j) Ar-N=C=S, EtOH, r.t., overnight; (k) Na2CO3 aq., reflux, overnight; (l) RI, KOH, r.t.,
overnight; (m) H2SO4 concentrated, r.t., 20 min.

1326
L. Navidpour, M. Amini, A. Shafiee
Vol 44
196 (38), 103 (13), 90 (100). Anal. Calcd. for C29H26N4O2S2: C,
66.13; H, 4.98; N, 10.64. Found: C, 66.25; H, 5.12; N, 10.46.
N,N-Dibenzyl-4-(3-methylthio-5-phenyl-4H-1,2,4-triazol-4-
yl)benzenesulfonamide (8). Following the arylation procedure,
8 was obtained (0.04 g, 1.8%); mp 190-192°C; ir (potassium
bromide): 1342, 1158 cm-1 (SO2); 1H nmr (deuteriochloroform):
ꢀ 7.87 (d, J = 8.6 Hz, 2H), 7.55-7.48 (m, 4H), 7.53-7.39 (m, 3H),
7.33-7.27 (m, 6H), 7.16-7.10 (m, 4H), 4.39 (s, 4H), 2.75 (s, 3H);
ms: m/z 526 (M+, 25), 435 (8), 331 (28), 266 (17), 251 (12), 196
(19), 104 (8), 91 (100). Anal. Calcd. for C29H26N4O2S2: C, 66.13;
H, 4.98; N, 10.64. Found: C, 66.02; H, 5.12; N, 10.81.
N,N-Dibenzyl-4-(3-methylthio-5-phenyl-4H-1,2,4-triazol-1-
yl)benzenesulfonamide (9). Following the arylation procedure,
9 was obtained (0.06 g, 3%); mp 153-155°C; ir (potassium
bromide): 1347, 1163 cm-1 (SO2); 1H nmr (deuteriochloroform):
ꢀ 8.14 (d, J = 8.7 Hz, 2H), 7.48-7.58 (m, 4H), 7.35-7.20 (m, 9H),
7.05-7.14 (m, 4H), 4.41 (s, 4H), 2.89 (s, 3H); ms: m/z 526 (M+,
18), 435 (7), 350 (5), 331 (18), 251 (10), 196 (20), 130 (15), 91
(100). Anal. Calcd. for C29H26N4O2S2: C, 66.13; H, 4.98; N,
10.64. Found: C, 66.22; H, 4.80; N, 10.75.
acid to give the title sulfonamides 25 (Scheme 4).
EXPERIMENTAL
Melting points were determined with a Reichert-Jung hot-
1
stage microscope and are uncorrected. H nmr (400 or 80 MHz)
spectra were recorded on a Varian Utility plus 400 spectrometer
or a Brucker 80 MHz spectrometer using deuteriochloroform or
dimethylsulfoxide-d6 as solvent. Chemical shifts (ꢀ) are reported
in ppm relative to TMS as internal standard. Infrared spectra
were acquired on a Nicolet Magna 550-FT spectrometer. Mass
spectra were obtained with
a
Finnigan Mat TSQ-70
spectrometer. Elemental microanalyses were within ± 0.4% of
the theoretical values for C, H and N.
3-Methylthio-4,5-bis(4-chlorophenyl)-4H-1,2,4-triazole (4).
A suspension of 1 (150 mg, 0.45 mmole) in ClSO3H (3 m1)
was refluxed overnight. The mixture was poured into ice. The
resulting mixture was extracted with chloroform, dried (Na2SO4)
and evaporated to give 4 (70 mg, 42%) as a white solid; mp 189-
190°C; 1H nmr (deuteriochloroform): ꢀ 7.72-7.41 (m, 4H), 7.35-
7.05 (m, 4H), 2.73 (s, 3H); ms: m/z 335 (M+, 5), 248 (5), 197
(10), 163 (12), 150 (100), 145 (48), 123 (32), 108 (18), 90 (48),
76 (33). The physical data was similar to those reported [24].
Anal. Calcd. for C15H11Cl2N3S: C, 53.58; H, 3.30; N, 12.50.
Found: C, 53.47; H, 3.39; N, 12.42.
N,N-Dibenzyl-4-fluorobenzenesulfonamide (6). To a solution
of dibenzylamine (5.06 g, 25.6 mmoles) in THF (100 ml) was
added dropwise 4-fluorobenzenesulfonyl chloride (5 g, 25.6
mmoles) dissolved in THF (50 ml) under N2 at 0ºC followed by
addition of triethylamine (3.55 ml, 25.6 mmoles). The reaction
mixture was stirred overnight at room temperature, filtered and the
precipitate was washed with THF. The filtrate was concentrated
and partitioned between water and ethyl acetate. The organic
phase was dried, evaporated and the residue crystallized from
diethyl ether to give 6 (6.47g, 71%) as a white solid; mp 85-87°C;
ir (potassium bromide): 1325, 1148 cm-1 (SO2); 1H nmr
(deuteriochloroform): ꢀ 7.82 (dd, J = 5.1, 8.9 Hz, 2H), 7.3-6.90
(m, 12H), 4.33 (s, 4H). Anal. Calcd. for C20H18FNO2S: C, 67.58;
H, 5.10; N, 3.94. Found: C, 67.45; H, 4.92; N, 3.87.
Arylation of 3-methylthio-5-phenyl-1H-1,2,4-triazole. To a
solution of 3-methylthio-5-phenyl-1H-1,2,4-triazole 5 (0.8 g, 4.2
mmoles) in DMSO (10 ml) was added sodium hydride (100 mg,
4.2 mmoles). After 20 minutes of stirring at room temperature,
N,N-dibenzyl-4-fluorobenzenesulfonamide 6 (1.49 mg, 0.42
mmoles) was added. The reaction mixture was heated at 120-
130 °C for 20 hours, cooled to room temperature, and poured out
into ice and extracted with ethyl acetate. The solvent was
evaporated and the residue was chromatographed (ethyl
acetate/hexane, 1:3). The fast moving fraction gave 7 (0.46 g,
21%). The slow moving fractions gave 8 (0.04 g, 1.8%) and 9
(0.06 g, 3%), respectively.
N,N-Dibenzyl-4-isothiocyanatobenzenesulfonamide (14).
4-Amino-N,N-dibenzylbenzenesulfonamide 13 (5.0 g, 14.2
mmoles) was dissolved in water (50 ml) containing concentrated
HCl (12.5 ml). To this, thiophosgene (1.63 g, 14.2 mmoles) was
added. Stirring was begun immediately and continued overnight.
The product was filtered, washed with water, and recrystallized
from hexane to give 14 (2.5 g, 45%) as a white solid; mp 119-
121°C; ir (potassium bromide): 2080 (NCS), 1337, 1158 cm-1
1
(SO2); H nmr (deuteriochloroform + dimethylsulfoxide-d6): ꢀ
7.78 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 7.25-6.85 (m,
10H), 4.33 (s, 4H). Anal. Calcd. for C21H18N2O2S2: C, 63.93; H,
4.60; N, 7.10. Found: C, 63.77; H, 4.44; N, 7.26.
General Procedure for the Preparation of 1-(4-Substituted
benzoyl)-4-(4-N,N-dibenzylaminosulfonylphenyl)thiosemi-
carbazides (16a-c). To a solution of 4-substituted benzoic acid
hydrazide 15 (1.5 mmoles) in ethanol (10 ml) was added N,N-
dibenzyl-4-isocyanatobenzenesulfonamide 14 (0.6 g, 1.5
mmoles) and the mixture was stirred at room temperature for 24
hours. Then, the product was filtered and crystallized from
ethanol to give the title compounds 16a-c as white solids.
1-Benzoyl-4-(4-N,N-dibenzylaminosulfonylphenyl)thiosemi-
carbazide (16a). Following the general procedure, 16a was
obtained (0.53 g, 66%); mp 174-176°C; ir (potassium bromide):
3309, 3255, 3198 (NH), 1655 (CO), 1337, 1158 cm-1 (SO2); 1H
nmr (deuteriochloroform + dimethylsulfoxide-d6): ꢀ 10.32 (s,
1H, NH), 9.81 (s, 1H, NH), 8.1-7.65 (m, 4H, aromatic), 7.68-7.4
(m, 3H, aromatic), 7.38-6.85 (m, 12H,aromatic), 4.30 (s, 4H,
CH2) ; 13C nmr (deuteriochloroform + dimethylsulfoxide-d6): ꢀ
171.82, 162.53, 143.55, 135.90, 135.88, 132.52, 132.23, 128.91,
128.77, 128.73, 128.71, 128.57, 128.09, 128.04, 127.95, 127.92,
123.13, 51.01. Anal. Calcd. for C28H26N4O3S2: C, 63.37; H, 4.94;
N, 10.56. Found: C, 63.20; H, 4.82; N, 10.72.
N,N-Dibenzyl-4-(3-methylthio-5-phenyl-4H-1,2,4-triazol-1-
yl)benzenesulfonamide (7). Following the arylation procedure,
7 was obtained (0.46 g, 21%); mp 113-115°C; ir (potassium
bromide): 1356, 1163 cm-1 (SO2); 1H nmr (deuteriochloroform):
ꢀ 8.22 (m, 2H), 7.99 (d, J = 8.7 Hz, 2H), 7.91 (d, J = 8.7 Hz,
2H), 7.55-7.45 (m, 3H), 7.36-7.23 (m, 6H), 7.18-7.10 (m, 4H),
4.24 (s, 4H), 2.91 (s, 3H); 13C nmr (deuteriochloroform): ꢀ
162.87, 155.15, 140.96, 140.43, 135.73, 130.65, 130.56, 129.08,
129.02, 129.01, 128.86, 128.30, 126.98, 123.71, 51.06, 16.48;
ms: m/z 526 (M+, 19), 435 (12), 331 (44), 266 (28), 251 (24),
1-(4-Fluorobenzoyl)-4-(4-N,N-dibenzylaminosulfonylphenyl)-
thiosemicarbazide (16b). Following the general procedure, 16b
was obtained (0.66 g, 79%); mp 171-173°C; ir (potassium bromide):
1
3257, 3191 (NH), 1680 (CO), 1327, 1153 cm-1 (SO2); H nmr
(deuteriochloroform + dimethylsulfoxide-d6): ꢀ 10.18 (s, 1H, NH),
9.72 (s, 1H, NH), 8.1-7.65 (m, 6H, aromatic), 7.38-6.85 (m, 12H,
aromatic), 4.30 (s, 4H, CH2). Anal. Calcd. for C28H25FN4O3S2: C,
61.30; H, 4.59; N, 10.21. Found: C, 61.16; H, 4.68; N, 10.08.
1-(4-Methoxybenzoyl)-4-(4-N,N-dibenzylaminosulfonyl-
phenyl)thiosemicarbazide (16c). Following the general

Nov-Dec 2007
Substituted 4,5-diaryl-4H-1,2,4-triazole-3-thiones
1327
procedure, 16c was obtained (0.67 g, 79%); mp 164-165°C; ir
(potassium bromide): 3263, 3135 (NH), 1670 (CO), 1332, 1158
cm-1 (SO2); 1H nmr (deuteriochloroform + dimethylsulfoxide-d6):
ꢀ 10.20 (s, 1H, NH), 9.71 (s, 1H, NH), 7.95-7.65 (m, 6H,
aromatic), 7.45-6.9 (m, 12H, aromatic), 4.30 (s, 4H, CH2), 3.87
(s, 3H, CH3). Anal. Calcd. for C29H28N4O4S2: C, 62.12; H, 5.03;
N, 9.99. Found: C, 61.98; H, 4.94; N, 10.14.
General Procedure for the Preparation of N,N-Dibenzyl-4-
(5-aryl-3-thio-2,4-dihydro-3H-1,2,4-triazol-4-yl)benzene
sulfonamides (17a-c). A stirring mixture of compounds 16a-c
(1.1 mmole) and saturated aqueous sodium carbonate solution
(15 ml) was refluxed overnight. After cooling, the solution was
acidified with hydrochloric acid and the precipitate was filtered
and washed with water. The precipitate was crystallized from
ethanol to give the title compounds 17a-c.
N,N-Dibenzyl-4-(3-ethylthio-5-phenyl-4H-1,2,4-triazol-4-
yl)benzenesulfonamide (18b). Following the general procedure,
18b was obtained (0.22 g, 81%); mp 148-150°C; ir (potassium
bromide): 1322, 1153 cm-1 (SO2); 1H nmr (deuteriochloroform):
ꢀ 7.87 (d, J = 8.6 Hz, 2H), 7.58-7.44 (m, 4H), 7.53-7.42 (m, 3H),
7.33-7.25 (m, 6H), 7.18-7.07 (m, 4H), 4.38 (s, 4H), 3.35 (q, J =
7.4 Hz, 2H), 1.48 (t, J = 7.4 Hz, 3H). Anal. Calcd. for
C30H28N4O2S2: C, 66.64; H, 5.22; N, 10.36. Found: C, 66.49; H,
5.36; N, 10.53.
N,N-Dibenzyl-4-[5-(4-fluorophenyl)-3-methylthio-4H-1,2,4-
triazol-4-yl]benzene sulfonamide (18c). Following the general
procedure, 18c was obtained (0.24 g, 88%); mp 182-184°C; ir
1
(potassium bromide): 1337, 1158 cm-1 (SO2); H nmr (deuterio-
chloroform): ꢀ 7.92 (d, J = 8.4 Hz, 2H), 7.45-6.80 (m, 16H), 4.39
(s, 4H), 2.79 (s, 3H). Anal. Calcd. for C29H25FN4O2S2: C, 63.95; H,
4.63; N, 10.29. Found: C, 63.81; H, 4.56; N, 10.40.
N,N-Dibenzyl-4-(5-phenyl-3-thio-2,4-dihydro-3H-1,2,4-
triazol-4-yl)benzene sulfonamide (17a). Following the general
procedure, 17a was obtained (0.51 g, 90%); mp 214-216°C; ir
(potassium bromide): 3354 (NH), 1326, 1153 cm-1 (SO2); 1H nmr
(deuteriochloroform + dimethylsulfoxide-d6): ꢀ 13.80 (s, 1H),
N,N-Dibenzyl-4-[3-ethylthio-5-(4-fluorophenyl)-4H-1,2,4-
triazol-4-yl]benzene sulfonamide (18d). Following the general
procedure, 18d was obtained (0.21 g, 78%); mp 149-151°C; ir
(potassium bromide): 1337, 1153 cm-1 (SO2); 1H nmr (deutério-
chloroform): ꢀ 7.91 (d, J = 8.4 Hz, 2H), 7.48-6.75 (m, 16H),
6.39 (s, 4H), 3.34 (q, J = 7.3 Hz, 2H), 1.47 (t, J = 7.3 Hz, 3H).
Anal. Calcd. for C30H27FN4O2S2: C, 64.49; H, 4.87; N, 10.03.
Found: C, 64.33; H, 4.66; N, 10.21.
N,N-Dibenzyl-4-[3-methylthio-5-(4-methoxyphenyl)-4H-
1,2,4-triazol-4-yl]benzene sulfonamide (18e). Following the
general procedure, 18e was obtained (0.21 g, 75%); mp 172-
174°C; ir (potassium bromide): 1337, 1158 cm-1 (SO2); 1H nmr
(deuteriochloroform): ꢀ 7.90 (d, J = 8.4 Hz, 2H), 7.41-7.88 (m,
14H), 6.79 (d, J = 8.8 Hz, 2H), 4.39 (s, 4H), 3.79 (s, 3H), 2.77
(s, 3H). Anal. Calcd. for C30H28N4O3S2: C, 64.72; H, 5.07; N,
10.06. Found: C, 64.59; H, 5.23; N, 9.98.
7.89 (d, J = 8.5 Hz, 2H), 7.75-6.85 (m, 17H), 4.33 (s, 4H); 13
C
nmr (deuteriochloroform + dimethylsulfoxide-d6): ꢀ 164.85,
135.40, 130.92, 129.65, 129.12, 128.95, 128.81, 128.75, 128.60,
128.50, 128.44, 128.17, 50.67. Anal. Calcd. for C28H24N4O2S2:
C, 65.60; H, 4.72; N, 10.93. Found: C, 65.47; H, 4.55; N, 11.09.
N,N-Dibenzyl-4-[5-(4-fluorophenyl)-3-thio-2,4-dihydro-3H-
1,2,4-triazol-4-yl]benzenesulfonamide (17b). Following the
general procedure, 17b was obtained (0.5 g, 86%); mp 226-
228°C; ir (potassium bromide): 3257 (NH), 1327, 1153 cm-1
1
(SO2); H nmr (deuteriochloroform + dimethylsulfoxide-d6): ꢀ
13.95 (s, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.70-6.7 (m, 16H), 4.32
(s, 4H). Anal. Calcd. for C28H23FN4O2S2: C, 63.38; H, 4.37; N,
10.56. Found: C, 63.53; H, 4.22; N, 10.44.
N,N-Dibenzyl-4-(3-ethylthio-5-(4-methoxyphenyl)-4H-1,2,4-
triazol-4-yl)benzene sulfonamide (18f). Following the general
procedure, 18f was obtained (0.23 g, 80%); mp 135-137°C; ir
N,N-Dibenzyl-4-[5-(4-methoxyphenyl)-3-thio-2,4-dihydro-
3H-1,2,4-triazol-4-yl]benzenesulfonamide (17c). Following
the general procedure, 17c was obtained (0.52 g, 88%); mp 210-
212°C; ir (potassium bromide): 3375 (NH), 1332, 1153 cm-1
1
(potassium bromide): 1337, 1158 cm-1 (SO2); H nmr (deutério-
chloroform): ꢀ 7.89 (d, J = 8.5 Hz, 2H), 7.45-6.95 (m, 14H), 6.79
(d, J = 8.8 Hz, 2H), 4.39 (s, 4H), 3.79 (s, 3H), 3.34 (q, J = 7.3 Hz,
2H), 1.74 (t, J = 7.3 Hz, 3H). Anal. Calcd. for C31H30N4O3S2: C,
65.24; H, 5.30; N, 9.82. Found: C, 65.12; H, 5.22; N, 9.99.
General Procedure for the Preparation of 4-(3-Alkylthio-
5-aryl-4H-1,2,4-triazol-4-yl)benzene sulfonamides (19a-f). A
suspension of 18a-e (0.25 mmole) in concentrated H2SO4 (2 ml)
was stirred at room temperature for 20 minutes. The mixture was
poured into ice. The resulting solid was collected by filtration,
washed with water, and dried. Purification by flash
chromatography (silica gel), eluting with CH3Cl/MeOH (9:1),
gave the title compounds 19a-f.
1
(SO2); H nmr (deuteriochloroform + dimethylsulfoxide-d6): ꢀ
14.05 (s, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H),
7.38-7.85 (m, 12H), 6.78 (d, J = 9 Hz, 2H), 4.35 (s, 4H), 3.75 (s,
3H). Anal. Calcd. for C29H26N4O3S2: C, 64.18; H, 4.83; N, 10.32.
Found: C, 64.33; H, 5.91; N, 10.22.
General Procedure for the Preparation of N,N-Dibenzyl-4-
(3-alkylthio-5-aryl-4H-1,2,4-triazol-4-yl)benzene sulfonamides
(18a-f). To a stirring solution of compounds 17a-c (0.5 mmole)
and sodium hydroxide (1 mmole) in ethanol (5 ml) was added
alkyl iodide (0.2 ml) and the mixture was stirred overnight. The
volatiles were evaporated. The residue was poured into water
and extracted with ethyl acetate and dried (Na2SO4). Purification
by flash chromatography (silica gel), eluting with EtOAc, gave
the title compounds 18a-f.
N,N-Dibenzyl-4-(3-methylthio-5-phenyl-4H-1,2,4-triazol-4-
yl)benzenesulfonamide (18a). Following the general procedure,
18a was obtained (0.22 g, 84%); mp 190-192°C; ir (potassium
bromide): 1347, 1167 cm-1 (SO2); 1H nmr (deuteriochloroform):
ꢀ 7.87 (d, J = 8.6 Hz, 2H), 7.55-7.48 (m, 4H), 7.53-7.39 (m, 3H),
7.33-7.27 (m, 6H), 7.16-7.10 (m, 4H), 4.39 (s, 4H), 2.75 (s, 3H);
13C nmr (deuteriochloroform + dimethylsulfoxide-d6): ꢀ 154.83,
153.21, 142.26, 137.57, 135.20, 130.17, 128.86, 128.78, 128.67,
128.47, 128.33, 128.30, 128.01, 126.29, 50.53, 14.99. Anal.
Calcd. for C29H26N4O2S2: C, 66.13; H, 4.98; N, 10.64. Found: C,
66.24; H, 4.82; N, 10.50.
4-(3-Methylthio-5-phenyl-4H-1,2,4-triazol-4-yl)benzene
sulfonamide (19a). Following the general procedure, 19a was
obtained (73 mg, 85%); mp 235-237°C; ir (potassium bromide):
1
3447, 3309 (NH2), 1347, 1168 cm-1 (SO2); H nmr (dimethyl-
sulfoxide-d6): ꢀ 7.93 (d, J = 8.4 Hz, 2H), 7.75-7.52 (m, 4H), 7.36
(s, 5H), 2.63 (s, 3H); 13C nmr (dimethylsulfoxide-d6): ꢀ 155.09,
153.53, 145.52, 136.98, 130.21, 128.97, 128.48, 128.18, 127.85,
126.46, 15.07; ms: m/z 346 (M.+, 67), 314 (10), 266 (17), 234
(8), 180 (13), 171 (20), 159 (24), 104 (27), 77 (37), 46 (100).
Anal. Calcd. for C15H14N4O2S2: C, 52.01; H, 4.07; N, 16.17.
Found: C, 52.18; H, 4.23; N, 16.02.
4-(3-Ethylthio-5-phenyl-4H-1,2,4-triazol-4-yl)benzene
sulfonamide (19b). Following the general procedure, 19b was
obtained (75 mg, 83%); mp 251-253°C; ir (potassium bromide):

1328
L. Navidpour, M. Amini, A. Shafiee
Vol 44
1
3422, 3304 (NH2), 1350, 1163 cm-1 (SO2); H nmr (deuterio-
chloroform + dimethylsulfoxide-d6): ꢀ 8.05 (d, J = 8.4 Hz, 2H),
7.60 (s, 5H), 7.44-7.30 (m, 4H), 3.18 (q, J = 7.2 Hz, 2H), 1.43 (t,
J = 7.2 Hz, 3H); ms: m/z 360 (M+, 24), 332 (25), 252 (18), 185
(18), 171 (42), 149 (25), 122 (32), 104 (35), 77 (38), 61 (100).
Anal. Calcd. for C16H16N4O2S2: C, 53.31; H, 4.47; N, 15.54.
Found: C, 53.20; H, 4.31; N, 15.68.
196 (8), 91 (9). Anal. Calcd. for C21H21N3O3S: C, 63.78; H, 5.35;
N, 10.63. Found: C, 63.60; H, 5.49; N, 10.55.
General Procedure for the Preparation of 1-(4-N,N-
Dibenzylaminosulfonylbenzoyl)-4-arylthiosemicarbazides
(22a-e).To a solution of 4-(N,N-dibenzylaminosulfonyl)benzoic
acid hydrazide 21 (1.5 g, 3.8 mmoles) in ethanol (10 ml) was
added respective isothiocyanate (3.8 mmoles) and the mixture
was stirred at room temperature for 24 hours. The product was
filtered and crystallized from ethanol to give the title compounds
22a-e as white solids.
4-[5-(4-Fluorophenyl)-3-methylthio-4H-1,2,4-triazol-4-yl]-
benzenesulfonamide (19c). Following the general procedure,
19c was obtained (70 mg, 76%); mp 245-247°C; ir (potassium
bromide): 3432, 3309 (NH2), 1347, 1163 cm-1 (SO2); H nmr
1
1-(4-N,N-Dibenzylaminosulfonylbenzoyl)-4-phenylthio-
semicarbazide (22a). Following the general procedure, 22a was
obtained (1.79 g, 89%); mp 192-194°C; ir (potassium bromide):
(dimethylsulfoxide-d6): ꢀ 7.96 (d, J = 8.3 Hz, 2H), 7.62 (d, J =
8.3 Hz, 2H), 7.45-7.25 (m, 4H), 7.17 (d, J = 8.8 Hz, 2H), 3.17
(q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); ms: m/z 364 (M+,
65), 346 (26), 330 (10), 282 (14), 278 (15), 252 (8), 208 (10),
198 (14), 177 (28), 164 (34), 122 (52), 120 (65), 107 (50), 76
(44), 76 (58), 46 (100). Anal. Calcd. for C15H13FN4O2S2: C,
49.44; H, 3.60; N, 15.37. Found: C, 49.61; H, 3.52; N, 15.49.
4-[3-Ethylthio-5-(4-fluorophenyl)-4H-1,2,4-triazol-4-yl]-
benzenesulfonamide (19d). Following the general procedure,
19d was obtained (75 mg, 80%); mp 264-266°C; ir (potassium
1
3365, 3288 (NH), 1675 (CO), 1311, 1148 cm-1 (SO2); H nmr
(deuteriochloroform + dimethylsulfoxide-d6): ꢀ 10.45 (s, 1H),
9.44 (s, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.5 Hz, 2H),
7.75-6.90 (m, 15H), 4.34 (s, 4H); ms: m/z 531 (M+, 3), 477 (5),
453 (22), 387 (11), 356 (100), 337 (22), 296 (14), 281 (8), 190
(11), 89 (10).Anal. Calcd. for C28H26N4O3S2: C, 63.37; H, 4.94;
N, 10.56. Found: C, 63.25; H, 4.80; N, 10.38.
1-(4-N,N-Dibenzylaminosulfonylbenzoyl)-4-(4-fluoro-
phenyl)thiosemicarbazide (22b). Following the general
procedure, 22b was obtained (1.88 g, 90%); mp 197-199°C; ir
(potassium bromide): 3365, 3288 (NH), 1675 (CO), 1311, 1148
bromide): 3442, 3298 (NH2), 1344, 1163 cm-1 (SO2); H nmr
1
(dimethylsulfoxide-d6): ꢀ 7.93 (d, J = 8.3 Hz, 2H), 7.60 (d, J =
8.3 Hz, 2H), 7.45-7.25 (m, 4H), 7.15 (d, J = 8.8 Hz, 2H), 3.17
(q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); ms: m/z 378 (M+,
10), 349 (58), 283 (8), 278 (10), 196 (19), 191 (27), 150 (8), 122
(22), 120 (47), 77 (35), 61 (49), 46 (100). Anal. Calcd. for
C16H15FN4O2S2: C, 50.78; H, 4.00; N, 14.80. Found: C, 50.59; H,
3.82; N, 14.96.
1
cm-1 (SO2); H nmr (deuteriochloroform + dimethylsulfoxide-
d6): ꢀ 10.45 (s, 1H), 9.44 (s, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.86
(d, J = 8.5 Hz, 2H), 7.75-6.90 (m, 14H), 4.34 (s, 4H); ms: m/z
547 (M+, 5), 477 (8), 404 (10), 367 (22), 338 (100), 282 (28),
245 (5), 183 (10), 172 (9), 87 (10), 49 (13). Anal. Calcd. for
C28H25FN4O3S2: C, 61.30; H, 4.59; N, 10.21. Found: C, 61.17; H,
4.75; N, 10.10.
4-(4-Chlorophenyl)-1-(4-N,N-dibenzylaminosulfonylbenz-
oyl)thiosemicarbazide (22c). Following the general procedure,
22c was obtained (1.95 g, 91%); mp 198-200°C; ir (potassium
bromide): 3373, 3288 (NH), 1671 (CO), 1319, 1151 cm-1 (SO2);
1H nmr (deuteriochloroform + dimethylsulfoxide-d6): ꢀ 9.54 (s,
1H), 8.10 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.75-6.85
(m, 14H), 4.33 (s, 4H); ms: m/z 566 (M+, 15), 564 (5), 543 (6),
519 (4), 494 (5), 447 (4), 420 (11), 382 (43), 352 (100), 293
(37), 279 (6), 189 (23), 163 (38), 108 (5), 90 (13). Anal. Calcd.
for C28H25ClN4O3S2: C, 59.51; H, 4.46; N, 9.91. Found: C,
59.36; H, 4.64; N, 10.08.
4-(4-Bromophenyl)-1-(4-N,N-dibenzylaminosulfonylbenz-
oyl)thiosemicarbazide 22d). Following the general procedure,
22d was obtained (2.1 g, 91%); mp 200-202°C; ir (potassium
bromide): 3371, 3287 (NH), 1670 (CO), 1319, 1151 cm-1 (SO2);
1H nmr (deuteriochloroform + dimethylsulfoxide-d6): ꢀ 10.55 (s,
1H), 9.58 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz,
2H), 7.75-6.90 (m, 14H), 4.34 (s, 4H); ms: m/z 610 (M+, 2), 608
(2), 578 (2), 576 (2), 560 (4), 477 (5), 435 (13), 395 (15), 364
(100), 345 (12), 304 (10), 196 (11), 91 (3). Anal. Cacld. for
C28H25BrN4O3S2: C, 55.17; H, 4.13; N, 9.19. Found: C, 55.29; H,
4.28; N, 9.36.
4-[3-Methylthio-5-(4-methoxyphenyl)-4H-1,2,4-triazol-4-
yl]benzenesulfonamide (19e). Following the general procedure,
19e was obtained (40 mg, 43%); mp 271-273°C; ir (potassium
bromide): 3442, 3304 (NH2), 1345, 1158 cm-1 (SO2); H nmr
1
(dimethylsulfoxide-d6): ꢀ 7.97 (d, J = 8.7 Hz, 2H), 7.60-7.48 (m,
4H), 7.27 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 3.75 (s,
3H), 2.61 (s, 3H); ms: m/z 376 (M+, 5), 298 (17), 286 (18), 268
(20), 253 (7), 210 (12), 164 (25), 149 (27), 133 (75), 91 (57), 76
(63), 46 (100). Anal. Calcd. for C16H16N4O3S2: C, 51.05; H, 4.28;
N, 14.88. Found: C, 51.23; H, 4.12; N, 14.72.
4-[3-Ethylthio-5-(4-methoxyphenyl)-4H-1,2,4-triazol-4-yl]-
benzenesulfonamide (19f). Following the general procedure,
19f was obtained (45 mg, 47%); mp 261-263°C; ir (potassium
bromide): 3324, 3302 (NH2), 1342, 1168 cm-1 (SO2); H nmr
1
(dimethylsulfoxide-d6): ꢀ 7.95 (d, J = 8.7 Hz, 2H), 7.65-7.50 (m,
4H), 7.29 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 3.75 (s,
3H), 3.15 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H); ms: m/z
390 (M+, 95), 361 (95), 357 (43), 290 (26), 282 (10), 208 (82),
203 (74), 185 (22), 148 (57), 132 (77), 91 (71), 75 (98), 46
(100). Anal. Calcd. for C17H18N4O3S2: C, 52.29; H, 4.65; N,
14.35. Found: C, 52.42; H, 4.88; N, 14.20.
4-N,N-Dibenzylaminosulfonylbenzoic acid hydrazide (21).
To a solution of methyl 4-N,N-dibenzylaminosulfonyl benzoate
20 (5.5 g, 13.9 mmoles) in methanol (20 ml) was added
hydrazine hydrate (3.48 g, 69.6 mmoles) and the mixture was
stirred at room temperature for 10 hours. To the reaction mixture
water was added water (20 ml). The precipitate was collected by
filtration and crystallized from methanol to give 21 (4.2 g, 75%)
as a white solid; mp 124-125°C; ir (potassium bromide): 3474,
1-(4-N,N-Dibenzylaminosulfonylbenzoyl)-4-(4-methyl-
phenyl)thiosemicarbazide (22e). Following the general
procedure, 22e was obtained (1.87 g, 91%); mp 180-182°C; ir
(potassium bromide): 3365, 3287 (NH), 1671 (CO), 1321, 1152
1
cm-1 (SO2); H nmr (deuteriochloroform + dimethylsulfoxide-
3344, 3258 (NH), 1625 (CO), 1334, 1158 cm-1 (SO2); H nmr
(deuteriochloroform): ꢀ 7.40-6.85 (m, 14H), 4.35 (s, 4H), 4.08
(bs, 1H); ms: m/z 395 (M+, 14), 364 (100), 304 (29), 272 (4),
d6): ꢀ 10.49 (s, 1H), 9.32 (s, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.89
(d, J = 8.5 Hz, 2H), 7.50-6.95 (m, 14H), 4.35 (s, 4H), 2.34 (s,
3H); ms: m/z 545 (M+, 9), 497 (12), 462 (38), 433 (17), 395
1

Nov-Dec 2007
Substituted 4,5-diaryl-4H-1,2,4-triazole-3-thiones
1329
(15), 364 (100), 345 (31), 303 (27), 288 (6), 196 (30), 193 (10),
91 (14). Anal. Calcd. for C29H28N4O3S2: C, 63.95; H, 5.18; N,
10.29. Found: C, 63.83; H, 5.09; N, 10.45.
alkyl iodide (0.5 ml) and the mixture was stirred overnight. The
volatiles were evaporated. Purification by flash chromatography
(silica gel), eluting with CH3Cl/MeOH (20:1), and crystalliza-
tion from ethanol gave the title compounds 24a-j.
General Procedure for the Preparation of N,N-Dibenzyl-4-
(4-aryl-3-thio-2,4-dihydro-3H-1,2,4-triazol-5-yl)benzene
sulfonamides (23a-e). A stirring mixture of compounds 22a-e
(3 mmoles) and saturated aqueous sodium carbonate solution
(25 ml) was refluxed overnight. After cooling, the solution was
acidified with hydrochloric acid and the precipitate was
collected by filtration and washed with water. The precipitate
was crystallized from ethanol to give the title compounds 23a-e.
N,N-Dibenzyl-4-(4-phenyl-3-thio-2,4-dihydro-3H-1,2,4-
triazol-5-yl)benzene sulfonamide (23a). Following the general
procedure, 23a was obtained (1.35 g, 88%); mp 245-247°C; ir
(potassium bromide): 3365, 3287 (NH), 1671 (CO), 1321, 1152
N,N-Dibenzyl-4-(3-methylthio-4-phenyl-4H-1,2,4-triazol-5-
yl)benzenesulfonamide (24a). Following the general procedure,
24a was obtained (0.4 g, 78%); mp 168-170°C; ir (potassium
1
bromide): 1325, 1158 cm-1 (SO2); H nmr (deuteriochloroform):
ꢀ 7.72 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.42-6.85
(m, 15H), 4.30 (s, 4H), 2.75 (s, 3H)13C nmr (deuteriochloroform
+ dimethylsulfoxide-d6): ꢀ 154.82, 153.42, 141.40, 135.41,
133.77, 130.73, 130.55, 130.44, 128.55, 128.50, 127.87, 127.29,
50.79, 14.77. Anal. Calcd. for C29H26N4O2S2: C, 66.13; H, 4.98;
N, 10.64. Found: C, 66.23; H, 4.80; N, 10.56.
N,N-Dibenzyl-4-(3-ethylthio-4-phenyl-4H-1,2,4-triazol-5-
yl)benzenesulfonamide (24b). Following the general procedure,
24b was obtained (0.44 g, 83%); mp 178-180°C; ir (potassium
1
cm-1 (SO2); H nmr (deuteriochloroform + dimethylsulfoxide-
d6): ꢀ 8.89 (s, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.5 Hz,
2H), 7.52-6.95 (m, 15H), 4.29 (s, 4H); ms: m/z 513 (M+, 5), 462
(8), 395 (17), 362 (100), 303 (16), 135 (5); 13C nmr (deuterio-
chloroform + dimethylsulfoxide-d6): ꢀ 165.53, 143.29, 139.90,
137.12, 136.31, 129.69, 128.99, 128.96, 128.77, 128.23, 127.54,
125.78, 51.70. Anal. Calcd. for C28H24N4O2S2: C, 65.60; H, 4.72;
N, 10.93. Found: C, 65.74; H, 4.63; N, 10.81.
1
bromide): 1322, 1155 cm-1 (SO2); H nmr (deuteriochloroform):
ꢀ 7.75 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.40-6.80
(m, 15H), 4.31 (s, 4H), 3.31 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2
Hz, 3H). Anal. Calcd. for C30H28N4O2S2: C, 66.64; H, 5.22; N,
10.36. Found: C, 66.46; H, 5.11; N, 10.49.
N,N-Dibenzyl-4-[4-(4-fluorophenyl)-3-methylthio-4H-1,2,
4-triazol-5-yl]benzene sulfonamide (24c). Following the
general procedure, 24c was obtained (0.48 g, 88%); mp 176-
N,N-Dibenzyl-4-[4-(4-fluorophenyl)-3-thio-2,4-dihydro-
3H-1,2,4-triazol-5-yl]benzenesulfonamide (23b). Following the
general procedure, 23b was obtained (1.36 g, 86%); mp 250-
252°C; ir (potassium bromide): 3440, 3327 (NH), 1337, 1161 cm-1
(SO2); 1H nmr (deuteriochloroform + dimethylsulfoxide-d6): ꢀ
8.44 (s, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H),
7.68-6.88 (m, 14H), 4.33 (s, 4H). Anal. Calcd. for C28H23FN4O2S2:
C, 63.38; H, 4.37; N, 10.56. Found: C, 63.25; H, 4.21; N, 10.43.
N,N-Dibenzyl-4-[4-(4-chlorophenyl)-3-thio-2,4-dihydro-
3H-1,2,4-triazol-5-yl]benzenesulfonamide (23c). Following
the general procedure, 23c was obtained (1.46 g, 90%); mp 231-
233°C; ir (potassium bromide): 3416, 3310 (NH), 1330, 1160
1
178°C; ir (potassium bromide): 1328, 1157 cm-1 (SO2); H nmr
(deuteriochloroform): ꢀ 7.73 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4
Hz, 2H), 7.42-6.85 (m, 14H), 4.32 (s, 4H), 2.76 (s, 3H). Anal.
Calcd. for C29H25FN4O2S2: C, 63.95; H, 4.63; N, 10.29. Found:
C, 63.83; H, 4.49; N, 10.15.
N,N-Dibenzyl-4-[3-ethylthio-4-(4-fluorophenyl)-4H-1,2,4-
triazol-5-yl]benzene sulfonamide (24d). Following the general
procedure, 24d was obtained (0.41 g, 75%); mp 158-160°C; ir
(potassium bromide): 1327, 1156 cm-1 (SO2); 1H nmr
(deuteriochloroform): ꢀ 7.74 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.2
Hz, 2H), 7.31-6.75 (m, 14H), 4.32 (s, 4H), 3.33 (q, J = 7.2 Hz,
2H), 1.46 (t, J = 7.2 Hz, 3H). Anal. Calcd. for C30H27FN4O2S2: C,
64.49; H, 4.87; N, 10.03. Found: C, 64.63; H, 4.99; N, 10.20.
N,N-Dibenzyl-4-[4-(4-chlorophenyl)-3-methylthio-4H-1,2,
4-triazol-5-yl]benzene sulfonamide (24e). Following the
general procedure, 24e was obtained (0.47 g, 85%); mp 137-
1
cm-1 (SO2); H nmr (deuteriochloroform + dimethylsulfoxide-
d6): ꢀ 8.75 (s, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz,
2H), 7.75-6.90 (m, 14H), 4.32 (s, 4H). Anal. Calcd. for
C28H23ClN4O2S2: C, 61.47; H, 4.24; N, 10.24. Found: C, 61.29;
H, 4.40; N, 10.34.
N,N-Dibenzyl-4-[4-(4-bromophenyl)-3-thio-2,4-dihydro-
3H-1,2,4-triazol-5-yl]benzenesulfonamide (23d). Following the
general procedure, 23d was obtained (1.63 g, 92%); mp 190-
192°C; ir (potassium bromide): 3426, 3328 (NH), 1329, 1158 cm-1
(SO2); 1H nmr (deuteriochloroform + dimethylsulfoxide-d6): ꢀ 8.55
(s, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 7.55-6.95
(m, 14H), 4.34 (s, 4H). Anal. Calcd. for C28H23BrN4O2S2: C, 56.85;
H, 3.92; N, 9.47. Found: C, 56.76; H, 4.06; N, 9.22.
1
139°C; ir (potassium bromide): 1330, 1152 cm-1 (SO2); H nmr
(deuteriochloroform): ꢀ 7.75 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4
Hz, 2H), 7.35-6.89 (m, 14H), 4.33 (s, 4H), 2.75 (s, 3H). Anal.
Calcd. for C29H25ClN4O2S2: C, 62.07; H, 4.49; N, 9.98. Found:
C, 62.22; H, 4.66; N, 10.16.
N,N-Dibenzyl-4-[4-(4-chlorophenyl)-3-ethylthio-4H-1,2,4-
triazol-5-yl]benzene sulfonamide (24f). Following the general
procedure, 24f was obtained (0.45 g, 80%); mp 148-150°C; ir
N,N-Dibenzyl-4-[4-(4-methylphenyl)-3-thio-2,4-dihydro-
3H-1,2,4-triazol-5-yl]benzenesulfonamide (23e). Following
the general procedure, 23e was obtained (1.41 g, 90%); mp 237-
239°C; ir (potassium bromide): 3430, 3315 (NH), 1333, 1159
1
(potassium bromide): 1325, 1149 cm-1 (SO2); H nmr (deutério-
chloroform): ꢀ 7.74 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H),
7.33-6.78 (m, 14H), 4.31 (s, 4H), 3.32 (q, J = 7.2 Hz, 2H), 1.46
(t, J = 7.2 Hz, 3H). Anal. Calcd. for C30H27ClN4O2S2: C, 62.65;
H, 4.73; N, 9.74. Found: C, 62.79; H, 4.59; N, 9.59.
1
cm-1 (SO2); H nmr (deuteriochloroform + dimethylsulfoxide-
d6): ꢀ 8.35 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz,
2H), 7.42-6.85 (m, 14H), 4.29 (s, 4H), 2.45 (s, 3H); ms: m/z 527
(M+, 9), 514 (100), 498 (12), 463 (9), 432 (10), 404 (8), 364
(14), 332 (13). Anal. Calcd. for C29H26N4O2S2: C, 66.13; H, 4.98;
N, 10.64. Found: C, 66.01; H, 4.85; N, 10.77.
N,N-Dibenzyl-4-[4-(4-bromophenyl)-3-methylthio-4H-1,2,
4-triazol-5-yl]benzene sulfonamide (24g). Following the
general procedure, 24g was obtained (0.48 g, 80%); mp 168-
1
170°C; ir (potassium bromide): 1328, 1160 cm-1 (SO2); H nmr
(deuteriochloroform): ꢀ 7.76 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4
Hz, 2H), 7.52-6.85 (m, 14H), 4.32 (s, 4H), 2.76 (s, 3H). Anal.
Calcd. for C29H25BrN4O2S2: C, 57.52; H, 4.16; N, 9.25. Found:
C, 57.69; H, 4.25; N, 9.38.
General Procedure for the Preparation of N,N-Dibenzyl-4-
(3-alkylthio-4-aryl-4H-1,2,4-triazol-5-yl)benzenesulfonamides
(24a-j). To a stirring solution of compounds 23a-e (1 mmole)
and sodium hydroxide (2 mmoles) in ethanol (5 ml) was added

1330
L. Navidpour, M. Amini, A. Shafiee
Vol 44
79 (18), 51 (23), 40 (39). Anal. Calcd. for C15H13FN4O2S2: C,
49.44; H, 3.60; N, 15.37. Found: C, 49.56; H, 3.78; N, 15.21.
4-[3-Ethylthio-4-(4-fluorophenyl)-4H-1,2,4-triazol-5-yl]-
benzenesulfonamide (25d). Following the general procedure,
25d was obtained (65 mg, 35%); mp 242-244°C; ir (potassium
N,N-Dibenzyl-4-[4-(4-bromophenyl)-3-ethylthio-4H-1,2,4-
triazol-5-yl]benzene sulfonamide (24h). Following the general
procedure, 24h was obtained (0.61 g, 85%); mp 152-154°C; ir
(potassium bromide): 1327, 1159 cm-1 (SO2); 1H nmr
(deuteriochloroform): ꢀ 7.73 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4
Hz, 2H), 7.55-6.90 (m, 14H), 4.32 (s, 4H), 3.33 (q, J = 7.2 Hz,
2H), 1.45 (t, J = 7.2 Hz, 3H). Anal. Calcd. for C30H27BrN4O2S2:
C, 58.15; H, 4.39; N, 9.04. Found: C, 58.29; H, 4.22; N, 8.88.
N,N-Dibenzyl-4-[4-(4-methylphenyl)-3-methylthio-4H-1,2,
4-triazol-5-yl]benzene sulfonamide (24i). Following the
general procedure, 24i was obtained (0.42 g, 78%); mp 175-
1
bromide): 3302 (NH), 1334, 1169 cm-1 (SO2); H nmr (dimethyl-
sulfoxide-d6): ꢀ 7.79 (d, J = 8.4 Hz, 2H), 7.58-7.51 (m, 4H), 7.46-
7.37 (m, 4H), 3.16 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H);
ms: m/z 378 (M+, 41), 350 (81), 350 (100), 284 (4), 277 (14), 251
(46), 211 (10), 197 (20), 167 (12), 136 (24), 123 (87), 95 (25), 57
(25), 43 (40), 40(76). Anal. Calcd. for C16H15FN4O2S2: C, 50.78;
H, 4.00; N, 14.80. Found: C, 50.66; H, 4.09; N, 14.62.
1
177°C; ir (potassium bromide): 1325, 1156 cm-1 (SO2); H nmr
(deuteriochloroform): ꢀ 7.72 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.5
Hz, 2H), 7.38-6.88 (m, 14H), 4.31 (s, 4H), 2.75 (s, 3H), 2.34 (s,
3H). Anal. Calcd. for C30H28N4O2S2: C, 66.64; H, 5.22; N, 10.36.
Found: C, 66.77; H, 5.10; N, 10.21.
N,N-Dibenzyl-4-[3-ethylthio-4-(4-methylphenyl)-4H-1,2,4-
triazol-5-yl]benzene sulfonamide (24j). Following the general
procedure, 24j was obtained (0.44 g, 80%); mp 163-165°C; ir
(potassium bromide): 1328, 1160 cm-1 (SO2); 1H NMR
(deuteriochloroform): ꢀ 7.74 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5
Hz, 2H), 7.35-6.92 (m, 14H), 4.31 (s, 4H), 3.29 (q, J = 7.2 Hz,
2H), 2.35 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). Anal. Calcd. for
C31H30N4O2S2: C, 67.12; H, 5.45; N, 10.10. Found: C, 67.01; H,
5.61; N, 10.28.
General Procedure for the Preparation of 4-(3-Alkylthio-
4-aryl-4H-1,2,4-triazol-5-yl)benzenesulfonamides (25a-j). A
suspension of 24a-j (0.5 mmole) in concentrated H2SO4 (2 ml)
was stirred at room temperature for 20 minutes. The mixture was
poured into ice. The resulting solid was collected by filtration,
washed with water, and dried. Purification by flash
chromatography (silica gel), eluting with CH3Cl/MeOH (9:1),
gave the title compounds 25a-j.
4-[4-(4-Chlorophenyl)-3-methylthio-4H-1,2,4-triazol-5-yl]-
benzenesulfonamide (25e). Following the general procedure,
25e was obtained (83 mg, 43%); mp 196-198°C; ir (potassium
bromide): 3436 (NH), 1339, 1162 cm-1 (SO2); 1H nmr (dimethyl-
sulfoxide-d6): ꢀ 7.80 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz,
2H), 7.55 (d, J = 8.4 Hz, 2H), 7.52-7.42 (m, 4H), 2.64 (s, 3H);
ms: m/z 382 (M+, 33), 380 (100), 374 (20), 366 (38), 345 (24),
330 (10), 293 (7), 250 (16), 237 (12), 125 (9), 64 (25). Anal.
Calcd. for C15H13ClN4O2S2: C, 47.30; H, 3.44; N, 14.71. Found:
C, 47.48; H, 3.59; N, 14.59.
4-[4-(4-Chlorophenyl)-3-ethylthio-4H-1,2,4-triazol-5-yl]-
benzenesulfonamide (25f). Following the general procedure,
25f was obtained (63 mg, 38%); mp 184-186°C; ir (potassium
bromide): 3402 (NH), 1341, 1164 cm-1 (SO2); 1H nmr (dimethyl-
sulfoxide-d6): ꢀ 7.80 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz,
2H), 7.55 (d, J = 8.4 Hz, 2H), 7.52-7.42 (m, 4H), 3.17 (q, J = 7.2
Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); ms: m/z 396 (M+, 22), 394
(56), 369 (45), 366 (100), 331 (14), 313 (9), 251 (28), 213 (12).
Anal. Calcd. for C16H15ClN4O2S2: C, 48.66; H, 3.83; N, 14.19.
Found: C, 48.85; H, 3.74; N, 14.10.
4-[4-(4-Bromophenyl)-3-methylthio-4H-1,2,4-triazol-5-yl]-
benzenesulfonamide (25g). Following the general procedure,
25g was obtained (80 mg, 38%); mp 204-206°C; ir (potassium
bromide): 3268 (NH), 1341, 1164 cm-1 (SO2); 1H nmr (dimethyl-
sulfoxide-d6): ꢀ 7.80 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz,
2H), 7.55 (d, J = 8.4 Hz, 2H), 7.46 (bs, 2H), 7.42 (d, J = 8.4 Hz,
2H), 2.64 (s, 3H); ms: m/z 425 (M+, 100), 423 (100), 393 (11),
391 (11), ,345 (10), 340 (12), 338 (7), 313 (10), 237 (7), 197
(15), 195 (15), 171 (11), 169 (11). Anal. Calcd. for
C15H13BrN4O2S2: C, 42.36; H, 3.08; N, 13.17. Found: C, 42.48;
H, 2.90; N, 13.01.
4-[4-(4-Bromophenyl)-3-ethylthio-4H-1,2,4-triazol-5-yl]-
benzenesulfonamide (25h). Following the general procedure,
25h was obtained (90 mg, 42%); mp 190-192°C; ir (potassium
bromide): 3352 (NH),1336, 1163 cm-1 (SO2); 1H nmr (dimethyl-
sulfoxide-d6): ꢀ 7.78 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.8 Hz,
2H), 7.52 (d, J = 8.8 Hz, 2H), 7.42 (bs, 2H), 7.37 (d, J = 8.8 Hz,
2H), 3.17 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); ms: m/z
439 (M+, 25), 437 (25), 424 (15), 422 (15), 374 (10), 359 (34),
331 (19), 329 (19), 278 (35), 226 (25), 224 (25), 198 (28), 196
(28), 185 (69), 183 (69), 118 (25), 105 (32). Anal. Calcd. for
C16H15BrN4O2S2: C, 43.74; H, 3.44; N, 12.75. Found: C, 43.60;
H, 3.26; N, 12.91.
4-(3-Methylthio-4-phenyl-4H-1,2,4-triazol-5-yl)benzene
sulfonamide (25a). Following the general procedure, 25a was
obtained (56 mg, 33%); mp 243-245°C; ir (potassium bromide):
1
3299 (NH), 1334, 1170 cm-1 (SO2); H nmr (dimethylsulfoxide-
d6): ꢀ 7.77 (d, J = 8.4 Hz, 2H), 7.62-7.56 (m, 2H), 7.53 (d, J = 8.4
Hz, 2H), 7.48-7.38 (m, 3H), 7.21-6.75 (bs, 2H), 2.64 (s, 3H); 13C
nmr (dimethylsulfoxide-d6): ꢀ 154.41, 154.26, 145.66, 134.43,
131.10, 130.97, 130.55, 129.49, 129.28, 128.46, 126.70, 15.28;
ms: m/z 346 (M+, 100), 331 (8), 313 (10), 266 (8), 237 (6), 118
(10), 91 (14), 78 (12), 43 (18). Anal. Calcd. for C15H14N4O2S2: C,
52.01; H, 4.07; N, 16.17. Found: C, 51.88; H, 3.95; N, 16.32.
4-(3-Ethylthio-4-phenyl-4H-1,2,4-triazol-5-yl)benzene sulfon-
amide (25b). Following the general procedure, 25b was
obtained (72 mg, 40%); mp 189-191°C; ir (potassium bromide):
3283 (NH), 1340, 1166 cm-1 (SO2); 1H nmr (dimethylsulfoxide-
d6): ꢀ 7.75 (d, J = 8.4 Hz, 2H), 7.58-7.52 (m, 3H), 7.51 (d, J =
8.4 Hz, 2H), 7.44-7.34 (m, 4H), 3.17 (q, J = 7.2 Hz, 2H), 1.32 (t,
J = 7.2 Hz, 3H); ms: m/z 360 (M+, 34), 344 (46), 324 (32), 277
(23), 209 (10), 195 (92), 147 (85), 82 (81), 53 (100). Anal.
Calcd. for C16H16N4O2S2: C, 53.31; H, 4.47; N, 15.54. Found: C,
53.19; H, 4.41; N, 15.39.
4-[4-(4-Fluorophenyl)-3-methylthio-4H-1,2,4-triazol-5-yl]-
benzenesulfonamide (25c). Following the general procedure,
25c was obtained (48 mg, 27%); mp 236-238°C; ir (potassium
bromide): 3432 (NH), 1342, 1165 cm-1 (SO2); 1H nmr
(dimethylsulfoxide-d6): ꢀ 7.79 (d, J = 8.4 Hz, 2H), 7.64-7.45 (m,
6H), 7.42 (t, J = 8.8 Hz, 2H), 2.63 (s, 3H); ms: m/z 364 (M+, 8),
350 (8), 341 (13), 303 (100), 278 (2), 277 (13), 251 (92), 231
(7), 186 (26), 175 (80), 173 (60), 162 (38), 128 (76), 106 (43),
4-[4-(4-Methylphenyl)-3-methylthio-4H-1,2,4-triazol-5-yl]-
benzenesulfonamide (25i). Following the general procedure,
25i was obtained (68 mg, 38%); mp 219-221°C; ir (potassium
bromide): 3273 (NH), 1344, 1175 cm-1 (SO2); 1H nmr
(dimethylsulfoxide-d6): ꢀ 7.78 (d, J = 8.4 Hz, 2H), 7.54 (d, J =
8.4 Hz, 2H), 7.43 (bs, 2H), 7.37 (d, J = 8 Hz, 2H), 7.29 (d, J = 8
Hz, 2H), 2.63 (s, 3H), 2.39 (s, 3H); ms: m/z 361 (M+, 18), 360

Nov-Dec 2007
Substituted 4,5-diaryl-4H-1,2,4-triazole-3-thiones
1331
REFERENCES
(100), 358 (72), 344 (3), 327 (17), 279 (13), 272 (12), 131 (12),
105 (8). Anal. Calcd. for C16H16N4O2S2: C, 53.31; H, 4.47; N,
15.54. Found: C, 53.48; H, 4.59; N, 15.68.
[1] Pennig, T.; Talley, J. J.; Bertenshaw, S.; Carter, J.; Collins,
P.; Doctor, S.; Graneto, M.; Lee, L.; Malecha, J.; Miyashiro, J.;
Rogers, R.; Rogier, D.; Yu, S.; Anderson, G.; Burton, E.; Cogburn,
J.; Gregory, S.; Koboldt, C.; Perkins, W.; Siebert, K.; Veenhuizen,
A.; Zhang, Y.; Isakson, P. J. Med. Chem. 1997, 40, 1347.
[2] Riendeau, D.; Percival, M. D.; Brideau, C.; Charleson, S.;
Dube, D.; Ethier, D.; Falguevret, J. -P.; Friesen, R. W.; Gordon, R.;
Greig, G.; Guay, I.; Manacini, J.; Quellet, M.; Wong, E.; Xu, L.;
Boyce, S.; Visco, D.; Girad, Y.; Prasit, P.; Zamboni, R.; Rodger, J.
W.; Gresser, M.; Ford-Hutchinson, A. W.; Young, R. N.; Chan, C. -
C. J. Pharmacol. Exp. Ther. 2001, 296, 558.
4-[3-Ethylthio-4-(4-methylphenyl)-4H-1,2,4-triazol-5-yl]-
benzenesulfonamide (25j). Following the general procedure,
25j was obtained (78 mg, 41%); mp 216-217°C; ir (potassium
bromide): 3271 (NH), 1343, 1170 cm-1 (SO2); 1H nmr
(dimethylsulfoxide-d6): ꢀ 7.79 (d, J = 8.4 Hz, 2H), 7.55 (d, J =
8.4 Hz, 2H), 7.43 (bs, 2H), 7.36 (d, J = 8 Hz, 2H), 7.27 (d, J = 8
Hz, 2H), 3.16 (q, J = 7.2 Hz, 2H), 2.38 (s, 3H), 1.34 (t, J = 7.2
Hz, 3H); ms: m/z 375 (M+, 87), 373 (85), 358 (23), 345 (100),
328 (12), 326 (10), 296 (20), 267 (20), 266 (32), 251 (11), 159
(14). Anal. Calcd. for C17H18N4O2S2: C, 54.52; H, 4.84; N, 14.96.
Found: C, 54.39; H, 4.99; N, 14.82.
[3] Davies, I. W.; Marcoux, J. -F.; Corley, E. G.; Journet, M.;
Cai, D. -W.; Palucki, M.; Wu, J.; Larsen, R. D.; Rossen, K.; Pye, P.
J.; Dimichele, L.; Dormer, P.; Reider, P. J. J. Org. Chem. 2000, 65,
8415.
Acknowledgement. This research was supported by grants
from the Research Council of Tehran University of Medical
Sciences and INSF (Iran National Science Foundation).
[4] Turini, M. E.; DuBois, R. N. Ann. Rev. Med. 2002, 53, 35.