Syntheses of 5-Alkylthio-1,3-diaryl-1,2,4-triazoles

Article abstract of DOI:10.1002/jhet.5570410209

Arylation of the readily available 3-alkythio-5-aryl-1,2,4-triazoles gave 5-alkylthio-1,3-diaryl-1,2,4-triazoles in moderate yield. The structures of the latter were confirmed by NOE and ¹³C-NMR.

Full text of DOI:10.1002/jhet.5570410209

Mar-Apr 2004
201
Syntheses of 5-Alkylthio-1,3-diaryl-1,2,4-triazoles
Latifeh Navidpour, Leila Karimi, Mohsen Amini, Mohssen Vosooghi,
Abbas Shafiee*
Department of Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran
University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran
Received September 15, 2003
Arylation of the readily available 3-alkythio-5-aryl-1,2,4-triazoles gave 5-alkylthio-1,3-diaryl-1,2,4-tria-
13
zoles in moderate yield. The structures of the latter were confirmed by NOE and C-NMR.
J. Heterocyclic Chem., 41, 201 (2004).
Triazoles and in particular the 1,2,4-triazole nucleus
have been incorporated into a wide variety of therapeuti-
cally interesting drug candidates including anti-inflamma-
tory, CNS stimulants, sedatives, antianxiety and antimicro-
bial agents [2,3].
Their antifungal activity is also documented [4,5].
Newer classes of antifungals including azole derivatives
such as Fluconazole, an orally active triazole agent, and
Itrazonazole are systemic antifungal agents actually
employed in patients with impaired immunity such as
those who have AIDS or are neutropenic as a result of can-
cer therapy.
Moreover, many infections due to Candida spp are actu-
ally refractory to antifungal therapy. While these new
classes of compounds are now frequently used in treatment
of fungal infections, resistance of these drugs is rising,
which clearly indicates an urgent need for new antifungal
agents [6]. To overcome rapid development of drug resis-
tance, new agents should preferably have chemical charac-
teristics that clearly differ from those of existing agents.
In the present paper we report on the arylation of 3-
alkylthio-5-(4-substituted phenyl)-lH-1,2,4-triazole (1)
with fluorobenzene activated by a methylsulfonyl group to
prepare diaryltriazole derivatives. Alkylation and arylation
of 5- amino-3-methylthio-1,2,4-triazole derivative with
activated alkyl or aryl halide have been studied [7,8] and
the N1-arylated and alkylated regioisomers were obtained
as the main product.
The main product of direct arylation of 5-aryl-3-
thioalkyl-1H-1,2,4-triazole (1, Scheme 1) was in all cases
the corresponding 2-arylated derivative 2. However, N1-
arylated derivative 3 was also formed in low yield. Only
3a was isolated and characterized. The amount of N4- a r y l-
ation was insignificant. In order to elucidate the definite
structure of 2a and 3a, N4-arylated derivative 9 was
prepared via an alternative procedure with conclusive
structure [9] (Scheme 2).
The differentiation between the structure 3a, 2a and 9
was possible on the basis of a D-NOE experiment.
Irradiation of the methylthio group of 3a (Figure1) did not
result in an enhancement of any of the aromatic hydrogen
signals, therefore the 4-methylsulfonylphenyl moiety is in
position 1 of triazole ring. Furthermore, the observation of
NOE enhancement on the phenyl hydrogen atoms signals

202
L. Navidpour, L. Karimi, M. Amini, M. Vosooghi, A. Shafiee
Vol. 41
Table 1
Analytical Data of Compounds 2a-j
Comp.
No.
X
R
M.p.(°C)
Yield
(%)
Molecular
Formula
Analysis %
Calcd./Found
H
C
N
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
H
F
F
Cl
Cl
CH
CH
OCH
OCH
CH
163-164
132-133
173-175
140-142
134-145
123-124
133-135
135-137
149-150
137-139
21
24
28
33
36
25
20
21
32
33
C
C
C
C
C
C
C
C
C
C
H
N O S
55.63/55.42
56.80/57.05
52.88/52.60
54.09/53.87
50.58/50.69
51.83/51.56
56.80/56.99
57.88/57.49
54.38/54.40
55.50/55.88
4.37/4.60
4.77/4.58
3.88/4.05
4.27/4.39
3.71/3.49
4.09/4.36
4.77/4.69
5.13/4.91
4.56/4.69
4.92/4.81
12.16/11.89
11.69/11.65
11.56/11.47
11.13/11.33
11.06/11.29
10.67/10.51
11.69/11.91
11.25/11.49
11.19/10.98
10.79/10.55
3
16 15
3
2
2
2
C H
H N O S
17 17 3 2
H FN O S
16 14 3 2
2
5
5
5
5
5
CH
3
2
C H
H
FN O S
2
17 16
3 2
2
CH
H
ClN O S
3
16 14
3
2
2
2
C H
H
ClN O S
2
17 16
3
2
2
2
2
2
CH
H
N O S
3
3
3
17 17
3
2
C H
H N O S
18 19 3 2
2
CH
H
N O S
3
3
3
17 17
3
3
2j
C H
H
N O S
2
18 19
3
3
Table 2
Analytical Data of Compounds 6-9 and 3a
(Figure 1) following irradiation of the methylthio group, a
NOE enhancement was observed on the aromatic hydro-
gen atoms a and b signals. This indicates that the presence
of 4-methylsulfonylphenyl group is in positions 2 or 4 of
triazole ring. For compound 9, a cross NOE effect between
the two-aryl groups and also between the thiomethyl group
and aromatic hydrogens of the 4-methylsulfonylphenyl
groups were observed. The structure of compounds 3a, 2a
and 9 could also be confirmed by 13C-NMR. It is known
[10-12] that where heteroaromatic carbon atoms have oth-
erwise identical chemical environment, the carbon
attached to a pyridine-like nitrogen atom is more deshilded
than that bound to pyrrole-like nitrogen. The difference
between the two types of chemical shifts values in isomers
where the structure is fixed by alkyl groups, and also in the
case of different tautomeric forms measured at low tem-
peratures, is about 8-12 ppm. Multi-regression analysis of
different azoles also led to the same results [9].
Comp. M.p. Yield Molecular
(°C) (%) Formula
Analysis %
Calcd./Found
H
No.
C
N
6
7
8
9
3a
178-180 95
205-207 90
240-242 52
208-210 90
C
C
C
C
C
H
NO S 61.07/61.22 4.76/4.60 5.09/5.29
N O S 58.11/58.29 5.22/5.46 14.52/14.58
14 13
3
H
14 15
3 2
N O S 54.36/54.45 3.95/3.77 12.68/12.21
H
15 13
3 2 2
H N O S 55.63/55.97 4.37/4.39 12.16/12.47
16 15 3 2 2
H N O S 55.63/55.65 4.37/4.56 12.16/12.22
16 15 3 2 2
184-186
3
a' in 3a by irradiation of hydrogen-a and also enhancement
of the signal for hydrogen-a when the a'-hydrogen was
irradiated clearly showed that the two aryl groups are in
neighboring positions 1 and 5. For compound 2 a
In compound 3a (Figure 1), C3 is situated between two
pyridine-like nitrogen atoms, therefore its chemical shift is
higher than C5, which is situated between pyrrole-like and
pyridine-like nitrogen atoms. These rules are also valid for
2a and similar discussion could be given. For compound 9
both C5 and C3 are situated between pyridine-like and pyr-
role-like nitrogen atoms. The difference of the chemical
shift is the result of the effect of phenyl and thiomethyl
group on carbon chemical shift.
On the basis of the above discussion, the chemical shift
of compounds 2a-2j were assigned and summarized in
Table 3.
N1-Aryl and N1-alkyl regioisomers for 5-amino-3-
thiomethyl 1,2,4-triazole were reported as main product

Mar-Apr 2004
Syntheses of 5-Alkylthio-1,3-diaryl-1,2,4-triazoles
203
Table 3
1
13
H and C-NMR of Compounds 2a-2j
1
13
Comp.
No.
H-NMR
C-NMR
2a
8.17 (m, 2H, H
), 8.10 (d, J=8.8 Hz, 2H, H ), 7.96
162.45 (C -triazole), 154.83 (C ), 141.64 (C -triazole), 139.47 (C ),
3 6 5 9
13,17
8,10
(d, J=8.8 Hz, 2H, H ), 7.4-7.5 (m, 3H, H
), 3.10
130.10 (C ), 129.76 (C ), 128.83 (C ), 128.63 (C
),
7,11
14,15,16
12
15
8,10
13,17
(s, 3H, SO CH ), 2.81 (s, 3H, SCH ).
126.55 (C
), 123.32 (C ), 44.05 (SO CH ), 16.2 (SCH ).
14,16 7,11 2 3 3
2
3
3
2b
8.18 (m, 2H, H
), 8.08 (d, J=8.8 Hz, 2H, H ), 7.94
162.43 (C -triazole), 154.12 (C ), 141.55 (C -triazole), 139.25
3 6 5
13,17
8,10
(d, J=8.8 Hz, 2H, H ), 7.4-7.5 (m, 3H, H
), 3.43
(C ), 130.12 (C ), 129.61 (C ), 128.65 (C ), 128.42 (C
),
7,11
14,15,16
9
12
15
8,10
13,17
(q, J=7 Hz, 2H, CH ), 3.10 (s, 3H, SO CH ), 1.50 (t,
126.41 (C
), 123.33 (C ), 44.22 (SO CH ), 28.3 (CH ),
14,16 7,11 2 3 2
2
2
3
J=7 Hz, 3H, CH ).
16.2(CH ).
3
3
2c
8.15 (dd, J=8.8 Hz, J=5.6 Hz, 2H, H
), 8.10 (d, J=
164.92 (C -triazole), 162.15 (d, J=85 Hz, C ), 154.32 (C ),
3 15 6
13,17
9.2 Hz, 2H, H ),7.96 (d, J=9.2 Hz, 2H, H ),7.15 (t,
141.64 (C -triazole), 139.57 (C ), 128.88 (C ), 128.64 (d,
8,10
7,11
5
9
8,10
J=8.8 Hz, 2H, H
), 3.12 (s, 3H, SO CH ),
J=8.3 Hz, C
), 126.30(d, J=3.4 Hz, C ), 123.61 (C ),
13,17 12 7,11
14, 16
2
3
2.85 (s, 3H, SCH ).
115.70 (d, J=22 Hz, C
), 44.32 (SO CH ), 14.50 (CH ).
14,16 2 3 3
3
2d
8.15 (dd, J=8.8 Hz, J=5.6 Hz, 2H, H
), 8.09 (d, J=
164.98 (C -triazole), 162.07 (d, J=85 Hz, C ), 154.19 (C ), 141.53
13,17
3 15 6
9.2 Hz, 2H, H ), 7.95 (d, J=9.2 Hz, 2H, H ), 7.14
(C -triazole), 139.38 (C ), 128.75 (C ), 128.44 (d, J=8.3 Hz,
8,10
7,11
5
9
8,10
(t, J=8.8 Hz, 2H, H
), 3.42 (q, J=7 Hz, 2H, CH ),
C
), 126.34 (d, J=3.4 Hz, C ), 123.43 (C ), 115.59 (d,
14, 16
2
13,17 12 7,11
3.11 (s, 3H, SO CH ), 1.49 (t, J=7 Hz, 3H, CH ).
J=22 Hz, C
), 44.52 (SO CH ), 28.25 (SCH ), 14.58 (CH ).
2
3
3
14,16 2 3 2 3
2e
2f
8.06 (m, 6H, H
3.12 (s, 3H, SO CH ), 2.85 (s, 3H, SCH ).
,
,
), 7.43 (d, J=8 Hz, 2H, H
),
),
161.50 (C -triazole), 155.02 (C ), 141.50 (C -triazole), 139.4
13 17 7,8,10,11
14,16
3
6
5
(C ), 135.80 (C ), 128.85 (C
), 128.61 (C ), 127.82
2
3
3
9
15
8,10,13,17 12
(C
), 123.31 (C ), 44.50 (SO CH ), 16.03 (SCH ).
7,11 2 3 3
14,16
8.02 (m, 6H, H
,
,
), 7.42 (d, J=8 Hz, 2H, H
161.59 (C triazole), 154.34 (C ), 141.52 (C -triazole),
13 17 7,8,10,11
14,16
3- 6 5
3.41 (q, J=7 Hz, 2H, SCH ), 3.10 (s, 3H, SO CH ),
139.49 (C ), 135.67 (C ), 128.84 (C ), 128.79(C
),
13,17
2
2
3
9
15
8,10
1.48 (t, J=7 Hz, 3H, CH ).
128.64 (C ), 127.81 (C
), 123.51 (C ), 44.57 (SO CH ),
3
12
14,16 7,11 2 3
28.29 (SCH ), 14.62(CH ).
2
3
2g
2h
2i
8.02 (m, 6H, H
3.09 (s, 3H, SO CH ), 2.83 (s, 3H, SCH ), 2.40 (s,
,
,
), 7.25 (d, J=8 Hz, 2H, H
),
),
162.50 (C -triazole), 154.59 (C ), 141.64 (C -triazole),
3 6 5
13 17 7,8,10,11
14,16
139.82 (C ), 139.29 (C ), 129.28 (C ), 128.76 (C
),
2
3
3
9
12
8,10
13,17
3H, CH ).
127.26 (C ), 126.42 (C
), 123.24 (C ), 44.51 (SO CH ),
3
15
14,16 7,11 2 3
21.43 (C -CH ), 16.02 (SCH ).
15
3
3
7.98 (m, 6H, H
3.42 (q, J=7 Hz, 2H, SCH ), 3.09 (s, 3H, SO CH ), 2.40
,
,
), 7.25 (d, J=8 Hz, 2H, H
162.45 (C -triazole), 154.43 (C ), 141.65 (C -triazole), 139.83
3 6 5
13 17 7,8,10,11
14,16
(C ), 139.28 (C ), 129.22 (C ), 128.75 (C
), 127.28 (C ),
2
2
3
9
12
8,10
13,17 15
(s, 3H, CH ), 1.44 (t, J=7 Hz, 3H, CH ).
126.40 (C
), 123.46 (C ), 44.54 (SO CH ), 28.26 (SCH ),
14,16 7,11 2 3 2
3
3
21.43 (C -CH ), 14.60 (CH ).
15
3
3
8.15 (d, J=8.8 Hz, 2H, H
), 8.12 (d, J=8.4 Hz, 2H,
162.25 (C -triazole), 160.93(C ), 154.82 (C ), 141.71 (C -
13,17
3 15 6 5
H
), 7.95 (d, J=8.4 Hz, 2H, H ), 6.96 (d, J=8.8 Hz,
triazole), 139.22 (C ), 128.80 (C
), 128.02 (C ), 123.23
8,10
7,11
9
13,17 8,10
2H, H
), 3.86 (s, 3H, OCH ), 3.09 (s, 3H, SO CH ),
(C ), 122.77 (C ), 113.99 (C
), 55.32(OCH ),
14,16 3
14,16
3
2
3
7,11
12
2.83 (s, 3H, SCH ).
44.57 (SO CH ), 16.06(SCH ).
2 3 3
3
2j
8.12(d, J=8.8 Hz, 2H, H
), 8.09(d, J=8.4 Hz, 2H,
162.19 (C -triazole), 160.82(C ), 154.89 (C ), 141.69 (C -
3 15 6 5
13,17
H
), 7.95(d, J=8.4 Hz, 2H, H ), 6.99(d, J=8.8 Hz,
triazole), 139.27 (C ), 128.86 (C
), 128.12 (C ), 123.28
8,10
7,11
9
13,17 8,10
2H, H
), 3.89(s, 3H, OCH ), 3.45(q, J= 7 Hz, 2H,
(C ), 122.70 (C ), 113.95 (C
), 55.37(OCH3), 44.62
14,16
14,16
3
7,11
12
SCH ), 3.10 (s, 3H, SO2CH ), 1.48(t, J=7 Hz, 3H, CH ).
(SO CH ), 28.26 (SCH ), 16.10 (CH ).
2 3 2 3
2
3
3
were carried out with a Perkin-Elmer Model 240-C apparatus
(Perkin Elmer, Norwalk, CT, USA). The results of the elemental
analyses (C, H, N) were within ± 0.4% of the calculated amounts.
The analytical data of compounds 6-9 and 3a are summarized in
Table 2.
via direct arylation and alkylation [9,10]. Amino group at
C5 as expected oriented the alkylation or arylation to N1.
Our result showed that the presence of an aryl group
instead of an amino group in C5 changed the orientation of
arylation from N1 to N2 (Scheme 1). Apparently, the aryl
group at C5 because of its hindrance oriented the next aryl
group to the N2 position. Therefore, Scheme 1 could be
used for the preparation of 1,3-diaryl-1,2,4-triazoles.
General Procedure for Arylation of 3-Alkylthio-5-(4-substituted-
phenyl)-1H-1,2,4-triazoles.
To a solution of 3-alkylthio-5-(4-substituted phenyl)-1,2,4-tri-
azole [13,14] (6.9 mmol) in DMSO (10 ml) was added sodium
hydride (168 mg, 6.9 mmol). After 20 min of stirring at room
temperature, 4-fluorophenyl methyl sulfone (1.2 g, 6.9 mmol)
was added. The reaction mixture was heated at 120-130 °C for 20
h, cooled to room temperature, and poured onto ice. The residue
was filtered and the crude yellowish solid was chromatographed
(silica gel, chloroform-methanol 20:1 v/v). The fast moving frac-
tion gave compound 3 (only 3a was separated and crystallized
from ethanol, yield 3 %). The slow moving fraction was crystal-
lized from ethanol to give compounds 2a-j (see Tables 1 and 3).
EXPERIMENTAL
Melting points were determined on a Reichert hot stage appa-
13
1
ratus and are uncorrected. H and C-NMR spectra were
recorded on a Varian Utility plus 400 spectrometer (400 MHz for
1
13
H-NMR and 100 MHz for C-NMR) using chloroform-d and
1
DMSO-d as solvent. Chemical shifts (δ) are reported in ppm rel-
6
ative to TMS as internal standard. Infrared spectra were recorded
on a Nicolet Magna FT-IR 550 spectrometer. Elemental analyses

204
L. Navidpour, L. Karimi, M. Amini, M. Vosooghi, A. Shafiee
Vol. 41
1-[4-(Methylsulfonyl)phenyl]-3-(methylthio)-5-phenyl-1 H-
1,2,4-triazole (3a).
4-(4-Methylsulfonylphenyl)-3-methylthio-5-phenyl-4H-1,2,4-
triazole (9).
1
This compound has mp 184-186 °C, H NMR (400 MHz,
To a solution of compound 8 (330 mg, 1 mmol) and ethanol (5
ml) methyl iodide (0.2 ml) and 10 % sodium hydroxide solution
(1 ml) were added. The mixture was stirred overnight. It was
diluted with water (10 ml). The precipitate was filtered and crys-
tallized from n-butanol to give 310 mg (90 %) of 9 mp, 208-210
CDCl ): δ = 2.68 (s, 3H, SCH ), 3.09 (s, 3H, SO CH ), 7.46 (m,
13
3
5H, phenyl), 7.57 (d, 2H, H ), 7.97 (d, 2H, H ) ppm;
3
2
3
C
NMR (100 MHz, CDCl ): δ = 163.06 (C -triazole), 155.36 (C ),
7,11
8,10
3
142.01 (C -triazole), 140.02 (C ), 130.80 (C ), 130.20 (C ),
3
6
5
128.98 (C ), 128.43 (C
9
), 128.75 (C
15
12
), 125.53 (C ),
1
°C; H NMR (400 MHz, CDCl +DMSO-d /1:1): δ = 8.08 (d,
8,10 13,17
44.46 (SO CH ), 14.33 (SCH ) ppm.
14,16
7,11
3
J=7.8 Hz, 2H, H ), 7.51 (d, J= 7.8 Hz, 2H, H ), 7.27 (m, 5H,
6
2
3
3
8,10 7,11
phenyl), 3.09 (s, 3H, SO CH ), 2.75 (s, 3H, SCH ) ppm;
13
C
NMR (100 MHz, CDCl +DMSO-d ): δ = 154.63 (C ), 152.93
2
3
3
N-(4-Methylsulfonylphenyl)benzamide (6).
3
6
6
To a solution of 4-methylsulfonylaniline (300 mg, 1.75 mmol)
in THF (20 ml) was added dropwise benzoyl chloride (250 mg,
1.78 mmol) dissolved in THF (5 ml) under N at 0 °C followed
(C -triazole), 141.58 (C -triazole), 138.44 (C ), 129.87 (C ),
5 3 9 15
128.96 (C ), 128.56 (C
8,10
), 128.07 (C
), 128.06 (C ),
13,17
14,16 7,11
125.86 (C ), 44.12 (SO CH ), 14.85 (SCH ) ppm.
12 2 3 3
2
by addition of triethylamine (0.25 ml, 1.8 mmol). The reaction
mixture was stirred for 18 h at 24 °C, filtered to remove
Et N•HCl, concentrated and recrystallized from methanol to give
Acknowledgement.
This research was supported by a grant from the research
council of Tehran University of Medical Sciences.
3
1
450 mg (95%) of 6, mp: 178-180 °C; H NMR (400 MHz,
CDCl ): δ = 7.96-6.7 (m, 9H, aromatic), 3.05 (s, 3H, SO CH )
3
ppm; IR (KBr): ν = 3319 (NH), 1665 (CO) cm . The spectral
2
3
-1
REFERENCES AND NOTES
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N-(4-Methylsulfonylphenyl)benzene Carbohydrazonamide (7).
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Corresponding author. E-mail: ashafiee@ams.ac.ir
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6
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3
2
-1
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K. Shett, J. Pharm. Sci., 58, 1398 (1969).
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152 (1980).
Compound 7 (500 mg, 1.73 mmol) was dissolved in THF (100
ml) under N , and 1,1'-thiocarbonyldiimidazole ( 340 mg, 2
mmol) was added. The solution was stirred for 18 h at room tem-
perature. The solvent was removed under reduced pressure. The
residue was taken up in ethyl acetate and washed with 0.1 N HCl
2
solution, water and brine prior to drying (Na SO ). The solvent
2
was evaporated and the residue was recrystallized from acetoni-
4
1
trile to give 320 mg (52%) of 8; mp 240-242 °C; H NMR (400
MHz, DMSO-d ): δ = 8.05 (d, J=7.8 Hz, 2H, H ), 7.56 (d,
6
J=7.8 Hz, 2H, H ), 7.30 (m, 5H, phenyl), 3.14 (s, 3H, SO CH )
8,10
7,11
ppm; IR (KBr): ν = 3104 (NH) cm .
2
3
-1