Synthesis of new 4,5-substituted 4H-1,2,4-triazole-3-thiols and their sulfanyl derivatives

Article abstract of DOI:10.1134/S1070363215030160

Abstract Reaction of hydrazides of 4-alkoxybenzoic acids with benzyl isothiocyanate followed by cyclization with thiosemicarbazide afforded a series of new 4,5-substituted 4H-1,2,4-triazole-3-thiols. S-Alkylation of the latter led to the formation of the

Full text of DOI:10.1134/S1070363215030160

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 3, pp. 622–627. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © M.A. Kaldrikyan, N.S. Minasyan, R.G. Melik-Ogandzhanyan, 2015, published in Zhurnal Obshchei Khimii, 2015, Vol. 85, No. 3,
pp. 459–464.
Synthesis of New 4,5-Substituted 4H-1,2,4-Triazole-3-thiols
and Their Sulfanyl Derivatives
a
b
a
M. A. Kaldrikyan , N. S. Minasyan , and R. G. Melik-Ogandzhanyan
a
Scientific-Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of the Republic of Armenia, ave. Azatutyan 26, Yerevan, 0014 Armenia
e-mail: tag.hovsepyan@mail.ru
b
Mndzhoyan Institute of Fine Organic Chemistry, Molecular Structure Research Center, Yerevan, Armenia
Received October 20, 2014
Abstract—Reaction of hydrazides of 4-alkoxybenzoic acids with benzyl isothiocyanate followed by cyclization
with thiosemicarbazide afforded a series of new 4,5-substituted 4H-1,2,4-triazole-3-thiols. S-Alkylation of the
latter led to the formation of the corresponding 4,5-substituted sulfanyl derivatives of 4H-1,2,4-triazoles.
Keywords: 1,2,4-triazole-3-thiol, thiosemicarbazide, benzyl isothiocyanate, S-alkylation, halogenated carboxylic
acids, chloroethanol, chloroacetamide
DOI: 10.1134/S1070363215030160
Previously, we have reported the synthesis of a
number of alkoxyphenyl-, alkoxyphenethyl- and
benzofuryl derivatives of 4H-1,2,4-triazoles, which
have shown high antitumor activity [1–6]. In this work
we prepared new 4-benzyl-1,2,4-triazole-3-thiol
derivatives. In addition, the substitution reaction of the
hydrogen of SH-group with various halides was studied.
Synthesis of the target compounds was carried out
as Scheme 1.
1,4-Substituted thiosemicarbazides IIa–IIf were
obtained by boiling hydrazides of 4-alkoxybenzoic
acids Ia–If with benzylisothiocyanate in ethanol.
Cyclization of thiosemicarbazides IIa–IIf into 5-(4-
Scheme 1.
Δ
1
1
R O
CONHNH2 + S=C=NCH C H
R O
CONHNHCNHCH C H
2
6
5
2
6
5
EtOH
S
Iа−If
IIа−IIf
N
N
N
N
2
KOH
H O
R X
1
1
R O
R O
SR2
2
N
SH
CH C H
KOH
N
CH C H
2 6 5
2
6
5
IIIа−IIIf
IVа−IVz'
1
1
2
1
2
I–III, R = CH
CH(CH )COOН (b); R = CH
COOН (e); R = C
3
(a), C
2
H
5
(b), C
3
H
7
(c), i-C
3
H
7
(d), C
4
H
9
(e), i-C
4
H
9
(f); IV, R = CH
3
, R = CH
COOН (d); R = C
2
COOН (a); R = CH
3
, R =
, R = CH(CH )·
, R = CH(CH )COOН (h);
, R = CH(CH
, R = CH(C )COOН (n); R = i-C
1
2
1
2
1
2
3
3
, R = CH(C
, R = CH(C
R = CH(C )COOН (i); R = i-C
, R = CH(C )COOН (l); R = C
4
H
9
)COOН (c); R = C
2
H
5
, R = CH
, R = CH COOН (g); R = C
, R = CH COOН (j); R = i-C
, R = CH
2
2
H
5
3
1
2
1
2
1
2
2
H
5
4
H
9
)COOН (f); R = C
3
H
7
2
3
H
7
3
1
2
1
2
1
2
1
R = C
3
H
7
,
4
H
9
3
H
7
2
3
H
7
3
)COOН (k); R = i-
2
1
2
1
2
1
2
C
CH
i-C
CH
3
H
2
7
4
H
9
4
H
9
2
COOН (m); R = C
4
H
9
4
H
9
4
H
9
, R =
1
2
1
2
1
2
1
COOН (o); R = CH
, R = CH
3
, R = CH
2
CH
2
OH (p); R = C
2
H
5
, R = CH
2
CH
2
OH (q); R = C
3
H
2
7
, R = CH
CH OH (u); R = CH
, R = CH
2
CH
2
OH (r); R =
2
1
2
1
2
1
2
3
H
7
2
CH
2
OH (s); R = C
4
H
9
, R = CH
2
CH
2
OH (t); R = i-C
4
H
9
, R = CH
(x); R = i-C
2
3
, R =
1
2
1
2
1
2
1
2
CОNH
2
(v); R = C
2
H
5
, R = CH
2
CОNH
2
(w); R = C , R = CH
3
H
7
2
CОNH
2
3
H
7
2
CОNH
2
(y); R =
2
1
2
C
4
H
9
, R = CH CОNH
2
2
(z); R = i-C
4
H
9
, R = CH CОNH (z').
2
2
6
22

SYNTHESIS OF NEW 4,5-SUBSTITUTED 4H-1,2,4-TRIAZOLE-3-THIOLS
623
1
alkoxyphenyl)-4-benzyl-4H-1,2,4-triazole-3-thiols IIIa–
IIIf was performed by heating the reaction mixture in
H NMR spectrum (300 MHz), δ, ppm (J, Hz): 1.04 t
(3H, ОСH СH CH , J 7.4), 1.74–1.85 m (2H,
2
2
3
a
4.5% aqueous solution KOH followed by
ОСH СH CH ), 3.94 t (2H, ОСH СH CH , J 6.5),
2 2 3 2 2 3
acidification with acetic acid. S-Alkylation of 1,2,4-
triazole-3-thiols IIIa–IIIf was carried out with
chloroacetic, 2-bromopropionic and 2-bromocaproic
acids in a threefold excess of aqueous KOH or
chloroethanol and chloroacetamide in alcoholic
solution of an equimolar amount of KOH.
4.77 t (2H, NНCH , J 6.0), 6.85–6.90 m (2H, ArH),
7.31–7.35 m (2H, ArH), 7.09–7.12 m (2H, ArH), 7.18–
7.29 m (3H, Ar), 7.22 br.s (1H, NН), 9.03–9.98 br.s
2
(2H, NНNН). Found, %:
N
12.56;
S
9.58.
С H N O S. Calculated, %: N 12.23; S 9.33.
1
8
21
3
2
1-(4-Isopropoxyphenyl)carbonyl-4-benzyl-3-thio-
Triazole thiols IIIa–IIIf and S-substituted triazoles
IVa–IVz' were white crystalline substances. Their
composition and structures were confirmed by elemental
semicarbazide (IId). Yield 90%, mp 197–198°С, R
f
1
0.65. H NMR spectrum (300 MHz), δ, ppm (J, Hz):
1.34 d [6H, ОСH(CH , J 6.0], 4.66 septet [1H, ОСH·
(CH , J 6.0], 4.77 d (2H, NНCH , J 6.0), 6.85–6.90
m (2H, ArH), 7.86–7.91 m (2H, ArH), 7.15–7.21 m
1H, ArH), 7.24–7.35 m (4H, ArH), 8.26 br.t (1H,
NН), 9.19 br.s (1H, NН), 10.09 br.s (1H, NН). Found,
)
3 2
1
analysis and H NMR spectroscopy (see Experimental).
3
)
2
2
EXPERIMENTAL
(
1
H NMR spectra of DMSO-d6 solutions were
recorded on a Mercury-300 spectrometer relative to
internal TMS operating at 300 MHz. Melting points
were measured on a Boetius heating block. TLC was
performed on Silufol UV-254 plates eluting with the
mixtures benzene–acetone, 1 : 3 (IIa–IIf), benzene–
acetone, 2 : 1 (IIIa–IIIf), benzene–ethanol, 1.5 : 1
%: N 12.44; S 9.12. С18H N O S. Calculated, %: N
12.23; S 9.33.
21 3 2
1
-(4-Buthoxyphenyl)carbonyl-4-benzyl-3-thio-
semicarbazide (IIe). Yield 98%, mp 177–178°С, R
f
1
0
1
.68. H NMR spectrum (300 MHz), δ, ppm (J, Hz):
.00 t [3H, О(СH СH СH CH , J 7.4], 1.52 m (2H,
2
2
2
3
(IVa–IVo), and benzene–acetone–ethanol, 1 : 1 : 0.1
IVp–IVz'), developing with UV light.
ОСH СH СH CH ), 1.77 m (2H, ОСH СH СH CH ),
2
2
2
3
2
2
2
3
(
4
.02 t (2H, ОСH СH СH CH , J 6.4), 4.77 d (2H,
2 2 2 3
1-(4-Alkoxyphenyl)carbonyl-4-benzyl-3-thiosemi-
NНCH , J 6.0), 6.89–7.15 m (2H, ArH), 7.22–7.35 m
2
carbazides (IIa–IIf). A mixture of 10 mmol of
hydrazidеs of 4-alkoxybenzoic acids Ia–If and
(2H, ArH), 7.15–7.24 m (1H, ArH), 7.26–7.35 m (4H,
ArH), 8.25 br.t (1H, NН), 9.16 br.s (1H, NН), 10.08
br.s (1H, NН). Found, %: N 11.96; S 8.75.
С H N O S. Calculated, %: N 11.75; S 8.96.
1
0 mmol of benzyl isothiocyanate in 30 mL of ethanol
was refluxed for 5.4 h. The resulting crystals were
filtered off and recrystallized from ethanol.
1
9
23
3
2
1
-(4-Isobuthoxyphenyl)carbonyl-4-benzyl-3-thio-
1-(4-Methoxyphenyl)carbonyl-4-benzyl-3-thiosemi-
semicarbazide (IIе). Yield 90%, mp 196–197°С, R
f
1
carbazide (IIa). Yield 84%, mp 202–203°С, R 0.64.
f
0.67. H NMR spectrum (300 MHz), δ, ppm (J, Hz):
.04 d [6H, ОСH СH(CH ) , J 6.6], 2.08 m [1H,
1
H NMR spectrum (300 MHz), δ, ppm (J, Hz): 3.82 s
1
2
3 2
(
(
3H, CH ), 4.77 d (2H, NНCH , J 6.0), 6.87–6.92 m
2H, ArH), 7.88–7.94 m (2H, ArH), 7.15–7.36 m (5H,
3
2
ОСH СH(CH ) , J 6.6], 3.78 d [2H, ОСH СH(CH ) , J
2 3 2 2 3 2
6
.6], 4.77 d (2H, NНCH , J 6.0), 6.87–6.92 m (2H,
2
ArH), 8.29 br.t (1H, NН, J 6.0), 9.05 br.s (1H, NН),
.99 br.s (1H, NН). Found, %: N 13.45; S 10.37.
С H N O S. Calculated, %: N 13.32; S 10.16.
ArH), 7.87–7.92 m (2H, ArH), 7.14–7.21 m (1H,
ArH), 7.24–7.35 m (4H, ArH), 8.27 br.t (1H, NН, J
6.0), 9.18 br.s (1H, NН), 10.09 br.s (1H, NН). Found,
9
1
6
17
3
2
%
: N 11.89; S 8.68. С H N O S. Calculated, %: N
1
-(4-Ethoxyphenyl)carbonyl-4-benzyl-3-thiosemi-
19 23 3 2
1
1.75; S 8.96.
carbazide (IIb). Yield 90%, mp 196–197°С, R 0.65.
H NMR spectrum (300 MHz), δ, ppm (J, Hz): 1.43 t
3H, ОCH CH ), 4.09 q (2H, ОCH CH , J 6.9), 4.78 d
2H, NНCH , J 6.0), 6.87–6.92 m (2H, ArH), 7.87–
.93 m (2H, ArH), 7.15–7.36 m (5H, ArH), 8.29 br.t
1H, NНCH , J 6.0), 9.06–10.01 br.s (2H, NНNН).
Found, %: N 12.56; S 9.86. С H N O S. Calculated,
f
1
5
-(4-Alkoxyphenyl)-4-benzyl-4Н-1,2,4-triazole-3-
(
(
7
2 3 2 3
thiols (IIIa–IIIf). A mixture of 10 mmol of thiosemi-
carbazide IIa–IIf, 1 g of KОН, and 50 mL of water
was refluxed for 2 h. After cooling the mixture was
treated with acetic acid. The precipitate was filtered
off, washed with water, dried, and recrystallized from
2
(
2
1
7
19
3
2
%
: N 12.75; S 9.73.
-(4-Propoxyphenyl)carbonyl-4-benzyl-3-thiosemi-
carbazide (IIc). Yield 80%, mp 185–186°С, R 0.67.
7
0% aqueous ethanol.
1
4
-Benzyl-5-(4-methoxyphenyl)-4Н-1,2,4-triazole-
1
f
3-thiol (IIIa). Yield 94%, mp 205–206°С, R 0.69. H
f
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 3 2015

6
24
KALDRIKYAN et al.
NMR spectrum (300 MHz), δ, ppm (J, Hz): 3.82 s (3H,
ОCH ), 5.28 s (2H, NCH ), 6.87–6.92 m (2H, ArH),
ArH), 13.76 br.s (1H, SН). Found, %: N 12.61; S 9.72.
С H N OS. Calculated, %: N 12.37; S 9.44.
3
2
19 21
3
7
7
1
.32–7.37 m (2H, ArH), 7.08–7.12 m (2H, ArH), 7.18–
.30 m (3H, ArH), 13.78 br.s (1H, SН). Found, %: N
4.37; S 10.96. С H N OS. Calculated, %: N 14.13;
Substituted triazol-3-ylsulfanylacetic, -propionic,
and -hexanoic acids (IVa–IVo). A mixture of 6 mmol
of KОН, 30 mL of water, 2 mmol of triazole-3-thiol
IIIa–IIIf, and 2 mmol of the corresponding carboxylic
acid was refluxed for 2 h. The mixture was filtered and
treated with acetic acid. The precipitate was filtered
off, washed with water, dried, and recrystallized from
ethanol.
1
6
15
3
S 10.78.
4
-Benzyl-5-(4-ethoxyphenyl)-4Н-1,2,4-triazole-3-
1
thiol (IIIb). Yield 98%, mp 203–204°С, R 0.68. H
NMR spectrum (300 MHz), δ, ppm (J, Hz): 1.41 t (3H,
ОСH CH , J 7.0), 4.06 q (2H, ОСH CH , J 7.0), 5.24 s
f
2
3
2
3
(
(
2H, NCH ), 6.89–6.94 m (2H, ArH), 7.39–7.44 m
2H, ArH), 6.99–7.04 m (2H, ArH), 7.23–7.35 m (3H,
2
[
4-Benzyl-5-(4-methoxyphenyl)-4Н-1,2,4-triazol-
3
1
-ylsulfanyl]acetic acid (IVа). Yield 85%, mp 195–
ArH), 13.71 br.s (1H, SН). Found, %: N 13.61; S
1
1
96°С, R 0.58. H NMR spectrum (300 MHz), δ, ppm
f
0.46. С H N OS. Calculated, %: N 13.49; S 10.29.
17 17 3
(
(
(
J, Hz): 3.81 s (3H, ОCH ), 3.85 s (2H, SСН ), 5.25 s
3 2
4
-Benzyl-5-(4-propoxyphenyl)-4Н-1,2,4-triazole-
2H, NCH ), 6.84–7.02 m (4H, ArH), 7.20–7.35 m
2
1
3
-thiol (IIIc). Yield 90%, mp 180–181°С, R 0.67. H
f
3H, ArH), 7.40–7.46 m (2H, ArH), 13.75 br.s (1H,
NMR spectrum (300 MHz), δ, ppm (J, Hz): 1.04 t (3H,
ОСH СH CH , J 7.4), 1.74–1.86 m (2H, ОСH СH CH ),
3
6
7
СООН). Found, %: N 11.63; S 9.31. С H N O S.
1
8
17
3
3
2
2
3
2
2
3
Calculated, %: N 11.82; S 9.02.
.94 t (2H, ОСH СH CH , J 6.5), 5.28 s (2H, NCH ),
2 2 3 2
2-[4-Benzyl-5-(4-methoxyphenyl)-4Н-1,2,4-triazol-
.85–6.90 m (2H, ArH), 7.31–7.35 m (2H, ArH), 7.09–
.13 m (2H, ArH), 7.18–7.29 m (3H, ArH), 13.72 br.s
3
1
-ylsulfanyl]propionic acid (IVb). Yield 83%, mp
1
39–140°С, R 0.53. H NMR spectrum (300 MHz), δ,
(
1H, SН). Found, %: N 12.72; S 9.62. С H N OS.
f
18
19
3
ppm (J, Hz): 1.58 d (3H, SСНCH , J 7.1), 3.82 s (3H,
Calculated, %: N 12.91; S 9.85.
3
ОCH ), 4.19 q (1H, SСHCH , J 7.1), 5.25 s (2H,
3
3
4
-Benzyl-5-(4-isopropoxyphenyl)-4Н-1,2,4-tri-
NCH ), 6.88–7.00 m (4H, ArH), 7.21–7.37 m (3H,
2
azole-3-thiol (IIId). Yield 94%, mp 210–211°С, R
0
1
f
ArH), 7.41–7.47 m (2H, ArH), the signal of СООН
group was not observed due to broadening. Found, %:
N 11.25; S 8.77. С H N O S. Calculated, %: N
1
.70. H NMR spectrum (300 MHz), δ, ppm (J, Hz):
.33 d [6H, ОСH(CH ) , J 6.0], 4.61 septet [1H, ОСH·
3
2
1
9
19
3
3
(CH ) , J 6.0], 5.28 s (2H, NCH ), 6.82– 6.87 m (2H,
3 2 2
1
1.37; S 8.67.
ArH), 7.29–7.34 m (2H, ArH), 7.08–7.12 m (2H,
ArH), 7.18–7.29 m (3H, ArH), 13.77 br.s (1H, SН).
Found, %: N 12.74; S 9.66. С H N OS. Calculated,
2-[4-Benzyl-5-(4-methoxyphenyl)-4Н-1,2,4-triazol-
18
19
3
3-ylsulfanyl]hexanoic acid (IVc). Yield 87%, mp
1
%
: N 12.91; S 9.85.
133–134°С, R 0.58. H NMR spectrum (300 MHz), δ,
f
ppm (J, Hz): 0.93 t (3H, СH СH СH CH , J 7.0),
2
2
2
3
4
-Benzyl-5-(4-buthoxyphenyl)-4Н-1,2,4-triazole-
1
1.29–1.47 m (4H, СH СH СH CH ), 1.79–1.99 m (2H,
2 2 2 3
3
-thiol (IIIe). Yield 85%, mp 185–186°С, R 0.69. H
NMR spectrum (300 MHz), δ, ppm (J, Hz): 0.99 t (3H,
ОСH СH СH CH , J 7.3), 1.44–1.57 m (2H, ОСH СH ·
f
СH СH СH CH ), 3.82 s (3H, ОCH ), 4.07 d. d (1H,
2
2
2
3
3
SСH, J 7.3), 5.25 s (2H, NCH ), 6.91–6.99 m (4H,
2
2
2
2
3
2
2
ArH), 7.22–7.34 m (3H, ArH), 7.41–7.46 m (2H,
ArH), the signal of СООН group was not observed due
to broadening. Found, %: N 10.45; S 7.92.
С H N O S. Calculated, %: N 10.21; S 7.79.
СH CH ), 1.71–1.81 m (2H, ОСH СH СH CH ), 3.98
2
3
2
2
2
3
t (2H, ОСH СH СH CH , J 6.4), 5.24 s (2H, NCH ),
.89–6.93 m (2H, ArH), 7.39–7.44 m (2H, ArH), 7.00–
.05 m (2H, ArH), 7.23–7.35 m (3H, ArH), 13.76 br.s
2
2
2
3
2
6
7
2
2
25
3
3
(
1H, SН). Found, %: N 12.55; S 9.67. С H N OS.
19 21 3
[
4-Benzyl-5-(4-ethoxyphenyl)-4Н-1,2,4-triazol-3-
Calculated, %: N 12.37; S 9.44.
ylsulfanyl]acetic acid (IVd). Yield 85%, mp 170–
1
4
-Benzyl-5-(4-isobethoxyphenyl)-4Н-1,2,4-triazole-
171°С, R
(J, Hz): 1.41 t (3H, ОСH
SСН ), 4.08 q (2H, ОСH
NCH ), 6.89–6.94 m (2H, ArH), 7.39–7.44 m (2H,
f
0.58. H NMR spectrum (300 MHz), δ, ppm
CH , J 7.0), 3.85 s (2H,
CH , J 7.0), 5.24 s (2H,
1
3
-thiol (IIIf). Yield 88%, mp 205–206°С, R 0.65. H
2
3
f
NMR spectrum (300 MHz), δ, ppm (J, Hz): 1.03 d
6H, ОСH СH(CH ) , J 6.6], 2.07 m [1H, ОСH СH(CH ) ,
2
2
3
[
2
2
3 2
2
3 2
J 6.6], 3.74 d [2H, ОСH СH(CH ) , J 6.6], 5.28 s (2H,
ArH), 6.96–7.04 m (2H, ArH), 7.23–7.35 m (3H,
2
3 2
NCH ), 6.85–6.90 m (2H, ArH), 7.31–7.35 m (2H,
ArH), 13.75 br.s (1H, СООН). Found, %: N 11.64; S
2
ArH), 7.09–7.13 m (2H, ArH), 7.19–7.30 m (3H,
8.84. С19H N O S. Calculated, %: N 11.37; S 8.67.
19 3 3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 3 2015

SYNTHESIS OF NEW 4,5-SUBSTITUTED 4H-1,2,4-TRIAZOLE-3-THIOLS
625
2
-[4-Benzyl-5-(4-ethoxyphenyl)-4Н-1,2,4-triazol-
7.33 m (3H, ArH), the signal of СООН group was not
observed due to broadening. Found, %: N 9.36; S 7.45.
С H N O S. Calculated, %: N 9.55; S 7.29.
3
1
-ylsulfanyl]propionic acid (IVe). Yield 82%, mp
32–133°С, R 0.56. H NMR spectrum (300 MHz), δ,
1
f
24 29
3
3
ppm (J, Hz): 1.41 t (3H, ОСH CH , J 7.0), 1.58 d (3H,
2
3
[
4-Benzyl-5-(4-isopropoxyphenyl)-4Н-1,2,4-triazol-
SСHCH , J 7.2), 4.06 q (2H, ОСH CH , J 7.0), 4.19 q
3
2
3
3
1
(
-ylsulfanyl]acetic acid (IVj). Yield 92%, mp 141–
42°С, R 0.55. H NMR spectrum (300 MHz), δ, ppm
J, Hz): 1.34 d [6H, ОСH(CH ) , J 6.0], 3.84 s (2H,
SСН ), 4.61 septet [1H, ОСH(CH ) , J 6.0], 5.28 s
(
(
1H, SСH, J 7.2), 5.25 s (2H, NCH ), 6.89–7.00 m
4H, ArH), 7.22–7.34 m (3H, ArH), 7.38–7.45 m (2H,
1
2
f
3 2
ArH), 12.63 br.s (1H, СООН). Found, %: N 10.76; S
2
3 2
8
.58. С H N O S. Calculated, %: N 10.95; S 8.36.
20 21 3 3
(
2H, NCH ), 6.82–6.87 m (2H, ArH), 7.29–7.34 m
2
2
-[4-Benzyl-5-(4-ethoxyphenyl)-4Н-1,2,4-triazol-
(2H, ArH), 7.08–7.12 m (2H, ArH), 7.18–7.29 m
(3H, ArH), 12.57 br.s (1H, СООН). Found, %: N
10.66; S 8.58. С H N O S. Calculated, %: N 10.95; S
3
1
-ylsulfanyl]hexanoic acid (IVf). Yield 75%, mp
40–141°С, R 0.54. H NMR spectrum (300 MHz), δ,
1
f
20 21
3
3
ppm (J, Hz): 0.93 t (3H, СH СH СH CH , J 7.0),
8.36.
2
2
2
3
1
.30–1.47 m (4H, СH СH СH CH ), 1.41 t (3H,
2 2 2 3
2
-[4-Benzyl-5-(4-isopropoxyphenyl)-4Н-1,2,4-tri-
ОСH CH , J 7.0), 1.79–1.99 m (2H, SСHСH ), 4.06 q
2
3
2
azol-3-ylsulfanyl]propionic acid (IVk). Yield 85%,
mp 124–126°С, R 0.50. H NMR spectrum (300
MHz), δ, ppm (J, Hz): 1.33 d [6H, ОСH(CH ) , J 6.0],
.58 d (3H, SСHCH , J 7.2), 4.19 q (1H, SСHCH , J
.2), 4.61 septet [1H, ОСH(CH ) , J 6.0], 5.25 s (2H,
NCH ), 6.82–6.88 m (2H, ArH), 7.29–7.34 m (2H,
(
(
(
2H, ОСH CH , J 7.0), 4.07 t (1H, SСH, J 6.7), 5.25 s
2H, NCH ), 6.88–6.99 m (4H, ArH), 7.22–7.35 m
3H, ArH), 7.39–7.45 m (2H, ArH), 12.5 br.s (1H,
1
2
3
f
2
3
2
1
7
3
3
СООН). Found, %: N 9.98; S 7.75. С H N O S.
Calculated, %: N 9.87; S 7.53.
2
3
27
3
3
3
2
2
[
4-Benzyl-5-(4-propoxyphenyl)-4Н-1,2,4-triazol-
ArH), 7.08–7.12 m (2H, ArH), 7.18–7.29 m (3H, ArH),
3
1
-ylsulfanyl]acetic acid (IVg). Yield 92%, mp 167–
the signal of СООН group was not observed due to
1
68°С, R 0.55. H NMR spectrum (300 MHz), δ, ppm
broadening. Found, %: N 10.78; S 8.98. С21H N O S.
23 3 3
f
(
J, Hz): 0.93 t (3H, ОСH СH CH , J 7.1), 1.28 m (2H,
Calculated, %: N 10.57; S 8.86.
2
2
3
ОСH СH CH ), 3.94 t (2H, ОСH СH CH , J 6.5),
2
2
3
2
2
3
2
-[4-Benzyl-5-(4-isopropoxyphenyl)-4Н-1,2,4-tri-
4
.06 d. d (2H, SСН ), 5.25 s (2H, NCH ), 6.88–6.93 m
2 2
azol-3-ylsulfanyl]hexanoic acid (IVl). Yield 80%, mp
9–70°С, R 0.69. H NMR spectrum (300 MHz), δ,
f
ppm (J, Hz): 0.93 t (3H, СH СH СH CH , J 7.0),
1.30–1.47 m (4H, СH СH CH ), 1.33 d [6H, ОСH(CH ) ,
1
(
2H, ArH), 7.39–7.44 m (2H, ArH), 6.94–6.99 m (2H,
ArH), 7.21–7.33 m (3H, ArH), 12.68 br.s (1H, СООН).
Found, %: N 10.76; S 8.62. С H N O S. Calculated,
6
2
2
2
3
2
0
21
3
3
2 2 3 3 2
%: N 10.95; S 8.36.
J 6.0], 1.79–1.99 m (3H, SСHCH ), 4.07 t (1H,
2
SСHCH , J 6.7), 5.25 s (2H, NCH ), 6.88–6.99 m (4H,
ArH), 7.22–7.35 m (3H, ArH), 7.39–7.45 m (2H,
ArH), 12.5 br.s (1H, СООН). Found, %: N 9.77; S
2
2
2
-[4-Benzyl-5-(4-propoxyphenyl)-4Н-1,2,4-triazol-
3
1
-ylsulfanyl]propionic acid (IVh). Yield 75%, mp
30–131°С, R 0.69. H NMR spectrum (300 MHz), δ,
ppm (J, Hz): 1.05 t (3H, ОСH СH CH , J 7.4), 1.58 d
1
f
7
.48. С H N O S. Calculated, %: N 9.55; S 7.29.
24 29 3 3
2
2
3
(
3H, SСHCH , J 7.2), 1.74–1.86 m (2H, ОСH СH CH ),
[4-Benzyl-5-(4-buthoxyphenyl)-4Н-1,2,4-triazol-
3
2
2
3
3
.95 t (2H, ОСH СH CH , J 6.5), 4.19 q (1H, SСHCH ,
3-ylsulfanyl]acetic acid (IVm). Yield 85%, mp 70–
2
2
3
3
1
J 7.2), 5.25 s (2H, NCH ), 6.86–6.99 m (4H, ArH),
72°С, R 0.57. H NMR spectrum (300 MHz), δ, ppm
2
f
7
.21–7.35 m (3H, ArH), 7.39–7.45 m (2H, ArH), 13.75
(J, Hz): 0.99 t (3H, ОСH СH СH CH , J 7.3), 1.44–
2
2
2
3
br.s (1H, СООН). Found, %: N 10.68; S 8.71.
С H N O S. Calculated, %: N 10.57; S 8.86.
1.57 m (2H, ОСH СH СH CH ), 1.71–1.81 m (2H,
2 2 2 3
2
1
23
3
3
ОСH СH СH CH ), 3.95 m (1H, SСН ), 3.98 t (2H,
2
2
2
3
2
ОСH СH СH CH , J 6.4), 5.24 s (2H, NCH ), 6.89–
2
2
2
3
2
2
-[4-Benzyl-5-(4-propoxyphenyl)-4Н-1,2,4-triazol-
6
.93 m (2H, ArH), 7.39–7.44 m (2H, ArH), 7.00–7.05
3
1
-ylsulfanyl]hexanoic acid (IVi). Yield 91%, mp
02–103°С, R 0.57. H NMR spectrum (300 MHz), δ,
ppm (J, Hz): 0.92 t (3H, ОСH СH CH , J 7.1), 1.04 t
3H, СH СH СH CH , J 7.4), 1.28–1.47 m and 1.74–
1
m (2H, ArH), 7.23–7.35 m (3H, ArH), 12.66 br.s (1H,
f
СООН). Found, %: N 10.79; S 8.27. С H N O S.
2
1
23
3
3
2
2
3
Calculated, %: N 10.57; S 8.06.
(
2 2 2 3
1
.95 m (8H, ОСH СH CH , СH СH СH CH ), 3.94 t
2-[4-Benzyl-5-(4-buthoxyphenyl)-4Н-1,2,4-triazol-
2
2
3
2
2
2
3
(
6
7
2H, ОСH СH CH , J 6.5), 4.06 d. d (1H, SСH, J 7.2,
3-ylsulfanyl]hexanoic acid (IVn). Yield 87%, mp 79–
2
2
3
1
.5), 5.25 s (2H, NCH ), 6.88–6.93 m (2H, ArH),
80°С, R 0.50. H NMR spectrum (300 MHz), δ, ppm
2
f
.39–7.44 m (2H, ArH), 6.94–6.99 m (2H, ArH), 7.21–
(J, Hz): 0.93 t (3H, СH СH СH CH , J 7.0), 0.99 t
2
2
2
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 3 2015

6
26
KALDRIKYAN et al.
1
(
3H, ОСH СH СH CH , J 7.4), 1.30–1.47 m (4H, CH СH ·
R 0.59. H NMR spectrum (300 MHz), δ, ppm (J, Hz):
2
2
2
3
2
2
f
СH CH ), 1.43–1.56 m (2H, ОСH СH СH CH ),
1.04 t (3H, ОСH СH CH , J 7.4), 1.74–1.86 m (2H,
2
3
2
2
2
3
2
2
3
1
.70–1.80 m (2H, ОСH СH СH CH ), 1.79–1.99 m
ОСH СH CH ), 3.27 t (2H, SСH ), 3.72 t.d (2H,
2
2
2
3
2 2 3 2
(
2H, SСHCH ), 3.98 t (2H, ОСH СH СH CH , J 6.4),
СH ОН, J 6.4, 5.7), 3.95 t (2H, ОСH СH CH , J 6.5),
2 2 2 3
2
2
2
2
3
4
6
7
.07 d. d (1H, SСHCH , J 7.3, 6.6), 5.25 s (2H, NCH ),
.91–6.99 m (4H, ArH), 7.22–7.34 m (3H, ArH), 7.41–
.46 m (2H, ArH), 12.59 br.s (1H, СООН). Found, %:
4.74 t (1H, ОН, J 5.7), 5.28 s (2H, NCH ), 6.85–6.90
2
2
2
m (2H, ArH), 7.31–7.35 m (2H, ArH), 7.09–7.13 m
(2H, ArH), 7.18–7.29 m (3H, ArH). Found, %: N
11.57; S 8.86. С H N O S. Calculated, %: N 11.37; S
N 9.45; S 7.27. С H N O S. Calculated, %: N 9.26; S
25
31
3
3
20 23
3
2
7
.06.
8.67.
[4-Benzyl-5-(4-isobuthoxyphenyl)-4Н-1,2,4-triazol-
2-[4-Benzyl-5-(4-isopropoxyphenyl)-4Н-1,2,4-tri-
3
1
-ylsulfanyl]acetic acid (IVo). Yield 98%, mp 155–
azol-3-ylsulfanyl]ethanol (IVs). Yield 67%, mp 102–
1
1
56°С, R 0.58. H NMR spectrum (300 MHz), δ, ppm
103°С, R 0.63. H NMR spectrum (300 MHz), δ, ppm
f
f
(
J, Hz): 1.03 t [6H, СH СH(CH ) , J 6.6], 2.08 m [1H,
(J, Hz): 1.33 d [6H, ОСH(CH ) , J 6.0], 3.25 t (2H,
2
3 2
3 2
СH СH(CH ) , J 6.6], 3.75 d [2H, ОСH СH(CH ) , J
SСH ), 3.74 t.d (2H, СH ОН, J 6.4), 4.61 septet [1H,
2
3 2
2
3 2
2
2
6
.6], 3.95 s (2H, SСН ), 5.25 s (2H, NCH ), 6.88–6.94
ОСH(CH ) , J 6.0], 5.28 s (2H, NCH ), 4.75 t (1H,
2
2
3 2 2
m (2H, ArH), 7.36–7.43 m (2H, ArH), 6.97–7.02 m
2H, ArH), 7.22–7.35 m (3H, ArH), 12.65 br.s (1H,
СООН). Found, %: N 10.78; S 8.29. С H N O S.
ОН, J 5.7), 6.82–6.87 m (2H, ArH), 7.29–7.34 m (2H,
ArH), 7.08–7.12 m (2H, ArH), 7.18–7.29 m (3H, ArH).
Found, %: N 11.64; S 8.95. С H N O S. Calculated,
(
2
1
23
3
3
20 23
3
2
Calculated, %: N 10.57; S 8.06.
%: N 11.37; S 8.67.
-[4-Benzyl-5-(4-buthoxyphenyl)-4Н-1,2,4-triazol-
-ylsulfanyl]ethanol (IVt). Yield 92%, mp 67–68°С,
Substituted 4Н-1,2,4-triazol-3-sulfanylethanols
IVp–IVu) and 4Н-1,2,4-triazol-3-ylsulfanylacet-
2
(
3
1
amides (IVv–IVz'). A mixture of 1.0 mmol of KОН in
0 mL of ethanol, 10 mmol of triazole-3-thiol IIIa–
R 0.60. H NMR spectrum (300 MHz), δ, ppm (J, Hz):
f
2
0
.99 t (3H, ОСH СH СH CH , J 7.3), 1.44–1.56 m
2 2 2 3
IIIf, and 10 mmol of chloroethanol or chloroacetamide
was refluxed for 45–60 min. After cooling, water was
added, and the mixture was left standing overnight.
The formed crystals were filtered off, dried, and
recrystallized from 70% aqueous ethanol.
(
2H, ОСH СH СH CH ), 1.71–1.81 m (2H, ОСH ·
2 2 2 3 2
СH СH CH ), 3.72 t.d (2H, СH ОН, J 6.4), 3.85 s
(
t (1H, ОН, J 5.7), 5.24 s (2H, NCH ), 6.89–6.94 m
2
2
3
2
2H, SСH ), 3.98 t (2H, ОСH СH СH CH , J 6.4), 4.75
2 2 2 2 3
2
(
2H, ArH), 7.38–7.44 m (2H, ArH), 6.99–7.04 m (2H,
ArH), 7.23–7.35 m (3H, ArH). Found, %: N 11.30; S
.54. С H N O S. Calculated, %: N 10.95; S 8.36.
2-[4-Benzyl-5-(4-methoxyphenyl)-4Н-1,2,4-triazol-
8
3
-ylsulfanyl]ethanol (IVр). Yield 63%, mp 177–178°С,
f
21 25
3
2
1
R 0.50. H NMR spectrum (300 MHz), δ, ppm (J, Hz):
2
-[4-Benzyl-5-(4-isobuthoxyphenyl)-4Н-1,2,4-tri-
3
3
.25 t (2H, SСН ), 3.71 t.d (2H, СH ОН, J 6.4, 5.7),
2 2
azol-3-ylsulfanyl]ethanol (IVu). Yield 98%, mp 125–
126°С, R 0.59. H NMR spectrum (300 MHz), δ, ppm
(J, Hz): 1.03 d [6H, ОСH СH(CH ) , J 6.6], 2.08 m
1
.80 s (3H, ОCH ), 4.75 t (1H, ОH, J 5.7), 5.20 s (2H,
3
f
NCH ), 6.87–6.93 m (2H, ArH), 7.38–7.43 m (2H,
2
2
3 2
ArH), 6.96–7.02 m (2H, ArH), 7.22–7.34 m (3H,
[1H, ОСH СH(CH ) , J 6.6], 3.25 t (2H, SСH , J 6.4),
2 3 2 2
ArH). Found, %: N 12.48; S 9.54. С H N O S.
1
8
19
3
2
3.71 t.d (2H, СH ОН, J 6.4, 5.7), 3.75 d [2H, ОСH СH·
(
NCH ), 6.88–6.94 m (2H, ArH) and 7.36–7.43 m (2H,
ArH), 6.97–7.02 m (2H, ArH), 7.22–7.34 m (3H,
ArH). Found, %: N 10.72; S 8.67. С H N O S.
Calculated, %: N 10.95; S 8.36.
2
2
Calculated, %: N 12.30; S 9.39.
-[4-Benzyl-5-(4-ethoxyphenyl)-4Н-1,2,4-triazol-
-ylsulfanyl]ethanol (IVq). Yield 78%, mp 116–117°С,
CH ) , J 6.6], 4.76 t (1H, ОН, J 5.7), 5.20 s (2H,
3 2
2
2
3
1
R 0.55. H NMR spectrum (300 MHz), δ, ppm (J, Hz):
21 25
3
2
f
1
3
7
6
.41 t (3H, ОСH CH , J 7.0), 3.24 t (2H, SСН , J 6.4),
2 3 2
.71 t.d (2H, СH ОН, J 6.4), 4.06 q (2H, ОСH CH , J
2
2
3
[
4-Benzyl-5-(4-methoxyphenyl)-4Н-1,2,4-triazol-
.0), 4.75 t (1H, ОН, J 5.7), 5.20 s (2H, NCH ), 6.88–
2
3
2
(
(
(
-ylsulfanyl]acetamide (IVv). Yield 70%, mp 201–
.93 m (2H, ArH), 7.38–7.43 m (2H, ArH), 6.96–7.02
1
02°С, R 0.62. H NMR spectrum (300 MHz), δ, ppm
f
m (2H, ArH), 7.23–7.34 m (3H, ArH). Found, %: N
J, Hz): 3.83 s (3H, ОCH ), 3.85 s (2H, SСН ), 5.25 s
3 2
1
9
1.64; S 8.82. С H N O S. Calculated, %: N 11.82; S
19 21 3 2
2H, NCH ), 6.92–7.05 m (4H, ArH), 7.23–7.35 m
2
.02.
-[4-Benzyl-5-(4-propoxyphenyl)-4Н-1,2,4-triazol-
-ylsulfanyl]ethanol (IVr). Yield 98%, mp 89–90°С,
3H, ArH), 7.41–7.46 m (2H, ArH), 6.95 br.s and 7.54
2
br.s (2H, NH2). Found, %: N 15.62; S 9.26. С18H N O S.
Calculated, %: N 15.80; S 9.04.
18 4 2
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 3 2015

SYNTHESIS OF NEW 4,5-SUBSTITUTED 4H-1,2,4-TRIAZOLE-3-THIOLS
627
[
4-Benzyl-5-(4-ethoxyphenyl)-4Н-1,2,4-triazol-3-
ОСH
2
СH
2
СH
2
CH
3
, J 6.4), 5.24 s (2H, NCH
2
), 6.89–
ylsulfanyl]acetamide (IVw). Yield 83%, mp 164–
6.94 m (2H, ArH), 7.39–7.44 m (2H, ArH), 6.99–7.04
m (2H, ArH), 7.23–7.35 m (3H, ArH), 6.94 br.s and
1
1
65°С, R 0.70. H NMR spectrum (300 MHz), δ, ppm
f
(
J, Hz): 1.41 t (3H, ОСH CH , J 7.0), 3.85 s (2H,
7.54 br.s (2H, NH ). Found, %: N 14.35; S 8.41.
2
3
2
SСН ), 4.06 q (2H, ОСH CH , J 7.0), 5.24 s (2H,
С H N O S. Calculated, %: N 14.13; S 8.08.
2
2
3
21 24
4
2
NCH ), 6.89–6.94 m (2H, ArH), 7.39–7.44 m (2H,
ArH), 6.99–7.04 m (2H, ArH), 7.23–7.35 m (3H,
2
[4-Benzyl-5-(4-isobuthoxyphenyl)-4Н-1,2,4-triazol-
ArH), 6.96 br.s and 7.55 br.s (2H, NH ). Found, %: N
3-ylsulfanyl]acetamide (IVz'). Yield 73%, mp 137–
2
1
1
8
5.45; S 8.82. С H N O S. Calculated, %: N 15.20; S
.70.
138°С, R
f
0.58. H NMR spectrum (300 MHz), δ, ppm
1
9
20
4
2
(J, Hz): 1.03 d [6H, ОСH
СH(CH ) , J 6.6], 2.07 m
3 2
2
[
[
1H, ОСH СH(CH ) , J 6.6], 3.25 s (2H, SСH ), 3.74 d
2
3 2
2
[
4-Benzyl-5-(4-propoxyphenyl)-4Н-1,2,4-triazol-
2H, ОСH СH(CH ) , J 6.6], 5.24 s (2H, NCH ), 6.89–
2
3 2
2
3
1
(
(
-ylsulfanyl]acetamide (IVx). Yield 90%, mp 135–
36°С, R 0.58. H NMR spectrum (300 MHz), δ, ppm
J, Hz): 0.92 t (3H, ОСH СH CH , J 7.4), 1.74–1.86 m
2H, ОСH СH CH ), 3.86 s (2H, SСH ), 3.94 t (2H,
1
6.94 m (2H, ArH), 7.36–7.44 m (2H, ArH), 6.99–7.04
m (2H, ArH), 7.23–7.35 m (3H, ArH), 6.94 br.s and
7
f
2 2 3
.54 br.s (2H, NH ). Found, %: N 14.38; S 7.55.
2
2
2
3
2
С H N O S. Calculated, %: N 14.13; S 8.08.
2
1
24
4
2
ОСH СH CH , J 6.5), 5.28 s (2H, NCH ), 6.85–6.94 m
2
2
3
2
(
2H, ArH), 7.31–7.34 m (2H, ArH), 7.09–7.13 m (2H,
ArH), 7.18–7.29 m (3H, ArH), 6.96 br.s and 7.55 br.s
2H, NH ). Found, %: N 14.48; S 8.65. С H N O S.
REFERENCES
(
2
20 22
4
2
1
. Kaldrikyan, M.A., Grigoryan, L.A., and Melik-
Ogandzhanyan, R.G., Globus Nauki, 2007, vol. 7, p. 27;
Kaldrikyan, M.A., Grigoryan, L.A., and Melik-
Ogandzhanyan, R.G., Globus Nauki, 2008, vol. 8, p. 9.
Calculated, %: N 14.64; S 8.38.
[4-Benzyl-5-(4-isopropoxyphenyl)-4Н-1,2,4-triazol-
3
1
(
-ylsulfanyl]acetamide (IVy). Yield 80%, mp 171–
1
72°С, R 0.59. H NMR spectrum (300 MHz), δ, ppm
2. Kaldrikyan,
M.A.,
Grigoryan,
L.A.,
Melik-
f
Ogandzhanyan, R.G., and Arsenyan, F.G., Pharm.
Chem. J., 2009, vol. 43, no. 5, p. 252.
J, Hz): 1.33 d [6H, ОСH(CH ) , J 6.0], 3.85 s (2H,
3 2
SСH ), 4.61 septet [1H, ОСH(CH ) , J 6.0], 5.25 s
(
(
ArH), 6.94 br.s and 7.54 br.s (2H, NH ). Found, %: N
1
8
2
3 2
3
4
5
. Kaldrikyan,
M.A.,
Grigoryan,
L.A.,
Melik-
2H, NCH ), 6.89–6.94 m (2H, ArH), 7.32–7.34 m
2
Ogandzhanyan, R.G., and Arsenyan, F.G., Pharm.
Chem. J., 2011, vol. 45, no. 4, p. 211.
2H, ArH), 6.99–7.04 m (2H, ArH), 7.23–7.35 m (3H,
2
. Grigoryan,
L.A.,
Kaldrikyan,
M.A.,
Melik-
4.72; S 8.58. С H N O S. Calculated, %: N 14.64; S
20 22 4 2
Ogandzhanyan, R.G., and Arsenyan, F.G., Pharm.
Chem. J, 2012, vol. 46, no. 7, p. 402.
. Kaldrikyan, M.A., Melik-Ogandzhanyan, R.G., and
Arsenyan, F.G., Pharm. Chem. J., 2013, vol. 47, no. 4,
p. 191.
.38.
4-Benzyl-5-(4-buthoxyphenyl)-4Н-1,2,4-triazol-
[
3
1
-ylsulfanyl]acetamide (IVz). Yield 85%, mp 119–
1
20°С, R 0.60. H NMR spectrum (300 MHz), δ, ppm
f
(
1
J, Hz): 0.99 t (3H, ОСH СH СH CH , J 7.3), 1.44–
.56 m (2H, ОСH СH СH CH ), 1.71–1.81 m (2H,
2 2 2 3
2 2 2 3
6. Kaldrikyan, M.A., Minasyan, N.S., and Melik-
Ogandzhanyan, R.G., Russ. J. Org. Chem., 2013,
vol. 49, no. 10, p. 1550.
ОСH СH СH CH ), 3.85 s (2H, SСH ), 3.98 t (2H,
2
2
2
3
2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 3 2015