Synthesis of 1,2,4-triazole-3-thiols and their S-substituted derivatives

Article abstract of DOI:10.1134/S1070428010040184

New 1,2,4-triazole-3-thiols were synthesized by reactions of the corresponding carboxylic acid hydrazides with isothiocyanates and subsequent cyclization of intermediate 1,4-substituted thiosemicarbazides. Alkylation of 1,2,4-triazole-3-thiols with benzyl

Full text of DOI:10.1134/S1070428010040184

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 4, pp. 551–555. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © T.V. Kochikyan, M.A. Samvelyan, V.S. Arutyunyan, A.A. Avetisyan, R.A. Tamazyan, A.G. Aivazyan, 2010, published in Zhurnal
Organicheskoi Khimii, 2010, Vol. 46, No. 4, pp. 560–564.
Synthesis of 1,2,4-Triazole-3-thiols and Their
S-Substituted Derivatives
T. V. Kochikyana, M. A. Samvelyana, V. S. Arutyunyana, A. A. Avetisyan†a,
R. A. Tamazyanb, and A. G. Aivazyanb
a Erevan State University, ul. Aleka Manukyana 1, Erevan, 375025 Armenia
e-mail: melan29@rambler.ru
b Molecular Structure Research Center, Scientific–Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia, pr. Azatutyan 26, Erevan, 375014 Armenia
Received March 24, 2009
Abstract—New 1,2,4-triazole-3-thiols were synthesized by reactions of the corresponding carboxylic acid
hydrazides with isothiocyanates and subsequent cyclization of intermediate 1,4-substituted thiosemicarbazides.
Alkylation of 1,2,4-triazole-3-thiols with benzyl chlorides and bromacetophenones gave only S-substituted
derivatives.
DOI: 10.1134/S1070428010040184
Biological studies on synthetic analogs of naturally
occurring heterocyclic compounds showed that most of
them exhibit a broad spectrum of biological activity.
Among compounds of this series, of particular interest
are 1,2,4-triazoles which are mostly of synthetic origin.
Some 1,2,4-triazole derivatives exhibit hypotensive ef-
fect [1] and possess antitumor [2], fungicidal [3], anti-
bacterial [4], and other kinds of biological activity.
sulfur atom seemed to be promising. For instance,
biological effects of compounds possessing free and
substituted thiol groups could be compared.
3,4-Disubstituted 1,2,4-triazole-3-thiols IIIa–IIIe were
subjected to alkylation with various halogen deriva-
tives, specifically with substituted benzyl chlorides and
bromoacetophenones (Scheme 2). The optimal condi-
tions for the alkylation with benzyl chlorides included
the use of anhydrous acetone as solvent and anhydrous
potassium carbonate as base and prolonged heating
(10 h). The reactions of III with bromoacetophenones
were complete in 2 h in the absence of a base.
While searching for new useful properties in the
series of 1,2,4-triazoles we synthesized their new
derivatives. Reactions of carboxylic acid hydrazides
Ia–Id with allyl, phenyl, and furfurylmethyl isothio-
cyanates gave 1,4-disubstituted thiosemicarbazides
IIa–IIe. Optimal conditions for this reaction were
found. The best results were obtained by heating the
initial reactants in ethanol for a short time [5]. Com-
pounds IIa–IIe underwent intramolecular cyclization
in alkaline medium to form targeted 3,4-disubstituted
1,2,4-triazole-3-thiols IIIa–IIIe. It is advisable to carry
out this reaction with the use of 10% aqueous sodium
or potassium hydroxide. The cyclization was complete
in 4 h, and compounds IIIa–IIIe were formed in high
yield [6] (Scheme 1).
Scheme 1.
O
O
R2NCS
H
H
R1
NH2
R1
N
N
N
N
R2
H
H
S
Ia–Id
IIa–IIe
N
N
R1
OH–
SH
N
R2
IIIa–IIIe
From the viewpoint of biological activity, synthesis
of 1,2,4-triazole-3-thiol derivatives substituted at the
I, R1 = 2,4-Cl2C6H3O (a), 4-Cl-2-MeC6H3O (b), PhO (c),
i-Pr (d); II, III, R1 = 2,4-Cl2C6H3O, R2 = CH2=CHCH2 (a),
Ph (b); R1 = 4-Cl-2-MeC6H3O, R2 = CH2=CHCH2 (c); R1 =
PhO, R2 = Ph (d); R1 = i-Pr, R2 = 2-furylmethyl (e).
†
Deceased.
551

KOCHIKYAN et al.
lizing effect on red blood cell membranes. Compound
552
Scheme 2.
N
N
IIIe showed no stabilizing effect under analogous con-
ditions, presumably due to the presence of free thiol
group in its molecule.
R1
R3CH2Cl
R3
S
N
R2
IVa–IVf
EXPERIMENTAL
IIIa–IIIe
N
N
R3
The IR spectra were recorded on a Nicolet FTIR
Nexus spectrometer from samples dispersed in mineral
oil. The H NMR spectra were measured on a Varian
Mercury-300 spectrometer (300 MHz) using CDCl3 as
solvent. Thin-layer chromatography was performed on
Silufol UV-254 plates; spots were visualized by treat-
ment with iodine vapor. The melting points were deter-
mined on a Boetius melting point apparatus. Initial
carboxylic acid hydrazides Ia–Ie were synthesized
according to the procedure described in [8].
R1
R3COCH2Br
S
N
1
O
R2
Va–Vd
IV, R1 = 2,4-Cl2C6H3O, R2 = Ph, R3 = 3,4-Cl2C6H3 (a),
2,4-Cl2C6H3 (b); R1 = 4-Cl-2-MeC6H3O, R2 = CH2=CHCH2,
R3 = 2,4-Cl2C6H3 (c); R1 = i-Pr, R2 = 2-furylmethyl, R3 =
2,4-Cl2C6H3 (d); R1 = PhO, R2 = Ph, R3 = 2,4-Cl2C6H3 (e),
3,4-Cl2C6H3 (f); V, R1 = 2,4-Cl2C6H3O, R2 = Ph, R3 = Ph (a),
4-O2NC6H4 (b); R1 = PhO, R2 = R3 = Ph (c), R2 = Ph, R3 =
4-O2NC6H4 (d).
X-Ray analysis of 3-(2,4-dichlorobenzylsulfanyl)-
4-(2-furylmethyl)-5-isobutyl-4H-1,2,4-triazole
(IVd). The unit cell parameters (monoclinic crystal
system) were measured on an Enraf–Nonius CAD-4
automatic diffractometer at room temperature and were
refined by 22 reflections (spherical segment 10° < θ <
13°): a = 18.897(4), b = 5.939(1), c = 17.134(3) Å; β =
98.25(3)°; V = 1902.9(7) Å3; Z = 4; space group P21/c
The X-ray diffraction data were acquired using the
same instrument. Intensities of 11489 reflections were
measured in the range 0 ≤ h ≤ 24, –8 ≤ k ≤ 8, –26 ≤
l ≤ 26, θmax = 30° (MoKα irradiation, graphite mono-
chromator). All calculations were performed using
SHELXTL software package [9]. Averaging of sym-
metry-equivalent reflections left an array consisting of
5562 nonequivalent reflections (R = 0.08), 2719 of
which were characterized by I > 2σ(I). The structure
was solved by the direct method; the coordinates of
hydrogen atoms were determined from the Fourier
difference syntheses. The structure was refined by the
full-matrix least-squares procedure in anisotropic ap-
proximation for non-hydrogen atoms and isotropic
approximation for hydrogen atoms; the final diver-
gence factor was R = 0.062, S = 1.008.
We previously found [7] that 1,2,4-triazole-3-thiols
in solution give rise to thione–thiol tautomeric equilib-
rium; therefore, the alkylation may involve both endo-
cyclic nitrogen atom and exocyclic sulfur atom with
formation of N- and S-substituted isomers. We exam-
ined alkylation of compounds III in different solvents,
such as acetonitrile, acetone, and aqueous acetone. In
all cases, the products obtained under different condi-
tions were identical (no depression of the melting point
was observed on mixing). The structure of compound
IVd as S-substituted 1,2,4-triazole-3-thiol was unam-
biguously proved by X-ray analysis (see figure).
Preliminarily tests of compounds IIIe and IVd for
antioxidant activity revealed that the latter exerts stabi-
Cl15
C10
C9
N1
C3
N2
C11
C12
C8
C22
C24
C7
C4
S6
C13
N4
C23
C25
Cl14
C16
1,4-Disubstituted tiosemicarbazides IIa–IIe (gen-
eral procedure). A solution of 0.06 mol of allyl,
phenyl, or 2-furylmethyl isothiocyanate in 30 ml of
ethanol was added to a solution of 0.06 mol of car-
boxylic acid hydrazide Ia–Id in 30 ml of ethanol. The
mixture was thoroughly mixed, left to stand for 1 h at
room temperature, and heated for 2 h under reflux.
After cooling, the precipitate was filtered off, dried,
and recrystallized from ethanol or aqueous ethanol.
C21
C17
C18
C20
C19
Structure of the molecule of 3-(2,4-dichlorobenzylsulfanyl)-
4-(2-furylmethyl)-5-isobutyl-4H-1,2,4-triazole (IVd) accord-
ing to the X-ray diffraction data.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 4 2010

SYNTHESIS OF 1,2,4-TRIAZOLE-3-THIOLS AND THEIR S-SUBSTITUTED DERIVATIVES
553
4-Allyl-1-(2,4-dichlorophenoxyacetyl)thiosemi-
carbazide (IIa). Yield 97%, mp 162–164°C (from
ethanol–water, 1:3), Rf 0.59 (ethanol–benzene, 1:5).
IR spectrum, ν, cm–1: 3200–3300 (NH), 3050
(C–Harom), 1680 (C=O), 1640 (C=C), 1600, 1610
ethanol–water, 1:1), Rf 0.50 (ethanol–benzene, 1:5).
IR spectrum, ν, cm–1: 3190–3280 (NH), 3050
(C–Harom), 1690 (C=O), 1650 (C=C), 1215 (COC).
1H NMR spectrum, δ, ppm: 0.90 t (6H, CH3), 1.95 q
[1H, CH(CH3)2], 2.15 d (2H, CH2CO), 5.40 d (2H,
NHCH2), 6.30 s (1H, =CH), 6.45 s (1H, =CH), 7.60 s
(1H, =CH), 8.45 t (1H, NHCH2), 8.50 s (1H, NH),
9.55 s (1H, NH). Found, %: C 51.85; H 6.45; N 16.60;
S 12.45. C11H17N3O2S. Calculated, %: C 51.77;
H 6.67; N 16.47; S 12.55.
1
(C=Carom), 1210 (COC), 720 (C–Cl). H NMR spec-
trum, δ, ppm: 4.15 s (2H, NCH2), 4.65 s (2H, OCH2),
5.20 d and 5.25 d (1H each, =CH2), 5.90 q (1H, =CH),
7.10 m (1H, Harom), 7.25 m (1H, Harom), 7.55 m (1H,
Harom), 9.40 s (2H, NH), 9.90 s (1H, NH). Found, %:
C 43.25; H 3.75; Cl 21.35; N 12.70; S 9.45.
C12H13Cl2N3O2S. Calculated, %: C 43.11; H 3.89;
Cl 21.26; N 12.57; S 9.58.
4,5-Disubstituted 4H-1,2,4-triazole-3-thiols IIIa–
IIIe (general procedure). 1,4-Disubstituted thiosemi-
carbazide, 0.04 mol, was dissolved in a solution of
3.4 g (0.06 mol) of potassium hydroxide in 30.6 ml of
water, the mixture was heated for 4 h on a boiling
water bath, cooled, and acidified with dilute (1 :1)
hydrochloric acid to pH 2–3, and the precipitate was
filtered off, washed with water, dried, and recrystal-
lized from appropriate solvent.
1-(2,4-Dichlorophenoxyacetyl)-4-phenylthiosemi-
carbazide (IIb). Yield 91%, mp 159–160°C (from
ethanol–water, 1:3), Rf 0.65 (ethanol–benzene, 1:5).
IR spectrum, ν, cm–1: 3200–3300 (NH), 3080
(C–Harom), 1690 (C=O), 1600 (C=Carom), 1210 (COC),
1
720 (C–Cl). H NMR spectrum, δ, ppm: 4.70 s (2H,
4-Allyl-5-(2,4-dichlorophenoxymethyl)-4H-1,2,4-
triazole-3-thiol (IIIa). Yield 86%, mp 140°C (from
ethanol–water, 2:1), Rf 0.60 (ethanol–benzene, 1:6).
IR spectrum, ν, cm–1: 3050 (C–Harom), 2740 (SH), 1640
(C=C), 1610, 1600 (C=Carom), 1540 (C=N), 1210
(COC), 720 (C–Cl). 1H NMR spectrum, δ, ppm: 5.00 d
(2H, NCH2), 5.25 d (1H, =CH2), 5.35 d (2H, OCH2),
5.45 d (1H, =CH2), 6.10 q (1H, =CH), 7.35 m (1H,
OCH2), 7.20–7.40 m and 7.60 m (8H, Harom), 9.10 s
(1H, NH), 9.30 m (2H, NH). Found, %: C 48.55;
H 3.45; Cl 19.25; N 11.45; S 8.55. C15H13Cl2N3O2S.
Calculated, %: C 48.65; H 3.51; Cl 19.19; N 11.35;
S 8.65.
4-Allyl-1-(4-chloro-2-methylphenoxyacetyl)thio-
semicarbazide (IIc). Yield 80%, mp 174–175°C (from
ethanol), Rf 0.54 (etanol–benzene, 1:5). IR spectrum,
ν, cm–1: 3200–3300 (NH), 3080 (C–Harom), 1690
(C=O), 1645 (C=C), 1600 (C=Carom), 1200 (COC), 750
Harom), 7.45 m (1H, Harom), 7.50 m (1H, Harom), 13.90 s
(1H, SH). Found, %: C 45.65; H 3.30; Cl 22.35;
N 13.40; S 10.20. C12H11Cl2N3OS. Calculated, %:
C 45.57; H 3.48; Cl 22.47; N 13.29; S 10.13.
1
(C–Cl). H NMR spectrum, δ, ppm: 2.25 s (3H, CH3),
4.15 d (2H, NCH2), 4.60 s (2H, OCH2), 5.20 d and
5.25 d (1H each, =CH2), 5.85 q (1H, =CH), 6.90 m
(1H, Harom), 7.20 m (1H, Harom), 7.35 m (1H, Harom),
9.30 s (2H, NH), 9.85 s (1H, NH). Found, %: C 49.90;
H 5.00; Cl 11.45; N 13.50; S 10.10. C13H16ClN3O2S.
Calculated, %: C 49.76; H 5.10; Cl 11.32; N 13.40;
S 10.21.
5-(2,4-Dichlorophenoxymethyl)-4-phenyl-4H-
1,2,4-triazole-3-thiol (IIIb). Yield 93%, mp 191–
192°C (from ethanol–water, 5:1), Rf 0.66 (ethanol–
benzene, 1:6). IR spectrum, ν, cm–1: 3080 (C–Harom),
2750 (SH), 1610, 1600 (C=Carom), 1545 (C=N), 1210
(COC), 720 (C–Cl). 1H NMR spectrum, δ, ppm: 5.10 s
(2H, OCH2), 7.30 m (1H, Harom), 7.45 m (2H, Harom),
7.55 m (2H, Harom), 7.60 m (3H, Harom), 13.95 s (1H,
SH). Found, %: C 51.25; H 3.05; Cl 20.30; N 12.05;
S 8.95. C15H11Cl2N3OS. Calculated, %: C 51.14;
H 3.13; Cl 20.17; N 11.93; S 9.09.
1-Phenoxyacetyl-4-phenylthiosemicarbazide
(IId). Yield 95%, mp 133–134°C (from ethanol),
Rf 0.66 (ethanol–benzene, 1:5). IR spectrum, ν, cm–1:
3180–3300 (NH), 3050 (C–Harom), 1690 (C=O), 1610
1
(C=Carom), 1180 (COC). H NMR spectrum, δ, ppm:
4-Allyl-5-(4-chloro-2-methylphenoxymethyl)-4H-
1,2,4-triazole-3-thiol (IIIc). Yield 89%, mp 114–
115°C (from ethanol–water, 2:1), Rf 0.64 (ethanol–
benzene, 1:6). IR spectrum, ν, cm–1: 3080 (C–Harom),
2750 (SH), 1640 (C=C), 1600 (C=Carom), 1540 (C=N),
4.60 s (2H, OCH2), 6.80 m (1H, Harom), 6.95 m (2H,
Harom), 7.00 m (1H, Harom), 7.20 m (2H, Harom), 7.35 m
(2H, Harom), 7.70 m (2H, Harom), 9.45 s (2H, NH),
10.15 s (1H, NH). Found, %: C 59.95; H 4.85;
N 14.05; S 10.75. C15H15N3O2S. Calculated, %:
C 59.80; H 4.98; N 13.95; S 10.63.
1
1200 (COC), 750 (C–Cl). H NMR spectrum, δ, ppm:
2.10 s (3H, CH3), 5.00 d (2H, NCH2), 5.25 d (2H,
OCH2), 5.20 d and 5.40 d (1H each, =CH2), 6.00 q
(1H, =CH), 6.85 m (1H, Harom), 7.20 m (1H, Harom),
4-(2-Furylmethyl)-1-(3-methyl-1-oxobutyl)thio-
semicarbazide (IIe). Yield 83%, mp 153–154°C (from
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KOCHIKYAN et al.
554
7.35 m (1H, Harom), 13.85 s (1H, SH). Found, %:
C 52.90; H 4.60; Cl 12.15; N 14.35; S 10.70.
C13H14ClN3OS. Calculated, %: C 52.79; H 4.74;
Cl 12.01; N 14.21; S 10.83.
Yield 80%, mp 126–127°C (from ethanol), Rf 0.60
(ethanol–benzene, 1:5). IR spectrum, ν, cm–1: 3080,
3050 (C–Harom), 1610, 1600 (C=Carom), 1540 (C=N),
1
1210 (COC), 720 (C–Cl). H NMR spectrum, δ, ppm:
4.45 s (2H, SCH2), 5.10 s (2H, OCH2), 7.20 m (4H,
5-Phenoxymethyl-4-phenyl-4H-1,2,4-triazole-3-
thiol (IIId). Yield 96%, mp 170–172°C (from ethanol–
water, 2:1), Rf 0.58 (ethanol–benzene, 1:6). IR spec-
trum, ν, cm–1: 3050 (C–Harom), 2750 (SH), 1610
Harom), 7.30 m (2H, Harom), 7.60 m (4H, Harom), 7.70 m
(1H, Harom). Found, %: C 51.50; H 3.05; Cl 27.65;
N 8.30; S 6.35. C22H15Cl4N3OS. Calculated, %:
C 51.66; H 2.94; Cl 27.79; N 8.23; S 6.26.
1
(C=Carom), 1550 (C=N), 1180 (COC). H NMR spec-
4-Allyl-3-(4-chloro-2-methylphenoxymethyl)-5-
(2,4-dichlorobenzylsulfanyl)-4H-1,2,4-triazole
(IVc). Yield 85%, mp 85°C (from hexane), Rf 0.61
(ethanol–benzene, 1:6). IR spectrum, ν, cm–1: 3080,
3050 (C–Harom), 1640 (C=C), 1610 (C=Carom), 1540
trum, δ, ppm: 5.25 s (2H, OCH2), 6.85 m (3H, Harom),
7.00 m (1H, Harom), 7.20 m (2H, Harom), 7.45 m (2H,
Harom), 7.50 m (2H, Harom), 13.95 s (1H, SH). Found,
%: C 63.50; H 4.70; N 14.95; S 11.20. C15H13N3OS.
Calculated, %: C 63.60; H 4.59; N 14.84; S 11.31.
1
(C=N), 1180 (COC), 750 (C–Cl). H NMR spectrum,
4-(2-Furylmethyl)-5-isobutyl-4H-1,2,4-triazole-
3-thiol (IIIe). Yield 73%, mp 135–136°C (from
ethanol–water, 1:3), Rf 0.67 (ethanol–benzene, 1:6).
IR spectrum, ν, cm–1: 3080 (C–H), 2740 (SH), 1650
δ, ppm: 2.15 s (3H, CH3), 4.45 s (2H, SCH2), 4.55 s
(2H, OCH2), 4.90 d and 5.15 d (1H each, CH2=), 5.20 s
(2H, CH2CH=), 5.90 m (1H, CH=), 7.10 m (4H,
Harom), 7.40 m (2H, Harom). Found, %: C 52.95; H 3.85;
Cl 23.30; N 9.30; S 7.15. C20H18Cl3N3OS. Calculated,
%: C 52.81; H 3.96; Cl 23.43; N 9.24; S 7.04.
1
(C=C), 1550 (C=N), 1215 (COC). H NMR spectrum,
δ, ppm: 0.95 d (6H, CH3), 1.85 m [1H, CH(CH3)2],
2.60 d (2H, CHCH2), 4.75 s (2H, CH2N), 6.00 d (1H,
CH=), 6.45 d (1H, CH=), 7.50 t (1H, CH=), 13.25 s
(1H, SH). Found, %: C 55.80; H 6.15; N 17.01;
S 13.40. C11H15N3OS. Calculated, %: C 55.70; H 6.33;
N 17.72; S 13.50.
3-(2,4-Dichlorobenzylsulfanyl)-4-(2-furylmeth-
yl)-5-isobutyl-4H-1,2,4-triazole (IVd). Yield 69%,
mp 69–70°C (from hexane), Rf 0.52 (ethanol–benzene,
1:6). IR spectrum, ν, cm–1: 3080 (C–Harom), 3050
(C–H), 1650 (C=C), 1610, 1600 (C=Carom), 1550
3-Benzylsulfanyl-1,2,4-triazoles IVa–IVf (general
procedure). Anhydrous potassium carbonate, 0.7 g,
was added to a mixture of 5 mmol of 3,4-disubstituted
1,2,4-triazole-3-thiol III and 5 mmol of the corre-
sponding substituted benzyl chloride in 20 ml of anhy-
drous acetone. The mixture was heated for 10 h under
reflux and evaporated, the residue was cooled, treated
with 30 ml of water, and extracted with 70 ml of
diethyl ether, the extract was washed with water and
dried over anhydrous magnesium sulfate, the solvent
was removed, and the crystalline residue was purified
by recrystallization.
1
(C=N), 1215 (COC), 720 (C–Cl). H NMR spectrum,
δ, ppm: 0.90 s (6H, CH3), 1.80 m [1H, CH(CH3)2],
2.50 d (2H, CHCH2), 4.50 s (2H, SCH2), 4.85 s (2H,
NCH2), 6.00 s (1H, CH=), 6.40 s (1H, CH=), 7.10 m
(1H, C6H3), 7.25 m (1H, C6H3), 7.60 s (1H, CH=),
7.70 m (1H, C6H3). Found, %: C 54.45; H 4.90;
Cl 17.80; N 10.20; S 7.95. C18H19Cl2N3OS. Calculated,
%: C 54.55; H 4.80; Cl 17.93; N 10.61; S 8.08.
3-(2,4-Dichlorobenzylsulfanyl)-5-phenoxy-
methyl-4-phenyl-4H-1,2,4-triazole (IVe). Yield 88%,
mp 108–109°C (from ethanol–water, 10:1), Rf 0.64
(ethanol–benzene, 1:6). IR spectrum, ν, cm–1: 3080,
3050 (C–Harom), 1610, 1600 (C=Carom), 1550 (C=N),
3-(3,4-Dichlorobenzylsulfanyl)-5-(2,4-dichloro-
phenoxymethyl)-4-phenyl-4H-1,2,4-triazole (IVa).
Yield 75%, mp 75–76°C (from hexane), Rf 0.57
(ethanol–benzene, 1:6). IR spectrum, ν, cm–1: 3080,
3050 (C–Harom), 1610, 1600 (C=Carom), 1545 (C=N),
1
1180 (COC), 720 (C–Cl). H NMR spectrum, δ, ppm:
4.40 s (2H, SCH2), 5.05 s (2H, OCH2), 7.00 m (2H,
Harom), 7.05 m (1H, Harom), 7.15 m (1H, Harom), 7.30 m
(1H, Harom), 7.35 m (2H, Harom), 7.50–7.70 m (6H,
Harom). Found, %: C 59.65; H 4.00; Cl 16.20; N 9.60;
S 7.15. C22H17Cl2N3OS. Calculated, %: C 59.73;
H 3.85; Cl 16.06; N 9.50; S 7.24.
1
1210 (COC), 720 (C–Cl). H NMR spectrum, δ, ppm:
4.00 s (2H, SCH2), 5.05 s (2H, OCH2), 6.90 m (3H,
Harom), 7.20 m (2H, Harom), 7.30 m (1H, Harom), 7.60 m
(4H, Harom), 7.70 m (1H, Harom). Found, %: C 51.80;
H 2.80; Cl 27.90; N 8.35; S 6.15. C22H15Cl4N3OS. Cal-
culated, %: C 51.66; H 2.94; Cl 27.79; N 8.23; S 6.26.
3-(3,4-Dichlorobenzylsulfanyl)-5-phenoxy-
methyl-4-phenyl-4H-1,2,4-triazole (IVf). Yield 80%,
mp 126–127°C (from ethanol), Rf 0.60 (ethanol–ben-
zene, 1 : 6). IR spectrum, ν, cm–1: 3050, 3080
(C–Harom), 1600, 1615 (C=Carom), 1550 (C=N), 1180
3-(2,4-Dichlorobenzylsulfanyl)-5-(2,4-dichloro-
phenoxymethyl)-4-phenyl-4H-1,2,4-triazole (IVb).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 4 2010

SYNTHESIS OF 1,2,4-TRIAZOLE-3-THIOLS AND THEIR S-SUBSTITUTED DERIVATIVES
555
(COC), 730 (C–Cl). 1H NMR spectrum, δ, ppm: 4.40 s
(2H, SCH2), 5.00 s (2H, OCH2), 6.90 m (3H, Harom),
7.20 m (2H, Harom), 7.30 m (4H, Harom), 7.50 m (4H,
Harom). Found, %: C 59.85; H 3.70; Cl 16.15; N 9.65;
S 7.15. C22H17Cl2N3SO. Calculated, %: C 59.73;
H 3.85; Cl 16.06; N 9.50; S 7.24.
mp 80–51°C (from ethanol), Rf 0.60 (ethanol–benzene,
1:6). IR spectrum, ν, cm–1: 3050 (C–Harom), 1730
(C=O), 1600 (C=Carom), 1540 (C=N), 1200 (COC).
1H NMR spectrum, δ, ppm: 4.95 s (2H, SCH2), 5.20 s
(2H, OCH2), 7.20 m (2H, Harom), 7.30 m (3H, Harom),
7.45–7.60 m (8H, Harom), 8.05 m (2H, Harom). Found,
%: C 68.55; H 4.65; N 10.65; S 7.85. C23H19N3O2S.
Calculated, %: C 68.83; H 4.74; N 10.47; S 7.98.
3-(Phenacylsulfanyl)-4H-1,2,4-triazoles Va–Vd
(general procedure). A mixture of 5 mmol of 3,4-di-
substituted 1,2,4-triazole-3-thiol IIIb or IIId and
5 mmol of bromoacetophenone or 4-nitro-ω-bromo-
acetophenone in 15 ml of anhydrous acetone was
stirred for 0.5 h at room temperature and for 2 h on
heating under reflux. The solvent was removed, the
residue was cooled, treated with water, and made
alkaline by adding aqueous ammonia to pH 8–9, and
the precipitate was filtered off, washed with water,
dried, and recrystallized.
1-(4-Nitrophenyl)-2-[5-(phenoxymethyl)-4-
phenyl-4H-1,2,4-triazol-3-ylsulfanyl]ethanone (Vd).
Yield 95%, mp 195–196°C (from ethanol), Rf 0.71
(ethanol–benzene, 1:6). IR spectrum, ν, cm–1: 3080,
3050 (C–Harom), 1735 (C=O), 1610, 1600 (C=Carom),
1540 (C=N), 1200 (COC). 1H NMR spectrum, δ, ppm:
4.85 s (2H, SCH2), 5.40 s (2H, OCH2), 6.95 m and
7.00–7.05 m (3H, Harom), 7.30–7.50 m (5H, Harom),
7.55–7.64 m (4H, Harom), 7.94 m (2H, Harom). Found,
%: C 61.95; H 3.95; N 12.65; S 7.00. C23H18N4O4S.
Calculated, %: C 61.88; H 4.04; N 12.56; S 7.18.
2-[5-(2,4-Dichlorophenoxymethyl)-4-phenyl-4H-
1,2,4-triazol-3-ylsulfanyl]-1-phenylethanone (Va).
Yield 79%, mp 157–158°C (from ethanol), Rf 0.63
(ethanol–benzene, 1:4). IR spectrum, ν, cm–1: 3080,
3050 (C–Harom), 1730 (C=O), 1600, 1610 (C=Carom),
1540 (C=N), 1210 (COC), 720 (C–Cl). 1H NMR spec-
trum, δ, ppm: 4.90 s (2H, SCH2), 5.15 s (2H, OCH2),
7.20 m (2H, Harom), 7.30 m (1H, Harom), 7.45–7.60 m
(8H, Harom), 8.05 m (2H, Harom). Found, %: C 58.85;
H 3.55; Cl 15.00; N 9.05; S 6.70. C23H17Cl2N3OS. Cal-
culated, %: C 58.72; H 3.62; Cl 15.11; N 8.94; S 6.81.
REFERENCES
1. Arutyunyan, V.S., Kochikyan, T.V., Kovalev, G.V., Buga-
eva, L.I., and Antadze, M.G., Arm. Khim. Zh., 1985,
vol. 38, p. 688.
2. Tehranchian, S., Akbarzadeh, T., Fazeli, M.R., Jama-
lifar, H., and Safiee, A., Bioorg. Med. Chem. Lett., 2005,
vol. 15, p. 1023.
3. Itoh, H., Tanaka, H., Ohta, H., and Takeshiba, H., Chem.
Pharm. Bull., 2001, vol. 49, p. 909.
2-[5-(2,4-Dichlorophenoxymethyl)-4-phenyl-4H-
1,2,4-triazol-3-ylsulfanyl]-1-(4-nitrophenyl)etha-
none (Vb). Yield 90%, mp 180–181°C (from ethanol),
Rf 0.62 (ethanol–benzene, 1:6). IR spectrum, ν, cm–1:
3080, 3050 (C–Harom), 1735 (C=O), 1650, 1600
(C=Carom), 1545 (C=N), 1210 (COC), 720 (C–Cl).
1H NMR spectrum, δ, ppm: 4.95 s (2H, SCH2), 5.05 s
(2H, OCH2), 7.20 m (2H, Harom), 7.30 m (1H, Harom),
7.45–7.60 m (5H, Harom), 8.30 m (4H, Harom). Found,
%: C 53.65; H 3.05; Cl 13.85; N 10.95; S 6.05.
C23H16Cl2N4O4S. Calculated, %: C 53.59; H 3.11;
Cl 13.79; N 10.87; S 6.21.
4. Demirbaş, N., Uġuruoġlu, R., and Demirbaş, A., Bioorg.
Med. Chem., 2002, vol. 10, p. 3717.
5. Armenian Patent no. 2039; Ofits. Byull. Promyshl. Sobst.,
2007, no. 4, p. 11.
6. Armenian Patent no. 2040; Ofits. Byull. Promyshl. Sobst.,
2007, no. 4, p. 12.
7. Sagiyan, A.S., Manasyan, L.L., Simonyan, A.M., Kochi-
kyan, T.V., Arutyunyan, E.V., Arutyunyan, V.S., and Ave-
tisyan, A.A., Khim. Zh. Arm., 2008, vol. 61, p. 216.
8. Kochikyan, T.V., Arutyunyan, E.V., Arutyunyan, V.S.,
and Avetisyan, A.A., Russ. J. Org. Chem., 2008, vol. 44,
p. 849.
2-[5-(Phenoxymethyl)-4-phenyl-4H-1,2,4-triazol-
3-ylsulfanyl]-1-phenylethanone (Vc). Yield 77%,
9. Sheldrick, G.M., SHELXS97, SHELXL97, Göttingen,
Germany: Univ. of Göttingen, 1997.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 4 2010