Synthesis and reactions of new 4-methoxybenzyland 3-chloro-4-methoxybenzyl- substituted 1,2,4-triazoles and 1,3,4-thiadiazoles

Article abstract of DOI:10.1134/S1070428014050194

Intermolecular cyclization of 1-phenyl(benzyl, allyl)-4-(4-methoxybenzyl- or 3-chloro-4-methoxybenzyl) thiosemicarbazides afforded the corresponding 3,4,5-substituted 4H-1,2,4-triazoles. Reactions of Salkylation and aminomethylation of the latter were exa

Full text of DOI:10.1134/S1070428014050194

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 5, pp. 736–741. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © T.R. Hovsepyan, S.V. Dilanyan, N.S. Minasyan, R.G. Melik-Ohanjanyan, 2014, published in Zhurnal Organicheskoi Khimii, 2014,
Vol. 50, No. 5, pp. 746–751.
Synthesis and Reactions of New 4-Methoxybenzyl-
and 3-Chloro-4-methoxybenzyl-Substituted
1,2,4-Triazoles and 1,3,4-Thiadiazoles
T. R. Hovsepyana, S. V. Dilanyana, N. S. Minasyanb, and R. G. Melik-Ohanjanyana
a Mndzhoayan Institute of Fine Organic Chemistry, National Academy of Sciences of Armenia,
Azatutyan ave. 26, Yerevan, 0014 Armenia
e-mail: melik@raen.am
b Center of Studies of Molecular Structure, National Academy of Sciences of Armenia, Yerevan, Armenia
Received July 31, 2013
Abstract—Intermolecular cyclization of 1-phenyl(benzyl, allyl)-4-(4-methoxybenzyl- or 3-chloro-4-methoxy-
benzyl)thiosemicarbazides afforded the corresponding 3,4,5-substituted 4Н-1,2,4-triazoles. Reactions of S-
alkylation and aminomethylation of the latter were examined. Some 5-sulfanyl-substituted 1,3,4-thiadiazoles
were also synthesized.
DOI: 10.1134/S1070428014050194
Many compounds containing the five-membered
rings of 1,2,4-triazole and 1,3,4-thiadiazole are known
to find versatile applications due to the wide range of
their biological action, physicochemical and other
properties [1–4]. Sulfanyl-substituted 1,2,4-triazoles
and 1,3,4-thiadiazoles possess antibacterial [5],
antitumor [4, 6], antiviral [7], and other actions. We
formerly reported on the synthesis of a series of 1,2,4-
triazole and 1,3,4-thiadiazole derivatives containing in
their composition pharmacophoric fragments aiming at
the search for new biologically active substances
among them. In particular, compounds were found
with moderate or pronounced hypoglycemic [8, 9],
mutagenic [10], affecting DNA-methylation [11], and
Scheme 1.
X
X
N
N
KOH
CH3O
CH2CNHNHCNHR
CH3O
O
N
R
SH
O
S
IIa_IIf
H
Ia_If
H
HN
O,
R'Hlg
N
X
X
N
O
N
N
N
CH3O
CH3O
N
R
S
N
SR'
R
IVa_IVf
IIIa_IIIp
I, II, IV, X = H, R = Ph (a), Bn (b), All (c); X = Cl, R = Ph (d), Bn (e), All (f); III, X = H: R = Ph, R' = Bn (a), CH2CONH2
(b), CH(C4H9)COOН (c), CH2COOН (d); R = Bn, R' = CH2COOН (e), CH2CH2OН (f), CH2COOC2H5 (g), CH2CONH2 (h); R
= All, R' = CH2CONH2 (i), CH2COOН (j); X = Cl: R = Ph, R' = CH2COOC2H5 (k), CH2CONH2 (l), CH2CH2C6H4-2-Cl (m); R
= Bn, R' = CH2COOН (n), CH2CONH2 (o); R = All, R' = CH2COOC2H5 (p).
736

SYNTHESIS AND REACTIONS OF NEW 4-METHOXYBENZYL-
737
Scheme 2.
N
N
N
N
RHlg
SH
H2SO4
CH3O
CH3O
CH2CNHNHCSK
CH3O
S
SR
S
O
S
VIIa, VIIb
VI
V
R = CH2COOCH3 (a), CH2COOН (b).
antitumor [12, 13] actions. In order to extend the range
of new, more effective derivatives of this class
compounds and for elucidating the dependence
between the structure and biological activity we
developed in this study simple reactions permitting the
introduction of additional pharmacophoric groups and
the preparation of sets of compounds with close
structure (Schemes 1, 2).
Aminomethylation of triazoles IIa–IIf was
performed in the conditions of Mannich reaction using
morpholine as secondary amine in 20% excess.
Crystalline Mannich bases IVa–IVf were isolated after
keeping the reaction mixture at room temperature (20–
25°С) for 10–12 h. The presence of a chlorine atom in
the benzene ring favors the faster aminomethylation
(5–6 h) and higher yields (91–96%) of compounds
IVd–IVf.
Initial compounds were 1,4-substituted thiosemi-
carbazides I obtained in nearly quantitative yields by
the reaction of 4-methoxy-phenyl- and 3-chloro-4-
methoxyphenylacetic acids hydrazides with phenyl,
benzyl, and allyl isothiocyanates in alcohol solution
[8]. The variation of substituents X and R in the
structure of compounds may provide a possibility to
follow the changes in their biologic and physico-
chemical properties. In the synthesis of 4,5-substituted-
1,2,4-triazole-3-thiols IIa–IIf we used the method we
had developed [8–14] consisting in the intramolecular
cyclization of an appropriate thiosemicarbazide I in
4.5% water solution of KОН followed by the
acidification of the reaction mixture with glacial acetic
acid. Triazoles IIa–IIf were isolated as stable colorless
crystalline substances.
Under similar conditions 2-sulfanyl-substituted
1,3,4-thiadiazoles VIIa and VIIb were synthesized
along Scheme 2 proceeding from formerly described
1,3,4-thiadiazole-2-thiol (VI) [17]. The latter was
easily obtained by cyclization of potassium dithio-
carbazinate (V) in the presence of conc. H2SO4.
The purity, homogeneity, and the structure of
compounds synthesized were confirmed by TLC,
elemental analysis, and 1Н NMR spectra.
EXPERIMENTAL
TLC was carried out on Silufol UV-254 plates,
1
development under UV irradiation. H NMR spectra
were registered on a spectrometer Varian Mercury-
300VX at operating frequency 300 MHz from
solutions in DMSO-d6, internal reference TMS.
Melting points were measured on a heating microblock
Boёtius 72/2064 (Germany). Initial thiosemicarbazides
I were obtained by procedure [8].
The alkylation of triazoles IIa–IIf occurs at the 3-
thiol group characterized by a higher nucleophilicity as
shows the presence of the characteristic singlets of the
methylene protons belonging to the SCH2 group in the
region 3.2–4.3 ppm in the 1Н NMR spectra of sulfanyl-
substituted 1,2,4-triazoles [12–15].
4,5-Disubstituted 4Н-1,2,4-triazole-3-thiols IIa–
IIf. A solution of 10 mmol of an appropriate thiosemi-
carbazide Ia–If and 0.84 g (15 mmol) of KОН in
20 mL of water was boiled for 2 h, cooled, and
acidified with glacial acetic acid. The separated
precipitate was filtered off, washed with water, and
recrystallized from ethanol.
For the alkylation of 4Н-1,2,4-triazolyl-3-thiols IIa–
IIf we selected halides of special structure: chloro- or
bromo-substituted aliphatic or unsaturated acids, or their
esters and amides. In contrast to the alkylation of 1,2,4-
triazole-3-thiols with benzyl chlorides at prolonged
heating (10 h) in anhydrous acetone in the presence of
potassium carbonate [16] we carried out the alkylation by
boiling triazoles IIa–IIf and the corresponding halides (in
particular, arylalkyl chlorides) in ethanol (2–3 h) or water
(4–5 h) in the presence of a definite amount of KOH [13–
15]. As a result 3-sulfanyl-substituted 4Н-1,2,4-triazoles
IIa–IIf were synthesized as stable crystalline substances.
5-(4-Methoxybenzyl)-4-phenyl-4Н-1,2,4-triazole-
3-thiol (IIa), mp 162–163°С (161–163°С [8]).
5-(4-Methoxybenzyl)-4-benzyl-4Н-1,2,4-triazole-
3-thiol (IIb). Yield 91%, mp 167–168°С, Rf 0.71
1
(dioxane–benzene, 1 : 2). H NMR spectrum, δ, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 5 2014

HOVSEPYAN et al.
738
3.75 s (3H, ОCH3), 3.75 s (2H, CH2), 5.08 s (2H,
NCH2), 6.73–6.78 m (2Harom), 6.95–7.00 m (2Harom),
7.15–7.31 m (5Harom), 13.51 br.s (1Н, SH). Found, %:
C 65.48; H 5.61; N 13.65; S 10.14. С17H17N3OS.
Calculated, %: C 65.57; H 5.50; N 13.50; S 10.30.
mixture was acidified with glacial acetic acid, the
separated precipitate was filtered off, dried in air, and
recrystallized.
5-(4-Methoxybenzyl)-4-phenyl-3-benzyl-sulfanyl-4Н-
1,2,4-triazole (IIIa) was obtained from compound IIa
and benzyl chloride. Yield 78%, mp 74–75°С, Rf 0.44
5-(4-Methoxybenzyl)-4-allyl-4Н-1,2,4-triazole-3-
thiol (IIc), mp 91–92°С (91–92°С [8]).
1
(dioxane–benzene, 1 : 2). H NMR spectrum, δ, ppm:
3.73 s (3H, ОCH3), 3.84 s (2H, CH2), 4.31 s (2H,
SCH2), 6.64–6.69 m (2Harom), 6.76–6.81 m (2Harom),
6.86–6.93 m (2Harom), 7.36–7.47 m (3Harom), 7.19–7.27
m (5Harom). Found, %: C 71.35; H 5.51; N 10.65; S
8.42. С23H21N3OS. Calculated, %: C 71.29; H 5.46; N
10.84; S 8.27.
5-(3-Chloro-4-methoxybenzyl)-4-phenyl-4Н-1,2,4-
triazole-3-thiol (IId). Yield 98%, mp 208–209°С, Rf
0.59 (dioxane–benzene, 1 : 2). H NMR spectrum, δ,
ppm: 3.75 с (2H, CH2), 3.83 s (3H, ОCH3), 6.82–6.83
m (2Harom), 6.86–6.88 m (1Harom), 7.16–7.22 m
(2Harom) and 7.46–7.52 m (3Harom), 13.62 br.s (1Н,
SH). Found, %: C 57.80; H 4.31; N 12.40; S 9.37.
С16H14ClN3OS. Calculated, %: C 57.91; H 4.25; N
12.66; S 9.66.
1
2-[5-(4-Methoxybenzyl)-4-phenyl-4Н-1,2,4-tria-
zol-3-ylsulfanyl]acetamide (IIIb) was obtained from
compound IIa and 2-chloroacetamide. Yield 98%, mp
1
73–75°С, Rf 0.54 (dioxane–benzene, 1 : 2). H NMR
5-(3-Chloro-4-methoxybenzyl)-4-benzyl-4Н-1,2,4-tria-
zole-3-thiol (IIe). Yield 94%, mp 163–164°С, Rf 0.67
spectrum, δ, ppm: 3.72 s (3H, ОCH3), 3.80 s (2H,
CH2), 3.87 s (2H, SCH2), 6.64–6.69 m (2Harom), 6.79–
6.84 m (2Harom), 6.93 br, 7.48 br (1H, NH2), 7.15–7.21
m (2Harom), 7.44–7.51 m (3Harom). Found, %: C 61.11;
H 5.22; N 15.67; S 9.31. С18H18N4O2S. Calculated, %:
C 61.00; H 5.12; N 15.81; S 9.05.
1
(dioxane–benzene, 1 : 2). H NMR spectrum, δ, ppm:
3.78 s (2H, CH2), 3.83 s (3H, ОCH3), 5.17 s (2H,
NCH2), 6.83 d (1Harom, J 8.5 Hz), 6.94 d.d (1Harom
,
=CН, J 8.5, 2.2 Hz), 7.04 d (1Harom, J 2.2 Hz), 7.16–
7.30 m (5Harom), 13.59 br.s (1Н, SH). Found, %: C
59.24; H 4.60; N 12.41; S 9.11. С17H16ClN3OS.
Calculated, %: C 59.04; H 4.66; N 12.15; S 9.27.
2-[5-(4-Methoxybenzyl)-4-phenyl-4Н-1,2,4-tria-
zol-3-ylsulfanyl]capronic acid (IIIc) was obtained
from compound IIa and 2-bromocapronic acid. Yield
97%, mp 134–135°С, Rf 0.62 (dioxane–benzene, 1 : 2).
1H NMR spectrum, δ, ppm: 0.87–0.93 m (3H, CH3),
1.25–1.83 m [4H, (CH2)2], 1.71–1.93 m (2H, CH2),
3.73 s (3H, ОCH3), 3.87 s (2H, CH2), 4.03 t (1H, CН, J
5-(3-Chloro-4-methoxybenzyl)-4-allyl-4Н-1,2,4-
triazole-3-thiol (IIf). Yield 95%, mp 136–137°С, Rf
1
0.63 (dioxane–benzene, 1 : 2). H NMR spectrum, δ,
ppm: 3.83 s (3H, ОCH3), 3.93 s (2H, CH2), 4.54 d.t
(2H, NCH2, J 5.5, 1.5 Hz), 5.07 d.q (1H, =CН2, J 17.1,
1.5 Hz), 5.16 d (1H, =CН2, J 10.3, 1.5 Hz), 5.78 d.d.t
(1H, =CН, J 17.1, 10.3, 5.5 Hz), 6.95 d (1Harom, J 8.4
Hz), 7.11 d (1Harom, J 8.4, 2.2 Hz), 7.26 d (1Harom, J
2.2 Hz), 13.47 br.s (1Н, SH). Found, %: C 52.70; H
4.81; N 14.10; S 10.57. С13H14ClN3OS. Calculated, %:
C 52.79; H 4.81; N 14.21; S 10.84.
6.9 Hz), 6.64–6.69
m
(2Harom), 6.78–6.82
m
(2Harom),7.10–7.16 m (2Harom), 7.43–7.50 m (3Harom),
12.41 br.s (1Н, СООН). Found, %: C 64.10; H 6.18; N
10.38; S 7.43. С22H25N3O3S. Calculated, %: C 64.21;
H 6.12; N 10.21; S 7.79.
2-[5-(4-Methoxybenzyl)-4-phenyl-4Н-1,2,4-tria-
zol-3-ylsulfanyl]acetic acid (IIId) was obtained from
compound IIa and chloroacetic acid. Yield 89%, mp
Alkylation of 4,5-substituted 4Н-1,2,4-triazole-3-
thiols IIa–IIf. General procedure. A solution of
3 mmol of triazole IIa–IIf and 0.2 g (3.6 mmol) of
KОН in 15 mL of С2Н5ОН was boiled for 20–30 min,
then 3 mmol of an appropriate halide was added, and
the reaction mixture was boiled for 2–3 h more. On
cooling the reaction mixture was diluted with 30 mL of
water, the separated precipitate was filtered off, dried
in air, and recrystallized. The alkylation of haloacids
was performed in 15 mL of water in the presence of a
five-fold excess of KОН (15 mmol), the reaction
mixture was boiled for 4–5 h. On cooling the reaction
1
82–83°С, Rf 0.52 (dioxane–benzene, 1 : 2). H NMR
spectrum, δ, ppm: 3.72 s (3H, ОCH3), 3.84 s (2H,
CH2), 3.86 s (2H, SCH2), 6.64–6.69 m (2Harom), 6.78–
6.83 m (2Harom), 7.15–7.20 m (2Harom), 7.44–7.52 m
(3Harom), СООН br. Found, %: C 60.79; H 4.77; N
11.55; S 9.27. С18H17N3O3S. Calculated, %: C 60.83;
H 4.82; N 11.82; S 9.02.
2-[5-(4-Methoxybenzyl)-4-benzyl-4Н-1,2,4-tria-
zol-3-ylsulfanyl]acetic acid (IIIe) was obtained from
compound IIb and chloroacetic acid. Yield 81%, mp
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SYNTHESIS AND REACTIONS OF NEW 4-METHOXYBENZYL-
739
1
127–129°С, Rf 0.51 (dioxane–benzene, 1 : 2). H NMR
spectrum, δ, ppm: 3.74 s (3H, ОCH3), 3.88 s (2H,
CH2), 3.94 s (2H, SCH2), 5.02 s (2H, NCH2), 6.71–
6.76 m (2Harom), 6.99–7.04 m (2Harom), 6.92–6.97 m
(2Harom), 7.23–7.30 m (3Harom), 12.62 br (1Н, СООН).
Found, %: C 61.69; H 5.23; N 11.21; S 8.36.
С19H19N3O3S. Calculated, %: C 61.77; H 5.18; N
11.37; S 8.68.
17.1, 10.3, 5.2 Hz), 6.77–6.82 m (2Harom), 7.07–7.12 m
(2Harom), 6.91 br (1H), 7.51 br (1H, NH2). Found, %: C
56.50; H 5.78; N 17.81; S 10.32. С15H18N4O2S.
Calculated, %: C 56.58; H 5.70; N 17.60; S 10.07.
2-[5-(4-Methoxybenzyl)-4-allyl-4Н-1,2,4-triazol-
3-ylsulfanyl]acetic acid (IIIj) was obtained from
compound IIc and chloroacetic acid. Yield 88%, mp
154–156°С, Rf 0.41 (dioxane–benzene, 1 : 2). 1H NMR
spectrum, δ, ppm: 3.76 s (3H, ОCH3), 3.87 s (2H,
CH2), 4.02 s (2H, SCH2), 4.43 d.t (2H, NCH2, J 5.2,
1.5 Hz), 4.90 d.q (1H, =CН2, J 17.1, 1.5 Hz), 5.12 d.q
(1H, =CН2, J 10.4, 1.5 Hz), 5.63 d.d.q (1H, =CН, J
17.1, 10.4, 5.2 Hz), 6.77–6.82 m (2Harom), 7.07–7.12 m
(2Harom), 12.58 br.s (1Н, СООН). Found, %: C 56.52;
H 5.41; N 13.41; S 10.29. С15H17N3O3S. Calculated,
%: C 56.41; H 5.37; N 13.16; S 10.04.
2-[5-(4-Methoxybenzyl)-4-benzyl-4Н-1,2,4-triaz-
ol-3-ylsulfanyl]ethanol (IIIf) was obtained from
compound IIb and 2-chloroethanol. Yield 94%, mp
1
90–92°С, Rf 0.40 (dioxane–benzene, 1 : 1). H NMR
spectrum, δ, ppm: 3.19 t (2H, SCH2, J 6.4 Hz), 3.64–
3.70 m (2H, CH2OH), 3.74 s (3H, ОCH3), 3.93 s (2H,
CH2), 4.74 t (1H, ОH, J 6.0 Hz), 4.98 s (2H, NCH2),
6.71–6.76 m (2Harom), 6.99–7.04 m (2Harom), 6.89–6.94
m (2Harom), 7.22–7.29 m (3Harom). Found, %: C 64.34;
H 5.80; N 11.67; S 9.34. С19H21N3O2S. Calculated, %:
C 64.20; H 5.96; N 11.82; S 9.02.
Ethyl 2-[5-(3-chloro-4-methoxybenzyl)-4-phenyl-
4Н-1,2,4-triazol-3-ylsulfanyl]acetate (IIIk) was
obtained from compound IId and ethyl chloroacetate.
Yield 72%, mp 101–102°С, Rf 0.57 (dioxane–benzene,
Ethyl 2-[5-(4-methoxybenzyl)-4-benzyl-4Н-1,2,4-
triazol-3-ylsulfanyl]acetate (IIIg) was obtained from
compound IIb and ethyl chloroacetate. Yield 76%, mp
1
1 : 2). H NMR spectrum, δ, ppm: 1.27 t (3H, CH3, J
7.1 Hz), 3.83 s (3H, ОCH3), 3.87 s (2H, SCH2), 3.94 s
(2H, CH2), 4.15 q (2H, ОCH2, J 7.1 Hz), 6.82–6.83 m
(2Harom), 6.87–6.88 m (1Harom), 7.18–7.22 m (2Harom),
7.47–7.54 m (3Harom). Found, %: C 57.60; H 4.72; N
10.27; S 8.39. С20H20ClN3O3S. Calculated, %: C
57.48; H 4.82; N 10.06; S 7.67.
1
63–65°С, Rf 0.56 (dioxane–benzene, 1 : 2). H NMR
spectrum, δ, ppm: 1.25 t (3H, ОCH2CH3, J 7.1 Hz),
3.74 s (3H, ОCH3), 3.93 s (2H, CH2), 3.95 s (2H,
SCH2), 4.13 q (2H, ОCH2, J 7.1 Hz), 5.02 s (2H,
NCH2), 6.71–6.76 m (2Harom), 6.99–7.04 m (2Harom),
6.91–6.96 m (2Harom), 7.23–7.28 m (3Harom). Found,
%: C 63.53; H 5.75; N 10.28; S 8.41. С21H23N3O3S.
Calculated, %: C 63.45; H 5.83; N 10.57; S 8.07.
2-[5-(3-Chloro-4-methoxybenzyl)-4-phenyl-4Н-
1,2,4-triazol-3-ylsulfanyl]acetamide (IIIl) was
obtained from compound IId and 2-chloroacetamide.
Yield 77%, mp 152–154°С, Rf 0.77 (dioxane–benzene,
2-[5-(4-Methoxybenzyl)-4-benzyl-4Н-1,2,4-tria-
zol-3-ylsulfanyl]acetamide (IIIh) was obtained from
compound IIb and 2-chloroacetamide. Yield 74%, mp
148–149°С, Rf 0.39 (dioxane–benzene, 1 : 2). 1H NMR
spectrum, δ, ppm: 3.74 s (3H, ОCH3), 3.78 s (2H,
CH2), 3.95 s (2H, SCH2), 5.03 s (2H, NCH2), 6.71–
6.76 m (2Harom), 6.99–7.04 m (2Harom), 6.92 br (1H),
7.52 br (1H, NH2), 6.91–6.96 m (2Harom), 7.22–7.30 m
(3Harom). Found, %: C 61.80; H 5.57; N 15.47; S 8.92.
С19H20N4O2S. Calculated, %: C 61.93; H 5.47; N
15.21; S 8.70.
1
1 : 2). H NMR spectrum, δ, ppm: 3.81 s (2H, CH2),
3.83 s (3H, ОCH3), 3.87 s (2H, SCH2), 6.82–6.84 m
(2Harom), 6.88–6.90 m (1Harom), 6.94 br.s (1H, NH2),
7.19–7.26 m (2Harom), 7.47–7.54 m (3Harom and 1Н,
NH2). Found, %: C 55.71; H 4.53; N 14.57; S 8.41.
С18H17ClN4O2S. Calculated, %: C 55.60; H 4.41; N
14.41; S 8.25.
2-[5-(3-Chloro-4-methoxybenzyl)-4-phenyl-3-2-(2-
chlorophenethylsulfanyl)-4Н-1,2,4-triazole (IIIm) was
obtained from compound IId and 2-(2-chlorophenethyl)
chloride. Yield 49%, mp 107–109°С, Rf 0.48 (dioxane–
benzene, 1 : 2). 1H NMR spectrum, δ, ppm: 3.55 t (2H,
SCH2, J 6.4 Hz), 3.83 s (3H, ОCH3), 3.87 s (2H, CH2),
4.39 t (2H, ОСH2, J 6.4 Hz), 6.82–6.83m (2Harom), 6.85–
2-[5-(4-Methoxybenzyl)-4-allyl-4Н-1,2,4-triazol-
3-ylsulfanyl]acetamide (IIIi) was obtained from
compound IIc and 2-chloroacetamide. Yield 79%, mp
119–120°С, Rf 0.37 (dioxane–benzene, 1 : 2). 1H NMR
spectrum, δ, ppm: 3.76 s (3H, ОCH3), 3.77 s (2H,
CH2), 4.02 s (2H, SCH2), 4.44 d.t (2H, NCH2, J 5.2,
1.6 Hz), 4.90 d.q (1H, =CН2, J 17.1, 1.6 Hz), 5.12 d.q
(1H, =CН2, J 10.3, 1.6 Hz), 5.64 d.d.t (1H, =CН, J
6.91 m (2Harom), 7.11–7.25 m (4Harom), 7.30 d.d (1Harom
,
J 7.8, 1.6 Hz), 7.46–7.53 m (3Harom). Found, %: C
59.32; H 4.41; N 8.42; S 6.71. С24H21ClN3O2S.
Calculated, %: C 59.26; H 4.35; N 8.64; S 6.59.
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HOVSEPYAN et al.
740
2-[5-(3-Chloro-4-methoxybenzyl)-4-benzyl-4Н-
77%, mp 138–139°С, Rf 0.70 (dioxane–benzene, 1 : 1).
1H NMR spectrum, δ, ppm: 2.77–2.82 m [4H, N(CH2)2],
3.60–3.64 m [4H, О(CH2)2], 3.73 s (3H, ОCH3), 3.79 s
(2H, CH2), 5.05 s (2H, NCH2N), 6.66–6.71 m (2Harom),
6.76–6.81 m (2Harom), 7.11–7.16 m (2Harom), 7.43–7.49
m (3Harom). Found, %: C 63.44; H 6.22; N 14.39; S
8.47. С21H24N4O2S. Calculated, %: C 63.61; H 6.10; N
14.13; S 8.09.
1,2,4-triazol-3-ylsulfanyl]acetic acid (IIIn) was
obtained from compound IIe and chloroacetic acid. Yield
70%, mp 162–163°С, Rf 0.61 (dioxane–benzene, 1 : 2).
1H NMR spectrum, δ, ppm: 3.82 s (3H, ОCH3), 3.90 s
(2H, CH2), 3.96 s (2H, SCH2), 5.10 s (2H, NCH2), 6.83
d (1Harom, J 8.5 Hz), 6.93–6.98 m (2Harom), 7.19–7.29 m
(3Harom), 6.98 d.d (1Harom, J 8.5, 2.2 Hz), 7.09 d (1Harom
,
J 2.2 Hz), 12.68 br.s (1Н, СООН). Found, %: C 56.61;
H 4.56; N 10.66; S 7.62. С19H18ClN3O3S. Calculated,
%: C 56.50; H 4.49; N 10.40; S 7.94.
3-(4-Methoxybenzyl)-4-benzyl-1-morpholinomethyl-
1Н-1,2,4-triazole-5(4Н)-thione (IVb). Yield 73%, mp
104–106°С, Rf 0.71 (dioxane–benzene, 1 : 2). 1H NMR
spectrum, δ, ppm: 2.72–2.77 m [4H, N(CH2)2], 3.57–
3.63 m [4H, О(CH2)2], 3.75 s (3H, ОCH3), 3.80 s (2H,
CH2), 5.06 s (2H, NCH2), 5.13 s (2H, NCH2N), 6.74–
6.79 m (2Harom), 6.96–7.01 m (2Harom), 7.14–7.19 m
(2Harom), 7.22–7.33 m (3Harom). Found, %: C 64.43; H
6.20; N 13.45; S 7.58. С22H26N4O2S. Calculated, %: C
64.36; H 6.38; N 13.65; S 7.81.
2-[5-(3-Chloro-4-methoxybenzyl)-4-benzyl-4Н-
1,2,4-triazol-3-ylsulfanyl]acetamide (IIIo) was
obtained from compound IIe and 2-chloroacetamide.
Yield 75%, mp 158–159°С, Rf 0.31 (dioxane–benzene,
1
1 : 2). H NMR spectrum, δ, ppm: 3.80 s (2H, CH2),
3.82 s (3H, ОCH3), 3.97 s (2H, SCH2), 5.11 s (2H,
NCH2), 6.84 d (1Harom, J 8.5 Hz), 6.92–7.01 m (3Harom
and 1Н, NH2), 7.10 d (1Harom, J 2.2 Hz), 7.20–7.29 m
(3Harom), 7.53 br.s (1Н, NH2). Found, %: C 56.73; H
4.60; N 13.68; S 7.58. С19H19ClN4O2S. Calculated, %:
C 56.64; H 4.75; N 13.91; S 7.96.
3-(4-Methoxybenzyl)-4-allyl-1-morpholinomethyl-1Н-
1,2,4-triazole-5(4Н)-thione (IVc). Yield 69%, mp 83–
1
85°С, Rf 0.70 (dioxane–benzene, 1 : 2). H NMR
spectrum, δ, ppm: 2.69–2.74 m [4H, N(CH2)2], 3.57–
3.61 m [4H, О(CH2)2], 3.77 s (3H, ОCH3), 3.97 s (2H,
CH2), 4.52 d.t (2H, NCH2, J 5.5, 1.5 Hz), 5.01 s (2H,
NCH2N), 5.04 d.q (1H, =CН2, J 17.1, 1.5 Hz), 5.15 d.q
(1H, =CН2, J 10.3, 1.5 Hz), 5.74 d.d.t (1H, =CН, J
17.1, 10.3, 5.5 Hz), 6.81–6.86 m (2Harom), 7.09–7.14 m
(2Harom). Found, %: C 59.80; H 6.69; N 15.42; S 8.64.
С18H24N4O2S. Calculated, %: C 59.97; H 6.71; N
15.54; S 8.90.
Ethyl 2-[5-(3-Chloro-4-methoxybenzyl)-4-allyl-
4Н-1,2,4-triazol-3-ylsulfanyl]acetate (IIIp) was
obtained from compound IIf and ethyl chloroacetate.
Yield 74%, mp 65–67°С, Rf 0.51 (dioxane–benzene,
1
1 : 2). H NMR spectrum, δ, ppm: 1.25 t (3H, CH3, J
7.1 Hz), 3.86 s (3H, ОCH3), 3.94 s (2H, CH2), 4.03 s
(2H, SCH2), 4.13 q (2H, ОCH2, J 7.1 Hz), 4.49 d.t
(2H, NCH2, J 5.1, 1.6 Hz), 4.89 d.q (1H, =CН2, J 17.1,
1.6 Hz), 5.13 d.q (1H, =CН2, J 10.3, 1.6 Hz), 5.69 d.d.t
(1H, =CН, J 17.1, 10.3, 5.1 Hz), 6.94 d (1Harom, J
8.1 Hz), 7.10 d.d (1Harom, J 8.1, 2.2 Hz), 7.24 d
(1Harom, J 2.2 Hz). Found, %: C 53.40; H 5.31; N
11.31; S 8.59. С17H20ClN3O3S. Calculated, %: C
53.47; H 5.28; N 11.00; S 8.40.
3-(3-Chloro-4-methoxybenzyl)-4-phenyl-1-morpholi-
nomethyl-1Н-1,2,4-triazole-5(4Н)-thione (IVd). Yield
96%, mp 143–145°С, Rf 0.78 (dioxane–benzene, 1 : 1).
1H NMR spectrum, δ, ppm: 2.77–2.81 m [4H,
N(CH2)2], 3.60–3.65 m [4H, О(CH2)2], 3.79 s (2H,
CH2), 3.84 s (3H, ОCH3), 5.05 s (2H, NCH2N), 6.78–
6.87 m (3Harom), 7.17–7.21 m (2Harom), 7.47–7.52 m
(3Harom). Found, %: C 58.63; H 5.43; N 13.27; S 7.12.
С21H23ClN4O2S. Calculated, %: C 58.53; H 5.38; N
13.00; S 7.44.
Aminomethylation of 4,5-substituted 4Н-1,2,4-
triazole-3-thiols IIa–IIf. General procedure. In 5–
10 mL of methanol was dissolved 5 mmol of an
appropriate triazole IIa–IIf, 6 mmol of morpholine
was added, and after that 8 mmol of formaldehyde
water solution was added dropwise at shaking. The
reaction proceeded with heat liberation. The reaction
mixture was left standing for 8–10 h (5–6 h in case of
compounds IId–IIf), diluted with 15–20 mL of water,
the separated precipitate was filtered off and
recrystallized from ethanol.
3-(3-Chloro-4-methoxybenzyl)-4-benzyl-1-morpho-
lino-methyl-1Н-1,2,4-triazole-5(4Н)-thione (IVe).
Yield 92%, mp 93–95°С, Rf 0.72 (dioxane–benzene,
1
1 : 1). H NMR spectrum, δ, ppm: 2.72–2.77 m [4H,
N(CH2)2], 3.57–3.63 m [4H, О(CH2)2], 3.84 s (3H,
ОCH3), 3.84 s (2H, CH2), 5.06 s (2H, NCH2), 5.22 s
(2H, NCH2N), 6.84 d (1Harom, J 8.4 Hz), 6.93 d.d
(1Harom, J 8.4, 2.2 Hz), 7.08 d (1Harom, J 2.2 Hz), 7.13–
7.30 m (5Harom). Found, %: C 59.46; H 5.58; N 12.31;
3-(4-Methoxybenzyl)-4-phenyl-1-morpholino-
methyl-1Н-1,2,4-triazole-5(4Н)-thione (IVa). Yield
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 5 2014

SYNTHESIS AND REACTIONS OF NEW 4-METHOXYBENZYL-
741
3. Labanauskas, L., Kalcas, V., Udrenaite, E., Gaidelis, P.,
Brukstus, A., and Dauksas, V., Pharmazie, 2001,
vol. 56, p. 617.
4. Holla, B.S., Veerendra, B., Poorjary, M.K., and
Shivanonda, M.K., Eur. J. Med. Chem., 2003,
vol. 38, p. 759.
S 7.48. С22H25ClN4O2S. Calculated, %: C 59.38; H
5.66; N 12.59; S 7.21.
3-(3-Chloro-4-methoxybenzyl)-4-allyl-1-morpholino-
methyl-1Н-1,2,4-triazole-5(4Н)-thione (IVf). Yield 91%,
1
mp 87–88°С, Rf 0.70 (dioxane–benzene, 1 : 1). H
NMR spectrum, δ, ppm: 2.69–2.73 m [4H, N(CH2)2],
3.55–3.61 m [4H, О(CH2)2], 3.87 s (3H, ОCH3), 3.98 s
(2H, CH2), 4.58 d.t (2H, NCH2, J 5.5, 1.5 Hz), 5.00 s
(2H, NCH2N), 5.06 d.q (1H, =CН2, J 17.1, 1.5 Hz),
5.15 d.q (1H, =CН2, J 10.3, 1.5 Hz), 5.77 d.d.t (1H,
=CН, J 17.1, 10.3, 5.5 Hz), 6.97 d (1Harom, J 8.5 Hz),
7.11 d.d (1Harom, J 8.5, 2.2 Hz), 7.29 d (1Harom, J 2.2 Hz).
Found, %: C 54.68; H 5.79; N 14.41; S 7.87.
С18H23ClN4O2S. Calculated, %: C 54.74; H 5.87; N
14.19; S 8.12.
5. Foroumadi, A., Mansouri, S., Kiani, Z., and Rahmani, A.,
Eur. J. Med. Chem., 2003, vol. 38, p. 851.
6. Duran, A., Dogan, H.N., and Rollas, S., Farmaco, 2002,
vol. 57, p. 559.
7. Ramasamy, K.S., Tam, R.C., Bard, J., and Averett, D.,
J. Med. Chem., 2000, vol. 43, p. 1019.
8. Avetisyan, A.Kh., Ovsepyan, T.R., Dzhagatspanyan, I.A.,
Akopyan, N.E., Akopyan, A.G., Sapond-
zhyan, L.G., and Paronikyan, R.V., Khim.-Farm. Zh.,
1978, vol. 12, p. 40.
9. Avetisyan, A.Kh., Ovsepyan, T.R., Stepanyan, N.O., and
Sapondzhyan, L.G., Khim.-Farm. Zh., 1981, vol. 15,
p. 6972.
10. Hovsepyan, T.R., Avetisyan, A.Kh., Terdzhanyan, S.M.,
Kazaryan, E.V., Ter-Zakharyan, Yu.Z., Paronikyan, G.M.,
and Akopyan, L.G., Arm. Khim. Zh., 1990, vol. 43, p. 399.
11. Nersesyan, L.E., Danielyan, I.S., Agaronyan, A.S.,
Stepanyan, G.M., Hovsepyan, T.R., and Melik-
Ogandzhanyan, R.G., Abstracts of Papers, III
Nauchnaya konf. Armyanskogo khimicheskogo
5-(4-Methoxybenzyl)-1,3,4-thiadiazole-2-thiol
(VI) was obtained from compound V and H2SO4, mp
129–131°С (124–125°С [12]).
Methyl 2-[5-(4-methoxybenzyl)-1,3,4-thiadiazol-
2-ylsulfanyl]acetate (VIIa) was obtained from
compound VI and methyl chloroacetate. Yield 74%,
mp 46–47°С, Rf 0.53 (dioxane–benzene, 1 : 2). 1H NMR
spectrum, δ, ppm: 3.73 s (3H, ОCH3), 3.77 s (2H,
CH2), 4.28 s (2H, SCH2), 6.80–6.85 m (2Harom), 7.17–
7.22 m (2Harom). Found, %: C 50.41; H 4.44; N 9.03; S
20.66. С13H14N2O3S. Calculated, %: C 50.30; H 4.55;
N 9.16; S 20.53.
obshchestva “Uspekhi
v oblasti organicheskoi I
farmatsevticheskoi khimii” (III Sci. Conf. of Armenian
Chemical Society “Advances in the Field of Organic
and Pharmaceutical Chemistry”), Yerevan, 2012, p. 54.
12. Ovsepyan, T.R., Melik-Ogandzhanyan, R.G., Pano-
syan, G.A., Arsenyan, F.G., and Garibdzhanyan, B.T.,
Pharm. Chem. J., 2009, vol. 43, p. 645.
13. Hovsepyan, T.R., Grboyan, C.V., Arsenyan, F.H., and
Melik-Ohanjanyan, R.G., Pharm. Chem. J., 2012,
vol. 45, p. 705.
14. Hovsepian, T.R., Dilanian, E.R., Engoyan, A.P., and
Melik-Ohanjanian, R.G., Chem. Heterocycl. Comp.,
2004, vol. 40, p. 1194.
15. Dilanyan, E.R., Hovsepyan, T.R., and Melik-
Ohanjanyan, R.G., Chem. Heterocycl. Comp., 2008, vol. 44,
p. 1395.
2-[5-(4-Methoxybenzyl)-1,3,4-thiadiazole-2-yl-
sulfanyl]acetic acid (VIIb) was obtained from
compound VI and chloroacetic acid. Yield 67%, mp
1
>260°С, Rf 0.40 (dioxane–benzene, 1 : 1). H NMR
spectrum, δ, ppm: 3.78 s (3H, ОCH3), 4.03 s (2H,
CH2), 4.27 s (2H, SCH2), 6.78–6.84 m (2Harom), 7.12–
7.23 m (2Harom), 12.52 br.s (1Н, СООН). Found, %: C
48.71; H 4.28; N 9.45; S 21.64. С12H12N2O3S2.
Calculated, %: C 48.63; H 4.08; N 9.35; S 21.78.
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