Full text of DOI:10.1134/S1070363217050140

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 5, pp. 973–978. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © M.R. Hakobyan, T.R. Hovsepyan, L.E. Nersesyan, A.S. Agaronyan, I.S. Danielyan, R.V. Paronikyan, N.S. Minasyan, 2017,
published in Zhurnal Obshchei Khimii, 2017, Vol. 87, No. 5, pp. 782–787.
Functionalization
of 5-(4-Alkoxybenzyl)-4-R-4H-1,2,4-triazole-3-thiols.
Synthesis of Novel DNA Methylation Inhibitors
M. R. Hakobyana, T. R. Hovsepyana*, L. E. Nersesyana, A. S. Agaronyana,
I. S. Danielyana, R. V. Paronikyana, and N. S. Minasyanb
a A.L. Mnjoyan Institute of Fine Organic Chemistry,
Scientific-Technological Center of Organic and Pharmaceutical Chemistry, National Academy of Sciences of Armenia,
pr. Azatutyan 26, Yerevan, 0014 Armenia
*e-mail: tag.hovsepyan@mail.ru
b Molecular Structure Research Center, Scientific-Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia, Yerevan, Armenia
Received February 15, 2017
Abstract—Aminomethylation and cyanoethylation reactions of 5-(4-alkoxybenzyl)-4-methyl(phenyl, allyl)-4H-
1,2,4-triazole-3-thiols have been investigated. According to NMR spectroscopy data, the reactions occur at the
nitrogen atom Ν2. The effect of the synthesized compounds on cancer DNA methylation has been evaluated.
Keywords: 1,2,4-triazole, cyanoethylation, aminomethylation, thione-thiol tautomerism, DNA, methylation
DOI: 10.1134/S1070363217050140
Search for methods for the synthesis of functionally
substituted 4H-1,2,4-triazole derivatives is an urgent
task, since these compounds are part of many
biologically active substances and drugs that possess
antitumor, analgesic, antibacterial, and antiviral activity
[1–4].
tigate the ways of functionalization of triazoles 1a–1h,
taking into account the presence of two nucleophilic
sites (SH and NH groups) in tautomers A and B arising
due to thione-thiol tautomerism.
Aminomethylation of triazoles 1 occurred in the
presence of an excess of secondary amine (mor-
pholine) and formalin at room temperature (20–25°C)
in methanol to afford the corresponding Mannich
bases. The resulting 2-[(morpholin-4-yl)methyl]-2H-
1,2,4-triazole-3-thiones 2a–2e were pale yellow
crystalline substances, the structure of which was
confirmed by 1H and 13C NMR spectroscopy data. The
singlet signals of the NCH2N protons in the range of
4.99–5.06 ppm and the weak-field signals of the
carbon atoms at 62.4–63.5 ppm indicated the
occurrence of aminomethylation at the N2 atom of
tautomer B (Scheme 1).
We have earlier reported the synthesis, transforma-
tions, and positive results of biological screening for
1,2,4-triazole derivatives containing alkoxyl, halo-
genated benzyl, furyl, pyridyl, and other substituents
[5–7]. Particularly, some of them containing 2-furyl
and 4-chlorophenoxymethyl moieties have shown
pronounced or moderate antitumor effect; some
correlation between antitumor activity and the ability
to inhibit DNA methylation have been found [6–8].
Aiming to develop more efficient biologically
active agents, herein we studied 5-(4-alkoxybenzyl)-
4H-1,2,4-triazole-3-thiols. The starting 4,5-disub-
stituted 4H-1,2,4-triazole-3-thiols 1a–1d were syn-
thesized earlier via intramolecular cyclization of the
corresponding 1,4-disubstituted thiosemicarbazides in
an aqueous-alkaline medium [9]. Aminomethylation
and cyanoethylation reactions were performed to inves-
Similarly, cyanoethylation of triazoles 1 with acrylo-
nitrile proceeded in an aqueous medium in the presence
of triethylamine to form 2-(2-cyanoethyl)-2H-1,2,4-
triazole-3-thiones 3a–3c.
To further functionalize triazoles 1 and introduce
new pharmacophore groups, their reactions with
973

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HAKOBYAN et al.
Scheme 1.
X
X
X
AlkO
AlkO
AlkO
O
N
N N
N N
N NH
1a_1h
S
N
R1
SH
S
N
N
R1
R1
2a_2e
B
A
R2Hlg
CH2=CHCN
X
X
N
AlkO
AlkO
N N
N N
R2
S
S
N
N
R1
R1
3a_3d
4a_4n
1, Alk = Et, R1 = Me (a), Ph (b), Bn (c), All (d); Alk = Bu, R1 = Ph (e), All (f); Alk = i-Pent, R1 = Ph (g), All (h); 2, Alk =
Et, R1 = Me (a), Ph (b), All (c); Alk = Bu, R = Ph (d); Alk = i-Pent, R1 = Ph (e); 3, Alk = Et, R1 = Me (a), Ph (b); Alk = Bu,
R1 = Ph (c); Alk = i-Pent, R1 = Ph (d); 4, Alk = Et, R1 = Me, R2 = CH2COOH (a), CH(CH3)COOH (b), CH2CONH2 (c),
3-Br-4-MeOC6H3CH2 (d), 3-Ac-2MeOC6H3CH2 (e); R1 = Ph, R2 = CH(CH3)COOH (f), CH2CONH2 (g); R1 = Bn, R2 =
CH2COOH (h), 3-Br-4-MeOC6H3CH2 (i); R1 = All, R2 = CH2CONH2 (j); Alk = Bu, R1 = Ph, R2 = i-Pr (k), CH(C4H9)COOH
(l), CH2COOEt (m), CH2CONH2 (n); X = H (1a–1f, 2a–2d, 3a–3c, 4), Cl (1g, 1h, 2e, 3d).
various halogenated derivatives of aliphatic acids were
performed. The optimal conditions for alkylation were
selected. It was found that alkylation took place at the
thiol group of tautomer A, as evidenced by the singlet
signals of the protons SCH2 at 3.80–4.20 ppm in the 1H
NMR spectra of compounds 4a–4n. That was further
confirmed by the presence of the signal of SCH2 group
at 35.5 ppm in the 13C NMR spectrum of compound 4g.
Antibacterial activity of compounds 2–4 was
investigated by diffusion in agar [12]. Moderate ac-
tivity was manifested by the compounds containing the
morpholinomethyl fragment 2a–2e. Other compounds
exhibited significantly poorer activity in comparison
with the reference furazolidone [13].
Hence, methods for functionalization of 5-(4-
alkoxybenzyl)-4-R-4H-1,2,4-triazole-3-thiols were de-
veloped. Novel S- and N-substituted derivatives are of
interest for biological screening as well as for further
structural modifications.
Structure and purity of the obtained compounds
were confirmed by NMR, elemental analysis, and TLC
data.
The effect of some synthesized compounds on the
cancer DNA methylation was studied in vitro using
sarcoma 180 model as described in [10]. DNA
methylation is known to control all genetic processes
in the cell and to be the mechanism of cellular
differentiation, discrimination, and gene repression.
The cancer cell exhibit a contrasting character of DNA
methylation compared with the normal cells [11]. Our
studies showed that most of the tested compounds
inhibit the cancer DNA methylation. The most active
compounds were 2d, 4a, 4l and 4n: they inhibited the
cancer DNA methylation by 47.3, 43.2, 42.0, and
37.8%, respectively. That indicated the prospect of
finding potential antitumour agents among the studied
class of compounds.
EXPERIMENTAL
NMR spectra of the solutions in DMSO-d6–CCl4
(1 : 3) were recorded using a Varian Mercury-300VX
instrument relative to internal TMS. TLC was
performed using Silufol UV-254 plates and benzene–
dioxane (2 : 1) or ethyl acetate–benzene (1 : 1) as
eluent, developing with UV light. Melting points were
determined with a Boetius 72/2064 instrument.
4,5-Disubstituted 4H-1,2,4-triazole-3-thiols 1a–1h
were prepared as described in [9].
4-Benzyl-5-(4-ethoxybenzyl)-4H-1,2,4-triazole-3-
thiol (1c). Yield 92%, mp 139–141°C. 1H NMR
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FUNCTIONALIZATION OF 5-(4-ALKOXYBENZYL)-4-R-4H-1,2,4-TRIAZOLE-3-THIOLS
975
spectrum, δ, ppm: 1.38 t (3H, CH3, J = 7.0 Hz), 3.74
br.s (2H, CH2Аr), 3.97 q (2H, OCH2, J = 7.0 Hz), 5.08
s (2H, CH2Ph), 6.70–6.75 m (2HAr), 6.94–6.99 m
(2HAr), 7.15–7.20 m (2HAr), 7.21–7.32 m (3HAr), 13.55
br.s (1H, SH). Found, %: C 66.27%; H 5.63; N 12.67;
S 9.57. C18H19N3OS. Calculated, %: C 66.43; H 5.88;
N 12.91; S 9.85.
m (2HAr), 7.08–7.03 m (2HAr). Found, %: C 60.78; H
6.89; N 15.07; S 9.11.C19H26N4O2S. Calculated, %: C
60.93; H 6.99; N 14.96; S 9.23.
5-(4-Butoxybenzyl)-2-[(morpholin-4-yl)methyl]-
4-phenyl-2H-1,2,4-triazole-3-thione (2d). Yield 91%,
1
mp 95–97°C. H NMR spectrum, δ, ppm: 0.98 t (3H,
CH3, J = 7.3 Hz), 1.42–1.55 m (2H, CH3CH2), 1.67–
1.77 m (2H, C2H5CH2CH2O), 2.78–2.82 m [4H,
N(CH2)2], 3.61–3.65 m [4H, O(CH2)2], 3.80 br.s (2H,
CH2Ar), 3.96 q (2H, OCH2, J = 7.0 Hz), 5.06 s (2H,
NCH2N), 6.61–6.81 m (4HAr), 7.05–7.51 m (5HAr).
Found, %: C 65.52; H 6.79; N 12.57; S 7.21.
C24H30N4O2S. Calculated, %: C 65.72; H 6.89; N
12.77; S 7.31.
Aminomethylation of 4,5-disubstituted 2H-1,2,4-
triazole-3-thiones. Morpholine (1.2 mmol) and
formalin (1.5 mmol) were added in sequence to a
solution of triazole 1 (1 mmol) in methanol (5 mL).
The exothermic reaction proceeded. The resulting
mixture was stirred at room temperature for 8–10 h,
and then 10–15 mL of water was added. The
precipitate was filtered off and recrystallized from
ethanol.
5-(4-Isopentyloxy-3-chlorobenzyl)-2-[(morpholin-
4-yl)methyl]-4-phenyl-2H-1,2,4-triazole-3-thione
1
4-Methyl-2-[(morpholin-4-yl)methyl]-5-(4-ethoxy-
(2e). Yield 81%, mp 109–110°C. H NMR spectrum,
benzyl)-2H-1,2,4-triazole-3-thione (2a). Yield 77%,
mp 105–106°C. H NMR spectrum, δ, ppm: 1.39 t
δ, ppm: 0.98 d [6H, CH(CH3)2, J = 6.6 Hz], 1.65–1.70
m (2H, CHCH2), 1.82–1.95 m [1H, CH(CH3)2], 2.71–
2.80 m [4H, N(CH2)2], 3.58–3.63 m [4H, O(CH2)2],
3.75 br.s (2H, CH2Ar), 3.95 q (2H, OCH2, J = 7.0 Hz),
5.05 s (2H, NCH2N), 6.77–6.86 m (3HAr), 7.16–7.22 m
(2HAr), 7.45–7.52 m (3HAr). 13C NMR spectrum, δC,
ppm: 22.1 (CH3), 24.4 (CH3), 30.0 (CH2), 37.1 (CH2),
50.2 [N(CH2)2], 65.9 [O(CH2)2], 66.6, 68.5 (OCH2),
112.7, 121.8, 126.4, 127.3, 127.9, 128.7, 128.9. 129.8,
133.6, 148.9, 152.9, 169.2 (C=S). Found, %: C 61.47;
H 6.23; N 11.32; S 6.35. C25H31ClN4O2S. Calculated,
%: C 61.65; H 6.42; N 11.50; S 6.58.
1
(3H, CH3CH2O, J = 7.0 Hz), 2.70–2.74 m [4H,
N(CH2)2], 3.35 s (3H, NCH3), 3.56–3.61 m [4H,
O(CH2)2], 3.99 q (2H, OCH2CH3, J = 7.0 Hz), 4.02
br.s (2H, CH2Аr), 4.99 s (2H, NCH2N), 6.79–6.84 m
(2HAr), 7.10–7.15 m (2HAr). Found, %: C 58.27; H
6.71; N 16.39; S 9.41. C17H24N4O2S. Calculated, %: C
58.59; H 6.94; N 16.09; S 9.20.
2-[(Morpholin-4-yl)methyl]-4-phenyl-5-(4-ethoxy-
benzyl)-2H-1,2,4-triazole-3-thione (2b). Yield 64%,
1
mp 120–122°C. H NMR spectrum, δ, ppm: 1.37 t
(3H, CH3, J = 7.0 Hz), 2.77–2.82 m [4H, N(CH2)2],
3.60–3.65 m [4H, O(CH2)2], 3.78 br.s (2H, CH2Аr),
3.96 q (2H, OCH2, J = 7.0 Hz) 5.06 s (2H, NCH2N),
6.63–6.68 m (2HAr), 6.74–6.79 m (2HAr), 7.11–7.16 m
(2HAr), 7.42–7.52 m (3HAr). 13C NMR spectrum, δC,
ppm: 14.3 (CH3), 30.3 (CH2), 50.2 [N(CH2)2], 62.4
(NCH2), 65.9 [O(CH2)2], 68.5 (OCH2), 113.9 (2CH),
125.3, 127.9, 128.6, 128.9, 133.7, 149.3, 157.3, 169.1
(C=S). Found, %: C 64.11; H 6.17; N 13.21; S 7.61.
C22H26N4O2S. Calculated, %: C 64.36; H 6.38; N
13.65; S 7.81.
Cyanoethylation of 4,5-disubstituted 2H-1,2,4-
triazole-3-thiones. A mixture of 1 mmol of triazole 1,
1.6 g (30 mmol) of freshly distilled acrylonitrile, 4 mL
of water, and 3.0 g (30 mmol) of triethylamine was
refluxed for 7–8 h. The solvent was evaporated, and
the oily residue was carefully triturated with icy water.
The crystals formed were filtered off and recrystallized
from ethanol.
3-[4-Methyl-5-thioxo-3-(4-ethoxybenzyl)-4,5-di-
hydro-1H-1,2,4-triazol-1-yl]propionitrile (3a). Yield
1
89%, mp 82–84°C. H NMR spectrum, δ, ppm: 1.39 t
4-Allyl-2-[(morpholin-4-yl)methyl]-5-(4-ethoxy-
(3H, CH3CH2O, J = 7.0 Hz), 3.01 t (2H, CH2CN, J =
6.6 Hz), 3.36 s (3H, NCH3), 3.99 q (2H, OCH2, J =
7.0 Hz), 4.05 br.s (2H, CH2Аr), 4.38 t (2H, NCH2, J =
6.6 Hz), 6.78–6.83 m (2HAr), 7.11–7.16 m (2HAr). 13C
NMR spectrum, δC, ppm: 14.3 (CH3), 15.7, 29.9, 30.6,
43.8 (NCH2), 62.5 (OCH2), 114.3, 116.5, 125.1, 129.1,
150.2, 157.5, 166.7 (C=S). Found, %: C 59.32; H 5.38;
N 18.29; S 10.41. C15H18N4OS. Calculated, %: C
59.58; H 5.99; N 18.53; S 10.60.
benzyl)-2H-1,2,4-triazole-3-thione (2c). Yield 57%,
1
mp 66–68°C. H NMR spectrum, δ, ppm: 1.39 t (3H,
CH3, J = 7.0 Hz), 2.69–2.74 m [4H, N(CH2)2], 3.56–
3.61 m [4H, O(CH2)2], 3.97 br.s (2H, CH2Аr), 4.00 q
(2H, OCH2, J = 7.0 Hz), 4.52 d.t (2H, CH2Аll, J = 5.5,
1.5 Hz), 5.00 s (2H, NCH2N), 5.03 d.q (1H, =CH2, J =
17.1, 1.5 Hz), 5.51 d.q (1H, =CH2, J = 10.3, 1.5 Hz),
5.74 d.d.t (1H, =CH, J = 17.1, 10.3, 5.5 Hz), 6.78–6.83
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HAKOBYAN et al.
3-[5-Thioxo-4-phenyl-3-(4-ethoxybenzyl)-4,5-di-
2-{[4-Methyl-5-(4-ethoxybenzyl)-4H-1,2,4-triazol-
3-yl]sulfanyl}acetic acid (4a). Yield 97%, mp 169–
170°C. 1H NMR spectrum, δ, ppm: 1.38 t (3H,
CH3CH2, J = 7.0 Hz), 3.39 s (3H, NCH3), 3.84 s (2H,
SCH2), 3.98 q (2H, OCH2, J = 7.0 Hz), 4.06 br.s (2H,
CH2Ar), 6.75–6.80 m (2HAr), 7.05–7.10 m (2HAr).
Found, %: C 54.48; H 5.31; N 13.45; S 10.51.
C17H17N3O3S. Calculated, %: C 54.71; H 5.57; N
13.67; S 10.43.
hydro-1H-1,2,4-triazol-1-yl]propionitrile (3b). Yield
1
73%, oil. H NMR spectrum, δ, ppm: 1.38 t (3H,
CH3CH2O, J = 7.0 Hz), 3.05 t (2H, CH2CN, J =
6.6 Hz), 3.81 s (2H, CH2Ar), 3.98 q (2H, OCH2, J =
7.0 Hz), 4.45 m (2H, NCH2, J = 6.6 Hz), 6.71–6.78 m
(2HAr), 6.98–7.01 m (2HAr), 7.12–7.32 m (5HAr). 13C
NMR spectrum, δC, ppm: 14.3 (CH3), 15.8 (CH2),
30.2, 44.0, 46.7, 62.5 (ОCH2), 114.2, 116.4, 124.7,
126.6, 127.2, 128.1, 129.1, 134.6, 150.2, 157.5, 167.4
(C=S). Found, %: C 66.74; H 5.57; N 14.69; S 8.39.
C21H20N4OS. Calculated, %: C 66.99; H 5.35; N 14.88;
S 8.52.
2-{[4-Methyl-5-(4-ethoxybenzyl)-4H-1,2,4-triazol-
3-yl]sulfanyl}propanoic acid (4b). Yield 81%, mp
1
143–144°C. H NMR spectrum, δ, ppm: 1.37 t (3H,
CH3CH2О, J = 7.0 Hz), 1.45 d (3H, CH3H, J =
7.0 Hz), 3.38 s (3H, NCH3), 3.92 q (1H, CHCH3, J =
7.0 Hz), 3.97 q (2H, CH2CH3, J = 7.0 Hz), 4.06 br.s
(2H, CH2Ar), 6.74–6.80 m (2HAr), 7.05–7.10 m (2HAr).
Found, %: C 56.26; H 5.71; N 13.32; S 9.75.
C15H19N3O3S. Calculated, %: C 56.06; H 5.96; N
13.08; S 9.98.
3-[3-(4-Butoxybenzyl)-5-thioxo-4-phenyl-4,5-di-
hydro-1H-1,2,4-triazol-1-yl]propionitrile (3c). Yield
1
78%, oil. H NMR spectrum, δ, ppm: 0.98 m (3H,
CH3, J = 7.3 Hz), 1.41–1.53 m (2H, CH3CH2), 1.65–
1.79 m (2H, C2H5CH2CH2O), 3.05 t (2H, CH2CN, J =
6.6 Hz), 3.78 s (2H, CH2Ar), 3.88 t (2H, NCH2, J =
6.6 Hz), 6.61–6.67 m (2HAr), 6.77–6.82 m (2HAr), 7.12–
7.18 m (2HAr), 7.41–7.51 m (3HAr). 13C NMR spec-
trum, δC, ppm: 13.4 (CH3), 15.7 (CH2), 18.6 (CH2),
30.3, 30.6, 43.9 (NCH2), 66.7 (OCH2), 113.8, 116.5,
125.1, 127.8, 128.72, 128.75, 129.03, 129.06, 133.5,
150.5, 157.5, 167,4 (C=S). Found, %: C 67.59; H 6.27;
N 14.41; S 8.32. C22H24N4OS. Calculated, %: C 67.32;
H 6.16; N 14.27; S 8.17.
2-{[4-Methyl-5-(4-ethoxybenzyl)-4H-1,2,4-triazol-
3-yl]sulfanyl}acetamide (4c). Yield 85%, mp 136–
137°C. 1H NMR spectrum, δ, ppm: 1.37 t (3H,
CH3CH2О, J = 7.0 Hz), 3.38 s (3H, NCH3), 3.73 s
(2H, SCH2), 3.98 q (2H, OCH2, J = 7.0 Hz), 4.06 br.s
(2H, CH2Ar), 6.74–6.80 m (2HAr), 6.93 br.s (1H,
CОNH2), 7.05–7.11 m (2HAr), 7.54 br.s (1H, CONH2).
Found, %: C 54.61; H 5.63; N 18.37; S 10.23.
C14H18N4O2S. Calculated, %: C 54.88; H 5.92; N
18.29; S 10.47.
3-[3-(4-Isopentyloxy-3-chlorobenzyl)-5-thioxo-4-
phenyl-4,5-dihydro-1H-1,2,4-triazol-1-yl]propio-
1
nitrile (3d). Yield 81%, oil. H NMR spectrum, δ,
3-[(3-Bromo-4-methoxybenzyl)sulfanyl]-4-methyl-
5-(4-ethoxybenzyl)-4H-1,2,4-triazole (4d). Yield
94%, mp 105–106°C. 1H NMR spectrum, δ, ppm: 1.39
t (3H, CH3CH2О, J = 7.0 Hz), 3.11 s (3H, NCH3), 3.82
s (3H, OCH3), 3.99 q (2H, OCH2, J = 7.0 Hz), 4.03
br.s (2H, CH2Ar), 4.19 s (2H, SCH2), 6.76 d (1HAr),
6.76–6.81 m (2HAr), 7.02–7.07 m (2HAr), 7.08 d.d
(1HAr, J = 2.2 Hz), 7.45 d (1HAr, J = 2.2 Hz). Found,
%: C 53.26; H 4.71; N 9.12; S 7.32. C20H22BrN3O2S.
Calculated, %: C 53.57; H 4.95; N 9.37; S 7.15.
ppm: 0.98 d [6H, (CH3)2CH, J = 6.6 Hz], 1.61–1.71 m
(2H, CH2CN), 1.81–1.94 m [1H, CH(CH3)2], 3.75 s
(2H, CH2Ar), 33.03 t (2H, CH2CN, J = 6.6 Hz), 3.80 s
(2H, CH2Ar), 3.95 q (2H, OCH2, J = 7.0 Hz), 4.02 t
(2H, NCH2, J = 6.6 Hz), 6.75–6.85 m (3HAr), 7.12–
7.22 m (2HAr), 7.42–7.52 m (3HAr). Found, %: C
62.47; H 5.53; N 12.43; S 7.13. C23H25ClN4OS. Cal-
culated, %: C 62.64; H 5.71; N 12.70; S 7.27.
Alkylation of 4,5-disubstituted 4H-1,2,4-triazole-
3-thiol. A mixture of 1 mmol of triazole 1, 0.056 g
(1 mmol) of KOH, and 15 mL of ethanol was refluxed
for 20–30 min, then 1 mmol of the corresponding
halide was added, and the mixture was heating during
3–4 h. The solvent was distilled off, and 20–30 mL of
water was added. The precipitate was filtered off and
recrystallized from ethanol. When using aliphatic acids
halides, the reactions were carried out via boiling for 5–
6 h in water (15 mL) in the presence of a 3-fold excess
of KOH, followed by acidification and precipitation
with acetic acid.
1-[4-({[4-Methyl-5-(4-ethoxybenzyl)-4H-1,2,4-tri-
azol-3-yl]sulfanyl}methyl)-3-methoxyphenyl]etha-
1
none (4e). Yield 78%, mp 78–80°C. H NMR spec-
trum, δ, ppm: 1.39 t (3H, CH3CH2О, J = 7.0 Hz), 2.45
s (3H, COCH3), 3.16 s (3H, NCH3), 3.89 s (3H,
OCH3), 3.99 q (2H, OCH2, J = 7.0 Hz), 4.01 br.s (2H,
CH2Ar), 4.27 s (2H, SCH2), 6.73–6.78 m (2HAr), 6.96
d (1HAr, J = 8.6 Hz), 7.00–7.05 m (2HAr), 7.75 d
(1HAr, J = 2.2 Hz), 7.84 d. d (1HAr, J = 8.6 Hz).
Found, %: C 64.47; H 6.31; N 10.49; S 7.51.
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FUNCTIONALIZATION OF 5-(4-ALKOXYBENZYL)-4-R-4H-1,2,4-TRIAZOLE-3-THIOLS
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C22H25N3O3S. Calculated, %: C 64.21; H 6.12; N
10.21; S 7.79.
7.0 Hz), 3.76 s (2H, SCH2), 3.98 q (2H, OCH2, J =
7.0 Hz), 4.02 br.s (2H, CH2Ar), 4.43 d.t (2H, CH2All,
J = 5.2, 1.6 Hz), 4.89 d.t (1H, =CH2, J = 17.1,
1.6 Hz), 5.11 d.q (1H, =CH2, J = 10.3, 1.6 Hz), 5.63
d.d.t (1H, =CH, J = 17.1, 10.3, 5.2 Hz), 6.75–6.80 m
(2HAr), 6.91 br.s (1H, CONH2), 7.05–7.10 m (2HAr),
7.51 br.s (1H, CONH2). Found, %: C 57.61; H 6.27; N
16.53; S 9.37. C16H20N4O2S. Calculated, %: C 57.81;
H 6.06; N 16.86; S 9.65.
2-{[4-Phenyl-5-(4-ethoxybenzyl)-4H-1,2,4-triazol-
3-yl]sulfanyl}propanoic acid (4f). Yield 71%, mp
1
110–111°C. H NMR spectrum, δ, ppm: 1.37 t (3H,
CH3CH2O, J = 7.0 Hz), 1.52 d (3H, CH3CH, J =
7.1 Hz), 3.87 br.s (2H, CH2Ar), 3.95 q (2H, OCH2, J =
7.0 Hz), 4.16 q (1H, CH, J = 7.1 Hz), 6.61–6.66 m
(2HAr), 6.76–6.81 m (2HAr), 7.10–7.15 m (2HAr), 7.43–
7.53 m (3HAr), 12.60 br.s (1H, COOH). Found, %: C
62.33; H 5.27; N 10.68; S 8.57. C20H21N3O3S.
Calculated, %: C 62.64; H 5.52; N 10.96; S 8.36.
5-(4-Butoxybenzyl)-4-phenyl-3-(isopropylsulfanyl)-
1
4H-1,2,4-triazole (4k). Yield 70%, mp 56–58°C. H
NMR spectrum, δ, ppm: 0.98 t (3H, CH3CH2, J = 7.4
Hz), 1.35 d [6H, (CH3)2CH, J = 6.7 Hz], 1.41–1.54 m
(2H, CH3CH2), 1.66–1.76 m (2H, C2H5CH2), 3.71
septet (1H, CH, J = 6.7 Hz), 3.85 br.s (2H, CH2Ar),
3.87 t (2H, OCH2, J = 6.4 Hz), 6.61–6.66 m (2HAr),
6.75–6.80 m (2HAr), 7.04–7.09 m (2HAr), 7.41–7.51 m
(3HAr). Found, %: C 69.07; H 7.38; N 10.78; S 8.14.
C22H27N3OS. Calculated, %: C 69.26; H 7.13; N 11.01;
S 8.40.
2-{[4-Phenyl-5-(4-ethoxybenzyl)-4H-1,2,4-triazol-
3-yl]sulfanyl}acetamide (4g). Yield 95%, mp 113–
114°C. 1H NMR spectrum, δ, ppm: 1.37 t (3H,
CH3CH2О, J = 7.0 Hz), 3.80 s (2H, SCH2), 3.86 br.s
(2H, CH2Ar), 3.94 q (2H, OCH2, J = 7.0 Hz), 6.61–
6.66 m (2HAr), 6.77–6.82 m (2HAr), 6.93 br.s (1HAr),
7.50 br.s (1H, CONH2), 7.14–7.20 m (2HAr), 7.44–7.53
m (3HAr). 13C NMR spectrum, δC, ppm: 14.3 (CH3),
29.9 (CH2), 35.5 (SCH2), 62.4 (OCH2), 113.8, 126.94,
126.98, 128.9, 129.1, 129.2, 132.7. 150.1, 154.1,
157.1, 168.2 (C=O). Found, %: C 61.68; H 5.19; N
15.51; S 8.47. C19H20N4O2S. Calculated, %: C 61.93;
H 5.47; N 15.21; S 8.70.
2-{[4-Benzyl-5-(4-butoxybenzyl)-4H-1,2,4-triazol-
3-yl]sulfanyl}hexanoic acid (4l). Yield 96%, mp 113–
114°C. 1H NMR spectrum, δ, ppm: 0.89 t [3H,
CH3(CH2)3CH, J = 7.0 Hz], 0.98 t [3H, CH3(CH2)3,
J = 7.4 Hz], 1.25–1.39 m (4H, 2CH2), 1.41–1.54 m
(2H, CH2), 1.66–1.90 m (4H, 2CH2), 3.85 br.s (2H,
CH2Ar), 3.87 t (2H, OCH2, J = 6.4 Hz), 4.03 d.d (1H,
CH, J = 7.4, 6.8 Hz), 6.61–6.66 m (2HAr), 6.75–6.80 m
(2HAr), 7.11–7.16 m (2HAr), 7.43–7.53 m (3HAr).
Found, %: C 66.47; H 6.91; N 9.47; S 7.31. C25H31N3O3S.
Calculated, %: C 66.20; H 6.89; N 9.26; S 7.07.
2-{[4-Phenyl-5-(4-ethoxybenzyl)-4H-1,2,4-triazol-
3-yl]sulfanyl}acetic acid (4h). Yield 69%, mp 138–
140°C. 1H NMR spectrum, δ, ppm: 1.37 t (3H,
CH3CH2О, J = 7.0 Hz), 3.88 s (2H, SCH2), 3.94 br.s
(2H, CH2Ar), 3.96 q (2H, OCH2, J = 7.0 Hz), 5.02 s
(2H, NCH2), 6.69–6.74 m (2HAr), 6.91–6.96 m (2HAr),
6.97–7.02 m (2HAr), 7.20–7.30 m (3HAr), 12.69 br.s
(1H, COOH). Found, %: C 62.58; H 5.51; N 14.32; S
8.31. C20H22N4O2S. Calculated, %: C 62.80; H 5.80; N
14.65; S 8.38.
Ethyl 2-{[5-(4-butoxybenzyl)-4-phenyl-4H-1,2,4-
triazol-3-yl]sulfanyl}acetate (4m). Yield 58%, mp 77–
79°C. 1H NMR spectrum, δ, ppm: 0.98 t [3H,
CH3(CH2)3O, J = 7.4 Hz], 1.26 t (3H, CH3CH2O, J =
7.1 Hz), 1.42–1.54 m [2H, CH3CH2(CH2)2], 1.66–1.76
m (2H, C2H5CH2CH2O), 3.87 br.s (2H, CH2Br), 3.87 t
(2H, OCH2, J = 6.4 Hz), 3.94 s (2H, SCH2), 4.14 q
(2H, CH3CH2O, J = 7.1 Hz), 6.62–6.67 m (2HAr), 6.76–
6.81 m (2HAr), 7.13–7.18 m (2HAr), 7.44–7.54 m
(3HAr). Found, %: C 64.67; H 6.21; N 9.62; S 7.34.
C23H27N3O3S. Calculated, %: C 64.92; H 6.40; N 9.88;
S 7.54.
3-[(3-Bromo-4-methoxybenzyl)sulfanyl]-4-phenyl-
5-(4-ethoxybenzyl)-4H-1,2,4-triazole (4i). Yield 93%,
1
mp 115–116°C. H NMR spectrum, δ, ppm: 1.38 t
(3H, CH3CH2O, J = 7.0 Hz), 3.84 s (3H, OCH3), 3.89
br.s (2H, CH2Ar), 3.97 q (2H, OCH2, J = 7.0 Hz), 4.23
s (2H, SCH2), 4.79 s (2H, NCH2), 6.70–6.75 m (2HAr),
6.75–6.79 m (2HAr), 6.81 d (1HAr, J = 8.5 Hz), 6.94–
6.99 m (2HAr), 7.16 d. d (1HAr, J = 8.5, 2.2 Hz), 7.18–
7.23 m (3HAr), 7.45 d (1HAr, J = 2.2 Hz). Found, %: C
59.31; H 9.67; N 8.39; S 6.42. C26H26BrN3O2S.
Calculated, %: C 59.54; H 10.00; N 8.01; S 6.11.
2-{[5-(4-Butoxybenzyl)-4-phenyl-4H-1,2,4-triazol-3-
1
yl]sulfanyl}acetamide (4n). Yield 68%, mp 95–96°C. H
NMR spectrum, δ, ppm: 098 t [3H, CH3(CH2)3O, J =
7.3 Hz], 1.41–1.54 m (2H, CH3CH2CH2CH2O), 1.66–1.76
m (2H, C2H5CH2CH2O), 3.80 s (2H, SCH2), 3.86 br.s (2H,
CH2Ar), 3.87 t (2H, OCH2, J = 6.4 Hz), 6.62–6.67 m
2-{[4-Allyl-5-(4-ethoxybenzyl)-4H-1,2,4-triazol-3-
yl]sulfanyl}acetamide (4j). Yield 78%, mp 143–144°C.
1H NMR spectrum, δ, ppm: 1.38 t (3H, CH3CH2O, J =
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 5 2017

978
HAKOBYAN et al.
Melik-Ohanjanyan, R.G., Pharm. Chem. J., 2011,
vol. 45, no. 12, p. 705. doi 10.1007/511094-012-0706-3
7. Hovsepyan, T.R., Dilanyan, S.V., Hakobyan, M.R.,
Minasyan, N.S., Paronikyan, R.V., and Melik-
Ohanjanyan, R.G., Khim. Zh. Arm., 2016, vol. 69,
nos. 1–2, p. 121.
(2HAr), 6.77–6.82 m (2HAr), 6.94 br.s (1HAr), 7.49 br.s
(1HAr), 7.51 br.s (1H, CONH2), 7.16–7.21 m (2HAr), 7.44–
7.54 m (3HAr). Found, %: C 63.38; H 6.41; N 14.28; S 8.34.
C21H24N4O2S. Calculated, %: C 63.61; H 6.10; N 14.13; S
8.09.
8. Hovsepyan, T.R., Arsenyan, F.H., Nersesyan, L.E.,
Aharonyan, A.S., Danielyan, I.S., Paronikyan, R.V., and
Melik-Ohanjanyan, R.G., Pharm. Chem. J., 2015,
vol. 49, no. 4, p. 231. doi 10.1007/s11094-015-1261-5
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