Synthesis of New Substituted 1,2,4-Triazoles and 1,3,4-Thiadiazoles and Their Effects on DNA Methylation Level

Article abstract of DOI:10.1134/S1070363219040066

Continuing the search for biologically active compounds among functionally substituted azoles, new 1,2,4-triazole-3-thiols and 1,3,4-thiadiazoles derivatives bearing pharmacologically active carboxamide, hydroxyl or carboxyalkyl moieties, as well as N-acy

Full text of DOI:10.1134/S1070363219040066

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 4, pp. 673–679. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Authors(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 4, pp. 534–541.
Synthesis of New Substituted 1,2,4-Triazoles
and 1,3,4-Thiadiazoles and Their Effects on DNA Methylation Level
T. R. Hovsepyana*, M. R. Hakobyana, R. E. Muradyana, L. E. Nersesyana,
A. S. Agaronyana, I. S. Danielyana, and N. S. Minasyanb
a A.L. Mndzhoyan Institute of Fine Organic Chemistry of the Scientific and Technological Center
of Organic and Pharmaceutical Chemistry of the National Academy of Sciences of the Republic of Armenia,
pr. Azatutyan 26, Yerevan, 0014 Armenia
*e-mail: tag.hovsepyan@mail.ru
b Molecular Structure Research Center of the Scientific and Technological Center
of Organic and Pharmaceutical Chemistry of the National Academy of Sciences, Yerevan, Armenia
Received November 8, 2018; revised November 8, 2018; accepted November 15, 2018
Abstract—Continuing the search for biologically active compounds among functionally substituted azoles, new
1,2,4-triazole-3-thiols and 1,3,4-thiadiazoles derivatives bearing pharmacologically active carboxamide,
hydroxyl or carboxyalkyl moieties, as well as N-acyclonucleoside, N-cyano- or carboxyethyl fragments were
synthesized. Ability of some compounds obtained to inhibit the methylation of tumor DNA in vitro was
revealed. The compound with the highest activity was selected for further in vivo studies.
Keywords: 1,2,4-triazole, 1,3,4-thiadiazole, cyanoethylation, alkylation, acyclonucleoside, DNA methylation
DOI: 10.1134/S1070363219040066
In recent years, 1,2,4-triazole and 1,3,4-thiadiazole
derivatives are of great interest due to the fact that
many of them exhibit a wide spectrum of biological
activity [1, 2], have been used as drugs or are on the
way to introduction into medical practice as anti-
neoplastic [3–5], antibacterial [6, 7], antifungal [8, 9],
antiviral [10, 11], anticonvulsant [12, 13] and other
drugs.
Herein we reported the synthesis of new 1,2,4-
triazole-3-thiol and 1,3,4-thiadiazole derivatives bearing
3-bromophenoxymethylene and benzyl substituents at
the 5-position of heterocycles and some their trans-
formations (Scheme 1). The valuable biological
properties of 1,2,4-triazole-3-thiols [1] served as the
basis for the introduction of new functionalities into
the heteroring by the previously known methods [19].
The starting 4H-1,2,4-Triazole-3-thiols 1a–1e were
obtained by intramolecular cyclization of 1,4-disub-
stituted thio-semicarbazides by the method reported in
[14]. Aliphatic acids halides, 2-chloroacetamide, as
well as ethylene chlorohydrin (2-chloroethanol) were
chosen as alkylating agents. Structure of triazoles
Among some previously synthesized compounds
with 4-bromophenyl [14], 4-bromo(chloro)phenoxy-
methylene [15], 4-alkoxybenzyl [16, 17] substituents,
substances possessing a moderate antitumor effect on
tumor DNA methylation, mutagenic and antimutagenic
effects have been revealed [18]. Most of these
compounds are of little or no toxicity. Diversity of the
biological properties of 1,2,4-triazole and 1,3,4-
thiadiazole derivatives indicates a peculiar influence of
pharmacologically active substituents in certain posi-
tions of heterocycles on biological activity. In this
regard, it seems promising to expand the range of this
class of compounds by developing new ways of their
functionalization and continuing to study their pharma-
cological activity.
1
2a–2g was confirmed by the IR and H NMR spectro-
scopy data. The singlet signals of the SCH2 group in
1
the range of 3.80–4.10 ppm in the H NMR spectra of
compounds 2a–2g indicate that the alkylation proceeds
at the SH nucleophilic site of compounds 1a–1e.
The Mannich reaction of triazole 1b with mor-
pholine at room temperature resulted in the N2-amino-
methyl derivative 3a. The carboxy- or cyanoethylation
reactions with freshly distilled acrylonitrile and acrylic
673

674
HOVSEPYAN et al.
Scheme 1.
O
C
N N
S
H
(1) H2SO4
R1
N
NHR2
R1
(2) CH2=CHCN
NR2R3
N
C
S
H
4a, 4b
KOH, H2O
N N
N NH
R1
R1
SH
S
N
N
1a−1e
R2
R2
HlgR3, CH2O
HlgR3
R3
S
N N
N N
N
R1
R1
SR3
N
R2
R2
3a−3c
2a−2g
R1 = Ph, R2 = Ph (1a), C6H11 (1b); R1 = 3-BrC6H4O, R2 = Bn (1c), All (1d), C6H11 (1e); R1 = Ph, R2 = C6H11, R3 =
CH2CH2OH (2а); R1 = 3-BrC2H4O, R2 = Bn, R3 = CH2CH2OH (2b), CH2CONH2 (2c), CH2COOH (2d), CH(CH3)COOH
(2e); R1 = 3-BrC2H4O, R2 = C6H11, R3 = CH2COOH (2f); R1 = 3-BrC2H4O, R2 = All, R3 = CH2CONH2 (2g); R1 = Ph, R2 =
C6H11, R3 = morpholin-4-yl (3а); R1 = R2 = Ph, R3 = CH2CN (3b), CH2COOH (3c); R1 = Ph, R2 = H, R3 = COPh (4а); R1 =
Ph, R2 = CH2CH2CN, R3 = COPh (4b).
acid in the presence of triethylamine as a catalyst
spectra confirmed the formation of N-(5-benzyl-1,3,4-
thiadiazol-2-yl)-N-(2-cyanoethyl)benzamide 4b.
furnished N2-substituted 1,2,4-triazoles 3b and 3c. In
1
the H NMR spectrum of compound 3a, in contrast to
In order to functionalize the 1,2,4-triazole ring,
using compounds 5a and 5b as examples, an attempt
was made to introduce 2-(hydroxyethoxy)methyl frag-
ment into position 4, which has structural similarity to
the carbohydrate part of the structure of natural
nucleosides and is a component of the antiviral drug
acyclovir [21, 22] (Scheme 2).
the spectra of S-alkylated derivatives 2a–2g, a
relatively weak-field singlet signal of the NCH2N group
is observed in the 5.02 ppm region. In the spectra of
compounds 3b and 3c, there are triplet signals of the
NCH2CH2 group in the corresponding regions, which
confirm the structure of compounds obtained.
4-Benzoyl substituted thiosemicarbazide under-
went readily cyclization to the corresponding 1,3,4-
thiadiazole 4a when dehydrated in the presence of
concentrated sulfuric acid. Taking into account binucleo-
philic reactivity of 1,3,4-thiadiazole-2-amines, the
obtained N-(5-benzyl-1,3,4-thiadiazole-2-yl)benzamide
4a was subjected to cyanoethylation in order to clarify
to which reaction site—endocyclic N3 atom or amine
nitrogen atom in the side chain—a cyanoethyl group is
attached. In a similar reaction with 5-substituted 1,3,4-
thiadiazole-2-thiols, not the SH group, but the endo-
cyclic nitrogen atom N3 is subjected to cyanoethylation
The starting triazoles 6a, 6b were obtained by
alkylation of 1,2,4-triazole-3-thiols 5a, 5b [1, 18];
2-(chloromethoxy)ethyl benzoate was synthesized by
chloromethylation of 2-hydroxyethyl benzoate accord-
ing to the procedure [22, 23]. From the known
methods for the synthesis of acyclonucleosides
[21–23], we chosen the simplest and most accessible—
fusion of the starting materials at 110–120°C.
Intermediate benzoates were isolated by column
chromatography and, without further purification, were
debenzylated by reacting with sodium methoxide in
absolute methanol [24]. After appropriate purification
by column cromatography, compounds 7a and 7b were
1
[20]. In this case, the analysis of H and 13C NMR
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 4 2019

SYNTHESIS OF NEW SUBSTITUTED 1,2,4-TRIAZOLES AND 1,3,4-THIADIAZOLES
675
Scheme 2.
N
N
N
N
ClCH2COOC2H5
SCH2COOC2H5
SH
R
R
N
N
H
H
5a, 5b
6a, 6b
N
N
N
O
N
O
OC2H5
C H
OCO
CH
OCH
CH
Cl
CH3ONa
CH3OH
6
5
2
2
2
R
S
C
S
R
COOH
OH
N
N
O
7a, 7b
OCC6H5
O
R = Bn, 4-Br-C6H4.
isolated as pale yellow crystalline compounds. Struc-
ture of compounds obtained was proved by analytical
and spectral data, indicating that ethoxycarbonyl
groups are subjected to saponification in the reaction
medium with the formation of the corresponding
synthesized. Some of the compounds obtained inhibit
the methylation of tumor DNA, indicating the promise
of searching for anticancer drugs among the studied
class of compounds.
EXPERIMENTAL
1
sulfanylacetic acids. In the H NMR spectra, a broad
IR spectra were registered on a Nicolet Avatar 330
FT-IR spectrometer in petroleum oil. NMR spectra
were recorded on a Varian Mercury-300VX instrument
in DMSO-d6 relative to internal TMS. Melting points
were determined on a Boetius 72/2064 instrument. The
reaction progress and individuality of the obtained
compounds were monitored by TLC on Silica gel
60F254 plates (Germany), eluting with a benzene–
dioxane, 2 : 1 (1a–1e, 2a–2g, 3a–3c), benzene–
dioxane, 1 : 1 (4a, 4b), or benzene‒ethyl acetate, 1 : 1
(6, 7a, 7b), detecting with UV irradiation.
singlet signal of the OH group is characteristic in the
range of 4.46‒4.47 ppm.
The IR spectra of compounds 7a and 7b contain
the bands of stretching and bending vibrations of the
CH2OCH2, CH2OH, C=O, and COOH groups.
We studied the effect of functionalized 1,2,4-tri-
azoles 2, 3, 7, and 1,3,4-thiadiazoles 4a, 4b on the
level of tumor DNA methylation in vitro on the
sarcoma 180 (C-180) model according to the method
described in [25].
A clear difference between DNA samples from
tumor tissue after exposure to the studied compounds
was found only in relation to the content of 5-
methylcytosine (5-MC). Compounds 2f, 2a, 2g, which
suppress the methylation level of tumor DNA by 63.5,
43.2, and 40.5%, respectively, have the most activity
(see the table). Compounds 2c (32.4%), 2d (35.1%),
and 3a (35.1%) have weak demethylation activity.
Compounds 2b, 2e, and 7a cause an increase in the
amount of 5-methylcytosine. From the data obtained, it
can be seen that half of the compounds with tumor
DNA activity that inhibit methylation (2a, 2f, 3a)
contain the cyclohexyl group in the position 4 of the
heterocycle. Compounds 2f was chosen for further in
vivo screening.
4,5-Disubstituted 4H-1,2,4-triazole-3-thiols 1a–1e
were synthesized according to the method reported in
[16]; physico-chemical constants of triazoles 1a, 1b
correspond to literature data [2].
4-Benzyl-5-(3-bromophenoxymethyl)-4H-1,2,4-
triazole-3-thiol (1c). Yield 88%, mp 159–160°C. IR
spectrum, ν, cm–1: 3062, 2766, 1589, 1577, 1494,
1
1470, 1284, 1226, 1044, 941, 860. Н NMR spectrum,
δ, ppm (J, Hz): 4.97 s (2Н, OCH2), 5.32 s (2H, NCH2),
6.76 d. d. d (1HAr, J = 8.0, 2.5, 1.2), 6.92 d. d (1HAr,
J = 2.5, 1.7), 7.07 d. d. d (1HAr, J = 7.9, 1.7, 1.2), 7.14
d. d (1HAr, J = 8.0, 7.9), 7.22‒7.29 m (5HAr). 13С NMR
spectrum, δС, ppm: 46.0 (NCH2), 59.9 (OCH2), 113.1
(CH), 117.5 (CH), 121.8 (C), 124.1 (CH), 126.9 (2CH),
127.1 (CH), 127.9 (2CH), 130.1 (CH), 135.1 (C),
146.8 (C), 157.6 (C), 168.51 (C). Found, %: N 11.29; S
8.67. C16H14BrN3OS. Calculated, % : N 11.17; S 8.52.
In summary, a new series of functionally sub-
stituted 1,2,4-triazoles and 1,3,4-thiadiazoles were
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676
HOVSEPYAN et al.
The effect of compounds 1–7 on the level of tumor DNA methylation
Base content in DNA, mol%
Change in methylation
level, %
Compound
5-MC
G+C+5-MC
42.66
43.34
42.08
43.72
42.06
42.00
42.48
42.02
44.72
42.02
42.78
44.76
42.12
43.00
42.68
DNA source, (С-180)-control
0.74±0.02
0.42±0.02
1.03±0.02
0.05±0.01
0.48±0.02
1.53±0.01
0.27±0.02
0.44±0.02
0.48±0.02
0.68±0.01
0.53±0.01
0.61±0.02
0.72±0.02
1.05±0.01
0.61±0.01
2а
2b
2c
2d
2e
2f
43.2а
_
32.4а
35.1а
_
63.5а
40.5а
35.1а
_
2g
3a
3b
3c
4a
4b
7a
7b
28.4
17.6
_
_
17.6
а p < 0.05.
Alkylation of 4,5-disubstituted 4H-1,2,4-triazole-3-
thiols 1a–1e was performed as described in [16].
4-Allyl-5-(3-bromophenoxymethyl)-4H-1,2,4-tri-
azole-3-thiol (1d). Yield 89%, mp 108‒109°C. IR
spectrum, ν, cm–1: 3311, 3209, 3051, 2678, 1630, 1596,
1549, 1535, 1511, 1477, 1455, 1424, 1413, 1358, 1334,
1300, 1280, 1239, 1205, 1160, 1072, 1029, 939, 879,
2-[(5-Benzyl-4-cyclohexyl-4H-1,2,4-triazol-3-yl)-
sulfanyl]ethanol (2a). Yield 88%, mp 94‒95°C. IR
spectrum, ν, cm–1: 3164, 1691, 1519, 1494, 1456,
1440, 1412, 1377, 1367, 1332.6, 1282, 1199, 1073. 1Н
NMR spectrum, δ, ppm (J, Hz): 1.05‒1.45 m (5Н),
1.54‒1.78 m (3Н) and 1.86‒2.02 m (2Н, С6Н11), 3.28 t
(2Н, SСН2, J = 6.5), 3.71 q (2H, CH2OH, J = 6.5),
3.82‒3.93 m (1Н, NСН), 4.16 s (2Н, CСН2C), 4.77 t
(1Н, OH, J = 5.6), 7.17‒7.31 m (5НAr). Found, %: N
13.41; S 10.31. C17H23N3OS. Calculated, %: N 13.23;
S 10.10.
1
866. Н NMR spectrum, δ, ppm (J, Hz): 4.71 d. t (2H,
NCH2, J = 5.7, 1.5), 5.11 s (2H, OCH2), 5.10–5.25 m
(2H, =CH2), 5.85‒5.98 m (1H, =CH), 6.98 d. d. d
(1HAr, J = 8.2, 2.5, 1.0), 7.06 m (2HAr), 13.75 br. s
(1H, SH). Found, %: N 12.61; S 9.59. C12H12BrN3OS.
Calculated, %: N 12.88; S 9.83.
5-(3-Bromphenoxymethyl)-4-cyclohexyl-4H-1,2,4-
triazole-3-thiol (1e). Yield 91%, mp 123‒124°C. IR
spectrum, ν, cm–1: 3091, 3041, 2749, 1590, 1577, 1495,
1471, 1456, 1424, 1370, 1352, 1342, 1297, 1279, 1244,
2-{[4-Benzyl-5-(3-bromophenoxymethyl)-4H-
1,2,4-triazol-3-yl]sulfanyl}ethanol (2b). Yield 83%,
mp 84‒85°C. IR spectrum, ν, cm–1: 3311, 1592, 1577,
1
1
1222, 1031, 854, 771. Н NMR spectrum, δ, ppm (J,
1527, 1466, 1398, 1377, 1282, 1222, 1068, 1014. Н
Hz): 1.14‒1.29 m (1Н), 1.35‒1.52 m (2Н), 1.66‒1.74
m (1Н), 1.83‒1.94 m (4Н) and 2.09‒2.28 m (2Н,
С6Н11), 4.44‒4.58 m (1Н, NСН), 5.15 s (2Н, ОСН2),
6.99 d. d. d (1НAr, J = 8.2, 2.5, 1.1), 7.12 d. d. d (1НAr,
J = 7.7, 1.8, 1.1), 7.18‒7.24 m (2HAr), 13.68 s (1H,
SH). Found, %: N 11.26; S 8.52. C15H18BrN3OS.
Calculated, %: N 11.41; S 8.71.
NMR spectrum, δ, ppm (J, Hz): 3.28 t (2Н, SCH2, J =
6.4), 3.70 q (2H, CH2OH, J 6.5), 4.75 t (1Н, ОН, J =
5.7), 4.95 s (2H, OCH2), 5.21 s (2H, NCH2), 6.74 d. d.
d (1НAr, J = 8.0, 2.5, 1.2), 6.89 d. d (1НAr, J = 2.5, 1.2),
7.04 d. d. d (1HAr, J = 7.9, 1.7, 1.2), 7.12 d. d (1HAr,
J = 8.0, 7.9), 7.19‒7.27 m (5HAr). Found, %: N 9.48; S
7.31. C18H18BrN3O2S. Calculated, %: N 9.99; S 7.63.
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SYNTHESIS OF NEW SUBSTITUTED 1,2,4-TRIAZOLES AND 1,3,4-THIADIAZOLES
677
2-{[4-Benzyl-5-(3-bromophenoxymethyl)-4H-
1,2,4-triazol-3-yl]sulfanyl}acetamide (2c). Yield
98%, mp 186‒188°C. IR spectrum, ν, cm–1: 3388,
3106, 1698, 1638, 1593, 1578, 1473, 1457, 1440, 1395,
1378, 1282, 1220, 1025. 1Н NMR spectrum, δ, ppm (J,
Hz): 3.87 s (2Н, SCH2), 5.18 s (2H, OCH2), 5.27 s
(2H, NCH2), 6.85 d. d. d (1НAr, J = 8.2, 2.5, 1.0), 6.95
br. s (1Н), 7.52 br. s (1Н, NH2), 7.00‒7.08 m (3НAr),
7.10‒7.15 m (2НAr), 7.26‒7.34 m (3НAr). Found, %: N
12.81; S 7.28. C18H17BrN4O2S. Calculated, %: N
12.93; S 7.40.
СН2), 4.68 d. t (2Н, NCH2, J = 5.4, 1.6), 5.08 d. q (1Н,
=CH2, J = 17.0, 1.6), 5.23 s (2H, OCH2), 5.24 d. q (1Н,
=CH2, J = 10.5, 1.6), 5.94 d. d. t (1Н, =CH, J = 17.0,
10.5, 1.6), 6.92 br. s (1Н), 7.50 br. s (1Н, NH2), 7.01 d.
d. d (1Н, J = 8.2, 2.5, 1.0), 7.09 d. d. d (1Н, С6Н4, J =
7.8, 1.8, 1.0) and 7.18 d. d (1НAr, J = 8.2, 7.8), 7.21 d.
d (1НAr, J = 2.5, 1.8). Found, %: N 14.43; S 8.11.
C14H15BrN4O2S. Calculated, %: N 14.62; S 8.37.
5-Benzyl-2-[(morpholin-4-yl)methyl]-4-cyclohexyl-
2H-1,2,4-triazole-3-thione (3a). To a solution of tri-
azole 1c (0.27 g, 1 mmol) in 8‒10 mL of methanol
were added 0.12 g (1.3 mmol) of morpholine and 0.14 g
(1.6 mmol) of formalin. The obtained mixture was
stirred at room temperature for 8‒10 h. The precipitate
was filtered off, washed with 5‒10 mL of water and
recrystallized from ethanol. Yield 67%, mp 94‒96°C.
1Н NMR spectrum, δ, ppm: 1.09‒1.34 m (3Н), 1.40‒
1.67 m (3Н), 1.71‒1.83 m (2Н) and 2.08‒2.36 br. s
(2Н, С6Н11), 2.70–2.74 m [4Н, О(СН2)2], 3.56‒3.63 m
[4Н, О(СН2)2], 4.14 s (2Н, СН2), 4.25‒4.37 m (1Н,
NСН), 5.00 m (2Н, NСН2N), 7.18‒7.36 m (5НAr). 13С
NMR spectrum, δС, ppm: 24.2 (СН2), 25.3 (2СН2),
28.3 (2СН2), 31.5 (СН2), 50.2 (2СН2), 56.9 (NСН2),
65.8 (2СН2), 68.0 (NСН), 126.8 (СН), 127.8 (СН),
128.1 (СН), 134.7 (С), 148.6 (С), 167.6 (СS). Found,
%: N 14.87; S 8.41. C20H28N4OS. Calculated, %: N
15.04; S 8.60.
2-{[4-Benzyl-5-(3-bromophenoxymethyl)-4H-
1,2,4-triazol-3-yl]sulfanyl}acetic acid (2d). Yield
93%, mp 155–156°C. IR spectrum, ν, cm-1: 1948,
1706.1, 1592, 1579, 1472, 1443, 1400, 1341, 1282,
1219, 1202, 1190, 1018. 1Н NMR spectrum, δ, ppm (J,
Hz): 3.94 s (2H, SCH2), 3.01 br. s (1Н, СООН), 5.17 s
(2Н, ОСН2), 5.28 s (2Н, NCH2), 6.86 d. d. d (1НAr, J =
8.2, 2.5, 1.0), 6.99‒7.02 m (2НAr), 7.03‒7.07 m (1НAr),
7.11‒7.15 m (2Н) and 7.25‒7.31 m (3НAr). Found, %:
N 9.46; S 7.21. C18H16BrN3O3S. Calculated, %: N
9.67; S 7.38.
2-{[4-Benzyl-5-(3-bromophenoxymethyl)-4H-
1,2,4-triazol-3-yl]sulfanyl}propanoic acid (2e). Yield
91%, mp 145‒146°C. IR spectrum, ν, cm–1: 1721,
1587, 1578, 1464, 1451, 1377, 1360, 1284, 1225,
1
1194. Н NMR spectrum, δ, ppm (J, Hz): 1.57 d (3Н,
3-(5-Benzyl-3-thioxo-4-phenyl-2H-1,2,4-triazol-2-
yl)propanenitrile (3b). A mixture of 0.26 g (1 mmol)
of triazole 1a, 1.62 g (30 mmol) of freshly distilled
acrylonitrile, 4 mL of water and 3.0 g (30 mmol) of
triethylamine was refluxed for 8–10 h. The solution
was evaporated; the crystalline residue was recrystal-
lized from ethanol. Yield 62%, mp 74‒75°C. 1Н NMR
spectrum, δ, ppm (J, Hz): 3.08 t (2Н, СН2СN, J = 6.6),
3.90 s (2Н, СН2), 4.47 t (2Н, NСН2, J = 6.6), 6.88‒
6.96 m (2НAr), 7.11‒7.21 m (5НAr), 7.41‒7.51 m
(3НAr). 13С NMR spectrum, δС, ppm: 15.7 (СН2), 31.6
(СН2), 43.9 (NСН2), 116.4 (С≡N), 126.4 (СН), 127.8
(2СН), 127.9 (2СН), 128.10 (2СН), 128.7 (2СН),
129.0 (СН), 133.3 (С), 133.6 (С), 149.6 (С), 167.5 (С).
Found, %: N 17.23; S 9.73. C18H16N4S. Calculated, %:
N 17.48; S 10.00.
СНСН3, J = 7.1), 3.90 br. s (1Н, СООН), 4.20 q (1Н,
СН, J = 7.1), 5.17 s (2Н, ОСН2), 5.28 s (2Н, NCH2),
6.85 d. d. d (1НAr, J = 8.2, 2.4, 1.1), 7.00 d. d (1НAr,
J = 2.4, 1.7), 7.04‒7.10 m (3НAr), 7.14 d. d (1НAr, J =
8.2, 7.8), 7.25‒7.33 m (3НAr). Found, %: N 9.12; S
7.01. C19H18BrN3O3S. Calculated, %: N 9.37; S 7.15.
2-{[5-(3-Bromphenoxymethyl)-4-cyclohexyl-4H-
1,2,4-triazol-3-yl]sulfanyl}acetic acid (2f). Yield
81%, mp 79‒80°C. IR spectrum, ν, cm–1: 1723, 1589,
1
1577, 1465, 1376, 1280, 1221, 1183, 1027. Н NMR
spectrum, δ, ppm (J, Hz): 1.18‒1.48 m (3Н), 1.67‒1.77
m (1Н), 1.85‒1.97 m (4Н) and 2.00‒2.15 m (2Н,
С6Н11), 3.65 br. s (1Н, СООН), 4.00 s (2Н, SCH2),
4.08‒4.21 m (1Н, NCH), 5.26 s (2Н, ОСН2), 7.01 d. d.
d (1НAr, J = 8.2, 2.4, 1.0), 7.08‒7.12 m (1НAr), 7.19 d
(1НAr, J = 8.2), 7.21‒7.23 m (1НAr). Found, %: N 9.67;
S 7.38. C17H20BrN3O3S. Calculated, %: N 9.86; S 7.52.
3-(5-Benzyl-3-thioxo-4-phenyl-2H-1,2,4-triazol-2-
yl)propanoic acid (3c) was obtained similarly from
0.26 g (1 mmol) of triazole 1a and 0.22 g (3 mmol) of
2-{[4-Allyl-5-(3-bromophenoxymethyl)-4H-1,2,4-
triazol-3-yl]sulfanyl}acetamide (2g). Yield 79%, mp
147‒148°C. IR spectrum, ν, cm–1: 3394, 3105, 1698,
1637, 1592, 1579, 1533, 1467, 1378, 1282, 1219, 1022,
1
acrylic acid. Yield 82%, mp 157‒158°C. Н NMR
spectrum, δ, ppm (J, Hz): 2.83 t (2Н, СН2СО, J = 7.5),
3.86 s (2Н, СН2), 4.39 t (2Н, NСН2, J = 7.5), 6.86‒
6.92 m (2НAr), 7.11‒7.19 m (5НAr), 7.39‒7.48 m
1
762. Н NMR spectrum, δ, ppm (J, Hz): 3.86 s (2Н,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 4 2019

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HOVSEPYAN et al.
(3НAr). 13С NMR spectrum, δС, ppm: 31.2 (СН2), 31.8
(СН2), 44.2 (NСН2), 126.4 (СН), 127.9 (4СН), 128.1
(2СН), 128.7 (2СН), 128.9 (СН), 133.6 (С), 133.8 (С),
149.1 (С), 167.1 (С), 171.1 (С). Found, %: N 12.21; S
9.78. C18H17N3O2S. Calculated, %: N 12.38; S 9.44.
3.90 s (1H) and 4.14 s (1H, CH2S), 4.63 br. s (1Н,
ОН), 5.38 s (1Н) and 5.39 s (1Н, NCH2), 7.13‒7.29 m
(5НAr). Found, %: С 51.67; Н 5.18; N 12.71; S 9.69.
C14H17N3О4S. Calculated, %: С 51.99; Н 5.30; N
12.99; S 9.91.
N-(5-Benzyl-1,3,4-thiadiazol-2-yl)benzamide (4a)
was synthesized according to the procedure [20]. Yield
88%, mp 226‒227°C. IR spectrum, ν, cm–1: 1662,
1600, 1578, 1530, 1486, 1463, 1377, 1321, 1302,
2-{5-(4-Bromophenyl)-4-[(2-hydroxyethoxy)-
methyl]-4H-1,2,4-triazol-3-yl-sulfanyl}acetic acid
(7b). Yield 67%, mp 131‒132°C. IR spectrum, ν, cm–1:
3406, 3161, 1727, 1599, 1466, 1398, 1360, 1199,
1
1
1255, 694. Н NMR spectrum, δ, ppm (J, Hz): 4.32 s
1117, 1069, 1011. Н NMR spectrum, δ, ppm: 3.52‒
(2Н, СН2), 7.17‒7.32 m (2НAr), 7.40‒7.55 m (3Н) and
8.07‒8.13 m (2НAr), 12.59 m (1Н, NH). Found, %: N
14.57; S 10.61. C16H13N3ОS. Calculated, %: N 14.23;
S 10.86.
3.57 m (2Н, СН2), 3.58‒3.64 m (2Н, СН2), 4.0 m
(2НAr), 12.51 br. s (1Н, СООН). Found, %: С 40.03; Н
3.27; N 10.68; S 16.17. C13H14N3О4S. Calculated, %:
С 40.22; Н 3.64; N 10.82; S 8.26.
N-(5-Benzyl-1,3,4-thiadiazol-2-yl)-N-(2-cyano-
ethyl)benzamide (4b) was prepared similarly to
compound 3b. Yield 93%, mp 109‒110°C. IR
spectrum, ν, cm–1: 1608, 1572, 1547, 1497, 1483, 1416,
1389, 1366, 1320, 1298. 1Н NMR spectrum, δ, ppm (J,
Hz): 3.14 t (2Н, СН2СN, J = 6.5), 4.24 s (2H, CH2),
4.72 t (2H, NCH2, J = 6.5), 7.24‒7.35 m (5НAr), 7.39‒
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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