Alkylation of 1,2,4-triazole-3-thiols with haloalkanoic acid esters

Article abstract of DOI:10.1134/S1070428017060203

Alkylation of 4,5-disubstituted 4H-1,2,4-triazole-3-thiols with methyl chloroformate and ethyl chloroacetate chemoselectively afforded the corresponding S-alkyl derivatives, whereas the alkylation of 5-benzyl-4-phenyl-4H-1,2,4-triazole-3-thiol with methyl 3-bromopropanoate gave an inseparable mixture of S- and N-alkylation products. Hydrazinolysis of S-(5-benzyl-4-phenyl-4H-1,2,4-triazol-3-yl) methyl carbonothioate involved anomalous cleavage with formation of the initial 4,5-disubstituted 1,2,4-triazole and methyl hydrazinecarboxylate.

Full text of DOI:10.1134/S1070428017060203

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 6, pp. 935–940. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © M.A. Samvelyan, T.V. Ghochikyan, S.V. Grigoryan, R.A. Tamazyan, A. G. Aivazyan, 2017, published in Zhurnal Organicheskoi
Khimii, 2017, Vol. 53, No. 6, pp. 919–924.
Alkylation of 1,2,4-Triazole-3-thiols
with Haloalkanoic Acid Esters
M. A. Samvelyana,* T. V. Ghochikyana, S. V. Grigoryana, R. A. Tamazyanb, and A. G. Aivazyanb
a Yerevan State University, ul. Aleka Manukyana 1, Yerevan, 0025 Armenia
*e-mail: msamvelyan@ysu.am
b Molecular Structure Research Center, Scientific Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia, pr. Azatutyan 26, Yerevan, 0014 Armenia
Received December 7, 2016
Abstract—Alkylation of 4,5-disubstituted 4H-1,2,4-triazole-3-thiols with methyl chloroformate and ethyl
chloroacetate chemoselectively afforded the corresponding S-alkyl derivatives, whereas the alkylation of
5-benzyl-4-phenyl-4H-1,2,4-triazole-3-thiol with methyl 3-bromopropanoate gave an inseparable mixture of
S- and N-alkylation products. Hydrazinolysis of S-(5-benzyl-4-phenyl-4H-1,2,4-triazol-3-yl) methyl carbono-
thioate involved anomalous cleavage with formation of the initial 4,5-disubstituted 1,2,4-triazole and methyl
hydrazinecarboxylate.
DOI: 10.1134/S1070428017060203
Azole rings are structural fragments of many bio-
logically active compounds which have found applica-
tions in pharmacology and medicine. Among the azole
series, 1,2,4-triazoles have attracted great interest;
some 1,2,4-triazoles are used in medical practice as
antifungal and antimicrobial drugs (examples are
isavuconazole, paclobutrazol, epoxiconazole, tebuco-
nazole, flusilazole, etc.). Recent studies have shown
that 1,2,4-triazole derivatives exhibit a broad spectrum
of biological activity and that the nature of substituent
on the base ring is the main factor determining their
properties. Di- and trisubstituted 1,2,4-triazoles were
reported to display antibacterial [1–3], antifungal
[4, 5], antitumor [6, 7], anti-inflammatory [8, 9],
fungicidal [10, 11], and herbicidal properties [12, 13],
inhibit HIV-1 [14], etc. Apart from biological studies,
extensive search for new methods of synthesis of
1,2,4-triazoles [15] and their derivatives is performed
[16, 17]. Undoubtedly, research in this field is
important.
1,2,4-Triazolethiols are known to react with benzyl
and benzoyl halides under basic conditions to give
exclusively the corresponding S-substituted products
[18]. With the goal of extending the series of available
Scheme 1.
N
N
Cl(CH2)nCOOEt(Me)
R
S(CH2)nCOOEt(Me)
N
N
N
R'
2a–2j
R
SH
N
N
N
N
N
COOMe
COOMe
R'
Br(CH2)2COOMe
Ph
Ph
+
1a–1j
S
S
N
N
R = PhCH2, R' = Ph
Ph
Ph
3b
3a
1, R′ = Ph, R = HOCH2CH2CH2 (a), 4-BrC6H4 (b), Ph (c), pyridin-3-yl (d), 2-MeOC6H4 (e); R = 2-MeOC6H4, R′ = CH2=CHCH2 (f);
R = 2-MeC6H4, R′ = Ph (g), CH2=CHCH2 (h); R′ = Ph, R = Fu (i), PhCH2 (j); 2, n = 1: R′ = Ph, R = HOCH2CH2 (a), 4-BrC6H4 (b),
Ph (c), pyridin-3-yl (d), 2-MeOC6H4 (e); R = 2-MeOC6H4, R′ = CH2=CHCH2 (f); R = 2-MeC6H4, R′ = Ph (g), CH2=CHCH2 (h);
R = Fu, R′ = Ph (i); n = 0, R = PhCH2, R′ = Ph (j).
935

SAMVELYAN et al.
936
1,2,4-triazoles, in this work we studied the reactions
of 4,5-disubstituted 1,2,4-triazole-3-thioles with ethyl
chloroacetate, methyl chloroformate, and methyl
3-bromopropanoate. According to the 1H and 13C NMR
and X-ray diffraction data (Figs. 1, 2), esters 2a–2j
were the only products in the reactions of 1,2,4-tri-
azoles 1a–1j with ethyl chloroacetate and methyl
chloroformate (Scheme 1).
tively high reactivity of the alkylating agent which is
capable of reacting with both tautomers of 1j on pro-
1
longed heating. The H NMR spectrum of the product
mixture clearly showed triplet signals due to protons of
methylene groups attached to sulfur and nitrogen at
δ 3.31 and 4.43 ppm, respectively. The signals were
assigned with account taken of the chemical shift of
the SCH2 protons in 2a (δ 3.92 ppm) whose structure
was unambiguously determined by X-ray analysis, as
well as of our previous data according to which CH2
protons in N-alkyl derivatives resonate in the region
δ 4.27–4.33 ppm [19, 20].
The alkylation of 1j with methyl 3-bromopro-
panoate led to the formation of an inseparable mixture
of two compounds 3a and 3b (according to the TLC
data). Presumably, this result is determined by rela-
Compounds 2a–2j are convenient substrates for
further modification. The reaction of 2a–2i with hydra-
zine hydrate afforded the corresponding hydrazides
4a–4i in high yield. Surprisingly, in the reaction of 2j
with hydrazine hydrate we isolated initial triazole 1j
and methyl hydrazinecarboxylate (Scheme 2). The
most probable reason for anomalous splitting of 2j is
that polar ester group in its molecule is directly linked
to the sulfur atom, and nucleophilic attack promotes
cleavage of weaker C–S bond with formation of initial
thiol and hydrazinecarboxylate.
C12
O10
C8
C11
N1
N2
O9
C20
C5
C21
C3
C7
S6
C19
N4
C13
C18
O22
C14
C15
C17
Scheme 2.
N
N
C16
O
R
S
N
n = 1
Fig. 1. Structure of the molecule of ethyl {[5-(3-hydroxy-
propyl)-4-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl}acetate (2a)
according to the X-ray diffraction data. Non-hydrogen atoms
are shown as thermal vibration ellipsoids with a probability
of 50%.
HN
NH2
R'
N2H4·H2O
4a–4i
2a–2j
O
1j
+
H2N
b
n = 0
N
OMe
H
a
c
0
4, R′ = Ph, R = HOCH2CH2CH2 (a), 4-BrC6H4 (b),
Ph (c), pyridin-3-yl (d), 2-MeOC6H4 (e); R = 2-MeOC6H4,
R' = CH2=CHCH2 (f); R = 2-MeC6H4, R′ = Ph (g),
CH2=CHCH2 (h); R = Fu, R′ = Ph (i).
O22″
N2
Thus, it is advisable to alkylate 4,5-disubstituted
1,2,4-triazoles with α-halo esters. The reaction is
chemoselective and is complete in a short time with
high yields of the final products.
H22″
O22
N2′
H22
Biological testing has shown the absence of anti-
bacterial or antimicrobial activity of compounds 2a–2i
and generally weak antibacterial activity of 4a–4i.
Among the latter, compounds 4a and 4d showed
a moderate activity against gram-positive (St. epider-
midis) and gram-negative bacteria (E. coli); therefore,
they deserve some attention, and search for new
biologically active compounds in the series of
1,2,4-triazoles is reasonable.
Fig. 2. Hydrogen-bonded chain formed by molecules of
ethyl {[5-(3-hydroxypropyl)-4-phenyl-4H-1,2,4-triazol-3-yl]-
sulfanyl}acetate (2a) in crystal along the [0 1 0] axis; sym-
metry operation: i: –x, 0.5 + y, 0.5 – z; ii: –x, 0.5 + y, z.
Hydrogen bonds are shown with dashed lines.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 6 2017

ALKYLATION OF 1,2,4-TRIAZOLE-3-THIOLS WITH HALOALKANOIC ACID ESTERS
937
EXPERIMENTAL
water, and the precipitate was filtered off, washed with
water, dried, and recrystallized.
1
The H and 13C NMR spectra were recorded on
a Varian Mercury-300 spectrometer at 300 and
75 MHz, respectively, using DMSO−CCl4 (1:3) as sol-
vent. The melting points were measured on a Boetius
micro hot stage. Analytical thin-layer chromatography
was performed on Silufol UV-254 plates; spots were
visualized by treatment with iodine vapor.
Ethyl {[5-(hydroxypropyl)-4-phenyl-4H-1,2,4-
triazol-3-yl]sulfanyl}acetate (2a). Yield 65%, mp 71–
72°C (from H2O–EtOH, 3:1), Rf 0.56 (EtOH–PhH–
1
hexane, 1:3:3). H NMR spectrum, δ, ppm: 1.26 t
(3H, CH2CH3, J = 7.14 Hz), 1.76 t.t (2H, CH2CH2OH,
J = 7.5, 6.2 Hz), 2.58 t (2H, 5-CH2, J = 7.5 Hz),
3.42 t.d (2H, CH2OH, J = 6.2, 4.5 Hz), 3.93 s (2H,
SCH2), 4.14 q (2H, CH2CH3, J = 7.1 Hz), 4.18 br.t
(1H, OH, J = 4.5 Hz), 7.35–7.49 m (2H, Harom), 7.52–
7.62 m (3H, Harom). 13C NMR spectrum, δC, ppm: 13.7,
21.2, 29.2, 33.7, 59.5, 60.7, 126.8, 129.3, 129.4, 132.8,
148.3, 155.2, 167.2. Found, %: C 56.10; H 6.00;
N 13.14; S 10.03. C15H19N3O3S. Calculated, %:
C 56.06; H 5.96; N 13.07; S 9.98.
The X-ray diffraction data for compound 2a were
obtained at room temperature on an Enraf–Nonius
CAD-4 automated diffractometer (Mo Kα radiation,
graphite monochromator, θ/2θ scanning). The unit cell
parameters (monoclinic crystal system) were deter-
mined and refined from 24 reflections in the range
14.00 < θ < 14.92°. The structure was solved by the
direct method. A correction for absorption was applied
by the ψ-scan method [21]. The positions of hydrogen
atoms were calculated geometrically and were refined
according to the riding model assuming C–H bond
length 0.93–0.97 Å and Uiso(H) = 1.2–1.5Ueq(C). The
structure was refined by the full-matrix least-squares
method in anisotropic approximation for non-hydrogen
atoms and isotropic for hydrogens. All calculations
were performed using SHELXTL [22].
Ethyl {[5-(4-bromophenyl)-4-phenyl-4H-1,2,4-
triazol-3-yl]sulfanyl}acetate (2b). Yield 88%,
mp 158°C (from H2O–EtOH, 2:1), Rf 0.52 (EtOH–
1
PhH, 1:5). H NMR spectrum, δ, ppm: 1.29 t (3H,
CH2CH3, J = 7.1 Hz), 4.03 s (2H, SCH2), 4.17 q (2H,
CH2CH3, J = 7.1 Hz), 7.25–7.30 m (2H, Harom), 7.32–
7.39 m (2H, Harom), 7.41–7.46 m (2H, Harom), 7.53–
7.58 m (3H, Harom). 13C NMR spectrum, δC, ppm: 13.7,
33.6, 40.0, 60.8, 123.2, 125.4, 126.9, 129.1, 129.5,
131.0, 133.4, 150.8, 152.9, 167.0. Found, %: C 51.64;
H 3.92; Br 19.15; N 10.49; S 7.72. C18H16BrN3O2S.
Calculated, %: C 51.68; H 3.86; Br 19.10; N 10.45;
S 7.67.
Both aromatic rings in molecule 2a (1,2,4-triazole
and phenyl) are almost ideally planar; the maximum
deviations of atoms from the mean-square planes does
not exceed 0.0047(2) and 0.0066(2) Å, respectively.
The 1,2,4-triazole and phenyl ring planes form a di-
hedral angle of 73.694(4)°. Analysis of thermal vibra-
tion ellipsoids and Fourier difference maps indicated
the possibility of statistical disordering of the ester
group (O10, C11, C12). The final structural model was
refined with account taken of disordered positions with
populations of 30 and 70%. Molecules 2a in crystal
are linked through O22–H22 ···N2 hydrogen bonds
[2.886(3) Å] to form infinite chains along the [0 1 0]
axis, and the chains form a three-dimensional network
via van der Waals interactions. The X-ray diffraction
data for compound 2a were deposited to the
Cambridge Crystallographic Data Centre (CCDC entry
no. 1410455).
Ethyl [(4,5-diphenyl-4H-1,2,4-triazol-3-yl)sul-
fanyl]acetate (2c). Yield 98%, mp 178–180°C (from
H2O–EtOH, 2:5), Rf 0.50 (EtOH–PhH, 2:5). H NMR
1
spectrum, δ, ppm: 1.28 t (3H, CH2CH3, J = 7.1 Hz),
4.00 s (2H, SCH2), 4.15 q (2H, CH2CH3, J = 7.1 Hz),
6.95–7.39 m (6H, Harom), 7.45–7.60 m (4H, Harom).
13C NMR spectrum, δC, ppm: 33.7, 39.0, 39.2, 60.7,
115.9, 117.4, 120.8, 131.3, 131.5, 131.6, 148.6, 152.8,
156.5, 167.2. Found, %: C 63.74; H 5.00; N 12.45;
S 9.40. C18H17N3O2S. Calculated, %: C 63.70; H 5.05;
N 12.38; S 9.45.
Ethyl {[4-phenyl-5-(pyridin-3-yl)-4H-1,2,4-tri-
azol-3-yl]sulfanyl}acetate (2d). Yield 88%, mp 138°C
(from H2O–EtOH, 2:1), Rf 0.48 (EtOH–PhH, 1:5).
1H NMR spectrum, δ, ppm: 1.30 t (3H, CH3, J =
7.1 Hz), 4.06 s (2H, SCH2), 4.18 q (2H, OCH2, J =
7.1 Hz), 7.27 d.d (1H, C5H4N, J = 7.9, 4.8 Hz), 7.37–
7.44 m (2H, Harom), 7.53–7.60 m (4H, Harom), 7.68 d.t
(1H, C5H4N, J = 7.9, 1.9 Hz), 8.49–8.54 m (2H, Harom).
13C NMR spectrum, δC, ppm: 13.7, 33.7, 40.0, 60.8,
122.6, 126.2, 127.0, 129.6, 129.8, 133.1, 134.4, 147.9,
Alkylation of 4,5-disubstituted 4H-1,2,4-triazole-
3-thiols 1a–1j with halo esters (general procedure).
A mixture of 0.01 mol of 1,2,4-triazole 1a–1j,
0.006 mol of anhydrous potassium carbonate, and
0.01 mol of the corresponding halo ester in 15 mL of
anhydrous acetone was stirred for 1 h at room tem-
perature and for 10 h at 50–60°C. The solvent was
removed, the crystalline residue was treated with
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 6 2017

SAMVELYAN et al.
938
149.7, 151.1, 151.7, 167.0. Found, %: C 60.02; H 4.80;
N 16.50; S 9.46. C17H16N4O2S. Calculated, %:
C 59.98; H 4.74; N 16.46; S 9.42.
5.3, 1.6 Hz), 4.90 d.q (1H, =CH2, J = 17.1, 1.6 Hz),
5.12 d.q (1H, =CH2, J = 10.3, 1.6 Hz), 5.74 d.d.t (1H,
=CH, J = 17.1, 10.3, 5.3 Hz), 6.97–7.41 m (1H, Harom),
7.46–7.63 m (3H, Harom). 13C NMR spectrum, δC, ppm:
13.7, 20.7, 33.7, 39.0, 60.7, 124.4, 115.9, 117.4, 120.8,
131.3, 131.5, 131.6, 148.6, 152.8, 156.5, 167.2. Found,
%: C 60.58; H 6.07; N 13.30; S 10.05. C16H19N3O2S.
Calculated, %: C 60.54; H 6.03; N 13.24; S 10.10.
Ethyl {[5-(methoxyphenyl)-4-phenyl-4H-1,2,4-
triazol-3-yl]sulfanyl}acetate (2e). Yield 89%,
mp 162°C (from H2O–EtOH, 2:3), Rf 0.57 (EtOH–
1
PhH, 1:5). H NMR spectrum, δ, ppm: 1.26 t (3H,
CH2CH3, J = 7.1 Hz), 3.81 s (3H, OCH3), 4.03 s (2H,
SCH2), 4.17 q (2H, CH2CH3, J = 7.1 Hz), 7.25–7.30 m
(2H, Harom), 7.32–7.39 m (2H, Harom), 7.41–7.46 m
Ethyl {[5-(furan-2-yl)-4-phenyl-4H-1,2,4-triazol-
3-yl]sulfanyl}acetate (2i). Yield 85%, mp 124–125°C
(from H2O–EtOH, 2:3), Rf 0.56 (EtOH–PhH, 1:7).
1H NMR spectrum, δ, ppm: 1.29 t (3H, CH3, J =
6.7 Hz), 4.02 s (2H, SCH2), 4.17 q (2H, OCH2, J =
7.1 Hz), 6.22 d (1H, Fu, J = 3.97 Hz), 6.37–6.42 m
(1H, Fu), 7.38–7.44 m (2H, Harom), 7.50–7.53 m (1H,
13
(2H, Harom), 7.53–7.58 m (3H, Harom). C NMR spec-
trum, δC, ppm: 13.7, 33.6, 39.8, 40.0, 60.8, 96.5, 123.2,
124.8, 125.4, 126.9, 129.0, 129.5, 131.2, 133.4, 150.8,
155.9, 167.0. Found, %: C 61.82; H 5.14; N 11.43;
S 8.65. C19H19N3O3S. Calculated, %: C 61.77; H 5.18;
N 11.37; S 8.68.
13
Fu), 7.57–7.62 m (3H, Harom). C NMR spectrum, δC,
ppm: 13.7, 33.7, 60.8, 110.6, 110.8, 123.3, 127.1,
129.8, 133.1, 140.9, 143.5, 146.9, 150.1, 166.9. Found,
%: C 58.30; H 4.70; N 12.83; S 9.85. C16H15N3O3S.
Calculated, %: C 58.34; H 4.59; N 12.76; S 9.74.
Ethyl {[5-(2-methoxyphenyl)-4-(prop-2-en-1-yl)-
4H-1,2,4-triazol-3-yl]sulfanyl}acetate (2f). Yield
88%, mp 75–76°C (from PhH), Rf 0.52 (EtOH–PhH–
1
hexane, 1:3:3). H NMR spectrum, δ, ppm: 1.29 t
(3H, CH2CH3, J = 7.1 Hz), 3.84 s (3H, OCH3), 4.03 s
(2H, SCH2), 4.18 q (2H, CH2CH3, J = 7.1 Hz), 4.41 d.t
(2H, NCH2, J = 5.3, 1.6 Hz), 4.93 d.q (1H, =CH2, J =
17.1, 1.6 Hz), 5.14 d.q (1H, =CH2, J = 10.3, 1.6 Hz),
5.74 d.d.t (1H, =CH, J = 17.1, 10.3, 5.3 Hz), 7.05 t.d
(1H, Harom, J = 7.4, 0.9 Hz), 7.10 d.d (1H, Harom, J =
8.4, 0.9 Hz), 7.33 d.d (1H, Harom, J = 7.4, 1.8 Hz),
S-(5-Benzyl-4-phenyl-4H-1,2,4-triazol-3-yl)
O-methyl carbonothioate (2j). Yield 71%, mp 143°C
(from Et2O), Rf 0.51 (EtOH–PhH, 1:10). H NMR
1
spectrum, δ, ppm: 3.85 s (2H, PhCH2), 4.04 s (3H,
CH3), 6.83–6.98 m (2H, Harom), 7.05–7.24 m (5H,
13
H
arom), 7.36–7.54 m (3H, Harom). C NMR spectrum,
δC, ppm: 31.3, 53.8, 126.5, 127.7, 128.2, 128.8, 129.1,
132.9, 133.0, 148.2, 150.7, 169.7. Found, %: C 63.60;
H 5.10; N 12.30; S 9.50. C18H17N3O2S. Calculated, %:
C 63.70; H 5.05; N 12.38; S 9.45.
13
7.50 d.d.d (1H, Harom, J = 8.4, 7.4, 1.8 Hz). C NMR
spectrum, δC, ppm: 13.6, 34.5, 46.1, 54.9, 60.8, 110.9,
115.9, 117.4, 120.8, 131.3, 131.5, 131.6, 148.6, 152.8,
156.5, 167.2. Found, %: C 57.68; H 5.80; N 12.65;
S 9.65. C16H19N3O3S. Calculated, %: C 57.64; H 5.74;
N 12.60; S 9.62.
Compounds 3a and 3b (inseparable mixture).
Following the general alkylation procedure, the reac-
tion of 0.01 mol of 5-benzyl-4-phenyl-4H-1,2,4-tri-
azole-3-thiol with 0.01 mol of methyl 3-bromopropa-
noate in the presence of 0.006 mol of anhydrous
potassium carbonate gave 2.9 g of a crystalline prod-
uct. After repeated fractional recrystallization, the
product contained two compounds 3a and 3b (TLC)
with fairly similar Rf values.
Ethyl {[5-(2-methylphenyl)-4-phenyl-4H-1,2,4-
triazol-3-yl]sulfanyl}acetate (2g). Yield 95%, mp 80–
81°C (from H2O–EtOH, 8:5), Rf 0.59 (EtOH–PhH,
1:5). 1H NMR spectrum, δ, ppm: 1.29 t (3H, CH2CH3,
J = 7.1 Hz), 2.28 s (3H, CH3), 4.03 s (2H, SCH2),
4.18 q (2H, CH2CH3, J = 7.1 Hz), 6.97–7.41 m (6H,
Harom), 7.46–7.63 m (3H, Harom). 13C NMR spectrum,
δC, ppm: 13.7, 20.7, 33.7, 60.7, 125.1, 125.5, 127.6,
128.2, 129.7, 129.8, 130.1, 133.7, 137.1, 149.7, 167.6.
Found, %: C 64.62; H 5.38; N 11.55; S 9.00.
C19H19N3O2S. Calculated, %: C 64.57; H 5.42;
N 11.89; S 9.07.
Compounds 4a–4i (general procedure). Hydrazine
hydrate, 15 mmol (85% solution), was added to a mix-
ture of 10 mmol of ester 2a–2i and 20 mL of ethanol,
and the mixture was stirred for 2 h at room temperature
and for 8 h at 50–60°C. The solvent was removed, and
the crystalline residue was washed with water, dried,
and recrystallized.
Ethyl {[5-(2-methylphenyl)-4-(prop-2-en-1-yl)-
4H-1,2,4-triazol-3-yl]sulfanyl}acetate (2h). Yield
70%, viscous material, Rf 0.50 (EtOH–PhH, 1 :5).
1H NMR spectrum, δ, ppm: 1.29 t (3H, CH2CH3, J =
7.1 Hz), 2.28 s (3H, CH3), 4.03 s (2H, SCH2), 4.18 q
(2H, CH2CH3, J = 7.1 Hz), 4.39 d.t (2H, NCH2, J =
2-{[5-(3-Hydroxypropyl)-4-phenyl-4H-1,2,4-tri-
azol-3-yl]sulfanyl}acetohydrazide (4a). Yield 70%,
mp 149–150°C (H2O–EtOH, 3 :2), Rf 0.50 (EtOH–
1
PhH, 1 :7). H NMR spectrum, δ, ppm: 2.58 t (2H,
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ALKYLATION OF 1,2,4-TRIAZOLE-3-THIOLS WITH HALOALKANOIC ACID ESTERS
939
5-CH2, J = 7.5 Hz), 3.36–3.49 m (2H, CH2CH2OH),
3.93 s (2H, SCH2), 4.14 q (2H, CH2OH, J = 7.14 Hz),
4.18 br.s (1H, OH), 6.10 d (1H, NH2, J = 3.17 Hz),
6.29 d (1H, NH2, J = 5.6 Hz), 7.28–7.49 m (2H, Harom),
7.49–7.73 m (3H, Harom), 9.28 br.s (1H, NH). 13C NMR
spectrum, δС, ppm: 21.3, 29.2, 33.7, 59.5, 126.9, 129.3,
132.9, 149.2, 155.2, 156.5, 156.9, 167.2. Found, %:
C 50.85; H 5.52; N 22.83; S 9.04. C13H17N5O2S. Cal-
culated, %: C 50.80; H 5.57; N 22.78; S 9.00
(1H, NH). 13C NMR spectrum, δC, ppm: 13.7, 60.8,
117.2, 123.2, 124.8, 125.4, 126.9, 129.0, 129.5, 131.2,
133.4, 150.8, 155.9, 167.0. Found, %: C 57.50; H 4.75;
N 19.75; S 8.98. C17H17N5O2S. Calculated, %:
C 57.45; H 4.82; N 19.70; S 9.02.
2-{[5-(2-Methoxyphenyl)-4-(prop-2-en-1-yl)-4H-
1,2,4-triazol-3-yl]sulfanyl}acetohydrazide (4f). Yield
92%, mp 82–84°C (from H2O–EtOH, 3:2), Rf 0.55
1
(EtOH–PhH–hexane, 1:3:1). H NMR spectrum, δ,
2-{[5-(4-Bromophenyl)-4-phenyl-4H-1,2,4-tri-
azol-3-yl]sulfanyl}acetohydrazide (4b). Yield 91%,
mp 230–232°C (from EtOH), Rf 0.55 (EtOH–benzene,
ppm: 3.83 s (3H, OCH3), 4.10 br.s (2H, NH2), 4.41 d.t
(2H, NCH2, J = 5.2, 1.7 Hz), 4.91 d.q (1H, =CH2, J =
17.2, 1.7 Hz), 5.11 d.q (1H, =CH2, J = 17.2, 1.7 Hz),
5.75 d.d.t (1H, =CH, J = 17.1, 10.3, 5.3 Hz), 7.32–
7.51 m (4H, Harom), 9.34 br.s (1H, NH). 13C NMR
spectrum, δC, ppm: 34.7, 46.2, 55.1, 110.9, 115.9,
117.5, 120.2, 131.4, 131.5, 131.6, 149.5, 152.9, 156.7,
166.1. Found, %: C 52.70; H 5.33; N 22.00; S 10.00.
C14H17N5OS. Calculated, %: C 52.65; H 5.37; N 21.93;
S 10.04.
1
1:9). H NMR spectrum, δ, ppm: 3.87 s (2H, SCH2),
4.09 br.s (2H, NH2), 7.25–7.30 m (2H, Harom), 7.41–
7.46 m (2H, Harom), 7.52–7.57 m (5H, Harom), 9.29 br.s
(1H, NH). 13C NMR spectrum, δC, ppm: 33.8, 60.8,
123.1, 125.5, 127.1, 129.1, 129.5, 131.1, 133.5, 151.6,
152.9, 165.8. Found, %: C 47.58; H 3.52; N 17.37;
S 7.88. C16H14N5OS. Calculated, %: C 47.53; H 3.49;
N 17.32; S 7.93.
2-[(4,5-Diphenyl-4H-1,2,4-triazol-3-yl)sulfanyl]-
acetohydrazide (4c). Yield 97%, mp 201–203°C
(from H2O–EtOH, 1:5), Rf 0.55 (EtOH–PhH, 2:5).
1H NMR spectrum, δ, ppm: 3.78 s (2H, SCH2),
3.98 br.s (2H, NH2), 6.90–7.30 m (6H, Harom), 7.44–
7.59 m (4H, Harom), 9.27 br.s (1H, NH). 13C NMR
spectrum, δC, ppm: 33.7, 60.7, 115.9, 117.4, 120.8,
131.3, 131.6, 148.6, 151.3, 152.8, 156.5, 167.2. Found,
%: C 59.10; H 4.60; N 21.57; S 9.90. C16H15N5OS.
Calculated, %: C 59.06; H 4.65; N 21.52; S 9.85.
2-{[5-(2-Methylphenyl)-4-phenyl-4H-1,2,4-tri-
azol-3-yl]sulfanyl}acetohydrazide (4g). Yield 70%,
mp 112–113°C (from H2O–EtOH, 3:2), Rf 0.58
1
(EtOH–PhH, 1:5). H NMR spectrum, δ, ppm: 2.28 s
(3H, CH3), 4.03 s (2H, SCH2), 4.10 br.s (2H, NH2),
6.97–7.41 m (6H, Harom), 7.46–7.63 m (3H, Harom),
9.30 br.s (1H, NH). 13C NMR spectrum, δC, ppm: 33.7,
60.7, 124.4, 115.9, 117.4, 120.8, 131.3, 131.5, 131.6,
148.6, 152.8, 156.5, 167.2. Found, %: C 60.20; H 5.10;
N 20.70; S 9.50. C17H17N5OS. Calculated, %: C 60.16;
H 5.05; N 20.63; S 9.45.
2-{[4-Phenyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-
3-yl]sulfanyl}acetohydrazide (4d). Yield 90%,
mp 225°C (from H2O–EtOH, 1:5), Rf 0.55 (EtOH–
2-{[5-(2-Methylphenyl)-4-(prop-2-en-1-yl)-4H-
1,2,4-triazol-3-yl]sulfanyl}acetohydrazide (4h).
Yield 70%, mp 70–71°C (from H2O–EtOH, 12:10),
1
PhH–hexane, 3:3:1). H NMR spectrum, δ, ppm:
1
Rf 0.60 (EtOH–PhH, 1:5). H NMR spectrum, δ, ppm:
3.87 s (2H, SCH2), 4.12 br.s (2H, NH2), 7.27 d.d (1H,
C5H4N, J = 7.8, 4.8 Hz), 7.38–7.43 m (2H, Harom),
7.53–7.60 m (3H, Harom), 7.66 d.d.d (1H, C5H4N, J =
7.8, 2.1, 1.8 Hz), 8.51 d.t (1H, C5H4N, J = 4.8, 1.8 Hz),
8.53 d (1H, C5H4N, J = 2.1 Hz), 9.29 br.s (1H, NH).
13C NMR spectrum, δC, ppm: 33.7, 60.9, 115.9,
117.8, 121.8, 131.4, 131.7, 148.6, 149.7, 151.2, 152.8,
156.5, 167.4. Found, %: C 55.15; H 4.40; N 25.80;
S 9.95. C15H14N6OS. Calculated, %: C 55.20; H 4.32;
N 25.75; S 9.82.
2.90 s (3H, CH3), 4.09 br.s (2H, NH2), 4.39 d.t (2H,
NCH2, J = 5.3, 1.6 Hz), 4.90 d.q (1H, =CH2, J = 17.1,
1.6 Hz), 5.09 d.q (1H, =CH2, J = 17.1, 1.6 Hz),
5.72 d.d.t (1H, =CH, J = 17.1, 10.3, 5.3 Hz), 7.30–
7.50 m (4H, Harom), 9.34 br.s (1H, NH). 13C NMR
spectrum, δC, ppm: 34.7, 46.2, 55.1, 110.9, 115.9,
117.5, 120.2, 131.4, 131.5, 131.6, 149.5, 152.9, 156.7,
166.1. Found, %: C 55.45; H 5.70; N 23.15; S 10.52.
C14H17N5OS. Calculated, %: C 55.42; H 5.65;
N 23.08; S 10.57.
2-{[5-(2-Methoxyphenyl)-4-phenyl-4H-1,2,4-tri-
azol-3-yl]sulfanyl}acetohydrazide (4e). Yield 90%,
mp 170°C (from H2O–EtOH, 2:3), Rf 0.58 (EtOH–
2-{[5-(Furan-2-yl)-4-phenyl-4H-1,2,4-triazol-3-
yl]sulfanyl]acetohydrazide (4i). Yield 90%, mp 111–
112°C (from H2O–EtOH, 1:1), Rf 0.50 (EtOH–PhH,
1
PhH, 1:5). H NMR spectrum, δ, ppm: 3.81 s (3H,
1
OCH3), 4.03 s (2H, SCH2), 4.10 br.s (2H, NH2), 7.30–
7.35 m (2H, Harom), 7.32–7.39 m (2H, Harom), 7.41–
7.46 m (2H, Harom), 7.53–7.58 m (3H, Harom), 9.31 br.s
1:7). H NMR spectrum, δ, ppm: 3.84 s (2H, CH2),
4.08 br.s (2H, NH2), 6.13 d (1H, Fu, J = 3.97 Hz),
6.39 d (1H, Fu, J = 3.97 Hz), 7.39–7.45 m (2H, Harom),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 6 2017

SAMVELYAN et al.
940
8. Dos Santos Filho, J.M., José de Lima, G.C., and
Leite, L.F., J. Heterocycl. Chem., 2009, vol. 46, no. 4,
p. 722.
7.52 s (1H, Fu), 7.57–7.62 m (3H, Harom), 9.28 br.s
(1H, NH). 13C NMR spectrum, δC, ppm: 33.9, 110.5,
110.8, 123.4, 127.2, 129.3, 129.7, 134.2, 141.0, 143.5,
150.9, 166.7. Found, %: C 53.40; H 5.80; N 22.30;
S 10.25. C14H13N5O2S. Calculated, %: C 53.45;
H 5.70; N 22.21; S 10.17.
9. Puthiyapurayil, P., Poojary, B., and Buridipad, K.,
J. Heterocycl. Chem., 2014, vol. 51, no. S1, p. E55.
10. Mao, H.-Yu., Song, H., and Shi, De-Q., J. Heterocycl.
Chem., 2012, vol. 49, no. 3, p. 511.
Hydrazinolysis of S-(5-benzyl-4-phenyl-4H-
1,2,4-triazol-3-yl) O-methyl carbonothioate. Follow-
ing the general procedure for the synthesis of 4a–4i,
the reaction of 5 mmol of 2j with 7.5 mmol of 85% hy-
drazine hydrate in 10 mL of ethanol gave a crystalline
solid which was filtered off, washed with water, and
recrystallized. The product was identified as 5-benzyl-
4-phenyl-4H-1,2,4-triazole-3-thiol, mp 196–198°C
[23]. The filtrate was treated with methylene chloride,
the extract was dried and evaporated, and the residue
was distilled under reduced pressure, bp 111–113°C
(22 mm), mp 47–48°C [24].
11. Song, H.-X. and Shi, D.-Q., J. Heterocycl. Chem., 2014,
vol. 51, no. 5, p. 1345.
12. Liu, M.-Y. and Shi, D.-Q., J. Heterocycl. Chem., 2014,
vol. 51, no. S1, p. E335.
13. Zhang, H.-Y. and Shi, D.-Q., J. Heterocycl. Chem.,
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