Alkylation, amino(hydroxy)methylation, and cyanoethylation of 5-substituted 4-phenyl-4H-1,2,4-triazole-3-thiols

Article abstract of DOI:10.1134/S1070363216020171

Reactions of 1,2,4-triazole-3-thiols with 2-bromopropionic acid, 2-bromocaproic acid, ethylene chlorohydrine, chloroacetamide, 3-bromo-4-methoxybenzyl chloride, 2-methoxy-5-acetylbenzyl chloride, and 2-(2-chlorophenoxy)ethyl chloride in the presence of KO

Full text of DOI:10.1134/S1070363216020171

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 2, pp. 305–311. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © M.A. Kaldrikyan, N.S. Minasyan, R.G. Melik-Ogandzanyan, 2016, published in Zhurnal Obshchei Khimii, 2016, Vol. 86, No. 2,
pp. 277–283.
Alkylation, Amino(hydroxy)methylation, and Cyanoethylation
of 5-Substituted 4-Phenyl-4H-1,2,4-triazole-3-thiols
M. A. Kaldrikyana, N. S. Minasyanb, and R. G. Melik-Ogandzanyana†
a Scientific and Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia,
Mnjoyan Institute of Fine Organic Chemistry, Yerevan, Armenia
b Scientific and Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia,
Molecular Structure Research Center, ave. Azatutyan 26, Yerevan, 0014 Armenia
e-mail: nunemin@gmail.com
Received July 16, 2015
Abstract—Reactions of 1,2,4-triazole-3-thiols with 2-bromopropionic acid, 2-bromocaproic acid, ethylene
chlorohydrine, chloroacetamide, 3-bromo-4-methoxybenzyl chloride, 2-methoxy-5-acetylbenzyl chloride, and
2-(2-chlorophenoxy)ethyl chloride in the presence of KOH have afforded new 3-sulfanyl-1,2,4-triazoles in high
yields. Aminomethylation of 1,2,4-triazole-3-thiols in the presence of formaldehyde has given the
corresponding 2-aminomethyl-2H-1,2,4-triazole-3(4H)-thiones. Interaction of triazole-3-thiols with formalin
and acrylonitrile has resulted in the formation of N2-hydroxymethyl- and 3-(2-cyanoethyl)sulfanyl derivatives.
Keywords: 1,2,4-triazole-3-thiol, S-alkylation, chloroacetic acid, 2-brompropropionic acid, 2-bromocaproic
acid, 3-bromomethoxybenzyl chloride, chloroacetamide, ethylene chlorohydrin, morpholine, piperidine,
cyanoethylation
DOI: 10.1134/S1070363216020171
The prospects of finding new physiologically active
substances among 1,2,4-triazole derivatives arise from
a wide range of their biological activity. For instance,
certain triazole thiols and thiones exhibit antiviral,
antibacterial, anti-inflammatory, anti-tuberculosis, and
antitumor activity [1].
alcoholic solution in the presence of an equimolar
amount of KOH. In the both cases, new 3-sulfanyl-
1,2,4-triazoles 2a–2o were obtained with high yields
(Scheme 1).
N2-Aminomethylation of triazoles 1a–1d with the
secondary amines (piperidine or morpholine) occurred
in the presence of formalin in ethanolic medium. The
reaction yielded the corresponding 2-[(morpholin-4-
yl)- and (piperidin-1-yl)methyl]-2H-1,2,4-triazole-3(4H)-
thiones 3a–3h. N2-Hydroxymethyl derivatives 4a–4d
were obtained when reacting triazole-3-tiols 1a–1d
with formalin.
We have earlier obtained 1,2,4-triazole derivatives
with significant anti-tumor activity [2–6]. Herein, we
report on S-alkylation, N2-amino(hydroxy)methylation,
and cyanoethylation of 5-alkoxyphenyl-4-phenyl-4H-
1,2,4-triazole-3-thiols.
S-Alkylation of 1,2,4-triazole-3-thiols 1a–1d with
2-bromopropanoic and 2-bromocaproic acids was
carried out in the aqueous solution in the presence of
three-fold excess of KOH. The reactions with chloro-
ethanol, chloroacetamide, 3-bromo-4-methoxybenzyl
chloride, 2-methoxy-5-acetylbenzyl chloride, and 2-(2-
chlorophenoxy)ethyl chloride were performed in the
It has been known that cyanoethylation of 4-phenyl-
1,2,4-triazoline-3-thiones occurs at the nitrogen of
thioamide group [7]. We performed reactions of 5-(4-
alkoxyphenyl)-4-phenyl(benzyl)-4H-triazole-3-thiols
with acrylonitrile in the presence of triethylamine.
Acrylonitrile was found to react only at the N2H group
to form the corresponding 2-(2-cyanoethyl)triazoline-
3-thiones 5a–5f. The attempt to obtain 3-(2-cyano-
ethyl)sulfanyl derivatives failed (Scheme 2).
† Deceased.
305

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KALDRIKYAN et al.
Scheme 1.
R3
N
N
N
N
N
N
N
N
R1O
R1O
R1O
N
SR2
S
SH
2а_2o
3а_3h
1a_1d
N
OH
N
R1O
N
S
4а_4d
R1 = CH3 (1а), C2H5 (1b), C3H7 (1c), C4H9 (1d); R1 = CH3, R2 = CH(CH3)COOH (2а); R1 = C2H5, R2 = CH(CH3)COOH
(2b); R1 = C2H5, R2 = CH(C4H9)COOH (2c); R1 = C3H7, R2 = CH(CH3)COOH (2d); R1 = C3H7, R2 = CH(C4H9)COOH (2e);
R1 = C4H9, R2 = CH(CH3)COOH (2f); R1 = C4H9, R2 = CH(C4H9)COOH (2g); R1 = CH3, R2 = CH2CH2OH (2h); R1 = CH3,
R2 = CH2CONH2 (2i); R1 = CH3, R2 = CH2C6H3(3-Br-4-ОCH3) (2j); R1 = CH3, R2 = CH2C6H3(2-OCH3-5-COCH3) (2k);
R1 = CH3, R2 = CH2CH2OC6H4-2-Cl (2l); R1 = C3H7, R2 = CH2C6H3(3-Br-4-OCH3) (2m); R1 = C4H9, R2 = CH2C6H3·
(2-OCH3-5-COCH3) (2n); R1 = C4H9, R2 = CH2C6H3(3-Br-4-ОCH3) (2o); R1 = CH3, R3 = ОC4H8N- (3а); R1 = CH3, R3 =
C5H10N- (3b); R1 = C2H5, R3 = ОC4H8N- (3c); R1 = C2H5, R3 = C5H10N- (3d); R1 = C3H7, R3 = ОC4H8N- (3e); R1 = C3H7,
R3 = C5H10N- (3f); R1 = C4H9, R3 = ОC4H8N- (3g); R1 = C4H9, R3 = C5H10N- (3h); R1 = CH3 (4а), C2H5 (4b), C3H7 (4c),
C4H9 (4d).
Scheme 2.
N
N
N
N
N
CH2=CHCN
N
N
R1O
R1O
SH
S
R2
R2
5a_5f
R1 = CH3, R2 = C6H5 (5а); R1 = CH3, R2 = CH2C6H5 (5b); R1 = C2H5, R2 = C6H5 (5c); R1 = C2H5, R2 = CH2C6H5 (5d); R1 =
CH2C6H5, R2 = C6H5 (5e); R1 = CH2C6H5, R2 = CH2C6H5 (5f).
Purity, identity, and structure of the synthesized
compounds were confirmed by TLC, elemental
analysis, 1H and 13C NMR spectroscopy methods.
for 2a–g or benzene–acetone mixture (2 : 1) for 2h–2o,
3a–3h, 4a–4d.
5-Alkoxyphenyl-4-phenyl-4H-1,2,4-triazole-3-thioles
1a–1d were obtained via cyclization of 1,4-substituted
thiosemicarbazides as described in [8]. 5-Alkoxy-
(benzyloxy)phenyl-4-benzyl-4H-1,2,4-triazole-3-thioles
were obtained via the procedure reported in [9].
EXPERIMENTAL
1H and 13C NMR spectra were registered using a
Mercury-300 spectrometer operating at 300 MHz, in
DMSO-d6 relative to internal TMS. Melting points
were determined using a Boёtius instrument. TLC
analysis was performed using Silufol UV-254 plates,
eluting with a benzene–ethanol–acetone mixture (1 : 1 : 1)
2-(4H-1,2,4-Triazol-3-ylsulfanyl)propanoic and
hexanoic acids (2a–2g). A mixture of 6 mmol of
KOH, 30 mL of water, 2 mmol of triazole-3-thiol 1a–
1d, and 2 mmol of 2-bromopropanoic or 2-bromo-
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ALKYLATION, AMINO(HYDROXY)METHYLATION, AND CYANOETHYLATION
307
hexanoic acid was refluxed during 2 h. The precipitate
was filtered off. Acetic acid was added to the filtrate to
pH = 5. The formed precipitate was filtered off,
washed with water, dried, and recrystallized from
ethanol.
COOH). Found, %: N 11.14; S 8.58. C20H21N3O3S.
Calculated, %: N 10.95; S 8.67.
2-[5-(4-Propoxyphenyl)-4-phenyl-4H-1,2,4-tri-
azol-3-ylsulfanyl]hexanoic acid (2e). Yield 80.0%,
1
mp = 154–150°C, Rf = 0.58. H NMR spectrum, δ,
2-[5-(Methoxyphenyl)-4-phenyl-4H-1,2,4-triazol-
3-ylsulfanyl]propanoic acid (2a). Yield 81.6%, mp =
202–203°C, Rf = 0.61. H NMR spectrum, δ, ppm (J,
ppm (J, Hz): 0.92 t (3H, CH3, J = 7.1), 1.02 t (3H,
CH3, J = 7.4), 1.28−1.45 m [4H, (CH2)2], 1.77 q.t (2H,
CH2, J1 = 7.4, J2 = 6.5), 1.78−1.98 m (2H, CH2), 3.89 t
(2H, OCH2, J = 6.5), 4.16 d.d (1H, SCH, J1 = 7.1, J2 =
6.5), 6.74−6.79 m (2H, C6H4), 7.22−7.27 m (2H,
C6H4), 7.27−7.33 m (2H, C6H5), 7.49−7.55 m (3H,
C6H5), 12.20 br.s (1H, COOH). 13C NMR spectrum,
δC, ppm: 10.1, 13.4, 21.6, 21.8, 28.3, 31.4, 49.3, 68.7,
113.8, 118.5, 127.2, 128.9, 129.2, 129.3, 134.0, 149.6,
153.7, 159.4, 171.3. Found, %: N 9.68; S 7.74.
C23H27N3O3S. Calculated, %: N 9.87; S 7.53.
1
Hz): 1.58 d (3H, CH3, J = 7.2), 3.77 s (3H, OCH3),
4.27 q (1H, CH, J = 7.2), 6.76−6.82 m (2H, C6H4),
7.24−7.29 m (2H, C6H4), 7.27−7.33 m (2H, C6H5),
7.48−7.58 m (3H, C6H5), 12.5 br.s (1H, COOH). 13C
NMR spectrum, δC, ppm: 18.0, 44.3, 54.6, 113.4,
118.7, 127.3, 128.9, 129.3, 129.4, 134.0, 149.6, 153.7,
160.0, 171.7. Found, %: N 11.67; S 9.92. C18H17N3O3S.
Calculated, %: N 11.82; S 9.02.
2-[4-Phenyl-5-(4-ethoxyphenyl)-4H-1,2,4-triazol-
3-ylsulfanyl]propanoic acid (2b). Yield 95%, mp =
194–195°C, Rf = 0.63. H NMR spectrum, δ, ppm (J,
2-[5-(4-Butoxyphenyl)-4-phenyl-4H-1,2,4-tri-
azol-3-ylsulfanyl]propanoic acid (2f). Yield 74.6%,
mp = 174–176°C, Rf = 0.62. H NMR spectrum, δ,
1
1
Hz): 1.37 t (3H, CH2CH3, J = 7.0), 1.58 d (3H,
CHCH3, J = 7.1), 4.00 q (2H, CH2CH3, J = 7.0), 4.26 q
(1H, CHCH3, J = 7.1), 6.73−6.79 m (2H, C6H4),
7.21−7.27 m (2H, C6H4), 7.27−7.53 m (2H, C6H5),
7.43−7.55 m (3H, C6H5), 12.3 br.s (1H, COOH). 13C
NMR spectrum, δC, ppm: 14.3, 18.3, 44.5, 62.7, 113.9,
118.5, 127.3, 128.9, 129.3, 129.4, 133.9, 149.8, 153.7,
159.3, 171.8. Found, %: N 11.45; S 8.48. C19H19N3O3S.
Calculated, %: N 11.37; S 8.67.
ppm (J, Hz): 0.97 t (3H, CH3, J = 7.3), 1.41−1.53 m
(2H, CH2CH3), 1.58 d (3H, CHCH3, J = 7.1),
1.67−1.77 m (2H, CH2CH2O), 3.92 t (2H, OCH2, J =
6.4), 4.27 q (1H, CH, J1 = 7.1), 6.73−6.78 m (2H,
C6H4), 7.21−7.27 m (2H, C6H4), 7.27−7.33 m (2H,
C6H5), 7.47−7.57 m (3H, C6H5), 7.15 br.s (1H, COOH).
13C NMR spectrum, δC, ppm: 13.4, 18.1, 18.7, 30.6,
44.6, 66.9, 113.9, 118.5, 127.3, 129.0, 129.3, 129.4,
134.0, 149.7, 153.8, 159.5, 171.9. Found, %: N 10.78;
S 8.27. C21H23N3O3S. Calculated, %: N 10.57; S 8.06.
2-[4-Phenyl-5-(4-ethoxyphenyl)-4H-1,2,4-triazol-
3-ylsulfanyl]hexanoic acid (2c). Yield 97.5%, mp =
2-[5-(4-Butoxyphenyl)-4-phenyl-4H-1,2,4-tri-
azol-3-ylsulfanyl]hexanoic acid (2g). Yield 94.5%,
1
168–169°C, Rf = 0.60. H NMR spectrum, δ, ppm (J,
1
Hz): 0.92 t (3H, CH3, J = 7.1), 1.28−1.45 m [4H,
(CH2)2], 1.38 t (3H, CH3, J = 7.0), 1.76–7.98 m (2H,
CH2), 4.00 q (2H, OCH2, J = 7.0), 4.16 d.d (1H, SCH,
J1 = 7.3, J2 = 6.6), 6.73−6.78 m (2H, C6H4), 7.22−7.27
m (2H, C6H4), 7.27−7.33 m (2H, C6H5), 7.48−7.55 m
(3H, C6H5), 11.9 br.s (1H, COOH). 13C NMR spec-
trum, δC, ppm: 1.4, 14.3, 21.6, 28.4, 31.4, 49.3, 62.7,
113.8, 118.5, 127.2, 128.9, 129.2, 129.3, 134.0, 149.6,
153.8, 159.3, 171.3. Found, %: N 10.50; S 7.65.
C22H25N3O3S. Calculated, %: N 10.21; S 7.79.
mp = 144–146°C, Rf = 0.57. H NMR spectrum, δ,
ppm (J, Hz): 0.91 t (3H, CH3, J = 7.1), 0.97 t (3H,
CH3, J = 7.4); 1.27−1.40 m (4H), 1.40−1.53 m (2H),
1.67−1.77 m (2H) and 1.79−1.95 m (2H, CH3CH2CH2·
CH2CH, CH3CH2CH2CH2O); 3.92 t (2H, OCH2, J =
6.4), 4.16 d.d (1H, CH, J1 = 7.4, J2 = 6.4), 6.72−6.78 m
(2H, C6H4), 7.21−7.27 m (2H, C6H4), 7.26−7.33 m
(2H, C6H5), 7.47−7.56 m (3H, C6H5), 6.95 br.s (1H,
COOH). 13C NMR spectrum, δC, ppm: 13.4, 13.5, 18.6,
21.7, 28.3, 30.6, 31.5, 49.9, 66.9, 113.8, 128.9, 129.1,
129.3, 134.0, 149.9, 153.7, 159.4, 171.6. Found, %: N
9.73; S 7.42. C24H29N3O3S. Calculated, %: N 9.55; S 7.29.
2-[5-(4-Propoxyphenyl)-4-phenyl-4H-1,2,4-triazol-
3-ylsulfanyl]propanoic acid (2d). Yield 79.5%, mp =
1
182–183°C, Rf = 0.64. H NMR spectrum, δ, ppm (J,
5-(4-Alkoxyphenyl)-3-(R-sulfanyl)-4-phenyl-4H-
1,2,4-triazoles (2h–2o). 10 mmol of ethylene chlor-
ohydrin [or chloroacetamide, 3-bromo-4-methoxy-
benzyl chloride, 2-methoxy-5-acetylbenzyl chloride, 2-
(2-chlorophenoxy)ethyl chloride] was added to a
solution of 10 mmol of KOH and 10 mmol of triazole-
Hz): 1.02 t (3H, CH3, J = 7.4), 1.58 d (3H, CH3, J =
7.2), 1.77 q.t (2H, CH2, J1 = 7.4, J2 = 6.5), 3.89 t (2H,
OCH2, J = 6.5), 4.27 q (1H, CH, J = 7.2), 6.74−6.79 m
(2H, C6H4), 7.22−7.27 m (2H, C6H4), 7.27−7.33 m
(2H, C6H5), 7.50−7.55 m (3H, C6H5), 12.65 br.s (1H,
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KALDRIKYAN et al.
3-thiol 1a–1d in 40 mL of EtOH (MeOH). The mixture
was refluxed during 45–60 min and then cooled to
ambient; 60 mL of water was added. The formed solid
was filtered off, washed with water, and recrystallized
from ethanol.
113.4, 118.7, 124.7, 127.1, 128.8, 129.1, 129.2, 129.4,
129.5, 130.7, 133.9, 150.5, 153.7, 159.9, 160.4, 194.5.
Found, %: N 9.55; S 7.38. C25H23N3O3S. Calculated,
%: N 9.43; S 7.19.
5-(4-Methoxyphenyl)-4-phenyl-3-(2-chlorophen-
2-[5-(4-Methoxyphenyl)-4-phenyl-4H-1,2,4-tri-
azol-3-ylsulfanyl]ethanol (2h). Yield 87.0%, mp =
146–147°C, Rf = 0.55. H NMR spectrum, δ, ppm (J,
oxyethylsulfonyl)-4H-1,2,4-triazole (2l). Yield
50.5%, mp = 134–135°C, Rf = 0.58. H NMR spec-
1
1
trum, δ, ppm (J, Hz): 3.60 t (2H, SCH2, J = 6.4), 3.77 s
(3H, OCH3), 4.33 t (2H, OCH2, J = 6.4), 6.77−6.82 m
(2H, C6H4), 6.89 t. d (1H, C6H4Cl, J1 = 7.6, J2 = 1.5),
7.16 d.d (1H, C6H4Cl, J1 = 8.3, J2 = 1.5), 7.24−7.29 m
(2H, C6H4), 7.20−7.34 m (4H, C6H5 и C6H4Cl),
7.47−7.57 m (3H, C6H5). 13C NMR spectrum, δC, ppm:
30.5, 54.5, 66.9, 113.4, 113.5, 118.6, 121.0, 121.9, 127.1,
127.4, 128.8, 129.2, 129.3, 129.5, 133.9, 150.3, 153.3,
153.7, 159.9. Found, %: N 9.64; S 7.51. C23H20ClN3O2S.
Calculated, %: N 9.59; S 7.32.
Hz): 3.26 t (2H, SCH2, J = 6.4), 3.72 t.d (2H, OCH2,
J1 = 6.4, J2 = 5.7), 3.77 s (3H, OCH3), 4.75 t (1H, OH,
J = 5.7), 6.76−6.81 m (2H, C6H4), 7.23−7.28 m (2H,
C6H4), 7.27−7.33 m (2H, C6H5), 7.47−7.57 m (3H,
13
C6H5). C NMR spectrum, δC, ppm: 34.4, 54.6, 59.9,
113.4, 118.7, 127.2, 128.8, 129.2, 129.3, 134.0, 151.1,
153.5, 159.9. Found, %: N 12.72; S 9.65. C17H17N3O2S.
Calculated, %: N 12.83; S 9.79.
2-[5-(4-Methoxyphenyl)-4-phenyl-4H-1,2,4-tri-
azol-3-ylsulfanyl]acetamide (2i). Yield 86.2%, mp =
3-(3-Bromo-4-methoxybenzylsulfanyl)-5-(prop-
1
244–245°C, Rf = 0.64. H NMR spectrum, δ, ppm (J,
oxyphenyl)-4-phenyl-4H-1,2,4-triazole (2m). Yield
1
Hz): 3.77 s (3H, OCH3), 3.87 s (2H, SCH2), 6.76− 6.82
m (2H, C6H4), 6.97 br.s (1H, NH2), 7.24−7.29 m (2H,
C6H4), 7.28−7.34 m (2H, C6H5), 7.46−7.56 m (3H,
C6H5), 7.53 br.s (1H, NH2). 13C NMR spectrum, δC,
ppm: 5.6, 54.7, 113.5, 118.6, 127.2, 128.9, 129.4, 129.5,
133.8, 150.9, 153.7, 159.9, 168.2. Found, %: N 16.65;
S 9.58. C17H16N4O2S. Calculated, %: N 16.46; S 9.41.
98.0%, mp = 136–137°C, Rf = 0.65. H NMR spec-
trum, δ, ppm (J, Hz): 1.02 t (3H, CH2CH3, J = 7.4),
1.70–1.83 m (2H, CH2CH3), 3.86 s (3H, OCH3), 3.89 t
(2H, OCH2, J = 6.5), 4.33 s (2H, SCH2), 6.73–6.78 m
(2H, C6H4), 6.89 d (1H, C6H3Br, J = 8.5), 7.14−7.18 m
(2H, C6H3Br), 7.20−7.26 m (2H, C6H4), 7.30 d.d (1H,
13
C6H5, J1 = 8.5, J2 = 2.2), 7.45−7.51 m (4H, C6H5). C
NMR spectrum, δC, ppm: 10.0, 21.8, 35.0, 55.5, 68.6,
110.6, 111.5, 113.8, 127.0, 128.8, 129.0, 129.2, 130.4,
133.1, 133.8, 150.2, 153.6, 154.6, 159.4. Found, %: N
8.35; S 6.47. C25H24BrN3O2S. Calculated, %: N 8.23; S
6.28.
3-(3-Bromo-4-methoxybenzylsulfanyl)-5-methoxy-
phenyl-4-phenyl-4H-1,2,4-triazole (2j). Yield 93.7%,
1
mp = 119–120°C, Rf = 0.63. H NMR spectrum, δ,
ppm (J, Hz): 3.77 s (3H, OCH3), 3.85 s (3H, OCH3),
4.33 s (2H, SCH2), 6.75−6.81 m (2H, C6H4), 6.89 d
(1H, C6H3, J = 8.4), 7.14−7.20 m (2H, C6H5),
7.23−7.27 m (2H, C6H4), 7.30 d.d (1H, C6H3, J = 8.4,
J = 2.2), 7.46 d (1H, C6H3, J = 2.2), 7.47−7.51 m (3H,
3-(5-Acetyl-2-methoxybenzylsulfanyl)-5-(4-but-
oxyphenyl)-4-phenyl-4H-1,2,4-triazole (2n). Yield
1
70.0%, mp = 122–123°C, Rf = 0.55. H NMR spec-
13
C6H5). C NMR spectrum, δC, ppm: 35.1, 54.5, 55.5,
trum, δ, ppm (J, Hz): 0.97 t (3H, CH2CH3, J = 7.3),
1.40−1.53 m (2H, CH2), 1.67−1.77 m (2H, CH2), 2.50
s (3H, COCH3), 3.88 s (3H, OCH3), 3.92 t (2H, OCH2,
J = 6.4), 4.38 s (2H, SCH2), 6.72−6.77 m (2H, C6H4),
6.97 d (1H, H3, C6H3, J = 8.7), 7.12−7.17 m (2H,
C6H5), 7.19−7.24 m (2H, C6H4), 7.42−7.51 m (3H,
C6H5), 7.85 d.d (1H, H4, C6H3, J1 = 8.7, J2 = 2.3), 7.95
d (1H, H6, C6H3, J = 2.3). 13C NMR spectrum, δC,
ppm: 13.3, 18.6, 25.7, 30.5, 31.0, 55.4, 66.8, 109.9,
113.8, 118.5, 124.7, 127.1, 128.8, 129.0, 129.2, 129.4,
129.5, 130.7, 133.9, 150.4, 153.7, 160.4, 194.4. Found,
%: N 8.80; S 6.75. C28H29N3O2S. Calculated, %: N
8.61; S 6.57.
110.6, 111.5, 113.3, 112.6, 127.0, 128.8, 123.0, 129.1,
129.2, 130.0, 133.2, 133.8, 150.2, 153.6, 154.6, 159.8.
Found, %: N 8.54; S 6.83. C23H20BrN3O2S. Calculated,
%: N 8.71; S 6.64.
3-(5-Acetyl-2-methoxybenzylsulfanyl)-5-(4-meth-
oxyphenyl)-4-phenyl-4H-1,2,4-triazole (2k). Yield
1
93.3%, mp = 83–84°C, Rf = 0.61. H NMR spectrum,
δ, ppm (J, Hz): 2.50 s (3H, COCH3), 3.77 s (3H,
OCH3), 3.88 s (3H, OCH3), 4.38 s (2H, SCH2),
6.75−6.80 m (2H, C6H4), 6.97 d (1H, H3, C6H3, J =
8.7), 7.11−7.18 m (2H, C6H5), 7.21−7.26 m (2H, C6H4),
7.42−7.52 m (3H, C6H5), 7.85 d.d (1H, H4, C6H3, J1 =
8.7, J2 = 2.2,), 7.95 d (1H, H6, C6H3, J = 2.2). 13C
NMR spectrum, δC, ppm: 25.8, 31.0, 54.6, 55.4, 109.9,
3-(3-Bromo-4-methoxybenzylsulfanyl)-5-(4-but-
oxyphenyl)-4-phenyl-4H-1,2,4-triazole (2o). Yield
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309
1
75.8%, mp = 121–122°C, Rf = 0.64. H NMR spec-
trum, δ, ppm (J, Hz): 0.97 t (3H, CH2CH3, J = 7.4),
1.40−1.53 m (2H, CH2CH3), 1.57−1.77 m (2H,
CH2CH2O), 3.86 s (3H, OCH3), 3.92 t (2H, OCH2, J =
6.4), 4.33 s (2H, SCH2), 6.72−6.78 m (2H, C6H4), 6.89
d (1H, H5, C6H3, J = 8.4), 7.13−7.19 m (2H, C6H5),
7.20−7.25 m (2H, C6H4), 7.43−7.53 m (3H, C6H5),
7.30 d.d (1H, H6, C6H3, J1 = 8.4, J2 = 2.1), 7.49 d (1H,
2-[(Piperidin-1-yl)methyl]-4-phenyl-5-(4-ethoxy-
phenyl)-2H-1,2,4-triazole-3(4H)-thione (3d). Yield
97.4%, mp = 165–166°C, Rf = 0.70. 1H NMR spectrum,
δ, ppm (J, Hz): 1.38 t (3H, OCH2CH3, J = 7.0),
1.39−1.48 m (2H), 1.55−1.64 m (4H) and 2.79−2.85 m
(4H, C5H10N), 4.00 q (2H, OCH2, J = 7.0), 5.10 s (2H,
NCH2N), 6.73−6.79 m (2H, C6H4), 7.16−7.21 m (2H,
C6H4), 7.26−7.32 m (2H, C6H5), 7.47−7.54 m (3H,
C6H5). Found, %: N 14.45; S 8.37. C22H26N4OS.
Calculated, %: N 14.20; S 8.12.
H2, C6H3, J = 2.1). C NMR spectrum, δC, ppm: 13.3,
13
18.6, 35.1, 55.5, 66.8, 110.7, 111.5, 113.8, 118.5,
127.0, 128.8, 129.0, 129.1, 129.2, 130.1, 133.1, 133.9,
150.2, 153.7, 154.6, 159.4. Found, %: N 8.24; S 6.28.
C26H26BrN3O2S. Calculated, %: N 8.01; S 6.11.
2-[(Morpholin-4-yl)methyl]-5-(4-propoxyphenyl)-
4-phenyl-2H-1,2,4-triazole-3(4H)-thione (3e). Yield
1
72.6%, mp = 97–98°C, Rf = 0.74. H NMR spectrum,
δ, ppm (J, Hz): 1.02 t (3H, CH2CH3, J = 7.4),
1.71−1.83 m (2H, CH2CH3), 2.83−2.88 m (4H) and
3.60−3.67 m (4H, OC4H8N), 3.89 t (2H, OCH2, J =
6.5), 5.13 s (2H, NCH2N), 6.74−6.80 m (2H, C6H4),
7.16−7.22 m (2H, C6H4), 7.27−7.33 m (2H, C6H5),
7.48−7.54 m (3H, C6H5). Found, %: N 13.45; S 7.52.
C22H26N4O2S. Calculated, %: N 13.64; S 7.81.
5-(4-Alkoxyphenyl)-2-aminomethyl-4-phenyl-2H-
1,2,4-triazole-3(4H)-thione (3a–3h). 2 mL of mor-
pholine (piperidine) and 8 mL of formalin were added
in sequence to a solution of 10 mmol of triazole-3-thiol
1a–1d in 10 mL of EtOH. The mixture was incubated
at 20–25°C during 6–7 h. The precipitate was filtered
off and recrystallized from 70% EtOH.
2-[(Piperidin-1-yl)methyl]-5-(4-propoxyphenyl)-
5-(4-Methoxyphenyl)-2-[(morpholin-4-yl)methyl]-
4-phenyl-2H-1,2,4-triazole-3(4H)-thione (3e). Yield
4-phenyl-2H-1,2,4-triazole-3(4H)-thione (3a). Yield
1
87.5%, mp = 133–134°C, Rf = 0.72. H NMR spec-
1
90%, mp = 141–142°C, Rf = 0.72. H NMR spectrum,
trum, δ, ppm (J, Hz): 1.02 t (3H, CH2CH3, J = 7.4),
1.39−1.48 m (2H) and 1.55−1.64 m (4H, CH2,
C5H10N), 1.71–1.83 m (2H CH2CH3), 2.79–2.85 m
[4H, N(CH2)2], 3.89 t (2H, OCH2, J = 6.5), 5.10 s (2H,
NCH2N), 6.73−6.78 m (2H, C6H4), 7.15−7.21 m (2H,
C6H4), 7.26−7.31 m (2H, C6H5), 7.48−7.53 m (3H,
C6H5). Found, %: N 13.52; S 7.62. C23H28N4OS.
Calculated, %: N 13.71; S 7.48.
δ, ppm (J, Hz): 2.83–2.87 m (4H) and 3.61–3.65 m
(4H, OC4H8N), 3.78 s (3H, OCH3), 5.13 s (2H, NCH2N),
6.76−6.82 m (2H, C6H4), 7.18−7.24 m (2H, C6H4),
7.28−7.32 m (2H, C6H5), 7.48−7.54 m (3H, C6H5).
Found, %: N 14.74; S 8.59. C20H22N4O2S. Calculated,
%: N 14.64; S 8.38.
5-(4-Methoxyphenyl)-2-[(piperidin-1-yl)methyl]-
4-phenyl-2H-1,2,4-triazole-3(4H)-thione (3b). Yield
85.0%, mp = 174–175°C, Rf = 0.73. 1H NMR spectrum,
δ, ppm (J, Hz): 1.39−1.48 m (2H), 1.55−1.64 m (4H)
and 2.79−2.85 m (4H, C5H10N), 3.78 s (3H, OCH3),
5.13 s (2H, NCH2N), 6.75−6.81 m (2H, C6H4),
7.19−7.24 m (2H, C6H4), 7.28−7.32 m (2H, C6H5),
7.48−7.55 m (3H, C6H5). Found, %: N 14.53; S 8.64.
C21H24N4OS. Calculated, %: N 14.72; S 8.42.
5-(4-Butoxyphenyl)-2-[(morpholin-4-yl)methyl]-
4-phenyl-2H-1,2,4-triazole-3(4H)-thione (3g). Yield
1
83.5%, mp = 124–125°C, Rf = 0.74. H NMR spec-
trum, δ, ppm (J, Hz): 0.97 t (3H, CH2CH3, J = 7.4),
1.41−1.53 m (2H, CH2CH3), 1.68−1.78 m (2H, CH2),
2.83−2.88 m (4H) and 3.61−3.66 m (4H, OC4H8N),
3.93 t (2H, OCH2, J = 6.4), 5.13 s (2H, NCH2N),
6.73−6.78 m (2H, C6H4), 7.17−7.22 m (2H, C6H4),
7.24−7.33 m (2H, C6H5), 7.48−7.53 m (3H, C6H5).
Found, %: N 13.35; S 7.24. C23H24N4O2S. Calculated,
%: N 13.19; S 7.55.
2-[(Morpholin-4-yl)methyl]-4-phenyl-5-(4-ethoxy-
phenyl)-2H-1,2,4-triazole-3(4H)-thione (3c). Yield
76.0%, mp = 172–173°C, Rf = 0.72. 1H NMR spectrum,
δ, ppm (J, Hz): 1.38 t (3H, OCH2CH3, J = 7.0),
2.83−2.89 m (4H) and 3.61−3.66 m (4H, OC4H8N),
4.01 q (2H, OCH2, J = 7.0), 5.13 s (2H, NCH2N),
6.73−6.79 m (2H, C6H4), 7.16−7.23 m (2H, C6H4),
7.24−7.33 m (2H, C6H5), 7.48−7.54 m (3H, C6H5).
Found, %: N 14.25; S 8.28. C21H24N4O2S. Calculated,
%: N 14.13; S 8.08.
5-(4-Butoxyphenyl)-2-[(piperidin-1-yl)methyl]-4-
phenyl-2H-1,2,4-triazole-3(4H)-thione (3h). Yield
1
85.0%, mp = 136–137°C, Rf = 0.75. H NMR spec-
trum, δ, ppm (J, Hz): 0.97 t (3H, CH2CH3, J = 7.4),
1.39–1.53 m (4H, CH2), 1.55−1.64 m (4H, CH2),
1.68−1.77 m (2H, CH2), 2.79−2.84 m [4H, N(CH2)2],
3.93 t (2H, OCH2, J = 6.4), 5.10 s (2H, NCH2N),
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KALDRIKYAN et al.
6.72−6.78 m (2H, C6H4), 7.15−7.20 m (2H, C6H4),
7.26−7.31 m (2H, C6H5), 7.48−7.53 m (3H, C6H5).
Found, %: N 13.42; S 7.67. C24H30N4OS. Calculated,
%: N 13.25; S 7.58.
5-R-4-R'-2-(2-Cyanoethyl)-1,2,4-triazole-3-thiones
(5a–5f). A mixture of 0.01 mol of the corresponding
1,2,4-triazolethiol 1, 10 mL of freshly distilled acrylo-
nitrile, 20 mL of triethylamine, and 20 mL of water
was refluxed during 5–6 h. After cooling, the pre-
cipitate was filtered off and dried.
2-Hydroxymethyl-4-phenyl-5-R-2H-1,2,4-triazole-
3(4H)-thiones (4a–4d). 4.5 mL of formalin was added
to a solution of 25 mmol of 1,2,4-triazole-3-thiol 1a–
1d in 30 mL of EtOH. The mixture was refluxed
during 20 min. After partial evaporation of EtOH, the
formed precipitate was filtered off and dried.
5-(4-Methoxyphenyl)-4-phenyl-2-(2-cyanoethyl)-
2H-1,2,4-triazole-3(4H)-thione (5a). Yield 90.0%,
1
mp = 205–206°C, Rf = 0.75. H NMR spectrum, δ,
ppm (J, Hz): 3.11 t (2H, CH2CN, J = 6.7), 3.78 s (3H,
OCH3), 4.53 t (2H, NCH2, J = 6.7), 6.78−6.83 m (2H,
C6H4), 7.20−7.25 m (2H, C6H4), 7.28−7.35 m (2H,
C6H5), 7.49−7.54 m (3H, C6H5). Found, %: N 16.84; S
9.69. C18H16N4OS. Calculated, %: N 16.65; S 9.53.
2-Hydroxymethyl-5-(4-methoxyphenyl)-4-phenyl-
2H-1,2,4-triazole-3(4H)-thione (4a). Yield 92.5%,
1
mp = 252–253°C, Rf = 0.70. H NMR spectrum, δ,
ppm (J, Hz): 1.08 t (3H, CH3, J = 7.4), 5.55 s (2H,
NCH2), 6.65 t (1H, CH2OH, J = 7.6), 6.75−6.78 m
(2H, C6H4), 7.18−7.24 m (2H, C6H4), 7.28−7.35 m
(2H, C6H5), 7.45−7.53 m (3H, C6H5). Found, %: N
13.65; S 10.45. C16H15N3O2S. Calculated, %: N 13.40;
S 10.32
4-Benzyl-5-(4-methoxyphenyl)-2-(2-cyanoethyl)-
2H-1,2,4-triazole-3(4H)-thione (5b). Yield 85.7%,
1
mp = 59–60°C, Rf = 0.60. H NMR spectrum, δ, ppm
(J, Hz): 3.10 t (2H, CH2CN, J = 6.6), 3.82 s (3H,
OCH3), 4.53 t (2H, NCH2, J = 6.6), 5.34 s (2H, NCH2),
6.90−6.96 m (2H, C6H4), 7.06−7.13 m (2H, C6H5),
7.20−7.33 m (3H, C6H5), 7.37−7.43 m (2H, C6H4).
Found, %: N 15.82; S 9.33. C19H19N4OS. Calculated,
%: N 15.94; S 9.12.
2-Hydroxymethyl-4-phenyl-5-(4-ethoxyphenyl)-
2H-1,2,4-triazole-3(4H)-thione (4b). Yield 93.7%,
1
mp = 268–269°C, Rf = 0.74. H NMR spectrum, δ,
ppm (J, Hz): 1.38 t (3H, CH3, J = 7.0), 4.01 d (2H,
OCH2, J = 7.0), 5.55 d (2H, NCH2, J = 7.0), 6.63 t
(1H, CH2OH, J = 7.6), 6.74−6.79 m (2H, C6H4),
7.19−7.24 m (2H, C6H4), 7.28−7.34 m (2H, C6H5),
7.46−7.54 m (3H, C6H5). Found, %: N 12.56; S 9.88.
C17H17N3O2S. Calculated, %: N 12.83; S 9.79.
4-Phenyl-2-(2-cyanoethyl)-5-(4-ethoxyphenyl)-2H-
1,2,4-triazole-3(4H)-thione (5c). Yield 80.0%, mp =
1
198–199°C, Rf = 0.68. H NMR spectrum, δ, ppm (J,
Hz): 1.38 t (3H, OCH2CH3, J = 7.0), 3.11 t (2H,
CH2CN, J = 6.7), 4.01 q (2H, OCH2, J = 7.0), 4.53 t
(2H, NCH2, J = 6.7), 6.75−6.80 m (2H, C6H4), 7.18−7.23
m (2H, C6H4), 7.28−7.35 m (2H, C6H5), 7.49−7.54 m
(3H, C6H5). Found, %: N 15.81; S 9.27. C19H19N4OS.
Calculated, %: N 15.94; S 9.12.
2-Hydroxymethyl-5-(4-propoxyphenyl)-4-phenyl-
2H-1,2,4-triazole-3(4H)-thione (4c). Yield 90.0%,
1
mp = 167–168°C, Rf = 0.76. H NMR spectrum, δ,
ppm (J, Hz): 1.02 t (3H, CH2CH3, J = 7.4), 1.71−1.83
m (2H, CH2), 3.89 t (2H, OCH2, J = 6.4), 5.55 d (2H,
NCH2, J = 7.6), 6.63 t (1H, CH2OH, J = 7.6),
6.74−6.79 m (2H, C6H4), 7.19−7.24 m (2H, C6H4),
7.28−7.34 m (2H, C6H5), 7.46−7.54 m (3H, C6H5).
Found, %: N 12.49; S 9.58. C18H19N3O2S. Calculated,
%: N 12.30; S 9.39.
4-Benzyl-2-(2-cyanoethyl)-5-(4-ethoxyphenyl)-2H-
1,2,4-triazole-3(4H)-thione (5d). Yield 83.3%, mp =
1
81–82°C, Rf = 0.70. H NMR spectrum, δ, ppm (J,
Hz): 1.42 t (3H, OCH2CH3, J = 7.0), 3.10 t (2H,
CH2CN, J = 6.7), 4.07 q (2H OCH2, J = 7.0), 4.52 t
(2H NCH2, J = 6.7), 5.34 s (2H, NCH2), 6.82−6.92 m
(2H, C6H4), 7.07−7.11 m (2H, C6H4), 7.19−7.30 m
(3H, C6H5), 7.35−7.41 m (2H, C6H5). Found, %: N
15.74; S 9.12. C19H19N4OS. Calculated, %: N 15.94; S
9.12.
5-(4-Butoxyphenyl)-2-hydroxymethyl-4-phenyl-2H-
1,2,4-triazol-3(4H)-thione (4d). Yield 93.0%, mp =
1
141–142°C, Rf = 0.72. H NMR spectrum, δ, ppm (J,
Hz): 0.97 t (3H, CH2CH3, J = 7.3), 1.43−1.53 m (2H,
CH2), 1.68−1.77 m (2H, CH2), 3.93 t (2H, OCH2, J =
6.4), 5.55 d (2H, NCH2, J = 7.6), 6.65 t (1H, CH2OH,
J = 7.6), 6.74−6.79 m (2H, C6H4), 7.19−7.24 m (2H,
C6H4), 7.28−7.34 m (2H, C6H5), 7.46−7.54 m (3H,
C6H5). Found, %: N 11.72; S 9.26. C19H21N3O2S.
Calculated, %: N 11.82; S 9.02.
5-(4-Benzyloxyphenyl)-4-phenyl-2-(2-cyanoethyl)-
2H-1,2,4-triazole-3(4H)-thione (5e). Yield 87.5%,
1
mp = 177–178°C, Rf = 0.60. H NMR spectrum, δ,
ppm (J, Hz): 3.11 t (2H, CH2CN, J = 6.7), 4.53 t (2H,
NCH2, J = 6.7), 5.06 s (2H, OCH2), 6.86−6.91 m (2H,
C6H4), 7.20−7.26 m (2H, C6H4), 7.27–7.39 m (7H, Ar),
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ALKYLATION, AMINO(HYDROXY)METHYLATION, AND CYANOETHYLATION
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3. Kaldrikyan, M.A., Grigoryan, L.A., Melik-Ogandzha-
nyan, R.G., and Arsenyan, F.G., Pharm. Chem. J., 2011,
vol. 45, no. 4, p. 211. DOI: 10.1007/s11094-011-0596-9.
7.49−7.54 m (3H, Ar). Found, %: N 13.75; S 7.82.
C24H20N4OS. Calculated, %: N 13.58; S 7.77.
4-Benzyl-5-(4-benzyloxyphenyl)-2-(2-cyanoethyl)-
4. Kaldrikyan,
M.A.,
Grigoryan,
L.A.,
Melik-
2H-1,2,4-triazole-3(4H)-thione (5f). Yield 83.3%,
Ogandzhanyan, R.G., and Arsenyan, F.G., Pharm.
Chem. J., 2012, vol. 46, no. 9, p. 531. DOI: 10.1007/
s11094-012-0840-y.
1
mp = 112–113°C, Rf = 0.76. H NMR spectrum, δ,
ppm (J, Hz): 3.10 t (2H, CH2CN, J = 6.7), 4.52 t (2H,
NCH2, J = 6.7), 5.12 s (2H, OCH2), 5.34 s (2H,
NCH2), 6.99−7.05 m (2H, C6H4), 7.06−7.11 m (2H,
C6H4), 7.20−7.44 m (10H, C6H5). Found, %: N 13.28;
S 7.32. C25H22N4OS. Calculated, %: N 13.1; 3 S 7.51.
5. Kaldrikyan, M.A., Melik-Oganjanyan, R.G., and
Arsenyan, F.H., Pharm. Chem. J., 2013, vol. 47, no. 4,
p. 191. DOI: 10.1007/s11094-013-0924-3.
6. Kaldrikyan, M.A., Minasyan, N.S., and Melik-
Ogandzhanyan, R.G., Russ. J. Org. Chem., 2013, vol. 49,
no. 10, p. 1550. DOI: 10.1134/S1070428013100254.
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