Alkylation and aminomethylation of new 4,5-Substituted 4H-1,2,4-Triazole-3- thiols

Full text of DOI:10.1134/S1070428013100254

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 10, pp. 1550–1554. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © M.A. Kaldrikyan, N.S. Minasyan, R.G. Melik-Ogandzhanyan, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49,
No. 10, pp. 1571–1574.
SHORT
COMMUNICATIONS
Alkylation and Aminomethylation
of New 4,5-Substituted 4H-1,2,4-Triazole-3-thiols
M. A. Kaldrikyan, N. S. Minasyan, and R. G. Melik-Ogandzhanyan
Mndzhoyan 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: melik@raen.am
Received August 3, 2012
DOI: 10.1134/S1070428013100254
We previously synthesized 5-[alkoxyphenyl(alk-
oxyphenethyl, benzofuryl)]-4-phenyl(allyl)-4H-1,2,4-
triazole-3-thiols some of which (specifically N- and
S-substituted derivatives) were found to exhibit anti-
tumor activity [1]. While continuing studies in this
line, we tried to find new efficient compounds among
substituted 1,2,4-triazole-3-thiols and reveal a possible
relation between their chemical structure and antitumor
activity. For this purpose, we have synthesized new
1,2,4-triazole-3-thiol derivatives containing a cyclo-
hexyl substituent on C4.
1,4-Substituted thiosemicarbazides IIa–IIf were
synthesized by heating the corresponding 4-alkoxy-
benzohydrazides with cyclohexyl isothiocyanate. The
cyclization of thiosemicarbazides IIa–IIf in 4.5%
aqueous potassium hydroxide gave 5-alkoxyphenyl-4-
cyclohexyl-4H-1,2,4-triazole-3-thiols IIIa–IIIf which
were subjected to S-alkylation with α-halo carboxylic
O
O
H
N
H
N
NH2
N
N
H
·
N
H
+
S
S
RO
RO
Ia–If
IIa–IIf
N
N
N
SR'
R'Hlg
N
N
SH
RO
N
IVa–IVs
KOH
N
N
N
O
RO
, CH2O
O
RO
HN
N
IIIa–IIIf
S
Va, Vb
I–III, R = Me (a), Et (b), Pr (c), i-Pr (d), Bu (e), i-Bu (f); IV, R = Me, R′ = CH2COOH (a), CH(Me)COOH (b), CH(Bu)COOH (c);
R = Et, R′ = CH2COOH (d), CH(Me)COOH (e); R = Pr, R′ = CH2COOH (f), CH(Me)COOH (g); R = i-Pr, R′ = CH2COOH (h),
CH(Me)COOH (i); R = Bu, R′ = CH2COOH (j), CH(Me)COOH (k); R = i-Bu, R′ = CH2COOH (l), CH(Me)COOH (m);
R′ = CH2CH2OH, R = Me (n), Et (o), Pr (p), i-Pr (q), Bu (r), i-Bu (s); V, R = Me (a), Et (b).
1550

ALKYLATION AND AMINOMETHYLATION OF NEW 4,5-SUBSTITUTED ...
1551
acids in water in the presence of 3 equiv of KOH, as
well as with 2-chloroethanol in alcohol in the presence
of 1 eqiv of KOH.
(1H, NCH), 4.64 sept [1H, CH(CH3)2, J = 6.0 Hz],
6.97 m and 7.35 m (2H each, C6H4), 13.42 br.s (1H,
SH). Found, %: N 13.32; S 10.28. C17H23N3OS. Calcu-
lated, %: N 13.23; S 10.10.
Like other cyclic thioamides, triazole-3-thiols IIIa
and IIIb reacted as thione tautomers [2] with
morpholine and formaldehyde in ethanol according to
Mannich to afford 2-(morpholin-4-ylmethyl)-2,4-dihy-
dro-3H-1,2,4-triazole-3-thiones Va and Vb. The struc-
ture of the newly synthesized compounds was con-
5-(4-Butoxyphenyl)-4-cyclohexyl-4H-1,2,4-tri-
azole-3-thiol (IIIe). Yield 91%, mp 165–166°C,
1
Rf 0.67. H NMR spectrum, δ, ppm: 1.01 t (3H, CH3,
J = 7.4 Hz); 1.11 m (1H), 1.21–1.38 m (2H), 1.61 m
(1H), 1.68–1.84 m (4H), and 2.20 m (2H) (C6H11);
1.53 m (2H, CH2CH3), 1.79 m (2H, OCH2CH2), 4.03 t
(2H, OCH2, J = 6.4 Hz), 4.31 m (1H, NCH), 6.98 m
and 7.34 m (2H each, C6H4), 13.50 br (1H, SH).
Found, %: N 12.45; S 9.38. C18H25N3OS. Calculated,
%: N 12.67; S 9.67.
1
firmed by their elemental compositions and H NMR
spectra.
5-(4-Alkoxyphenyl)-4-cyclohexyl-4H-1,2,4-tri-
azole-3-thiols IIIa–IIIf (genearl procedure). A solu-
tion of 10 mmol of thiosemicarbazide IIa–IIf and 1 g
of potassium hydroxide in 50 ml of water was heated
for 2 h under reflux. The mixture was cooled and
treated with acetic acid to pH 5, and the precipitate
was filtered off, washed with water, dried, and recrys-
tallized from 70% ethanol.
4-Cyclohexyl-5-(4-methoxyphenyl)-4H-1,2,4-tri-
azole-3-thiol (IIIa). Yield 93%, mp 185–186°C,
Rf 0.60. 1H NMR spectrum, δ, ppm: 1.11–1.30 m (1H),
1.61 m (2H), 1.76 m (4H), and 2.19 m (2H) (C6H11);
3.87 s (3H, OCH3), 4.31 m (1H, NCH), 7.01 m and
7.37 m (2H each, C6H4), 13.57 br (1H, SH). Found, %:
N 14.31; S 11.25. C15H19N3OS. Calculated, %:
N 14.52; S 11.07.
4-Cyclohexyl-5-(4-isobutoxyphenyl)-4H-1,2,4-
triazole-3-thiol (IIIf). Yield 93%, mp 185–186°C,
1
Rf 0.60. H NMR spectrum, δ, ppm: 1.07 d [6H,
CH(CH3)2, J = 6.7 Hz]; 1.16–1.36 m (3H), 1.66 m
(1H), 1.77–1.92 m (4H), and 2.09 m (2H) (C6H11);
2.12 sept [1H, CH(CH3)2, J 6.7 Hz], 3.81 d (2H,
OCH2, J = 6.4 Hz), 4.31 m (1H, NCH), 7.00 m and
7.36 m (2H each, C6H4), 13.21 br (1H, SH). Found, %:
N 12.78; S 9.82. C18H25N3OS. Calculated, %: N 12.67;
S 9.67.
Substituted α-(4H-1,2,4-triazol-3-ylsulfanyl)-
acetic, -propionic, and -hexanoic acids IVa–IVm
(general procedure). A mixture of 6 mmol of potas-
sium hydroxide, 30 ml of water, 2 mmol of triazole-3-
thiol IIIa–IIIf, and 2 mmol of chloroacetic, 2-bromo-
propionic, or 2-bromohexanoic acid was heated for 2 h
under reflux. The solution was filtered, the filtrate was
adjusted to pH 5 by adding acetic acid, and the
precipitate was filtered off, washed with water, dried,
and recrystallized from ethanol.
4-Cyclohexyl-5-(4-ethoxyphenyl)-4H-1,2,4-tri-
azole-3-thiol (IIIb). Yield 98%, mp 223–224°C,
1
Rf 0.62. H NMR spectrum, δ, ppm: 1.10 m (1H),
1.20–1.38 m (2H), 1.61 m (1H), 1.67–1.85 m (4H),
and 2.19 m (2H) (C6H11); 1.45 t (3H, CH3, J = 7.0 Hz),
4.11 q (2H, OCH2, J = 7.0 Hz), 4.31 m (1H, NCH),
6.95 m and 7.35 m (2H each, C6H4), 13.55 br (1H,
SH). Found, %: N 13.65; S 10.37. C16H21N3OS. Cal-
culated, %: N 13.84; S 10.56.
[4-Cyclohexyl-5-(4-methoxyphenyl)-4H-1,2,4-tri-
azol-3-ylsulfanyl]acetic acid (IVa). Yield 83%,
1
mp 212–213°C, Rf 0.58. H NMR spectrum, δ, ppm:
4-Cyclohexyl-5-(4-propoxyphenyl)-4H-1,2,4-tri-
1.17–1.37 m (3H), 1.67 m (1H), 1.80–1.93 m (4H),
and 2.11 m (2H) (C6H11); 3.87 s (3H, OCH3), 3.99 m
(1H, NCH), 4.05 s (2H, SCH2), 7.02 m and 7.35 m
(2H each, C6H4), 12.3 br.s (1H, COOH). Found, %:
N 12.25; S 9.44. C17H23N2O3S. Calculated, %:
N 12.09; S 9.61.
azole-3-thiol (IIIc). Yield 92%, mp 205–206°C,
1
Rf 0.61. H NMR spectrum, δ, ppm: 1.06 t (3H, CH3,
J = 7.4 Hz); 1.16–1.36 m (3H), 1.65 m (1H), 1.77–
1.90 m (4H), and 2.03–2.18 m (2H) (C6H11); 1.85 m
(2H, CH2CH3), 4.05 m (1H, NCH), 4.08 t (2H, OCH2,
J = 6.4 Hz), 7.00 m and 7.40 m (2H each, C6H4),
13.36 br.s (1H, SH). Found, %: N 13.45; S 10.26.
C17H23N3OS. Calculated, %: N 13.23; S 10.10.
2-[4-Cyclohexyl-5-(4-methoxyphenyl)-4H-1,2,4-
triazol-3-ylsulfanyl]propanoic acid (IVb). Yield
1
4-Cyclohexyl-5-(4-isopropoxyphenyl)-4H-1,2,4-
triazole-3-thiol (IIId). Yield 98%, mp 196–197°C,
Rf 0.63. 1H NMR spectrum, δ, ppm: 1.10–1.34 m (3H),
1.67 m (1H), 1.76–1.90 m (4H), and 2.00–2.17 m (2H)
(C6H11); 1.37 d [6H, CH(CH3)2, J = 6.0 Hz], 4.02 m
83%, mp 174–175°C, Rf 0.53. H NMR spectrum, δ,
ppm: 1.15–1.36 m (3H), 1.66 m (1H), 1.78–1.91 m
(4H), and 2.00–2.16 m (2H) (C6H11); 1.65 d (3H, CH3,
J = 7.2 Hz), 3.87 s (3H, OCH3), 4.00 m (1H, NCH),
4.44 q (1H, CHCH3, J = 7.2 Hz), 7.02 m and 7.38 m
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KALDRIKYAN et al.
1552
(2H each, C6H4), 12.6 br.s (1H, COOH). Found, %:
N 11.45; S 8.96. C18H23N3O3S. Calculated, %:
N 11.62; S 8.87.
2.17 m (2H) (C6H11); 1.65 d (3H, SCHCH3, J =
7.2 Hz), 1.84 m (2H, CH2CH3), 4.00 m (1H, NCH),
4.00 t (2H, OCH2, J = 6.4 Hz), 4.44 q (1H, SCHCH3,
J = 7.2 Hz), 7.00 m and 7.36 m (2H each, C6H4),
12.57 br.s (1H, COOH). Found, %: N 10.92; S 8.45.
C20H27N3O3S. Calculated, %: N 10.78; S 8.23.
2-[4-Cyclohexyl-5-(4-methoxyphenyl)-4H-1,2,4-
triazol-3-ylsulfanyl]hexanoic acid (IVc). Yield 92%,
1
mp 144–145°C, Rf 0.60. H NMR spectrum, δ, ppm:
[4-Cyclohexyl-5-(4-isopropoxyphenyl)-4H-1,2,4-
triazol-3-ylsulfanyl]acetic acid (IVh). Yield 98%,
0.96 t (3H, CH2CH3, J = 7.1 Hz); 1.16–1.37 m (3H),
1.66 m (1H), 1.78–1.93 m (4H), and 1.99–2.17 m (2H)
(C6H11); 1.37–1.55 m (4H, CH2CH2CH3), 1.97 m (2H,
CHCH2), 3.88 s (3H, OCH3), 4.00 m (1H, NCH),
4.37 t (1H, SCHCH2, J = 6.9 Hz), 7.02 m and 7.37 m
(2H each, C6H4), 11.4 br.s (1H, COOH). Found, %:
N 10.18; S 8.14. C21H29N3O3S. Calculated, %:
N 10.41; S 7.94.
1
mp 193–194°C, Rf 0.55. H NMR spectrum, δ, ppm:
1.17–1.35 m (3H), 1.67 m (1H), 1.87 m (4H), and
2.13 m (2H) (C6H11); 1.38 d [6H, CH(CH3)2, J =
6.0 Hz], 4.00 m (1H, NCH), 4.05 s (2H, SCH2),
4.67 sept [1H, CH(CH3)2, J = 6.0 Hz], 6.97 m and
7.35 m (2H each, C6H4), 12.53 br.s (1H, COOH).
Found, %: N 11.28; S 8.65. C19H25N3O3S. Calculated,
%: N 11.19; S 8.53.
[4-Cyclohexyl-5-(4-ethoxyphenyl)-4H-1,2,4-tri-
azol-3-ylsulfanyl]acetic acid (IVd). Yield 98%,
1
[4-Cyclohexyl-5-(4-isopropoxyphenyl)-4H-1,2,4-
triazol-3-ylsulfanyl]propanoic acid (IVi). Yield 87%,
mp 187–188°C, Rf 0.57. H NMR spectrum, δ, ppm:
1.17–1.37 m (3H), 1.68 m (1H), 1.81–1.93 m (4H),
and 2.04–2.70 m (2H) (C6H11); 1.45 t (3H, CH2CH3,
J = 7.0 Hz), 3.99 m (1H, NCH), 4.05 s (2H, SCH2),
4.11 q (2H, OCH2, J = 7.0 Hz), 6.99 m and 7.36 m (2H
each, C6H4), 12.66 br.s (1H, COOH). Found, %:
N 11.75; S 8.99. C18H23N3O3S. Calculated, %:
N 11.65; S 8.87.
1
mp 118–119°C, Rf 0.50. H NMR spectrum, δ, ppm:
1.17–1.33 m (3H), 1.67 m (1H), 1.78–1.92 m (4H),
and 2.02–2.18 m (2H) (C6H11); 1.38 d [6H, CH(CH3)2,
J = 6.0 Hz], 1.65 d (3H, SCHCH3, J = 7.2 Hz), 4.01 m
(1H, NCH), 4.44 q (1H, SCHCH3, J = 7.2 Hz), 4.66 m
[1H, CH(CH3)2, J = 6.0 Hz], 6.97 m and 7.34 m (2H
each, C6H4), 12.5 br.s (1H, COOH). Found, %:
N 10.99; S 8.52. C20H27N3O3S. Calculated, %:
N 10.78; S 8.23.
2-[4-Cyclohexyl-5-(4-ethoxyphenyl)-4H-1,2,4-tri-
azol-3-ylsulfanyl]propionic acid (IVe). Yield 90%,
1
mp 168–169°C, Rf 0.58. H NMR spectrum, δ, ppm:
[5-(4-Butoxyphenyl)-4-cyclohexyl-4H-1,2,4-tri-
azol-3-ylsulfanyl]acetic acid (IVj). Yield 87%,
1.15–1.36 m (3H), 1.66 m (1H), 1.76–1.91 m (4H),
and 2.00–2.16 m (2H) (C6H11); 1.45 t (3H, CH2CH3,
J = 7.0 Hz), 1.65 d (3H, CHCH3, J = 7.2 Hz), 4.00 m
(1H, NCH), 4.11 q (2H, OCH2, J = 7.0 Hz), 4.43 q
(1H, SCHCH3, J = 7.2 Hz), 6.99 m and 7.36 m (2H
each, C6H4), 12.6 br.s (1H, COOH). Found, %:
N 11.35; S 8.34. C19H25N3O3S. Calculated, %:
N 11.19; S 8.53.
1
mp 136–137°C, Rf 0.57. H NMR spectrum, δ, ppm:
1.02 t (3H, CH2CH3, J = 7.4 Hz); 1.16–1.37 m (3H),
1.67 m (1H), 1.75–1.92 m (4H), and 2.04–2.21 m (2H)
(C6H11); 1.53 m (2H, CH2CH3), 1.80 m (2H,
OCH2CH2), 3.95 m (1H, NCH), 4.04 t (2H, OCH2, J =
6.4 Hz), 4.04 s (2H, SCH2), 5.90 br (1H, COOH),
6.98 m and 7.36 m (2H each, C6H4). Found, %:
N 10.52; S 8.46. C20H27N3O3S. Calculated, %:
N 10.78; S 8.23.
[4-Cyclohexyl-5-(4-propoxyphenyl)-4H-1,2,4-tri-
azol-3-ylsulfanyl]acetic acid (IVf). Yield 80%,
1
mp 175–176°C, Rf 0.54. H NMR spectrum, δ, ppm:
2-[5-(4-Butoxyphenyl)-4-cyclohexyl-4H-1,2,4-tri-
azol-3-ylsulfanyl]propanoic acid (IVk). Yield 77%,
1.08 t (3H, CH2CH3, J = 7.4 Hz); 1.17–1.37 m (3H),
1.67 m (1H), 1.80–1.92 m (4H), and 2.04–2.20 m (2H)
(C6H11); 1.84 m (2H, CH2CH3), 3.99 m (1H, NCH),
4.00 t (2H, OCH2, J = 6.4 Hz), 12.1 br.s (1H, COOH).
Found, %: N 11.42; S 8.65. C19H25N3O3S. Calculated,
%: N 11.19; S 8.53.
1
mp 147–148°C, Rf 0.57. H NMR spectrum, δ, ppm:
1.04 t (3H, CH2CH3, J = 7.4 Hz); 1.14–1.36 m (3H),
1.67 m (1H), 1.74–1.91 m (4H), and 2.02–2.21 m (2H)
(C6H11); 1.65 d (3H, SCHCH3, J = 7.2 Hz), 1.51 m
(2H, CH2CH3), 1.80 m (2H, OCH2CH2), 3.98 m (1H,
NCH), 4.05 t (2H, OCH2, J = 6.4 Hz), 4.43 q (1H,
SCHCH3), 6.98 m and 7.39 m (2H each, C6H4);
the COOH signal was strongly broadened. Found, %:
N 10.64; S 8.15. C21H29N3O3S. Calculated, %:
N 10.41; S 7.94.
2-[4-Cyclohexyl-5-(4-propoxyphenyl)-4H-1,2,4-
triazol-3-ylsulfanyl]propanoic acid (IVg). Yield
1
90%, mp 135–136°C, Rf 0.69. H NMR spectrum, δ,
ppm: 1.08 t (3H, CH2CH3, J = 7.4 Hz); 1.16–1.36 m
(3H), 1.66 m (1H), 1.78–1.91 m (4H), and 2.00–
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ALKYLATION AND AMINOMETHYLATION OF NEW 4,5-SUBSTITUTED ...
1553
[4-Cyclohexyl-5-(4-isobutoxyphenyl)-4H-1,2,4-
triazol-3-ylsulfanyl]acetic acid (IVl). Yield 80%,
Found, %: N 12.25; S 9.46. C18H25N3O2S. Calculated,
%: N 12.09; S 9.22.
1
mp 145–146°C, Rf 0.55. H NMR spectrum, δ, ppm:
2-[4-Cyclohexyl-5-(4-propoxyphenyl)-4H-1,2,4-
triazol-3-ylsulfanyl]ethanol (IVp). Yield 83%,
1.06 t [6H, CH(CH3)2, J = 6.7 Hz]; 1.17–1.36 m (3H),
1.67 m (1H), 1.79–1.93 m (4H), and 2.10 m (2H)
(C6H11); 2.14 sept [1H, CH(CH3)2, J = 6.7 Hz], 3.80 d
(2H, OCH2, J = 6.4 Hz); 3.99 m (1H, NCH), 4.04 s
(2H, SCH2), 7.00 m and 7.36 m (2H each, C6H4); the
COOH signal was strongly broadened. Found, %:
N 10.55; S 8.30. C20H27N3O3S. Calculated, %:
N 10.78; S 8.23.
1
mp 104–105°C, Rf 0.61. H NMR spectrum, δ, ppm:
1.08 t (3H, CH2CH3, J = 7.4 Hz); 1.14–1.35 m (3H),
1.66 m (1H), 1.77–1.91 m (4H), and 2.13 m (2H)
(C6H11); 1.84 m (2H, CH2CH3), 3.35 t (2H, SCH2, J =
6.5 Hz), 3.76 m (2H, CH2OH), 3.96 m (1H, NCH),
4.00 t (2H, OCH2, J = 6.5 Hz), 4.82 t (1H, OH, J =
5.7 Hz), 7.00 m and 7.35 m (2H each, C6H4). Found,
%: N 11.38; S 8.55. C19H27N3O2S. Calculated, %:
N 11.62; S 8.86.
2-[4-Cyclohexyl-5-(4-isobutoxyphenyl)-4H-1,2,4-
triazol-3-ylsulfanyl]propanoic acid (IVm). Yield
1
87%, mp 97–98°C, Rf 0.58. H NMR spectrum, δ,
2-[4-Cyclohexyl-5-(4-isopropoxyphenyl)-4H-
1,2,4-triazol-3-ylsulfanyl]ethanol (IVq). Yield 78%,
ppm: 1.07 t [6H, CH(CH3)2, J = 6.7 Hz]; 1.16–1.36 m
(3H), 1.66 m (1H), 1.77–1.92 m (4H), and 2.09 m (2H)
(C6H11); 1.65 d (3H, SCHCH3, J = 7.2 Hz), 12.12 sept
[1H, CH(CH3)2, J = 6.7 Hz], 3.81 d (2H, OCH2, J =
6.4 Hz), 4.00 m (1H, NCH), 4.44 q (1H, SCHCH3, J =
7.2 Hz), 7.00 m and 7.36 m (2H each, C6H4); the
COOH signal was strongly broadened. Found, %:
N 10.45; S 7.85. C21H29N3O3S. Calculated, %:
N 10.41; S 7.94.
1
mp 125–126°C, Rf 0.63. H NMR spectrum, δ, ppm:
1.15–1.33 m (3H), 1.67 m (1H), 1.77–1.91 m (4H),
and 2.07–2.23 m (2H, C6H11), 1.38 d [6H, CH(CH3)2,
J = 6.0 Hz], 3.35 t (2H, SCH2, J = 6.5 Hz), 3.76 m
(2H, CH2OH), 3.98 m (1H, NCH), 4.66 sept [1H,
CH(CH3)2, J = 6.0 Hz], 4.81 t (1H, OH, J = 5.7 Hz),
6.97 m and 7.34 m (2H each, C6H4). Found, %:
N 11.66; S 8.62. C19H27N3O2S. Calculated, %:
N 11.62; S 8.86.
Substituted 2-(4H-1,2,4-triazol-3-ylsulfanyl)-
ethanols IVn–IVs (general procedure). 2-Chloro-
ethanol, 10 mmol, was added to a solution of 1.0 mmol
of potassium hydroxide and 10 mmol of triazole-3-
thiol IIIa–IIIf in 20 ml of ethanol, and the mixture
was heated for 45–60 min under reflux. The mixture
was cooled, diluted with water, and left overnight, and
the precipitate was filtered off, dried, and recrystal-
lized from 70% ethanol.
2-[5-(4-Butoxyphenyl)-4-cyclohexyl-4H-1,2,4-tri-
azol-3-ylsulfanyl]ethanol (IVr). Yield 70%, mp 134–
135°C, Rf 0.60. 1H NMR spectrum, δ, ppm: 1.02 t (3H,
CH2CH3); 1.15–1.35 m (3H), 1.66 m (1H), 1.74–
1.96 m (4H), and 2.13 m (2H) (C6H11); 1.54 m (2H,
CH2CH3), 1.81 m (2H, OCH2CH2), 3.35 t (2H, SCH2,
J = 6.5 Hz), 3.76 m (2H, CH2OH), 3.96 m (1H, NCH),
4.04 t (2H, OCH2, J = 6.3 Hz), 4.82 t (1H, OH, J =
5.7 Hz), 6.99 m and 7.35 m (2H each, C6H4). Found,
%: N 11.32; S 8.75. C20H29N3O2S. Calculated, %:
N 11.19; S 8.53.
2-[4-Cyclohexyl-5-(4-methoxyphenyl)-4H-1,2,4-
triazol-3-ylsulfanyl]ethanol (IVn). Yield 60%,
1
mp 148–149°C, Rf 0.50. H NMR spectrum, δ, ppm:
1.14–1.36 m (3H), 1.67 m (1H), 1.78–1.91 m (4H),
and 2.06–2.21 m (2H) (C6H11); 3.35 t (2H, SCH2, J =
6.5 Hz), 3.76 m (2H, CH2OH), 3.88 s (3H, OCH3),
3.96 m (1H, NCH), 4.81 t (1H, OH, J = 5.7 Hz),
7.02 m and 7.37 m (2H each, C6H4). Found, %:
N 12.75; S 9.84. C17H23N3O2S. Calculated, %:
N 12.60; S 9.61.
2-[4-Cyclohexyl-5-(4-isobutoxyphenyl)-4H-1,2,4-
triazol-3-ylsulfanyl]ethanol (IVs). Yield 94%,
1
mp 126–127°C, Rf 0.59. H NMR spectrum, δ, ppm:
1.07 t [6H, CH(CH3)2, J = 6.7 Hz]; 1.15–1.35 m (3H),
1.66 m (1H), 1.77–1.99 m (4H), and 2.13 m (2H)
(C6H11); 2.12 sept [1H, CH(CH3)2, J = 6.7 Hz], 3.35 t
(2H, SCH2, J = 6.5 Hz), 3.75 m (2H, CH2OH), 3.81 d
(2H, OCH2, J = 6.4 Hz), 3.96 m (1H, NCH), 4.82 t
(1H, OH, J = 5.3 Hz), 7.00 m and 7.35 m (2H each,
C6H4). Found, %: N 11.28; S 8.35. C20H29N3O2S. Cal-
culated, %: N 11.19; S 8.53.
2-[4-Cyclohexyl-5-(4-ethoxyphenyl)-4H-1,2,4-tri-
azol-3-ylsulfanyl]ethanol (IVo). Yield 87%, mp 129–
1
130°C, Rf 0.55. H NMR spectrum, δ, ppm: 1.16–
1.34 m (3H), 1.67 m (1H), 1.78–1.94 m (4H), and
2.00–2.18 m (2H) (C6H11), 1.46 t (3H, CH2CH3, J =
7.0 Hz), 3.35 t (2H, SCH2), 3.75 m (2H, CH2OH),
3.99 m (1H, NCH), 4.10 q (2H, OCH2, J = 7.0 Hz),
4.82 t (1H, OH), 6.98 m and 7.35 m (2H each, C6H4).
4-Cyclohexyl-5-(4-methoxyphenyl)-2-(morpho-
lin-4-ylmethyl)-2H-1,2,4-triazole-3(4H)-thione (Va).
Morpholine, 1 ml, was added to a solution of 0.15 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 10 2013

KALDRIKYAN et al.
1554
(5 mmol) of thiol IIIa in 5 ml of ethanol, 4 ml of
a formaldehyde solution was gradually added under
shaking, and the mixture was kept for 6–7 h at 20–
25°C. The precipitate was filtered off and recrystal-
lized from 70% ethanol. Yield 0.12 g (70%), mp 104–
DMSO-d6 as solvent and tetramethylsilane as internal
reference. The melting points were determined on
a Boetius hot stage. Thin-layer chromatography was
performed on Silufol UV-254 plates using benzene–
acetone (2:1) (IIIa–IIIf, Va, Vb) or benzene–acetone–
ethanol (1:1 :0.1) (IVa–IVs) as eluent; spots were
visualized under UV light.
Initial 2-(4-alkoxybenzoyl)-N-cyclohexylhydrazine-
carbothioamides IIa–IIf were synthesized according to
the procedure described in [3].
1
105°C, Rf 0.71. H NMR spectrum, δ, ppm: 1.11–
1.31 m (3H), 1.63 m (1H), 1.78–1.99 m (4H), and
2.18 m (2H) (C6H11); 2.71 m (4H, NCH2, morpholine),
3.58 m (4H, OCH2, morpholine), 3.89 s (3H, OCH3),
4.37 m (1H, NCH), 5.04 s (2H, NCH2), 7.03 m and
7.40 m (2H each, C6H4). Found, %: N 14.56; S 8.35.
C20H28N4O2S. Calculated, %: N 14.42; S 8.25.
REFERENCES
4-Cyclohexyl-5-(4-ethoxyphenyl)-2-(morpholin-
4-ylmethyl)-2H-1,2,4-triazole-3(4H)-thione (Vb) was
synthesized in a similar way. Yield 75%, mp 138–
1. Kaldrikyan, M.A., Grigoryan, L.A., Melik-Ogan-
dzhanyan, R.G., and Arsenyan, F.G., Khim.-Farm. Zh.,
2009, vol. 43, no. 5, p. 11; Kaldrikyan, M.A., Grigo-
ryan, L.A., Melik-Ogandzhanyan, R.G., and Arse-
nyan, F.G., Khim.-Farm. Zh., 2011, vol. 45, no. 4, p. 15;
Grigoryan, L.A., Kaldrikyan, M.A., Melik-Ogandzha-
nyan, R.G., and Arsenyan, F.G., Khim.-Farm. Zh., 2012,
vol. 46, no. 6, p. 88.
1
139°C, Rf 0.59. H NMR spectrum, δ, ppm: 1.11–
1.30 m (3H), 1.62 m (1H), 1.78–1.99 m (4H), and
2.18 m (2H) (C6H11); 1.46 t (3H, CH2CH3, J = 6.9 Hz),
2.74 m (4H, NCH2, morpholine), 3.59 m (4H, OCH2,
morpholine), 4.12 q (2H, OCH2, J = 6.9 Hz), 4.37 m
(1H, NCH), 5.04 s (2H, NCH2), 7.00 m and 7.38 m
(2H each, C6H4). Found, %: N 13.75; S 7.68.
C21H30N4O2S. Calculated, %: N 13.91; S 7.96.
2. Guryanova, E.N. and Eitington, I.I., Zh. Obshch. Khim.,
1961, vol. 61, p. 31; Shegal, I.L. and Postovskii, I.Ya.,
Khim. Geterotsikl. Soedin., 1965, p. 133.
1
The H NMR spectra were recorded on a Varian
3. Kaldrikyan, M.A., Grigoryan, L.A., and Melik-Ogan-
Mercury-300 spectrometer at 300 MHz using
dzhanyan, R.G., Globus Nauki, 2007, vol. 7, p. 27.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 10 2013