Synthesis of 3,5-disubstituted 1,2,4-triazoles containing an amino group

Article abstract of DOI:10.1134/S1070428016100195

3,5-Disubstituted 1,2,4-triazoles containing linear and cyclic amine fragments have been synthesized by thermal cyclization of N′-(1-iminoalkyl) hydrazides prepared by condensation of imido esters with carboxylic acid hydrazides. The initial imido esters have been synthesized by the Pinner reaction, as well as by reaction of nitriles with methanol in the presence of a catalytic amount of sodium methoxide. A procedure has been developed for the synthesis of 5-substituted 3-(3-nitrophenyl)-1,2,4-triazoles which have been converted to 3-aminophenyl derivatives by reduction with hydrazine hydrate over Raney nickel.

Full text of DOI:10.1134/S1070428016100195

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 10, pp. 1490–1495. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © N.Yu. Khromova, M.M. Fedorov, S.I. Malekin, A.V. Kutkin, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52,
No. 10, pp. 1497–1502.
Synthesis of 3,5-Disubstituted 1,2,4-Triazoles
Containing an Amino Group
N. Yu. Khromova, M. M. Fedorov, S. I. Malekin, and A. V. Kutkin*
State Research Institute of Organic Chemistry and Technology, shosse Entuziastov 23, Moscow, 111024 Russia
*e-mail: dir@gosniiokht.ru
Received April 18, 2016
Abstract—3,5-Disubstituted 1,2,4-triazoles containing linear and cyclic amine fragments have been synthe-
sized by thermal cyclization of N′-(1-iminoalkyl) hydrazides prepared by condensation of imido esters with
carboxylic acid hydrazides. The initial imido esters have been synthesized by the Pinner reaction, as well as by
reaction of nitriles with methanol in the presence of a catalytic amount of sodium methoxide. A procedure has
been developed for the synthesis of 5-substituted 3-(3-nitrophenyl)-1,2,4-triazoles which have been converted
to 3-aminophenyl derivatives by reduction with hydrazine hydrate over Raney nickel.
DOI: 10.1134/S1070428016100195
Development of methods for the synthesis of
3,5-disubstituted 1,2,4-triazoles is important from the
practical viewpoint. These compounds attract interest
for medicinal chemistry and are promising as new
drugs due to their various biological activities,
including fungicidal and antiviral [1]. Substituted
1,2,4-triazoles are widely used in medicine as some
receptor agonists or antagonists with both donor and
acceptor properties [2]. 1,2,4-Triazole system consti-
tutes a structural fragment of potential therapeutic
agents, such as 3-amino-1,2,4-triazole derivative ATZ
and 3-sulfanyl-1,2,4-triazole derivative MTZ [3, 4].
1,2,4-Triazole fragments were introduced into peptide
molecules to surrogate cis-amide bonds in an attempt
to increase the bioavailability of the parent bioactive
molecules [5, 6].
Scheme 1.
NH
N
N
N
N
NH
O
H
∆
∆
HCl/H2O
N
R3
+
4 ·2HCl
R2
R3
R2
R
R2
N
N
N
R2
OR1
1a–1l
R3
NHNH2
2a–2e
H
H
H
O
3a–3t
4a–4t
5a–5t
1, R1 = Et, R2 = 3,4,5-(MeO)3C6H2 (a), 4-MeOC6H4(CH2)2 (b), 3,4-Cl2C6H3CH2 (c); R1 = Me, R2 = 3,4-Cl2C6H3 (d); R1 = Et,
R2 = Ph2CHCH2 (e), 3,4-(MeO)2C6H3CH2 (f), 3-EtO-4-MeOC6H3CH2 (g); R1 = Me, R2 = pyridin-3-yl (h), pyridin-4-yl (i); R1 = Et,
R2 = pyridin-3-ylmethyl (j), cyclopropyl (k), 1-(4-chlorophenyl)cyclopropyl (l);
Tr
N
2, R3 = TrNH(CH2)2 (a), TrNH(CH2)3 (b),
(c),
(d),
(e);
N
TrNH
Tr
3, 4, R3 = TrNH(CH2)2, R2 = 3,4,5-(MeO)3C6H2, (a), 4-MeOC6H4(CH2)2 (b), 3,4-Cl2C6H3CH2 (c), 3,4-Cl2C6H3 (d), Ph2CHCH2 (e),
pyridin-3-yl (f), pyridin-3-ylmethyl (g), cyclopropyl (h), 1-(4-chlorophenyl)cyclopropyl (i); R3 = TrNH(CH2)3, R2 = 3,4-Cl2C6H3 (j),
3-EtO-4-MeOC6H3CH2 (k), cyclopropyl (l), 1-(4-chlorophenyl)cyclopropyl (m); R3 =
, R2 = cyclopropyl (n);
TrNH
Tr
N
R3 =
, R2 = 4-MeOC6H4(CH2)2 (o), 3,4-Cl2C6H3CH2 (p), cyclopropyl (q); R3 =
,
N
Tr
R2 = 4-MeOC6H4(CH2)2 (r), 3,4-(MeO)2C6H3CH2 (s), pyridin-4-yl (t).
Tr = Ph3C; R2 and R4 in 5 are the same as R2 and R3 (with H instead of Tr), respectively, in 3 and 4.
1490

SYNTHESIS OF 3,5-DISUBSTITUTED 1,2,4-TRIAZOLES
1491
Scheme 2.
NH·HCl
NaOH (Et3N)
HCl/EtOH
1a–1c, 1e–1g, 1j–1l
R2
OEt
R2CN
MeONa/MeOH
1d, 1h, 1i
Several methods for the synthesis of 3,5-disub-
stituted 1,2,4-triazoles are known. The most general of
these is based on the reaction of hydrazine or substi-
tuted hydrazines with appropriate electrophile [7–9].
Another approach leading to 1,2,4-triazole ring closure
involves reaction of N-cyanoformimidates with hydra-
zine derivatives in triethylamine [10–12]. 4-Substituted
5-aryl-1,2,4-triazoles can be synthesized by cyclization
of the corresponding thiosemicarbazides [13–15].
to imidoester by treatment with a solution of sodium
methoxide in methanol. The nitro group was reduced
to amino with hydrazine hydrate over Raney nickel in
isopropyl alcohol.
Scheme 4.
O
H
HN
N
CN
N
H
R
O
∆
+
In this work we synthesized 3,5-disubstituted
1,2,4-triazoles 5a–5t containing linear and cyclic
amine fragments by cyclization of N′-(1-iminoalkyl)-
hydrazides 3a–3t which were prepared by condensa-
tion of the corresponding imidic esters 1a–1l with
carbohydrazides 2a–2e possessing a trityl-protected
amino group (modified Pellizzari reaction)
(Scheme 1). The reactions were carried out by heating
the reactants to the melting point under slightly
reduced pressure in the absence of a solvent. After the
cyclization, the trityl protection was removed by
treatment with dilute (1:3) aqueous HCl.
R
NHNH2
NO2
NO2
6a–6c
R
R
N
N
HN
N
HN
N
NH2NH2·H2O
Raney Ni, i-PrOH
∆
NO2
NH2
7a–7c
8a–8c
R = Me (a), H (b), Et (c).
Imidic esters 1a–1l were prepared from the corre-
sponding nitriles in two ways (Scheme 2): (1) by
bubbling gaseous HCl through a solution of nitrile in
ethanol, followed by neutralization of the resulting
hydrochloride with alkali or triethylamine (Pinner
reaction; compounds 1a–1c, 1e–1g, 1j–1l), and (2) by
reaction of nitriles with methanol in the presence of
a catalytic amount of metallic sodium (1d, 1h, 1i) [16].
Imidates 1a–1l were brought into reaction with
hydrazides 2a–2e without additional purification.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
AM-360 spectrometer at 360.13 MHz using tetra-
methylsilane as internal standard. The progress of
reactions was monitored by TLC on Kieselgel 60 F254
plates (Merck) using chloroform–methanol (9:1) as
eluent; compounds containing an aromatic ring were
detected under UV light; the others were detected by
treatment with iodine vapor.
3-Aminopropanoic (β-alanine), 4-aminobutyric,
4-(aminomethyl)cyclohexanecarboxylic, and piperi-
dine-3- and piperidine-4-carboxylic acid hydrazides
were prepared from the corresponding esters. The
amino group therein was preliminarily protected by
tritylation (Scheme 3). 3,5-Disubstituted 1,2,4-triazoles
containing a 3-aminophenyl group were synthesized as
shown in Scheme 4. 3-Nitrobenzonitrile was converted
Ethyl 3-aminopropanoate, ethyl 4-aminobutyrate,
ethyl 4-(aminomethyl)cyclohexanecarboxylate, ethyl
piperidine-3-carboxylate, ethyl piperidine-4-carbox-
ylate, and 3,4,5-trimethoxybenzonitrile were com-
mercial products (Aldrich). The solvents used were
purified according to [17].
Ethyl 3,4,5-trimethoxybenzene-1-carboximidate
(1a). Gaseous hydrogen chloride was bubbled through
a solution of 35.8 g (0.185 mol) of 3,4,5-trimetoxy-
benzonitrile and 15 mL of anhydrous ethanol in
150 mL of diethyl ether cooled to 0–5°C until a gain in
Scheme 3.
O
O
TrCl, Et3N
NH2NH2
2a–2e
R1O
R4
R1O
R3
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KHROMOVA et al.
1492
weight of 8 g. The mixture was kept for 48 h at 3–5°C,
and the precipitate was filtered off and washed with
diethyl ether (3×20 mL). Yield of 1a hydrochloride
45.7 g (89%). The product was mixed with 100 mL of
water and 150 mL of diethyl ether, the mixture was
cooled to 4–8°C, and 15 g of sodium hydrogen
carbonate was added with stirring. The mixture was
stirred for 10 min, the organic phase was separated and
dried over anhydrous sodium sulfate, and the solvent
was distilled off. Yield 38g (85%). Compound 1a was
then used without additional purification.
and dried under reduced pressure. Yield 70.2 g (93%).
Compound 3a was then heated under reduced pressure
(20 mm) until a melt was obtained (180°C). Yield
67.6 g (90%).
Triazoles 4b–4e, 4g–4i, 4k–4o, and 4q–4s were
synthesized in a similar way.
2-[5-(3,4-Dichlorophenyl)-4H-1,2,4-triazol-3-yl]-
N-(triphenylmethyl)ethan-1-amine (4d). A solution
of 0.05 g (2 mmol) of sodium in 10 mL of methanol
was added to a solution of 16.2 g (0.094 mol) of
3,4-dichlorobenzonitrile in 50 ml of methanol, the
mixture was stirred for 1 h at 20°C, a solution of
32.5 g (94 mmol) of carbohydrazide 2a in 150 mL of
methanol was added, and the mixture was stirred for
15 h at 40–50°C. The precipitate was filtered off and
washed with methanol (2×10 ml). Yield of 3a 41.3 g
(88%), Rf 0.35. The product, 41.3 g (0.083 mol) was
heated under reduced pressure (10–15 mm) to obtain
a melt (210°C), and heating was continued at that
temperature until water no longer evolved (10–
15 min). The melt was cooled and treated with 20 mL
of diethyl ether, and the precipitate was filtered off.
Yield 29.8 g (72%).
Compounds 1b (yield 80%), 1c (98%), 1d (86%),
1e (81%), 1f (69%), 1g (92%), 1h (83%), 1i (98%),
and 1j (67%) were synthesized in a similar way.
Carboximidates 1k (87%) and 1l (85%) were used as
hydrochlorides.
Ethyl 1-(triphenylmethyl)piperidine-4-carbox-
ylate. Chloro(triphenyl)methane, 33.4 g (0.12 mol),
was added in portions with stirring to a solution of
19 g (0.12 mol) of ethyl piperidine-4-carboxylate and
12.2 g (0.12 mol) of triethylamine in 150 mL of anhy-
drous chloroform. The mixture spontaneously warmed
up to 60°C and was stirred for 12 h at 20°C. It was
then washed with water (3×50 mL) and dried over
magnesium sulfate, and the solvent was removed under
reduced pressure. Yield 46.9 g (98%). The product was
used without additional purification.
Triazoles 4f (85%), 4j (80%), 4p (91%), and 4t
(94%) were synthesized in a similar way.
2-[5-(3,4,5-Trimethoxyphenyl)-4H-1,2,4-triazol-
3-yl]ethan-1-amine hydrochloride (5a). A mixture of
45.8 g (0.088 mol) of triazole 4a and 300 mL of
10% aqueous HCl was stirred for 3 h at 50–60°C. The
precipitate was filtered off and washed with water
(2×40 mL), the filtrate was evaporated under reduced
pressure (10–15 mm), and the residue was recrystal-
lized from ethanol. Yield 26.4 g (90%). 1H NMR spec-
trum (D2O), δ, ppm: 3.02–3.16 m (2H, CH2C), 3.11–
3.24 m (2H, CH2N), 3.70 s (3H, OCH3), 3.83 s (6H,
OCH3), 7.32 s (2H, CH). Found, %: C 49.64; H 6.05;
Cl 11.24; N 17.84. C13H18N4O3·HCl. Calculated, %:
C 49.60; H 6.08; Cl 11.26; N 17.80.
N-Trityl derivatives of 3-aminopropionic (90%),
4-aminobutyric (86%), 4-(aminomethyl)cyclohexane-
1-carboxylic (96%), and piperidine-3-carboxylic acid
esters (90%) were synthesized in a similar way.
3-(Triphenylmethylamino)propanehydrazide
(2a). A mixture of 39.5 g (0.11 mol) of ethyl 3-(tri-
phenylmethylamino)propanoate, 70 mL of ethanol,
50 mL of dioxane, and 30 mL of hydrazine hydrate
was refluxed for 25 h until the initial ester disappeared
(TLC). The mixture was poured into 300 mL of water,
and the precipitate was filtered off and dried under
reduced pressure. Yield 33.4 g (88%).
To obtain the corresponding base, 5 g of hydro-
chloride 5a was added with stirring to 20 mL of anhy-
drous ethanol, 5 mL of sodium methoxide solution
prepared from 0.34 g of sodium was added, and the
mixture was left to stand for 12 h. The precipitate was
filtered off, and the filtrate was evaporated under
reduced pressure. Yield 3.9 g (88%).
Carbohydrazides 2b (91%), 2c (84%), 2d (90%),
and 2e (91%) were synthesized in a similar way.
2-[5-(3,4,5-Trimethoxyphenyl)-4H-1,2,4-triazol-
3-yl]-N-(triphenylmethyl)ethan-1-amine (4a). Tri-
ethylamine, 22 g (0.2 mol), was added with stirring to
a solution of 39.9 g (0.145 mol) of 1a hydrochloride in
300 mL of benzene. The precipitate was filtered off,
41.5 g (0.12 mol) of hydrazide 2a was added to the
filtrate, and the mixture was refluxed for 2 h. After
cooling to 20°C, the mixture crystallized. The precip-
itate of 3a was filtered off, washed with diethyl ether,
Hydrochlorides 5b–5t were synthesized in a similar
way.
2-{5-[2-(4-Methoxyphenyl)ethyl]-4H-1,2,4-tri-
azol-3-yl}ethan-1-amine hydrochloride (5b). Yield
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 10 2016

SYNTHESIS OF 3,5-DISUBSTITUTED 1,2,4-TRIAZOLES
1493
1
76%. H NMR spectrum (DMSO-d6), δ, ppm: 3.01–
1H NMR spectrum (D2O), δ, ppm: 0.96–1.05 m (2H,
CH2), 1.14–1.20 m (2H, CH2), 2.12–2.21 m (1H, CH),
3.15 t (2H, CH2C, J = 6.9 Hz), 3.45 m (2H, CH2N).
Found, %: C 55.29; H 7.93; N 36.78. C7H12N4·HCl.
Calculated, %: C 55.24; H 7.95; N 36.81.
3.12 m (2H, CH2C), 3.08–3.20 m (2H, CH2N), 3.20–
3.27 m (4H, CH2), 3.69 s (3H, OCH3), 6.84 d and
7.16 d (2H each, Harom, J = 7.4 Hz), 8.42 br.s (3H, NH,
NH2). Found, %: C 55.27; H 6.79; Cl 12.49; N 19.80.
C13H18N4O·HCl. Calculated, %: C 55.22; H 6.77;
Cl 12.54; N 19.81.
2-{5-[1-(4-Chlorophenyl)cyclopropyl]-4H-1,2,4-
triazol-3-yl}ethan-1-amine hydrochloride (5i). Yield
1
2-{5-[(3,4-Dichlorophenyl)methyl]-4H-1,2,4-tri-
azol-3-yl}ethan-1-amine hydrochloride (5c). Yield
74%. H NMR spectrum (D2O), δ, ppm: 1.75–1.86 m
(4H, CH2), 3.32 m (2H, CH2C, J = 6.9 Hz), 3.52 m
(2H, CH2N, J = 6.9 Hz), 7.45–8.56 m (4H, Harom).
Found, %: C 52.23; H 5.41; Cl 23.66; N 18.70.
C13H15ClN4 ·HCl. Calculated, %: C 52.19; H 5.39;
Cl 23.70; N 18.73.
1
84%. H NMR spectrum (D2O), δ, ppm: 3.27 t (2H,
CH2C, J = 6.9 Hz), 3.42 t (2H, CH2N, J = 6.9 Hz),
4.30 s (2H, CH2), 7.20 d (1H, Harom, J = 6.9 Hz), 7.47 d
(1H, Harom, J = 6.9 Hz), 7.49 s (1H, Harom), 8.41 br.s
(3H, NH, NH2). Found, %: C 42.99; H 4.23; Cl 34.54;
N 18.24. C11H12Cl2N4·HCl. Calculated, %: C 42.95;
H 4.26; Cl 34.58; N 18.21.
3-[5-(3,4-Dichlorophenyl)-4H-1,2,4-triazol-3-yl]-
propan-1-amine hydrochloride (5j). Yield 80%.
1H NMR spectrum (D2O), δ, ppm: 2.13–2.17 m (2H,
CH2), 2.96 t (2H, CH2C, J = 6.9 Hz), 3.10 t (2H,
CH2N, J = 6.9 Hz), 7.37–7.42 m (2H, Harom), 7.55–
7.57 m (1H, Harom). Found, %: C 43.01; H 4.22;
Cl 34.58; N 18.19. C11H12Cl2N4·HCl. Calculated, %:
C 42.95; H 4.26; Cl 34.58; N 18.21.
2-[5-(3,4-Dichlorophenyl)-4H-1,2,4-triazol-3-yl]-
ethan-1-amine hydrochloride (5d). Yield 72%.
1H NMR spectrum (D2O), δ, ppm: 3.13 t (2H, CH2C,
J = 6.9 Hz), 3.35 t (2H, CH2N, J = 6.9 Hz), 7.19–
7.31 m (2H, Harom), 7.40 s (1H, Harom), 8.39 br.s (3H,
NH, NH2). Found, %: C 40.87; H 3.81; Cl 36.20;
N 19.12. C10H10Cl2N4·HCl. Calculated, %: C 40.91;
H 3.78; Cl 36.23; N 19.08.
3-{5-[(3-Ethoxy-4-methoxyphenyl)methyl]-4H-
1,2,4-triazol-3-yl}propan-1-amine hydrochloride
1
(5k). Yield 68%. H NMR spectrum (D2O), δ, ppm:
2-[5-(2,2-Diphenylethyl)-4H-1,2,4-triazol-3-yl]-
ethan-1-amine hydrochloride (5e). Yield 65%.
1H NMR spectrum (DMSO-d6), δ, ppm: 3.12–3.28 m
(4H, CH2), 3.67 d (2H, CH2, J = 6.9 Hz), 4.89 t (1H,
CH, J = 6.9 Hz), 7.16 t (2H, Harom, J = 7.0 Hz), 7.22–
7.29 m (4H, Harom), 7.32–7.37 m (4H, Harom), 8.36 br.s
(3H, NH, NH2). Found, %: C 65.77; H 6.47; Cl 10.74;
N 17.02. C18H20N4 ·HCl. Calculated, %: C 65.74;
H 6.44; Cl 10.78; N 17.04.
1.27 t (3H, CH3, J = 8.0 Hz), 2.03–2.07 m (2H, CH2),
2.93 t (2H, CH2C, J = 6.9 Hz), 3.01 t (2H, CH2N, J =
6.9 Hz), 3.47 s (3H, OCH3), 3.98–4.00 m (2H, CH2),
4.17 s (2H, CH2), 6.84–7.01 m (3H, Harom). Found, %:
C 55.16; H 7.12; Cl 10.82; N 17.13. C15H22N4O2·HCl.
Calculated, %: C 55.13; H 7.09; Cl 10.85; N 17.14.
3-(5-Cyclopropyl-4H-1,2,4-triazol-3-yl)propan-1-
amine hydrochloride (5l). Yield 76%. 1H NMR spec-
trum (D2O), δ, ppm: 1.34–1.42 m (2H, CH2), 1.50–
1.60 m (2H, CH2), 2.30 m (2H, CH2), 2.43–2.47 m
(1H, CH), 3.11–3.18 m (2H, CH2C), 3.25–3.29 m (2H,
CH2N). Found, %: C 47.37; H 7.48; Cl 17.45; N 27.70.
C8H14N4 · HCl. Calculated, %: C 47.41; H 7.46;
Cl 17.49; N 27.64.
2-[5-(Pyridin-3-yl)-4H-1,2,4-triazol-3-yl]ethan-1-
1
amine (5f). Yield 85%. H NMR spectrum (D2O), δ,
ppm: 3.23 t (2H, CH2C, J = 6.9 Hz), 3.40 t (2H, CH2N,
J = 6.9 Hz), 8.05–8.11 m (1H, Harom), 8.76 d (1H,
Harom, J = 7.3 Hz), 9.09 d (1H, Harom, J = 7.3 Hz), 9.23 s
(1H, Harom). Found, %: C 57.17; H 5.83; N 37.00.
C9H11N5. Calculated, %: C 57.13; H 5.86; N 37.01.
3-{5-[1-(4-Chlorophenyl)cyclopropyl]-4H-1,2,4-
triazol-3-yl}propan-1-amine hydrochloride (5m).
1
Yield 94%. H NMR spectrum (D2O), δ, ppm: 1.70–
2-{5-[(Pyridin-3-yl)methyl]-4H-1,2,4-triazol-
3-yl}ethan-1-amine hydrochloride (5g). Yield 91%.
1H NMR spectrum (D2O), δ, ppm: 3.06 t (2H, CH2C,
J = 6.9 Hz), 3.32 t (2H, CH2N, J = 6.9 Hz), 4.11 s (2H,
CH2), 7.31–7.41 m (1H, Harom), 7.70 d (1H, Harom, J =
7.3 Hz), 8.32–8.40 m (2H, Harom). Found, %: C 50.08;
H 5.91; Cl 14.76; N 29.25. C10H13N5·HCl. Calculated,
%: C 50.11; H 5.89; Cl 14.79; N 29.22.
1.80 m (4H, CH2), 2.19 m (2H, CH2), 3.05 t (2H,
CH2C, J = 6.9 Hz), 3.17 t (2H, CH2N, J = 6.9 Hz),
7.49–7.55 m (4H, Harom). Found, %: C 53.71; H 5.75;
Cl 22.62; N 17.92. C14H17ClN4·HCl. Calculated, %:
C 53.68; H 5.79; Cl 22.64; N 17.89.
1-[4-(5-Cyclopropyl-4H-1,2,4-triazol-3-yl)cyclo-
hexyl]methanamine hydrochloride (5n). Yield 76%.
1H NMR spectrum (D2O), δ, ppm: 1.14–1.18 m (2H,
CH2), 1.22–1.26 m (2H, CH2), 1.32–1.36 m (2H, CH2),
2-(5-Cyclopropyl-4H-1,2,4-triazol-3-yl)ethan-
1-amine hydrochloride (5h). Yield 17 g (79%).
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KHROMOVA et al.
1494
1.59–1.65 m (2H, CH2), 1.78–1.83 m (1H, CH), 1.95–
2.01 m (2H, CH2), 2.17–2.23 m (2H, CH2), 2.23–
2.28 m (1H, CH), 2.94–2.97 m (2H, CH2), 3.00–
3.05 m (1H, CH). Found, %: C 56.16; H 8.20;
Cl 13.79; N 21.85. C12H20N4 ·HCl. Calculated, %:
C 56.13; H 8.24; Cl 13.81; N 21.82.
N 16.57. C16H22N4O2·HCl. Calculated, %: C 56.72;
H 6.84; Cl 10.46; N 16.54.
4-[5-(Piperidin-4-yl)-4H-1,2,4-triazol-3-yl]pyri-
1
dine hydrochloride (5t). Yield 94%. H NMR spec-
trum (D2O), δ, ppm: 1.93–1.98 m (2H, CH2), 2.20–
2.26 m (2H, CH2), 3.09 t (2H, CH2, J = 7.0 Hz), 3.26–
3.30 m (1H, CH), 3.43–3.50 m (2H, CH2), 8.40 d and
8.75 d (2H each, Harom, J = 7.4 Hz). Found, %:
C 54.27; H 6.04; Cl 13.33; N 26.36. C12H15N5·HCl.
Calculated, %: C 54.24; H 6.07; Cl 13.34; N 26.35.
3-{5-[2-(4-Methoxyphenyl)ethyl]-4H-1,2,4-tri-
azol-3-yl}piperidine hydrochloride (5o). Yield 83%.
1H NMR spectrum (D2O), δ, ppm: 1.90–2.20 m (4H,
CH2), 3.10–3.69 m (9H, CH, CH2), 3.79 s (3H, OCH3),
6.90 d and 7.10 d (2H each, Harom, J = 7.4 Hz).
Found, %: C 59.56; H 7.20; Cl 10.94; N 17.34.
C16H22N4O·HCl. Calculated, %: C 59.53; H 7.18;
Cl 10.98; N 17.35.
N′-[Imino(3-nitrophenyl)methyl]acetohydrazide
(6a). 3-Nitrobenzonitrile, 65 g (0.4 mol), was dis-
solved in 300 mL of methanol, 0.6 g (0.017 mol) of
sodium and 74 g (0.6 mol) of acetohydrazide were
added, and the mixture was stirred for 15 h at 40–
50°C. The precipitate was filtered off and washed with
3-[5-(3,4-Dichlorophenyl)-4H-1,2,4-triazol-3-yl]-
1
piperidine hydrochloride (5p). Yield 91%. H NMR
1
methanol (2×40 mL). Yield 78 g (80%). H NMR
spectrum (D2O), δ, ppm: 1.84–1.88 m (2H, CH2),
2.06–2.10 m (1H, CH2), 2.22–2.26 m (1H, CH2), 3.07–
3.12 m (1H, CH), 3.22–3.25 m (1H, CH2), 3.35–
3.39 m (1H, CH2), 3.48–3.53 m (1H, CH2), 3.70–
3.73 m (1H, CH2), 7.18–7.22 m (1H, Harom), 7.25–
7.27 m (1H, Harom), 7.35 d (1H, Harom, J = 7.4 Hz).
Found, %: C 46.84; H 4.55; Cl 31.85; N 16.76.
C13H14Cl2N4·HCl. Calculated, %: C 46.80; H 4.53;
Cl 31.88; N 16.79.
spectrum (DMSO-d6), δ, ppm: 1.92 s and 2.15 s (3H,
CH3), 6.65 br.s (2H, NH), 7.67–7.71 m (1H, Harom),
8.20–8.25 m (2H, Harom), 8.58–8.61 m (1H, Harom),
9.68 s and 9.78 s (1H, NH). Found, %: C 48.68;
H 4.56; N 25.18. C9H10N4O3. Calculated, %: C 48.65;
H 4.54; N 25.21.
Hydrazides 6b (86%) and 6c (84%) were synthe-
sized in a similar way.
3-(5-Cyclopropyl-4H-1,2,4-triazol-3-yl)piperi-
dine hydrochloride (5q). Yield 76%. H NMR spec-
3-Methyl-5-(3-nitrophenyl)-4H-1,2,4-triazole
(7a). Hydrazide 6b, 8 g (0.32 mol), was heated under
reduced pressure (20 mm) until a melt was obtained
(170–200°C). Yield 69.9 g (98%). H NMR spectrum
(DMSO-d6), δ, ppm: 2.43 s (3H, CH3), 7.22 d (1H,
1
trum (D2O), δ, ppm: 1.24–1.27 m (2H, CH2), 1.46–
1.49 m (2H, CH2), 1.92–1.96 m (2H, CH2), 2.03–
2.08 m (1H, CH), 2.30–2.33 m (1H, CH2), 2.35–
2.38 m (1H, CH), 3.13–3.19 m (1H, CH2), 3.47–
3.78 m (4H, CH2). Found, %: C 52.54; H 7.47;
Cl 15.53; N 24.46. C10H16N4 ·HCl. Calculated, %:
C 52.51; H 7.49; Cl 15.50; N 24.50.
1
Harom, J = 7.5 Hz), 7.75 t (1H, Harom, J = 7.5 Hz), 8.25 d
(1H, Harom, J = 7.5 Hz), 8.71 s (1H, CH), 13.90 br.s
(1H, NH). Found, %: C 52.89; H 3.98; N 27.41.
C9H8N4O2. Calculated, %: C 52.94; H 3.95; N 27.44.
4-{5-[2-(4-Methoxyphenyl)ethyl]-4H-1,2,4-tri-
azol-3-yl}piperidine hydrochloride (5r). Yield 90%.
1H NMR spectrum (D2O), δ, ppm: 2.03–2.07 m (2H,
CH2), 2.33–2.37 m (2H, CH2), 3.13–3.15 m (2H, CH2),
3.25–3.29 m (2H, CH2), 3.35–3.43 m (3H, CH, CH2),
3.56–3.63 m (2H, CH2), 3.86 s (3H, OCH3), 7.00 d and
7.19 d (2H each, Harom, J = 7.4 Hz). Found, %:
C 59.54; H 7.14; Cl 11.01; N 17.34. C16H22N4O·HCl.
Calculated, %: C 59.53; H 7.18; Cl 10.98; N 17.35.
3-(3-Nitrophenyl)-4H-1,2,4-triazole (7b) was
synthesized in a similar way at 190–200°C. Yield 96%.
1H NMR spectrum (DMSO-d6), δ, ppm: 7.76 t (1H,
Harom, J = 7.5 Hz), 8.24 d (1H, Harom, J = 7.5 Hz),
8.42 d (1H, Harom, J = 7.5 Hz), 8.71 s (1H, Harom), 8.74 s
(1H, 5-H). Found, %: C 50.57; H 3.21; N 29.42.
C8H6N4O2. Calculated, %: C 50.53; H 3.18; N 29.46.
3-Ethyl-5-(3-nitrophenyl)-4H-1,2,4-triazole (7c)
was synthesized in a similar way at 250–280°C. Yield
1
4-{5-[(3,4-Dimethoxyphenyl)methyl]-4H-1,2,4-
triazol-3-yl}piperidine hydrochloride (5s). Yield
98%. H NMR spectrum (DMSO-d6), δ, ppm: 1.20 t
(3H, CH3, J = 8.0 Hz), 2.80 q (2H, CH2, J = 8.0 Hz),
7.73 t (1H, Harom, J = 7.5 Hz), 8.20 d (1H, Harom, J =
7.5 Hz), 8.36 d (1H, Harom, J = 7.5 Hz), 8.69 s
(1H, Harom), 13.9 br.s (1H, NH). Found, %: C 55.07;
H 4.65; N 25.64. C10H10N4O2. Calculated, %: C 55.04;
H 4.62; N 25.68.
1
89%. H NMR spectrum (D2O), δ, ppm: 2.04–2.13 m
(2H, CH2), 2.38–2.43 m (2H, CH2), 3.24–3.28 m (2H,
CH2), 3.40–3.43 m (1H, CH), 3.59–3.64 m (2H, CH2),
3.91 s (6H, OCH3), 4.34 s (2H, CCH2C), 7.01–7.14 m
(3H, Harom). Found, %: C 56.75; H 6.82; Cl 10.45;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 10 2016

SYNTHESIS OF 3,5-DISUBSTITUTED 1,2,4-TRIAZOLES
1495
2. Bayrak, H., Demirbas, A., Karaoglu, S.A., and
Demirbas, N., Eur. J. Med. Chem., 2009, vol. 44,
p. 1057.
3. Al-Masoudi, A., Al-Soud, Y.A., Al-Salini, N.J., and Al-
Masoudi, N.A., Chem. Heterocycl. Compd., 2006,
vol. 42, p. 1377.
3-(5-Methyl-4H-1,2,4-triazol-3-yl)aniline (8a).
Triazole 7a, 69.9 g (0.34 mol), was dissolved in
500 mL of propan-2-ol heated to 60–65°C, 110 mL of
hydrazine hydrate and 0.5–1.0 g of Raney nickel were
added, and the mixture was heated for 1 h at 70–75°C
(until it became colorless). The mixture was cooled to
20°C, the precipitate was filtered off, the filtrate was
evaporated, and the residue was washed with diethyl
ether and dried under reduced pressure (10–15 mm) at
20–25°C for 1 h. Yield 59 g (99%). 1H NMR spectrum
(DMSO-d6), δ, ppm: 2.35 s (3H, CH3), 5.02 br.s (2H,
NH2), 6.60 d (1H, Harom, J = 7.4 Hz), 7.02–7.15 m (2H,
4. Yeung, K.-S., Farkas, M.E., Kadow, J.F., and Mean-
well, N.A., Tetrahedron Lett., 2005, vol. 46, p. 3429.
5. Jenkins, S.M., Wadsworth, H.J., Bromidge, S.,
Orlek, B.S., Wyman, P.A., Riley, G.J., and Hawkins, J.,
J. Med. Chem., 1992, vol. 35, p. 2392.
6. Borg, S., Estenne-Bouhtou, G., Lutman, K., Csoregh, I.,
Hesselink, W., and Hacksell, U., J. Org. Chem., 1995,
vol. 60, p. 3112.
Harom), 7.25 s (1H, Harom), 13.43 br.s (1H, NH). Found,
%: C 62.08; H 5.80; N 32.12. C9H10N4. Calculated, %:
C 62.05; H 5.79; N 32.16.
7. El-Khawass, S.M. and Habib, N.S., J. Heterocycl.
Chem., 1989, vol. 26, p. 177.
8. Tarrago, G., Marzin, C., Najimi, D., and Pellegrin, V.,
J. Org. Chem., 1990, vol. 55, p. 420.
9. De Mendoza, J., Ontoria, J.M., Ortega, M.C., and
Torres, T., Synthesis, 1992, p. 398.
10. Heckendorn, R. and Winkler, T., Helv. Chim. Acta,
1980, vol. 63, p. 1.
11. Sveteik, J., Heterocycles, 1983, vol. 20, p. 1495.
Compounds 8b and 8c were synthesized in
a similar way.
3-(4H-1,2,4-Triazol-3-yl)aniline (8b). Yield 90%.
1H NMR spectrum (DMSO-d6), δ, ppm: 5.21 s (2H,
NH2), 6.62 d (1H, Harom, J = 7.4 Hz), 7.03–7.15 m (2H,
arom), 7.27 s (1H, Harom), 8.28 s (1H, 5-H). Found, %:
C 60.02; H 5.05; N 34.93. C8H8N4. Calculated, %:
C 59.99; H 5.03; N 34.98.
H
12. Mekheimer, R.A. and Shaker, R.M., J. Chem. Res.,
Synop., 1999, p. 76.
3-(5-Ethyl-4H-1,2,4-triazol-3-yl)aniline (8c).
Yield 86%. H NMR spectrum (DMSO-d6), δ, ppm:
1.25 s (3H, CH3, J = 8.0 Hz), 2.69 q (2H, CH2),
13. Colanceska-Ragenovic, K., Dimova, V., Kakurinov, V.,
Molnar, D.C., and Buzarovska, A., Molecules, 2001,
vol. 6, p. 815.
1
3.38 br.s (2H, NH2), 5.15 d (1H, NH), 6.58 d (1H,
14. Gautun, O.R. and Carlsen, P.H.J., Molecules, 2001,
vol. 6, p. 969.
Harom), 7.08 m (2H, Harom), 7.24 s (1H, Harom). Found,
%: C 63.79; H 6.42; N 29.79. C10H12N4. Calculated, %:
C 63.81; H 6.43; N 29.77.
15. Gautun, O.R. and Carlsen, P.H.J., Acta Chem. Scand.,
1991, vol. 45, p. 609.
16. Schaefer, F.C. and Peters, G.A., J. Org. Chem., 1961,
vol. 26, p. 412.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 10 2016