Synthesis of 5-azolyl-2,4-dihydro-3H-1,2,4-triazole-3-thiones and 5-azolyl-1,3,4-thiadiazol-2-amines based on derivatives of 5-arylisoxazole-3-carboxylic and 4,5-dichloroisothiazole-3-carboxylic acids

Article abstract of DOI:10.1007/s10593-021-02948-w

[Figure not available: see fulltext.] 2-Mercapto-1,3,4-triazoles and 2-amino-1,3,4-thiadiazoles were synthesized by successive transformations of 5-arylisoxazole- and 4,5-dichloroisothiazole-3-carboxylic acids and their derivatives. The amino group of 5-(

Full text of DOI:10.1007/s10593-021-02948-w

DOI 10.1007/s10593-021-02948-w
Chemistry of Heterocyclic Compounds 2021, 57(5), 594–598
Synthesis of 5-azolyl-2,4-dihydro-3H-1,2,4-triazole-3-thiones
and 5-azolyl-1,3,4-thiadiazol-2-amines based on
derivatives of 5-arylisoxazole-3-carboxylic
and 4,5-dichloroisothiazole-3-carboxylic acids
1
1
1
Sergey K. Petkevich *, Neliya А. Zhukovskaya , Evgenij А. Dikusar ,
1
2
3
Ekaterina А. Akishina , Peter V. Kurman , Eugeniya V. Nikitina ,
3
1
Vladimir P. Zaytsev , Vladimir I. Potkin
1
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus,
3 Surganova St., Minsk 220072, Belarus; e-mail: petkevich@ifoch.bas-net.by
1
2
3
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus,
/2 Akademika V. F. Kuprevicha St., Minsk 220141, Belarus; e-mail: peter_kurman@tut.by
RUDN University,
Miklukho-Maklaya St., Moscow 117198, Russia, e-mail: enikitina@sci.pfu.edu.ru
5
6
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2021, 57(5), 594–598
Submitted March 15, 2021
Accepted April 27, 2021
2
-Mercapto-1,3,4-triazoles and 2-amino-1,3,4-thiadiazoles were synthesized by successive transformations of 5-arylisoxazole- and 4,5-
dichloroisothiazole-3-carboxylic acids and their derivatives. The amino group of 5-(4,5-dichloroisothiazol-3-yl)-1,3,4-thiadiazol-2-amine
was acylated with 5-phenylisoxazole-3-carboxylic acid chloride. Simple approaches to the preparation of previously unknown
heterocyclic assemblies containing two or three azole rings with a high potential for biological activity are described.
Keywords: isothiazole, isoxazole, thiadiazoles, thiosemicarbazides, triazoles, heterocyclization.
Thiosemicarbazides are an important class of com-
pounds with a wide spectrum of biological activity. Back in
the middle of the XX century, their anti-tuberculosis,
antibacterial, antimalarial, antiparasitic, antitumor, anti-
corresponding triazoles and thiadiazoles with exocyclic
mercapto or amino groups for their subsequent biological
screening and use in the design of new materials, in
particular, metal complex catalysts.
1
viral, and antimicrobial properties were discovered. In
This work continues the series of publications by our
team of researchers concerning the transformations of
turn, triazoles containing an exocyclic mercapto group, as
well as thiadiazoles with an exocyclic amino group can
6
isoxazole and isothiazole derivatives.
2
exhibit various types of biological activity, whereas
One of the widely used methods of obtaining acylated
derivatives of thiosemicarbazide is the direct reaction of
thiosemicarbazide with acid chlorides of various acids. We
have synthesized acyl derivatives of thiosemicarbazides 7–9
containing an isoxazole or isothiazole fragment. Despite
the apparent simplicity of preparation, these compounds
have not been previously described in the literature.
isoxazole derivatives increase the activity of a number of
3
first-line cytostatics as synergists at the cellular level. In
addition, isoxazoles are used in the design of a novel class
4
of complexones – mimics of tweezer ligands. Their sulfur-
containing analogs isothiazoles are also used to create a
wide range of biologically active compounds and as ligands
5
for metal complexes.
Previously, the reaction of 5-arylisoxazole-3-carboxylic
acids 1, 2, and 4,5-dichloroisothiazole-3-carboxylic acid
The above data indicates a high relevance of research
aimed at developing effective methods for the synthesis of
isoxazole(isothiazole)-containing semicarbazides and the
2
(3) with SOCl in the presence of catalytic amounts of
DMF without solvent was used to synthesize acid chlorides
0
009-3122/21/57(5)-0594©2021 Springer Science+Business Media, LLC
594

Chemistry of Heterocyclic Compounds 2021, 57(5), 594–598
7,8
4
–6. In this work, we substituted SOCl
2
with (COCl)
2
in
Scheme 2
CH Cl solution, which led to an increase in the yields of
2
2
O
H
N
S
the target products and a decrease in the reaction time. The
reaction of acid chlorides 4–6 with thiosemicarbazide in
dry pyridine under reflux conditions gave thiosemicarb-
azide acyl derivatives 7–9 (Scheme 1).
1. EtONa, EtOH
, 10 h
N
H
NH2
N
2. HCl, H O
2
O
75–78%
R
7
8
R = H
R = Me
Scheme 1
H
R2
(COCl)2
CH Cl
R2
N
N
N
CO H
COCl 1. H2NNHC(S)NH2
Py, rt, 15 h
2
N
SH
S
2
2
NH
NH
R1
N
R1
N
DMF,
2. HCl, H2O
X
X
6
5–82%
N
N
O
1
–3
4–6
O
R
R
1
1
0 R = H
1 R = Me
10a R = H
11a R = Me
S
SH
NH
O
HN
NH
O
HN
NH
R2
NH2
R2
13
C NMR spectra exhibit signals at 196.1–196.6 ppm,
R1
N
R1
N
which also confirms the existence of a tautomeric structure
with the C=S fragment.
In contrast to isoxazole derivatives of thiosemicarbazide
7, 8, the cyclization of its dichloroisothiazole analog 9
proceeded differently. Treatment of acylthiosemicarbazide
X
X
7
–9
7–9 a
1
2
1
, 4, 7 R = Ph, R = H, X = O
1
2
2, 5, 8 R = 4-MeC H , R = H, X = O
6 4
1
2
3
, 6, 9 R = Cl, R = Cl, X = S
9
with ethanolic EtONa led to the formation of a mixture of
two inseparable reaction products 5-(4,5-dichloroisothiazol-
3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (12) and 5-(4-
chloro-5-ethoxyisothiazol-3-yl)-2,4-dihydro-3H-1,2,4-tri-
azole-3-thione (12а), the product of substitution of the
mobile chlorine atom in position 5 of the isothiazole ring
(Scheme 3). The use of a large excess of EtONa and an
increase in the time of heating the reaction mixture under
reflux did not lead to the selective formation of ethoxy
derivative 12а. It was not possible to isolate it as an
individual substance.
Acylthiosemicarbazides 7–9 can exist in the tautomeric
form 7–9 а, which is confirmed by the presence in the
H NMR spectra of four singlets with the same intensity in
the ranges of 7.62–7.75, 7.92–7.96, 9.46–9.51 ppm (3 NH
groups) and a downfield signal corresponding to the SH
group at 10.64–10.74 ppm, rather than three signals of the
NH groups with an integrated intensity of 1:1:2, as would
be expected for the thioamide form of compounds 7–9.
The synthesized acyl derivatives of thiosemicarbazide
1
7
–9 turned out to be convenient synthons for the
The presence of product 12а in the reaction mixture was
confirmed by H, C NMR spectroscopy and HPLC. The
H NMR spectrum contains a methyl group triplet at
1
13
preparation of the 1,2,4-triazole ring. We have investigated
various approaches to the synthesis of mercaptotriazoles
containing an arylisoxazole fragment in the side chain of
the triazole ring. It was found that the reaction in 2–10%
aqueous alkali proceeds nonselectively (possibly due to the
1
1.46 ppm and a methylene group quartet at 4.37 ppm. The
LC-MS spectra of compounds 12, 12а contain groups of
molecular ion peaks in which the ratio of the intensities of
the isotopic components indicates the presence of two
9
cleavage of the N–O bond in isoxazole) leading to
+
resinification. The treatment of the acylthiosemicarbazide
with MeONa in dry MeOH did not result in the formation
of the target product – the starting compound was isolated.
Replacing MeOH with i-PrOH resulted in an inseparable
mixture of products. We have found the optimal approach
to the preparation of 5-(5-arylisoxazol-3-yl)-2,4-dihydro-
chlorine atoms in molecule 12 with m/z 253 [М+Н]
+
(100%) and 275 [М+Na] (35%) (intensity ratio
100:98:32:3.5) and four chlorine atoms with m/z 527
+
[2M+H] (35%) (intensity ratio 77:100:49:11:1.4), and of
+
one chlorine atom with m/z 263 [М+Н] (100%), 285
Scheme 3
3
H-1,2,4-triazoles 10, 11, which involves treatment of
acylated thiosemicarbazide derivatives 7, 8 with EtONa in
EtOH under reflux conditions followed by treatment with
HCl (Scheme 2). The yields of mercaptotriazoles 10 and 11
were 75–78%.
It was shown that the synthesized thiols 10, 11 also exist
in the tautomeric thioamide form 10, 11 a, which is confirmed
by the data of IR and NMR spectroscopy. The IR spectra of
thioamides 10, 11 a contain absorption bands of NH groups
–
1
in the range of 3195–3317 cm , as well as an intense
–1
absorption band of the C=S group at 1661–1669 cm .
1
The H NMR spectra exhibit broadened singlets of two NH
groups in the 10.47–10.56 and 13.48–13.54 ppm ranges. The
5
95

Chemistry of Heterocyclic Compounds 2021, 57(5), 594–598
+
[
М+Na] (82%) (intensity ratio 100:33) and two chlorine
Experimental
+
atoms with m/z 547 [2M+H] (30%) in molecule 12а.
Various approaches to the synthesis of aminothiadiazoles
IR spectra were registered on a Thermo Niсolet Protege
460 Fourier transform spectrometer in KBr pellets. H and
10
1
are known. We have investigated two approaches to the
preparation of aminothiadiazoles comprising the reaction of
azolylthiosemicarbazones with anhydrous AcONa in the
presence of bromine as an oxidizing agent in glacial AcOH
13
C NMR spectra were acquired on a Bruker Avance 500
spectrometer (500 and 125 MHz, respectively) in DMSO-d
6
.
1
The residual solvent signals (2.50 ppm for H nuclei, 40.1 ppm
for С nuclei) were used as internal standard. The
13
or with K
2
CO
3
in the presence of iodine (oxidizer) in
13
1
,4-dioxane. It turned out that the reactions in both cases
proceeded indiscriminately and with low yields of the
target products. To obtain 5-azolyl-1,3,4-thiadiazol-2-amines
assignment of signals in the C NMR spectra was
performed using the DEPT technique. Liquid chromato-
mass spectrometry spectra were recorded on an Agilent
1200 LC-MS system with an Agilent 6410 Triple Quad
Mass Selective Detector with electrospray ionization in the
positive ion registration mode (MS2 scanning mode). An
Agilent ZORBAX Eclipse XDB-C18 (4.6 × 50 mm, 1.8 μm)
1
3, 14, we used an alternative synthesis method involving
the reaction of acid nitriles 15, 16 with thiosemicarbazide
in CF CO H. The target aminothiadiazoles 13, 14 were
3
2
obtained in 89–98% yields. Using aminothiazole 14 as a
model, amide 17 was obtained by the reaction with
column was used. Mobile phase – MeCN–H
2
O + 0.05%
5-phenylisoxazole-3-carboxylic acid chloride (4) in
HCO H, gradient elution from 40 to 90% MeCN in 10 min.
2
pyridine under reflux (Scheme 4).
0.5 ml/min flow rate was used. Elemental analysis was
performed on a vario MICRO cube CHNS-analyzer. The
halogen content was determined by classical microanalysis
by a modified Pregl's method. Melting points were
determined on a Kofler bench. Monitoring of the reaction
progress and assessment of the purity of synthesized
compounds were done by TLC on Merck Millipore Silica
Scheme 4
11
2
gel 60 F254 plates, eluent Et O, visualization by iodine
stain.
Reagents and solvents were supplied by Sigma-Aldrich
and Merck and used without additional purification.
5-Arylisoxazole-3-carboxylic acids 1, 2 and 4,5-dichloro-
isothiazole-3-carboxylic acid (3) were 7 synthesized
,12
according to previously described procedures. Nitriles of
p-tolylisoxazolecarboxylic acid 15 and dichloroisothiazole-
carboxylic acid 16 were accessed according to previously
7,13
described procedures.
Synthesis of acylated thiosemicarbazides 7–9 a
(General method). The corresponding acid chloride 4–6
(1.54 mmol) was added in portions at 15°С to a suspension
of thiosemicarbazide (0.14 g, 1.54 mmol) in dry pyridine
(5 ml), and the resulting mixture was stirred for 15 h. The
mixture was poured into aqueous NaCl (150 ml) and
acidified with HCl to pH ~5. The formed precipitate was
The IR spectra of aminothiadiazoles 13, 14 contain
7,8
absorption bands of the NH group in the region of 3134–
–
1
1
3
445 cm . The Н NMR spectra of the amines contain
singlets of NH groups with chemical shifts of 7.77–7.81 ppm.
2
For compounds 13, 14, signals corresponding to aromatic
protons are observed, while for aminothiazole 13, a signal
of the methyl group with a chemical shift of 2.36 ppm is
also present.
filtered off, washed with warm H
2
O, and dried under
Due to the extremely low solubility of acylated
derivative 17 in solvents suitable for recording LC-MS
spectra, the mass spectrum of compound 17 could not be
recorded. Its structure was confirmed by NMR
spectroscopy, and its composition was confirmed by
elemental analysis. In the IR spectra of acylated derivative
reduced pressure over P
further purification.
2-[(5-Phenylisoxazol-3-yl)carbonyl]hydrazine-1-carb-
imidothionic acid (7a). Yield 0.33 g (82%), light-yellow
powder, mp 177–178°С (decomp.). IR spectrum, ν, cm :
3438, 3308, 3189, 3152, 3075, 3040, 2976, 1707, 1609,
1571, 1529, 1497, 1469, 1449, 1420, 1301, 1232, 1094,
2 5
O . The substance did not require
–1
1
7, an absorption band of the amide NH group with a
–
1
1
frequency of 3375 cm was observed, the vibration of the
1070, 948, 870, 768, 690, 672, 567. H NMR spectrum,
–1
C=O group corresponded to an absorption band at 1693 cm .
In addition, a broadened singlet of the amide group NH
with a chemical shift of 14.01 ppm was observed in the
δ, ppm: 7.43 (1H, s, Н-4 isoxazole); 7.53–7.59 (3Н, m,
Н Ar); 7.75 (1Н, br. s, NH); 7.90–7.95 (2Н, m, Н Ar); 7.96
(1Н, br. s, NH); 9.51 (1Н, br. s, NH); 10.74 (1Н, br. s, SH).
1
13
H NMR spectrum of amide 17.
C NMR spectrum, δ, ppm: 100.9 (CH isoxazole); 126.3
In conclusion, a convenient approach to the preparation
of 5-azolyl-2,4-dihydro-3H-1,2,4-triazole-3-thiones and
-azolyl-1,3,4-thiadizol-2-amines on the basis of available
-arylisoxazole-3-carboxylic and 4,5-dichloroisothiazole-
-carboxylic acids and their nitriles was developed.
(2CH Ar); 130.0 (2CH Ar); 131.5 (CH Ar); 126.8; 158.8; 159.1;
+
170.7; 182.5. Mass spectrum, m/z (Irel, %): 547 [2M+Na]
+
+
5
5
3
(28), 285 [M+Na] (71), 263 [M+H] (100). Found, %:
C 50.21; H 3.96; N 21.44; S 12.27. C11 S.
Calculated, %: C 50.37; H 3.84; N 21.36; S 12.22.
10 4 2
H N O
5
96

Chemistry of Heterocyclic Compounds 2021, 57(5), 594–598
2-{[5-(p-Tolyl)isoxazol-3-yl]carbonyl}hydrazine-1-carb-
3
(J, Hz): 2.33 (3Н, s, CH ); 5.88 (1H, s, Н-4 isoxazole);
imidothionic acid (8a). Yield 0.32 g (76%), light-yellow
powder, mp 202–204°С (decomp.). IR spectrum, ν, cm :
7.28 (2Н, d, J = 7.8, Н Ar); 7.89 (2Н, d, J = 7.8, Н Ar);
10.47 (1Н, br. s, NH); 13.48 (1Н, br. s, NH). C NMR
–1
13
3
1
1
429, 3294, 3196, 3170, 3051, 3039, 2961, 2922, 2855,
695, 1614, 1566, 1528, 1506, 1450, 1420, 1297, 1227,
188, 1097, 1033, 1003, 947, 869, 810, 768, 561, 518.
3
spectrum, δ, ppm: 21.7 (CH ); 100.0 (CH isoxazole); 129.1
(2CH Ar); 129.7 (2CH Ar); 126.4; 134.1; 144.3; 156.6;
+
171.5; 196.1. Mass spectrum, m/z (Irel, %): 259 [M+H]
1
H NMR spectrum, δ, ppm (J, Hz): 2.36 (3Н, s, CH
1H, s, H-4 isoxazole); 7.36 (2Н, d, J = 8.0, Н Ar); 7.73
1Н, br. s, NH); 7.81 (2Н, d, J = 8.0, Н Ar); 7.95 (1Н, br. s,
3
); 7.34
(100). Found, %: C 55.68; H 3.98; N 21.74; S 12.24.
C H N OS. Calculated, %: C 55.80; H 3.90; N 21.69;
12 10 4
S 12.41.
Synthesis of 5-azolyl-1,3,4-thiadiazol-2-amines 13, 14
(General method). Thiosemicarbazide (1.0 g, 11 mmol)
was added at 15°С to a solution of the corresponding nitrile
(
(
1
3
NH); 9.50 (1Н, br. s, NH); 10.71 (1Н, br. s, SH). C NMR
spectrum, δ, ppm: 21.7 (СН
3
); 100.3 (CH isoxazole); 126.3
(
2CH Ar); 130.5 (2CH Ar); 124.2; 141.5; 158.9; 159.0;
+
1
70.9; 182.5. Mass spectrum, m/z (Irel, %): 575 [2M+Na]
3 2
15, 16 (10 mmol) in CF CO H (10 ml), and the resulting
+
+
(
40), 299 [M+Na] (79), 277 [M+H] (100). Found, %:
C 52.04; H 4.41; N 20.40; S 11.70. C12 S.
Calculated, %: C 52.16; H 4.38; N 20.28; S 11.60.
-[(4,5-Dichloroisothiazol-3-yl)carbonyl]hydrazine-
-carbimidothionic acid (9a). Yield 0.27 g (65%), light-
yellow powder, mp 216–217°С (decomp.). IR spectrum,
mixture was stirred at reflux for 6 h. After cooling, the
mixture was poured into aqueous NaCl (150 ml) and
acidified with HCl to pH ~5. The precipitate was filtered
12 4 2
H N O
2
2
off, washed with warm H O, and dried under reduced
1
2 5
pressure over P O . The substance did not require further
purification.
–1
ν, cm : 3438, 3285, 3195, 3145, 3018, 2968, 1691, 1611,
5-[5-(p-Tolyl)isoxazol-3-yl]-1,3,4-thiadiazol-2-amine
(13). Yield 2.53 g (98%), cream-colored powder, mp 156–
1534, 1484, 1468, 352, 1295, 1213, 1166, 974, 882, 762, 515,
1
–1
4
99. H NMR spectrum, δ, ppm: 7.62 (1Н, br. s, NH); 7.92
158°С. IR spectrum, ν, cm : 3406, 3286, 3134, 3025,
(
1Н, br. s, NH); 9.46 (1Н, br. s, NH); 10.64 (1Н, br. s, SH).
2919, 2856, 1611, 1597, 1569, 1535, 1506, 1437, 1404,
13
C NMR spectrum, δ, ppm: 124.4; 149.8; 156.9; 158.9; 182.5.
1335, 1214, 1184, 1121, 1071, 1053, 1034, 948, 931, 795,
+
1
Mass spectrum, m/z (Irel, %): 413 [2M+Na–NHC(S)NH
3
(
2
] (34),
500. H NMR spectrum, δ, ppm (J, Hz): 2.36 (3Н, s, CH
3
);
+
+
92 [2M+2Н–NHC(S)NH
2
] (100), 194 [M–NHC(S)NH
2
]
7.35 (2Н, d, J = 8.1, Н Ar); 7.47 (1H, s, Н-4 isoxazole);
13
47). Found, %: C 22.01; H 1.33; Cl 25.95; N 20.87;
7.77 (2Н, br. s, NH
spectrum, δ, ppm: 21.6 (CH
2
); 7.83 (2Н, d, J = 8.1, Н Ar). C NMR
); 97.8 (CH isoxazole); 126.4
S 23.39. C Cl OS . Calculated, %: C 22.15; H 1.49;
5
H
4
2
N
4
2
3
Cl 26.15; N 20.66; S 23.65.
(2CH Ar); 130.4 (2CH Ar); 124.2; 141.4; 145.6; 157.6;
+
Synthesis of 5-(5-arylisoxazol-3-yl)-2,4-dihydro-3H-
170.4; 170.9. Mass spectrum, m/z (Irel, %): 281 [M+Na]
+
1
,2,4-triazole-3-thiones 10, 11 а (General method). The
(21), 259 [M+H] (100). Found, %: C 55.79; H 3.78;
corresponding acylthiosemicarbazide 7, 8 (0.84 mmol)
was added at 15°С to a solution of Na (0.1 g, 4.35 mmol)
in 96% EtOH (12 ml), and the reaction mixture was heated
under reflux with stirring for 10 h. It was then poured into
aqueous NaCl (150 ml) and acidified with HCl to pH ~5.
N 21.84; S 12.48. C12
H 3.90; N 21.69; S 12.41.
5-(4,5-Dichloroisothiazol-3-yl)-1,3,4-thiadiazol-2-amine
(14). Yield 2.25 g (89%), cream-colored powder, mp 192–
10 4
H N OS. Calculated, %: C 55.80;
–1
194°С. IR spectrum, ν, cm : 3445, 3312, 3179, 2924,
The precipitate was filtered off, washed with warm H
2
O,
2853, 1608, 1500, 1388, 1346, 1159, 1121, 1052, 915, 837,
1
dried under reduced pressure over P
from EtOH.
2
O
5
, and recrystallized
749, 702. H NMR spectrum, δ, ppm: 7.81 (2Н, s, NH
2
).
13
C NMR spectrum, δ, ppm: 121.6; 150.1; 151.0; 155.0;
+
5-(5-Phenylisoxazol-3-yl)-2,4-dihydro-3H-1,2,4-triazole-
170.6. Mass spectrum, m/z (Irel, %): 253 [M+H] (100).
3
-thione (10а). Yield 0.16 g (78%), cream-colored powder,
Found, %: C 23.70; H 0.89; Cl 28.19; N 22.02; S 25.42.
C H Cl N S . Calculated, %: C 23.73; H 0.80; Cl 28.01;
5 2 2 4 2
–
1
mp 194–195°С (decomp.). IR spectrum, ν, cm : 3317,
3
1
235, 3063, 2923, 1669, 1608, 1596, 1578, 1548, 1449,
324, 1295, 1199, 1127, 979, 764, 684. H NMR spectrum,
N 22.14; S 25.33.
1
N-[5-(4,5-Dichloroisothiazol-3-yl)-1,3,4-thiadiazol-2-yl]-
5-phenylisoxazole-3-carboxamide (17). 5-Phenylisoxazole-
3-carboxylic acid chloride 4 (0.42 g, 2.0 mmol) was added
at 15°С to a solution of 5-(4,5-dichloroisothiazol-3-yl)-
1,3,4-thiadiazol-2-amine (14) (0.50 g, 2.0 mmol) in dry
pyridine (10 ml). The resulting mixture was stirred at reflux
for 6 h, poured into aqueous NaCl (150 ml), and acidified
with HCl to pH ~5. The precipitate was filtered off, washed
δ, ppm: 5.95 (1H, s, Н-4 isoxazole); 7.45–7.51 (2Н, m,
Н Ar); 7.54–7.60 (1Н, m, Н Ar); 7.98–8.04 (2Н, m, Н Ar);
1
3
1
0.56 (1Н, br. s, NH); 13.54 (1Н, br. s, NH). C NMR
spectrum, δ, ppm: 100.7 (CH isoxazole); 129.0 (2CH Ar);
1
1
29.3 (2CH Ar); 134.0 (CH Ar); 127.9; 136.6; 156.7;
71.4; 196.6. Mass spectrum, m/z (Irel, %): 245 [M+H]
+
(
C
100). Found, %: C 54.01; H 3.49; N 22.91; S 13.02.
OS. Calculated, %: C 54.09; H 3.30; N 22.94;
11
H
8
N
4
with warm H
. The product was recrystallized from EtOH. Yield
0.70 g (83%), cream-colored powder, mp 165–167°С
2
O, and dried under reduced pressure over
S 13.12.
-[5-(p-Tolyl)isoxazol-3-yl]-2,4-dihydro-3H-1,2,4-tri-
azole-3-thione (11а). Yield 0.16 g (75%), cream-colored
2 5
Р О
5
–1
(decomp.). IR spectrum, ν, cm : 3375, 3149, 3115, 2975,
2885, 2754, 1693, 1609, 1589, 1529, 1496, 1472, 1447,
1390, 1346, 1311, 1215, 1163, 1089, 1006, 948, 920, 878,
–1
powder, mp 197–199°С (decomp.). IR spectrum, ν, cm :
3
1
1
313, 3195, 3135, 3073, 3030, 2923, 2765, 1661, 1603,
570, 1543, 1434, 1320, 1297, 1249, 1213, 1186, 1136,
008, 977, 802, 725, 629, 586. H NMR spectrum, δ, ppm
1
840, 797, 762, 689, 677, 635, 615, 524. H NMR spectrum,
1
δ, ppm: 7.56–7.61 (3Н, m, Н Ar); 7.65 (1H, s, Н-4
5
97

Chemistry of Heterocyclic Compounds 2021, 57(5), 594–598
Lett. 2012, 22, 380. (h) Radhika, C.; Venkatesham, A.;
isoxazole); 7.94–7.99 (2Н, m, Н Ar); 14.01 (1Н, br. s, NH).
1
3
Sarangapani, M. Med. Chem. Res. 2012, 21, 3509. (i) Zhai, L.;
Zhang, Y.-L.; Kang, J. S.; Oelschlaeger, P.; Xiao, L.;
Nie, S.-S.; Yang, K.-W. ACS Med. Chem. Lett. 2016, 7, 413.
. Kulchitsky, V. A.; Potkin, V. I.; Zubenko, Y. S.; Chernov, A. N.;
Talabaev, M. V.; Demidchik, Y. E.; Petkevich, S. K.;
Kazbanov, V. V.; Gurinovich, T. A.; Roeva, M. O.;
Grigoriev, D. G.; Kletskov, A. V.; Kalunov, V. N. Med.
Chem. 2012, 8, 22.
C NMR spectrum, δ, ppm: 101.0 (CH isoxazole); 126.4
2CH Ar); 130.0 (2CH Ar); 131.7 (CH Ar); 122.5; 126.6;
51.0; 153.0; 154.6; 158.0; 160.7; 167.5; 171.6. Found, %:
C 42.24; H 1.89; Cl 16.90; N 16.44; S 15.25.
Cl . Calculated, %: C 42.46; H 1.66; Cl 16.71;
N 16.51; S 15.11.
(
1
3
15
C H
7
2 5 2 2
N O S
1
13
Supplementary information file containing H and
C
4. Kletskov, A. V.; Bumagin, N. A.; Petkevich, S. K.;
Dikusar, E. A.; Lyakhov, A. S.; Ivashkevich, L. S.;
Kolesnik, I. A.; Potkin, V. I. Inorg. Chem. 2020, 59, 10384.
NMR spectra for compounds 7–11 a, 13, 14, and 17 is
available at the journal website at http://link.springer.com/
journal/10593.
5. Kletskov, A. V.; Bumagin, N. A.; Zubkov, F. I.; Grudinin, D. G.;
Potkin, V. I. Synthesis 2020, 159.
6
. (a) Bumagin, N. A.; Kletskov, A. V.; Petkevich, S. K.;
Kolesnik, I. A.; Lyakhov, A. S.; Ivashkevich, L. S.;
Baranovsky, A. V.; Kurman, P. V.; Potkin, V. I. Tetrahedron
This work was supported by the Russian Foundation for
Basic Research (grant 20-53-00028 Bel_a) and the
Belarusian Republican Foundation for Fundamental
Research (grant X20R-056).
2
018, 74, 3578. (b) Kletskov, A. V.; Potkin, V. I.; Dikusar, E. A.;
Zolotar, R. M. Nat. Prod. Commun. 2017, 12, 105.
c) Bumagin, N. A.; Petkevich, S. K.; Kletskov, A. V.;
(
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