Synthesis of 5-(pyrazol-1-yl)-1,2,3-thiadiazoles

Article abstract of DOI:10.1007/s10593-017-2045-5

[Figure not available: see fulltext.] A method is proposed for the synthesis of ethyl 5-(3-aryl-4-formyl-1H-pyrazol-1-yl)-1,2,3-thiadiazole-4-carboxylates by a reaction of acetophenone (4-ethoxycarbonyl-1,2,3-thiadiazol-5-yl)hydrazones with a Vilsmeier–Haack complex. The obtained heterocyclic assemblies provide interesting substrates for further modification and study of biological activity.

Full text of DOI:10.1007/s10593-017-2045-5

DOI 10.1007/s10593-017-2045-5
Chemistry of Heterocyclic Compounds 2017, 53(2), 236–238
SHORT COMMUNICATION
Synthesis of 5-(pyrazol-1-yl)-1,2,3-thiadiazoles
Olga A. Vysokova1, Tatiana A. Kalinina1, Marina A. Tokareva1,
Tatiana A. Pospelova1, Tatiana V. Glukhareva1*, Yuri Yu. Morzherin1†
1
Ural Federal University named after the First President of Russia B. N. Yeltsin,
19 Mira St., Yekaterinburg 620002, Russia; е-mail: taniagluhareva@yandex.ru
Submitted November 8, 2016
Accepted December 10, 2016
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2017, 53(2), 236–238
A method is proposed for the synthesis of ethyl 5-(3-aryl-4-formyl-1H-pyrazol-1-yl)-1,2,3-thiadiazole-4-carboxylates by a reaction of
acetophenone (4-ethoxycarbonyl-1,2,3-thiadiazol-5-yl)hydrazones with a Vilsmeier–Haack complex. The obtained heterocyclic
assemblies provide interesting substrates for further modification and study of biological activity.
Keywords: heterocyclic assemblies, acetophenone hydrazones, 5-(pyrazol-1-yl)-1,2,3-thiadiazoles, pyrazoles, 1,2,3-thiadiazoles,
Vilsmeier–Haack reaction.
Synthesis of heterocyclic assemblies has attracted the
attention of researchers due to the possibilities for
combining useful properties of several monoheterocyclic
compounds in the molecule of a single compound.
Compounds with various types of biological activity
have been identified among heterocyclic assemblies that
contain 1,2,3-thiadiazole ring (Fig. 1). Thus, for example,
(1,2,3-thiadiazol-5-yl)-1,3,4-oxadiazoles 1 have shown
strong herbicidal, antiviral, and fungicidal activity,1,2 (1,3,4-
thiadiazol-2-yl)-1,2,3-thiadiazoles 2 exhibited fungicidal
and antiviral activity,1 while (1,2,4-triazol-3-yl)-1,2,3-thia-
diazoles 3, 4 were strong inhibitors of HIV-1 reverse
transcriptase.3 Cytotoxic effects on tumor cells were found
in the case of (1,2,3-thiadiazol-5-yl)tetrazoles 5.4
In this work, we present a synthesis of previously
unreported (5-pyrazol-1-yl)-1,2,3-thiadiazoles 9a–e by a
reaction of acetophenone (1,2,3-thiadiazol-5-yl)hydrazones
10a–e with a Vilsmeier–Haack complex (Scheme 1). The
There are only a few published examples of heterocyclic
assemblies containing both 1,2,3-thiadiazole and pyrazole
rings (Fig. 1). All of the described compounds were
derivatives of (5-pyrazol-3-yl)-1,2,3-thiadiazole and exhi-
bited various types of biological activity. For example, it
was found that the assemblies 6 were inhibitors of protein
prenylation, which is a process associated with many
medical conditions.5 (1,2,3-Thiadiazol-5-yl)-2,4-dihydro-
pyrazol-3-ones 7 were inhibitors of anaplastic lymphoma
kinase,6 while assembly 8 showed antibacterial activity
against Gram-positive bacteria.7,8
Thus, heterocyclic assemblies containing 1,2,3-thia-
diazole and pyrazole rings present interest as potentially
biologically active compounds.
Figure 1. Biologically active heterocyclic assemblies containing a
1,2,3-thiadiazole ring.
† Deceased.
0009-3122/17/53(02)-0236©2017 Springer Science+Business Media New York
236

Chemistry of Heterocyclic Compounds 2017, 53(2), 236–238
Scheme 1
starting hydrazones 10a–e were synthesized from ethyl
5-chloro-1,2,3-thiadiazole-4-carboxylate (11)9 by nucleo-
philic substitution reaction of the chlorine atom with
hydrazine group,10 followed by a condensation reaction of
the formed 5-hydrazino-1,2,3-thiadiazole hydrochloride 12
with acetophenones 13a–e according to a previously
described procedure.10
The overall yields of (pyrazol-1-yl)-1,2,3-thiadiazoles
9a–e calculated from the starting 5-chloro-1,2,3-thiadiazole
11 were in the range of 34–40%.
reaction mixture was heated at 65–70°C for 8 h, then
cooled and poured onto ice (100 g). The precipitate that
formed was filtered off, washed with water, recrystallized
from EtOH, and dried.
Ethyl 5-(4-formyl-3-phenyl-1Н-pyrazol-1-yl)-1,2,3-thia-
diazole-4-carboxylate (9а). Yield 382 mg (58%), light-
yellow powder, mp 161–162°С. IR spectrum, ν, cm–1:
3126, 1719 (СHO), 1688 (CO), 1532, 1440, 1364, 1304,
1
1245, 1200, 1154, 750, 704. H NMR spectrum, δ, ppm
(J, Hz): 1.46 (3H, t, J = 7.2, OCH2CH3); 4.53 (2H, q,
J = 7.2, OCH2CH3); 7.49–7.51 (3H, m, Н Ph); 7.85–7.87
(2H, m, H Ph); 9.58 (1H, s, H-5'); 10.05 (1H, s, CHO).
13C NMR spectrum, δ, ppm: 13.9 (OCH2CH3); 62.3
(OCH2CH3); 123.3; 128.7 (CH Ar); 128.8 (CH Ar); 129.5;
130.1 (CH Ar); 139.7; 140.1 (C-5'); 155.1; 159.6; 159.7;
185.0 (CHO). Mass spectrum, m/z (Irel, %): 329 [M+H]+ (17),
328 [M]+ (69), 300 [M–N2]+ (49), 271 (17), 227 (72), 215
(16), 199 (19), 184 (13), 172 (23), 155 (49), 140 (16), 128
(65), 115 (27), 103 (28), 89 (20), 84 (23), 77 (100), 70 (20),
It should be noted that during the interaction of (1,2,3-thia-
diazol-5-yl)hydrazones 10a–e with Vilsmeier–Haack
complex in phosphorus oxychloride there was no
transformation of 1,2,3-thiadiazole ring to 1,2,3-triazole
ring, while such a rearrangement was previously observed
by us in the case of acetophenone 1,2,3-thiadiazolyl-
hydrazones in the presence of thionyl chloride11 or
phosphorus pentachloride.12
Thus, we have proposed a method for the synthesis of
5-(pyrazol-1-yl)-1,2,3-thiadiazoles
containing
highly
50 (40). Found, %:
С15H12N4O3S. Calculated, %: C 54.87; H 3.68; N 17.06.
Ethyl 5-[4-formyl-3-(4-methylphenyl)-1Н-pyrazol-
C 55.03; H 3.95; N 16.92.
reactive functionalities, namely, formyl and ethoxy-
carbonyl groups. The further modification of these
heterocyclic assemblies offers promising avenues for the
preparation of new biologically active compounds.
1-yl]-1,2,3-thiadiazole-4-carboxylate (9b). Yield 308 mg
(45%), beige powder, mp 177–178°C. IR spectrum, ν, cm–1:
3134, 1695, 1533, 1439, 1356, 1203, 1160, 979, 824, 779,
729. 1H NMR spectrum, δ, ppm (J, Hz): 1.38 (3H, t, J = 6.8,
OCH2CH3); 2.39 (3H, s, ArCH3); 4.50 (2H, q, J = 6.8,
OCH2CH3); 7.35 (2H, d, J = 8.0, H Ar); 7.78 (2H, d, J = 8.0,
H Ar); 9.53 (1H, s, H-5'); 10.04 (1H, s, CHO). 13C NMR
spectrum, δ, ppm: 14.3 (OCH2CH3); 21.6 (ArCH3); 63.2
(OCH2CH3); 124.4; 126.8; 129.1 (CH Ar); 129.7 (CH Ar);
138.7; 139.7; 140.9 (C-5'); 157.2; 160.8; 160.9; 184.1 (CHO).
Mass spectrum, m/z (Irel, %): 343 [M+H]+ (22), 342 [M]+
(100), 314 (33), 285 (20), 241 (80), 229 (16), 213 (18), 186
(25), 169 (39), 142 (31), 128 (28), 115 (29), 91 (65), 77 (13),
65 (42). Found, %: C 55.99; H 4.23; N 16.07. С16H14N4O3S.
Calculated, %: C 56.13; H 4.12; N 16.36.
Experimental
IR spectra were recorded on a Bruker Alpha FT-IR
1
spectrometer equipped with a ZnSe ATR accessory. Н and
13С NMR spectra were acquired on a Вruker Avance II
spectrometer (400 and 100 MHz, respectively) in DMSO-d6
with TMS as internal standard at the Laboratory of Complex
Investigation and Expert Evaluation of Organic Materials,
Collective Use Center of the Ural Federal University. Mass
spectra were recorded on a GCMS-QP2010 Plus gas
chromato-mass spectrometer (EI ionization at 70 eV).
Elemental analysis was performed on a РerkinЕlmer 2400
Series II CHNS-analyzer. Melting points were determined on
a Stuart SMP3 apparatus. The reaction progress and
individuality of the synthesized compounds were determined
by TLC on Silufol UV-254 plates, using EtOAc–hexane,
1:2, as mobile phase (visualization under UV light).
Ethyl 5-[4-formyl-3-(4-methoxyphenyl)-1Н-pyrazol-
1-yl]-1,2,3-thiadiazole-4-carboxylate (9c). Yield 387 mg
(54%), light-brown powder, mp 146–147°C. IR spectrum,
ν, cm–1: 3130, 2978, 2932, 1713 (СHO), 1693 (СO), 1610,
1520, 1426, 1310, 1253, 1206, 1162, 1026, 830, 780.
1H NMR spectrum, δ, ppm (J, Hz): 1.46 (3H, t, J = 7.2,
OCH2CH3); 3.86 (3H, s, OCH3); 4.54 (2H, q, J = 7.2,
OCH2CH3); 7.40 (2H, d, J = 8.0, H Ar); 7.86 (2H, d,
J = 8.0, H Ar); 9.56 (1H, s, H-5'); 10.04 (1H, s, CHO).
13C NMR spectrum, δ, ppm: 15.0 (OCH2CH3); 55.3
(OCH3); 62.2 (OCH2CH3); 114.1 (CH Ar); 121.7; 122.9;
130.3 (CH Ar); 139.2; 140.4 (C-5'); 154.9; 159.7; 160.1;
160.7; 184.9 (CHO). Mass spectrum, m/z (Irel, %): 359 [M+H]+
(16), 358 [M]+ (100), 257 (44), 214 (14), 202 (27), 185
The starting acetophenone (4-ethoxycarbonyl-1,2,3-thia-
diazol-5-yl)hydrazones 10a–e were obtained according to a
published procedure.10
Preparation of ethyl 5-(3-aryl-4-formyl-1H-pyrazol-
1-yl)-1,2,3-thiadiazole-4-carboxylates 9а–e (General method).
Phosphorus oxychloride (1.77 ml, 19 mmol) was added
dropwise over 1 h to anhydrous DMF (0.54 ml, 7 mmol),
while cooling at –5÷0°C. The obtained solution was stirred
at 0°C for 1 h, then treated by dropwise addition of
thiadiazolylhydrazone 10a–e (2 mmol) in DMF (1 ml). The
237

Chemistry of Heterocyclic Compounds 2017, 53(2), 236–238
(24), 158 (33), 145 (36), 133 (24), 130 (18), 115 (33), 107
(17), 111 (96), 84 (64), 75 (97), 70 (53), 44 (42). Found, %:
C 49.85; H 3.19; N 15.59. С15H11ClN4O3S. Calculated, %:
C 49.66; H 3.06; N 15.44.
(18), 102 (59), 92 (56), 77 (86), 64 (42), 44 (36), 38 (19).
Found, %: C 53.57; H 3.88; N 15.76. С16H14N4O4S.
Calculated, %: C 53.62; H 3.94; N 15.63.
Ethyl
5-[3-(4-ethoxyphenyl)-4-formyl-1Н-pyrazol-
This work was performed with financial support from
the Russian Science Foundation (grant 16-16-04022).
1-yl]-1,2,3-thiadiazole-4-carboxylate (9d). Yield 380 mg
(51%), beige powder, mp 153–154°C. IR spectrum, ν, cm–1:
3140, 2978, 1693, 1613, 1538, 1518, 1437, 1312, 1165,
References
1
1024, 920, 841, 777. H NMR spectrum, δ, ppm (J, Hz):
1.42 (3H, t, J = 7.2, OCH2CH3); 1.46 (3H, t, J = 7.2,
OCH2CH3); 4.11 (2H, q, J = 7.2, OCH2CH3); 4.53 (2H, q,
J = 7.2, OCH2CH3); 7.00 (2H, d, J = 8.8, H Ar); 7.84 (2H,
d, J = 8.8, H Ar); 9.57 (1H, s, H-5'); 10.04 (1H, s, CHO).
13C NMR spectrum, δ, ppm: 13.7 (OCH2CH3); 14.3
(OCH2CH3); 62.1 (OCH2CH3); 63.1 (OCH2CH3); 114.5
(CH Ar); 121.5; 123.0; 130.1 (CH Ar); 139.1; 140.1 (C-5');
154.8; 159.4; 159.5; 159.9; 184.6 (CHO). Mass spectrum,
m/z (Irel, %): 373 [M+H]+ (23), 372 [M]+ (100), 271 (56),
243 (26), 216 (29), 199 (18), 188 (18), 171 (23), 144 (24),
131 (30), 119 (25), 102 (22), 77 (34), 65 (47), 44 (19), 38
(19). Found, %: C 54.69; H 4.46; N 14.87. С17H16N4O4S.
Calculated, %: C 54.83; H 4.33; N 15.04.
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Ethyl
5-[3-(4-chlorophenyl)-4-formyl-1Н-pyrazol-
1-yl]-1,2,3-thiadiazole-4-carboxylate (9e). Yield 479 mg
(66%), light-brown powder, mp 176–177°C. IR spectrum,
ν, cm–1: 3129, 2982, 1707 (СHO), 1692 (CO), 1529, 1500,
1438, 1402, 1307, 1249, 1202, 1158, 1097, 1021, 840, 781.
1H NMR spectrum, δ, ppm (J, Hz): 1.46 (3H, t, J = 7.2,
OCH2CH3); 4.53 (2H, q, J = 7.2, OCH2CH3); 7.53 (2H, d,
J = 8.8, H Ar); 7.94 (2H, d, J = 8.8, H Ar); 9.60 (1H, s,
H-5'); 10.05 (1H, s, CHO). 13C NMR spectrum, δ, ppm:
13.9 (OCH2CH3); 62.3 (OCH2CH3); 123.1; 128.4; 128.8
(CH Ar); 130.5 (CH Ar); 134.9; 139.8; 140.8 (C-5'); 153.8;
159.5; 159.6; 184.8 (CHO). Mass spectrum, m/z (Irel, %):
364 [M(37Cl)]+ (17), 363 [M(35Cl)+H]+ (8), 362 [M(35Cl)]+
(40), 336 (9), 334 (25), 305 (12), 261 (62), 249 (18), 206
(24), 189 (31), 162 (38), 149 (30), 155 (28), 137 (34), 112
238