Synthesis and Intramolecular Heterocyclization of Selected Isonicotinic Acid Thiocarbazides

Article abstract of DOI:10.1134/S1070363219090299

The reaction of isonicotinic acid hydrazide with ethyl-, allyl-, and cinnamoyl isothiocyanates has afforded the corresponding alkylthiosemicarbazides and the products of their intramolecular heterocyclization, 1,2,4-triazoles.

Full text of DOI:10.1134/S1070363219090299

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 9, pp. 1923–1926. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 9, pp. 1457–1461.
LETTERS
TO THE EDITOR
Synthesis and Intramolecular Heterocyclization
of Selected Isonicotinic Acid Thiocarbazides
О. А. Nurkenova*, G. Zh. Karipovaa, Т. М. Seilkhanovb, Zh. B. Satpaevaa,
S. D. Fazylova, and A. Nukhulyc
a Institute of Organic Synthesis and Coal Chemistry of the Republic of Kazakhstan,
ul. Alikhanova 1, Karaganda, 100008 Kazakhstan
*e-mail: nurkenov_oral@mail.ru
b Sh. Ualikhanov Kokshetau State University, Kazakhstan, Kokshetau, 020000 Kazakhstan
c Pavlodar State Pedagogical University, Pavlodar, Kazakhstan
Received March 29, 2019; revised April 16, 2019; accepted April 19, 2019
Abstract—The reaction of isonicotinic acid hydrazide with ethyl-, allyl-, and cinnamoyl isothiocyanates has
afforded the corresponding alkylthiosemicarbazides and the products of their intramolecular heterocyclization,
1,2,4-triazoles.
Keywords: isonicotinic acid hydrazide, thiourea, isothiocyanates, alkylthiosemicarbazides, 1,2,4-triazoles
DOI: 10.1134/S1070363219090299
It is known that antituberculous effect of nicotinic
acid hydrazide and its derivatives is largely determined
by the structure of pharmacophore fragments in their
molecules [1–3]. In spite of numerous publications
on the synthesis, properties, and structure of various
hydrazide derivatives [4, 5], they are still of interest for
further investigation and improvement. In view of strong
antituberculous and antimicrobial activity of isonicotinic
acid thiosemicarbazide and 1,2,4-triazole derivatives [6,
7], it has seemed promising to investigate the products
of the reaction of nicotinic acid hydrazide with ethyl-,
allyl- and cinnamoyl isothiocyanates under different
conditions. The reactions were performed in ethanol to
afford the corresponding alkylthiosemicarbazides 1 and 2
(Scheme 1) It was found that acidification of compounds
1 and 2 in aqueous alkaline media led to intramolecular
heterocyclization into 1,2,4-triazole-5(4Н)-thiones 3, 4
(Scheme 1).
with 20% solution of sodium hydroxide, followed by
acidification.
Comparison of the properties of the samples of 4
synthesized via the two methods proved their complete
identity.
The obtained thiosemicarbazides 1, 2 and 1,2,4-triazole-
3-thiones 3–5 after crystallization from alcohol were
white crystalline compounds soluble in polar organic
solvents on heating. The structure of compounds 1–5
was confirmed by means of IR, 1Н NMR, and 13С NMR
spectroscopy as well as the data of two-dimensional COSY
(1H–1H) and HMQC (1H–13C) NMR experiments.
A similar heterocyclization reaction was performed
using N-cinnamoyl-2-isonicotinoylhydrazine carbothio-
amide 6. Compound 6 was synthesized via the reaction of
equimolar amounts of nicotinic acid hydrazide and cin-
namoyl isothiocyanate (obtained in its turn via the interac-
tion of cinnamoyl chloride with potassium thiocyanate in
acetone) in alcohol.Acidification of an alkaline solution of
compound 6 also led to intramolecular heterocyclization
into 7-phenyl-3-(pyridin-4-yl)-5Н-[1,2,4]-triazolo[3,4-b]-
[thiazine-5-one] 7 (Scheme 3).
It is known that 1,2,4-triazole-3-thiones can be ob-
tained via sintering of a hydrazide with thiourea [8].
Analogous reaction nicotinic acid hydrazide with allyl
thiourea and thiourea (sintering at 170°C during 4 h)
gave compounds 4 and 5 (Scheme 2). The target products
were isolated via the treatment of the reaction mixture
The obtained 1,2,4-triazole-5(4Н)-thiones 3–5, 7 are
interesting synthons for the preparation of new classes of
1923

1924
NURKENOV et al.
Scheme 1.
12
S
H
H
8 O
N
R
13
O
N
10
N
H
7
11
R
N
NH2
N
9
5
4
H
6
1
12
10
4
C=S
7
C
(1) NaOH
RꢀNCS
EtOH
11
5
6
3
2
N
(2) H+, H2O
NH
N
9
N
2
3
N
8
1
3, 4
1, 2
14
15
CH2CH=CH2 (2, 4).
13
13
14
CH2CH3 (1, 3),
R =
1
potentially bioactive compounds, due to the presence of
two nucleophilic centers in the structure—the exocyclic
S atom and endocyclic N atom.
(C=S). Н NMR spectrum, δ, ppm (J, Hz): 4.07 s (2Н,
Н14), 4.99–5.12 m (2Н, Н16), 5.75–5.81 m (1Н, Н15), 7.78
d (2Н, Н3,5, 3J = 5.5), 8.36 br. s (1Н, Н13), 8.75 d (2Н, Н2,6,
3J = 5.5), 9.48 s (1Н, Н9), 10.64 s (1Н, Н10). 13С NMR
spectrum, δС, ppm: 46.46 (С14), 115.80 (С16), 122.21
(С3,5), 135.43 (С15), 140.07 (С4), 150.70 (С2,6), 165.00
(С7), 182.17 (С11). Found, %: С 50.88; Н 5.17; N 23.78.
С10Н12N4ОS. Calculated, %: С 50.83; Н 5.12; N 23.71.
N-Ethyl-2-isonicotinoylhydrazinecarbothiamide
(1). Asolution of 2.6 g (0.036 mol) of ethyl isothiocyanate
in 5 mL of ethanol was added dropwise at stirring to a
solution of 4 g (0.036 mol) of nicotinic acid hydrazide
in 20 mL of ethanol. The reaction mixture was stirred
for 1 h at 50°С, the reaction course was monitored by
TLC. After the reaction was complete, the mixture was
cooled, the precipitate was filtered off, washed with small
amount of cold ethanol, and recrystallized from ethyl
acetate. Yield 5.95 g (88 %), mp 235–236°С (ethanol). IR
spectrum, ν, cm–1: 3198 (NH), 1689 (C=O), 1248 (C=S).
1Н NMR spectrum, δ, ppm (J, Hz): 1.02 t (3Н, Н15, 3J =
6.9), 3.41-3.45 m (2Н, Н14), 7.78 d (2Н, Н3,5, 3J = 6.0),
8.72 d (2Н, Н2,6, 3J = 6.0), 8.16 br. s (1Н, Н13), 9.34 br. s
(1Н, Н9) and 10.60 br. s (1Н, Н10). 13С NMR spectrum,
δС, ppm: 15.00 (С15), 39.08 (С14), 122.19 (С3,5), 140.06
(С4), 150.71 (С2,6), 164.95 (С7) and 181.63 (С11). Found,
%: С 48.25; Н 5.43; N 25.06. С9Н12N4ОS. Calculated,
%: С 48.20; Н 5.39; N 24.98.
4-Ethyl-3-(piridin-4-yl)-1Н-1,2,4-triazole-5(4H)-
thione (3). 20 mL of 2% aqueous solution of sodium
hydroxide was added to 1 g (4 mmol) of compound 1. The
reaction mixture was heated at 85°С during 2 h, cooled,
and neutralized to рН 6. The precipitate was filtered off.
Yield 0.8 g (96%), mp 225–226°С (water). IR spectrum,
ν, cm–1: 3194 (NH), 1557 (С=N), 1298 (C=S). 1Н NMR
spectrum, δ, ppm (J, Hz): 1.14 t (3Н, Н14, 3J = 6.9), 4.06 q
(2Н, Н13,3J = 6.9), 7.68 d (2Н, Н3,5, 3J = 6.0), 8.75 d (2Н,
Н2,6, 3J = 6.0), br. s 13.31 (1Н, Н9). 13С NMR spectrum,
δС, ppm: 13.96 (С14), 39.38 (С13), 122.99 (С3,5), 134.08
(С4), 149.51 (С7), 151,11 (С2,6) и 167.99 (С10). Found,
%: С 52. 59; Н 4.94; N 27.21. С9Н10N4S. Calculated, %:
С 52.41; Н 4.89; N 27.16.
N-Allyl-2-isonicotonoylhydrazinecarbothiamide
(2) was prepared similarly. Yield 84 %, mp 220–222°С.
IR spectrum, ν, cm–1: 3201 (NH), 1681 (C=O), 1220
4-Allyl-3-(pyridin-4-yl)-1Н-1,2,4-triazol-5(4H)-
thione (4) was obtained similarly. а. Yield 80%, mp
200–201°С. IR spectrum, ν, cm–1: 3188(NH), 1604
Scheme 2.
S
S
H
R
O
NH
N
N
H
O
6
5
3
H2N
NHR
NHR
NH2
N
11
7
C
1
N
12
C S
10
(1) NaOH
4
170oC
(2) H+, H2O
N
NH
2
8
9
N
N
4, 5
13
14
CH2CH=C1H52 (4);
H (5).
R =
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

SYNTHESIS AND INTRAMOLECULAR HETEROCYCLIZATION
1925
Scheme 3.
12
15
S
O
H
8
H
N
19
22
17
10
N
H
13
18
7
O
N
20
21
O
11
9
14
N
NH2
+
16
H
N
23
EtOH
3
2
5
4
C
S
O
6
N
N
6
1
19
20
21
18
9
17
1
S
S
22
SH
C
2
C
8
7
3
(1) NaOH
HN
N
N
N
HN
6
N
N
N
(2) H+, H2O
N
5
C
O
O
O
C
C
N
4
16
10
15
14
11
12
N
N
13
7
(С=N), 1301 (C=S). 1Н NMR spectrum, δ, ppm (J, Hz):
N-(2-Isonicotinoylhydrazinecarbonothioyl)-3-
phenylacrylamide (6). A mixture of 1.37 g (0.01 mol)
of isonicotinic acid hydrazide and 1.89 g (0.01 mol)
of cinnamoyl isothiocyanate was stirred at 70–75°C
for 2 h. After cooling, the precipitate was filtered off
and crystallized from isopropanol. Yield 1.3 g (40%),
white solid, mp 230–231°С. IR spectrum, ν, cm–1: 3194
(NH), 1686 (C=O), 1631 (C=N), 1215 (C=S). 1Н NMR
3
4.75–4.85 m (3Н, Н13, 15), 5.10 d (1Н, Н15, J = 10.5),
5.78–5.85 m (1Н, Н14), 7.66 d (2Н, Н3,5, 3J = 5.0), 8.72
3
d (2Н, Н2,6, J = 5.0), 13.48 br. s (1Н, H9). 13С NMR
spectrum, δС, ppm: 46.52 (С13), 117.81 (С15), 122.68
(С3,5), 132.21 (С14), 133.93 (С4), 149.76 (С7), 151.01
(С2,6), 168.72 (С10). Found, %: С 55.10; Н 4.68; N 25.70.
С10Н10N4S. Calculated, %: С 55.02; Н 4.62; N 25.67.
3
spectrum, δ, ppm (J, Hz): 7.02 d (1Н, Н16, J = 15.9),
b. A mixture of 2 g (0.015 mol) of nicotinic acid
hydrazide and 6.97 g (0.06 mol) of N-allylthiourea was
thoroughly grinded in a mortar, heated to 170°С in Wood’s
metal and kept at that temperature for 2 h. After cool-
ing, 20% solution of sodium hydroxide was added. The
formed suspension was filtered, the filtrate was acidified
with hydrochloric acid to рН = 5, the formed precipitate
was isolated by filtration through a glass filter and dried.
Yield 1.5 g (45.5%), mp 200-202°С.
7.42–7.44 m (3Н, Н20,21,22), 7.60–7.62 m (2Н, Н19,23),
3
7.75 d (1Н, Н17, J = 15.9), 7.78–7.79 m (2Н, Н3,5),
8.75-8.76 m (2Н, Н2,6), 11.42 br. s (1Н, Н9), 11.75 br. s
(1Н, Н13), 12.24 br. s (1Н, Н10). 13С NMR spectrum, δ,
ppm: 111.98 (С16), 122.03 (С3,5), 128.82 (С19,23), 129.68
(С20,22), 131.39 (С21), 134.54 (С18), 139.74 (С4), 145.34
(С17), 150.95 (С2,6), 163.71 (С7), 166.10 (С14), 181.66
(С11). Found, %: С 58.93; Н 4.35; N 17.23. С16Н14N4O2S.
Calculated, %: С 58.88; Н 4.32; N 17.17.
3-(Pyridin-4-yl)-1Н-1,2,4-triazole-5(4H)-thione (5)
was obtained similarly to compound 4 (procedure b) from
2 g (0.015 mol) of isonicotinic acid hydrazide and 4.57 g
(0.06 mol) of thiourea Yield 2.5 g (93.6%), mp ≥350°С.
IR spectrum, ν, cm–1: 3195 (NH), 1610 (С=N), 1272
(C=S). 1Н NMR spectrum, δ, ppm (J, Hz): 7.79 d (2Н,
Н3,5, 3J = 6.1), 8.67 d (2Н, Н2,6, 3J = 6.1), 13.90 br. s (2Н,
Н9,11). 13С NMR spectrum, δ, ppm: 119.98 (С3,5), 133.03
(С4), 148.85 (С7), 151.10 (С2,6) and 168.19 (С10). Found,
%: С 47.24; Н 3.45; N 31.51. С7Н6N4S. Calculated, %:
С 47.18; Н 3.39; N 31.44.
7-Phenyl-3-(pyridin-4-yl)-5Н-[1,2,4]triazolo[3,4-
b][1,3]thiazine-5-one (7) was prepared similarly to
compound 3 from 1 g (3 mmol) of compound 6. Yield
0.17 g (18 %), mp ≥320°С. IR spectrum, ν, cm–1: 1641
1
(C=O), 1554 (C=N). Н NMR spectrum, δ, ppm (J,
Hz): 6.48–7.77 m (6Н, Н2,18–22), 7.81 d (2Н, Н11,15, 3J =
5.0), 8.67 d (2Н, Н2,6, 3J = 5.0), 13.90 br. s (2Н, Н9,11).
13С NMR spectrum, δ, ppm: 119.26 (С2), 119.88 (С8),
120.02 (С11,15), 128.70 (С18,22), 128.96 (С19,21), 129.41
(С20), 133.52 (С17), 133.71 (С10), 134.74 (С5), 144.34
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

1926
NURKENOV et al.
(С9), 151.12 (С12,14), 171.68 (С7). Found, %: С 62.37;
Н 3.98; N 18.23. С16Н12N4OS. Calculated, %: С 62.32;
Н 3.92; N 18.17.
Santos,L.,Vitorino,S.,Reis,M.,Miranda,V.,Correia,H.F.,
Sousa, J.A., Kovalishyn, V., Latino, D.A.R.S., Ramos, J.,
and Viveiros, M., Eur. J. Med. Chem., 2014, no. 81,
p. 119.
1Н and 13С NMR spectra were registered in DMSO-
d6 using a JNM-ECA Jeol 400 spectrometer operating
at 399.78 and 100.53 MHz, respectively, with HMDS as
internal reference. IR spectra were recorded using a Ni-
colet 5700 spectrometer (KBr pellets). Elemental analysis
was performed using a Hewlett–Packard 185B analyzer.
Melting points were determined in glass capillaries using
a Stuart SMP 10 device. The reactions were monitored
by TLC on Sorbfil plates in the isopropanol—25% aque-
ous ammonia–water system (7 : 2 : 1), developing with
iodine vapors.
https://doi.org/10.1016/j.ejmech.2014.04.077
3. Machado, D., Couto, I., Perdigão, J., Rodrigues, L.,
Portugal, I., Baptista, P., Veigas, B., Amaral, L., and
Viveiros, M., PLoS ONE., 2012, no. 7(4), p. e34538.
https://doi.org/10.1371/journal.pone.0034538
4. Farhan, M.E. and Assy, M.G., Egypt. J. Chem., 2019,
vol. 62, no. 2, p. 171.
https://doi.org/10.21608/EJCHEM.2018.4427.1393
5. Nurkenov, O.A., Fazylov, S.D., Zhivotova, T.S.,
Satpayeva, Zh.B., Akhmetova, S.B., Kurmanbayeva, Zh.,
Karipova, G.K., and Isayeva, A.Zh., News of NАS RK,
Ser. Chem. Techn., 2015, vol. 1, no. 409, p. 9.
This study was financially supported by the Committee
of Science of the Ministry of Education and Science of
Kazakhstan Republic (grant no. АР05131054).
6. Ali, B., Khan, K.M., Arshia, Kanwal, Hussain Sh.,
Hussain Sf., Ashraf, M., Riaz, M., Wadood, A., and
Perveen, S., Bioorg. Chem., 2018, no. 79, p. 34.
https://doi.org/101016/j.bioorg.2018.04.004
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
REFERENCES
7. Ovsepyan T.R., Dilyan, S.V., Akopian, M.R., Mina-
syan, N.S., Paronikyan, R.G., Paronikyan, R.V., and
Melik-Ogandzhanyan, R.G., Khim. Zh. Arm., 2016,
vol. 69, nos. 1–2, p. 121.
1. Mona, E.F. and Mohammed, G.A., Egypt. J. Chem.,
2019, vol. 62, no. 2, p. 171.
8. Abdalla, S.M., Hegab, M.I., Abo Taleb, N.A., Hasabel-
naby, S.M., and Goudah, A., Eur. J. Med.
Chem., 2010, vol. 45, no. 4, p. 1267.
https://doi.org/10.21608/EJCHEM.2018.4427.1393
2. Martins, F., Santos, S., Ventura, C., Elvas-Leitao, R.,
https://doi.org/10.1016/j.ejmech.2009.10.028
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019