Synthesis of Fused Heterocycles Based on 1-Amino-1H-tetrazole-5-thiol and α,β-Unsaturated Aldehydes

Article abstract of DOI:10.1134/S1070363220070051

Abstract: 8-Phenyltetrazolo[5,1-b][1,3,4]thiadiazepine was obtained as a result of intermolecular cyclization of 1-amino-1H-tetrazole-5-thiol and 3-phenyl-2-propynal. The reaction of α-bromocinnamaldehyde with 1-amino-1H-tetrazole-5-thiol led to the formation of 7-benzylidene-7H-tetrazolo[5,1-b][1,3,4]thiadiazine. An effective method was developed for the synthesis of 1-[(3-phenylprop-2-yn-1-yl)amino]-1H-tetrazole-5-thiol, a key intermediate in the possible synthesis of 7-benzylidene-6,7-dihydro-5H-tetrazolo[5,1-b][1,3,4]thiadiazine.

Full text of DOI:10.1134/S1070363220070051

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 7, pp. 1202–1206. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Obshchei Khimii, 2020, Vol. 90, No. 7, pp. 1010–1015.
Synthesis of Fused Heterocycles Based
on 1-Amino-1H-tetrazole-5-thiol and α,β-Unsaturated Aldehydes
Yu. S. Gurenkovaa, I. V. Kornyakovb, V. A. Ostrovskya,
M. A. Skrylnikovaa, and A. V. Khramchikhina,*
a St. Petersburg State Institute of Technology (Technical University), St. Petersburg, 190013 Russia
b St. Petersburg State University, St. Petersburg, 199034 Russia
*e-mail: xram62@mail.ru
Received April 5, 2020; revised April 5, 2020; accepted April 15, 2020
Abstract—8-Phenyltetrazolo[5,1-b][1,3,4]thiadiazepine was obtained as a result of intermolecular cyclization of
1-amino-1H-tetrazole-5-thiol and 3-phenyl-2-propynal. The reaction of α-bromocinnamaldehyde with 1-amino-1H-
tetrazole-5-thiol led to the formation of 7-benzylidene-7H-tetrazolo[5,1-b][1,3,4]thiadiazine. An effective method
was developed for the synthesis of 1-[(3-phenylprop-2-yn-1-yl)amino]-1H-tetrazole-5-thiol, a key intermediate in
the possible synthesis of 7-benzylidene-6,7-dihydro-5H-tetrazolo[5,1-b][1,3,4]thiadiazine.
Keywords: 1-amino-1H-tetrazole-5-thiol, 8-phenyltetrazolo[5,1-b][1,3,4]thiadiazepine, 1-amino-4-(tetrahydro-2H-
pyran-2-yl)-1H-tetrazole-5(4H)-thione, 1-[(3-phenylprop-2-yn-1-yl)amino]-1H-tetrazole-5-thiol, 7-benzylidene-7H-
tetrazolo[5,1-b][1,3,4]thiadiazine
DOI: 10.1134/S1070363220070051
Tetrazole-derived compounds are widely used in
modern medicine and biochemistry [1]. Of particular
interest are fused heterocyclic systems containing a
tetrazole moiety. This group includes tetrazolothiadiazines.
According to the scarce literature data, they have
antioxidant and antibacterial effects [2, 3]. Despite
the promise of such compounds, the methods for their
directed synthesis are limited.
7-benzylidene-7H-tetrazolo[5,1-b][1,3,4]thiadiazine 3
was only 20%.
Recently, we have proposed the method for the
synthesis of tetrazolothiadiazines analogue, namely
(Z)-7-benzylidene-3-methyl-6,7-dihydro-5H-[1,2,4]-
triazolo[3,4-b][1,3,4]thiadiazine, starting from 4-amino-
5-methyl-4H-1,2,4-triazole-3-thiol and 3-phenyl-2-
propynal [6]. At the first stage, the corresponding
azomethine was obtained. After hydrogenation of the
C=N double bond and further cyclization of the resulting
secondary amine, (Z)-7-benzylidene-3-methyl-6,7-
dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine was
obtained. When using 1-amino-1H-tetrazole-5-thiol
1, at the first stage of the synthesis a seven-membered
heterocycle 8-phenyltetrazolo[5,1-b][1,3,4]thiadiazepine
5 was formed instead of the expected azomethine 6
(Scheme 2).
There are two fundamentally different methods for
the preparation of tetrazolothiadiazines. The first is based
on the reaction of dihalohetarenes [4] or α-haloketones
directly with 1-amino-1H-tetrazole-5-thiol [2]. The second
one involves the initial preparation of the corresponding
hydrazinylthiadiazine followed by the formation of the
tetrazole ring due to the conversion of the hydrazine
fragment into the azide one [5]. The reactions of 1-amino-
1H-tetrazole-5-thiol with acetylenic compounds have not
been previously used to obtain fused heterocycles. There
is also no data on the interaction of 1-amino-1H-tetrazole-
5-thiol with α,β-ethylene aldehydes.
In our opinion, this unexpected result is due to the
fact that 1-amino-1H-tetrazole-5-thiol 1 has a higher
acidity than 4-amino-5-methyl-4H-1,2,4-triazole-3-thiol.
The formation of thiadiazepine 5 involves two stages:
nucleophilic addition of the sulfur atom of 1-amino-
1H-tetrazole-5-thiol 1 to the triple bond of 3-phenyl-2-
We managed to carry out the reaction of 1-amino-
1H-tetrazole-5-thiol 1 with α-bromocinnamaldehyde
2 (Scheme 1). The reaction was accompanied by
polymerization of the mixture, and the yield of the target
1202

SYNTHESIS OF FUSED HETEROCYCLES
1203
Scheme 1.
Scheme 2.
Scheme 3.
propynal 4 followed by intramolecular condensation of
amino and carbonyl groups (Scheme 3).
was obtained (Scheme 5). It should be noted that structure
of the previously obtained adducts of vinyl ethers to
5-mercaptotetrazoles has been proved exclusively by 15N
NMR data [7]. For the first time, we were able to confirm
the structure of compound 7 by means of single crystal
X-ray diffraction method (Fig. 1).
On the one hand, high acidity of compound 1 increases
concentration of the highly nucleophilic thiolate anion.
On the other hand, the equilibrium protonation of the
oxygen of the carbonyl group sharply decreases the
electron density on the β-carbon of the triple bond of
aldehyde 4 (Scheme 4). As a result, the formation of a
seven-membered heterocycle thiadiazepine occurs. It
should be noted that tetrazolothiadiazepines were not
known before our study.
Compound 8 was obtained without heating and without
using a catalyst. Further hydrogenation and removal of
the 2-pyranyl protection led to the formation of the target
intermediate secondary amine, 1-[(3-phenylprop-2-yn-1-
yl)amino]-1H-tetrazole-5-thiol 10. An attempt to carry
out its cyclization under conditions similar to cyclization
of 5-methyl-4-[(3-phenylprop-2-yn-1-yl)amino]-4H-
1,2,4-triazole-3-thiol [6] did not lead to the formation of
7-benzylidene-6,7-dihydro-5H-tetrazolo[5,1-b][1,3,4]-
To avoid cyclization at the first stage of the synthesis,
we introduced a protective 2-pyranyl group into the
starting 1-amino-1H-tetrazole-5-thiol 1, and 1-amino-4-
(tetrahydro-2H-pyran-2-yl)-1H-tetrazole-5(4H)-thione 7
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 7 2020

1204
GURENKOVA et al.
pargyline). We are also sure that the cyclization of
compound 10 is possible when using catalytic systems
that activate the triple bond in nucleophilic addition
reactions (for example, based on palladium) [8].
EXPERIMENTAL
1H (400.13 MHz) and 13C (100.6 MHz) NMR spectra
(DMSO-d6) were recorded on a BrukerAVANCE III HD
400 NanoBay spectrometer. IR spectra were recorded on
a Shimadzu IRTracer-100 IR Fourier spectrometer in a
spectral range from 7800 to 350 cm–1 without sample
preparation. Elemental analysis was performed on a LECO
CHNS-932 analyzer. Diffraction data were collected on
an Oxford Diffraction Xcalibur diffractometer equipped
with an Atlas series CCD detector. Melting points were
determined on a Kofler thermostat.
Fig. 1. General view of the 1-amino-4-(tetrahydro-2H-pyran-
2-yl)-1H-tetrazole-5(4H)-thione 7 molecule in the crystal.
thiadiazine 11. Judging by the TLC data, even after
prolonged reflux in DMF, only the starting tetrazole-5-
thiol 10 was present in the reaction mixture. Probably,
this is due to the fact that 1-amino-1H-tetrazole-5-thiolate
anion has a significantly lower nucleophilicity than
4-amino-5-methyl-4H-1,2,4-triazole-3-thiolate anion.
1-Amino-1H-tetrazole-5-thiol (1). Methyldithio-
carbazate (70.76 g, 0.58 mol) obtained as described in
[9] was reacted with sodium azide (37.7 g, 0.58 mol) in
a mixture of 492 mL of ethanol and 98.2 mL of water.
The reaction mixture was boiled for 16 h. The solvent
was distilled off, and the precipitate was recrystallized
from an ethanol–water mixture (5 : 1). Sodium 1-amino-
Despite the failure in the cyclization reaction, it should
be emphasized that the obtained 1-[(3-phenylprop-2-yn-
1-yl) amino]-1H-tetrazole-5-thiol 10 can exhibit various
types of biological activity, so it is known that the ethynyl
fragment is part of many drugs (for example, terbinafine,
Scheme 4.
Scheme 5.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 7 2020

SYNTHESIS OF FUSED HETEROCYCLES
1205
1H-tetrazole-5-thiolate was obtained in yield of 27.82 g
(0.2 mol, 34.48%). To a suspension of 27.79 g (0.2 mol)
of sodium 1-amino-1Н-tetrazole-5-thiolate in 200 mL of
ethanol was added 7.3 g (0.2 mol) hydrochloric acid. The
resulting mixture was boiled for 5 min. After filtration,
the solvent was distilled off. The residue was a yellow
crystalline substance. The total yield of 1-amino-1H-
tetrazole-5-thiol with respect to carbon disulfide was 26.4 g
reaction within 6 h. The white crystalline precipitate was
filtered off and dried. Yield 4.1 g (80%), mp.136–137°С.
IR spectrum, ν, cm–1: 1030 (C–O–C), 1363 (C–N), 1455
(C6H5), 2961 (СH), 3299 (NH2). 1Н NMR spectrum, δ,
ppm (J, Hz): 1.50–1.63 m (2H, CH2), 1.65–1.80 m (1H,
CH), 1.87–2.04 m (2H, CH2), 2.05–2.22 m (1H, CH),
3.58–3.72 m (1Н, CH), 3.89–4.03 m (1H, CH), 5.72 d. d
(1H, CH, 3JHH = 9.9, 2.6), 6.65 s (2H, NH2). 13C NMR
spectrum, δС, ppm: 22.01 (CH2) 24.74 (CH2) 28.58 (CH2),
67.82 (CH2) 83.78 (CH) 163.09 (C=S). Found, %: C
35.62; H 5.23; N 35.02. C6H11N5OS. Calculated, %: C
35.81; H 5.51; N 34.80.
1
(26%), mp 162–163°С. Н NMR spectrum, δ, ppm:
6.47 br. s. 13C NMR spectrum, δС, ppm: 162.91.
7-Benzylidene-7H-tetrazolo[5,1-b][1,3,4]thia-
diazine (3). To a solution of 2 g (1.7 mmol) of 1-amino-
1H-tetrazole-5-thiol 1 in 10 mL of methanol were added
0.35 g (1.7 mmol) of α-bromocinnamaldehyde 2 and 0.26
g (2.6 mmol) of triethylamine. The resulting mixture
was boiled for 1.5 h, and then diluted with water. The
brown crystalline precipitate was filtered off, and then
recrystallized from methanol. Yield 0.78 g (20%), mp.
155–156°С. IR spectrum, ν, cm–1: 1441 (C6H5), 1576
(С=N), 3050 (СH). 1Н NMR spectrum, δ, ppm: 7.49–7.66
m (6H, Ph–CH=), 8.31 s (1H, CH=N). 13C NMR spectrum,
δС, ppm: 116.28 (Ph–CH=C), 129.80–133.61 (Ph), 138.29
(Ph–CH), 139.28 (S–C–N), 151.84 (CH=N). Found, %:
C 52.62; H 3.17; N 30.14. C10H7N5S. Calculated, %: C
52.39; H 3.08; N 30.55.
1-[(3-Phenylprop-2-yn-1-ylidene)amino]4-
(tetrahydro-2H-pyran-2-yl)-1H-tetrazole-5(4H)-
thione (8). To a solution of 1.5 g (7.5 mmol) of 1-amino-
4-(tetrahydro-2H-pyran-2-yl)-1H-tetrazole-5(4H)-thione
7 in 5 mL of methanol was added 0.97 g (7.5 mmol) of
3-phenyl-2-propynal. The reaction mixture was stirred
at room temperature for 6 h. During the reaction, the
starting 1-amino-4-(tetrahydro-2H-pyran-2-yl)-1H-
tetrazole-5(4H)-thione 7 was dissolved, and azomethine
was precipitated. The yellow crystalline precipitate was
filtered off and dried. Yield 1.8 g (76%), mp 123–124°С.
IR spectrum, ν, cm–1: 1488 (C6H5), 1362 (C–N) 1559
1
(С=N), 2300 (С≡C), 2938(СH). Н NMR spectrum, δ,
ppm (J, Hz): 1.50–1.65 m (2H, CH2), 1.69–1.85 m (1H,
CH), 1.90–2.06 m (2H, CH2), 2.10–2.23 m (1H, CH),
3.62–3.77 m (1Н, CH), 4.00 m (1Н, CH), 5.84 d. d (1H,
CH, 3JHH = 9.7, 2.3), 7.48–7.64 m (3H, Ph), 7.72 d (2H,
Ph, 3JHH = 7.1), 8.95 s (1H, CH=N). 13C NMR spectrum,
δС, ppm: 21.89 (CH2), 24.72 (CH2), 28.53 (CH2), 67.76
(CH2O), 83.30 (CHO), 84.23 (C≡CPh), 101.21 (CPh),
120.13–132.90 (Ph), 143.31 (CH=N), 160.57 (C=S).
Found, %: C 57.85; H 4.55; N 21.92. C15H15N5OS.
Calculated, %: C 57.49; H 4.82; N 22.35.
8-Phenyltetrazolo[5,1-b][1,3,4]thiadiazepine (5). To
a solution of 2 g (1.7 mmol) of 1-amino-1H-tetrazole-5-
thiol 1 in 5 ml of methanol was added 0.22 g (1.7 mmol)
of 3-phenyl-2-propynal. According to TLC data (ethyl
acetate–petroleum ether, 1:2), the reaction proceeded
in 10 min. The solution was diluted with water; the
yellow crystalline precipitate was filtered off, and then
recrystallized from methanol. Yield 3.28 g (84%), mp
149–150°С. IR spectrum, ν, cm–1: 1487 (C6H5), 1575
(С=N), 3031 (СH). 1Н NMR spectrum, δ, ppm (J, Hz):
7.02 d (1H, CH–CH=N, 3JHH = 4.0), 7.47–7.59 m (3H,
1-[(3-Phenylprop-2-yn-1-yl)amino]-4-(tetrahydro-
2H-pyran-2-yl)-1H-tetrazol-5(4H)-thione (9). To
a solution of 1 g (3.2 mmol) 1-[(3-phenylprop-2-yn-
1-ylidene)amino]-4-(tetrahydro-2H-pyran-2-yl)-1H-
tetrazole-5(4H)-thione 8 in 10 mLof methanol was added
in portions 0.36 g (9.6 mmol) of sodium borohydride,
avoiding significant foaming. Then the reaction mixture
was diluted with 40 mL of cold water. The formed pale
yellow crystalline precipitate was filtered off and dried.
Yield 0.92 g (92%), mp 78–79°С. IR spectrum, ν, cm–1:
1031 (C–O–C), 1368 (C–N), 1421 (C6H5), 2938 (СH),
3238(NH). 1НNMRspectrum, δ, ppm(J, Hz):1.51–1.63m
(2H, CH2), 1.67–1.80 m (1H, CH), 1.89–2.04 m (2H,
3
Ph), 7.76–7.89 m (2H, Ph), 8.50 d (1H, CH=N, JHH
=
4.0). 13C NMR spectrum, δС, ppm: 125.05 (CH–CH=N),
128.04–135.87 (Ph), 147.37 (C–Ph), 161.04 (CH=N),
161.19 (S–C–N). Found, %: C 52.03; H 2.99; N 30.35.
C10H7N5S. Calculated, %: C 52.39; H 3.08; N 30.55.
1-Amino-4-(tetrahydro-2H-pyran-2-yl)-1H-
tetrazol-5(4H)-thione (7). To a solution of 3 g
(25.6 mmol) of 1-amino-1H-tetrazole-5-thiol 1 in
20 mL of acetonitrile was added 2.15 g (25.6 mmol) of
3,4-dihydro-2H-pyran. Under vigorous stirring without
heating, 1-amino-1H-tetrazole-5-thiol 1 was gradually
dissolved, and the final product precipitated during the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 7 2020

1206
GURENKOVA et al.
CH2), 2.09–2.23 m (1H, CH), 3.60–3.72 m (1Н, CH),
3.98 d (1H, 3JHH = 11.4), 4.28 d. d (2H, CH2NH, 2JHH
1796.89(10) Å3, F(000) = 848.0, dcalc = 1.488 g/cm3,
μ = 0.329 mm–1. The crystallographic data were deposited
at the Cambridge Crystallographic Data Center (CCDC
1988902).
=
3
3
6.6, JHH = 4.8), 5.76 d. d (1H, CHO, JHH = 9.9, 2.4),
7.31–7.45 m (5H, Ph), 7.95 t (1H, NH, 3JHH = 4.7). 13
C
NMR spectrum, δС, ppm: 21.99 (CH2), 24.72 (CH2),
28.53 (CH2), 39.38 (CH2N), 67.83 (CH2O), 83.49 (CHO),
85.05 (C≡CPh), 85.35 (CPh), 122.33–131.70 (Ph), 162.40
(C=S). Found, %: C 57.01; H 5.26; N 22.45. C15H17N5OS.
Calculated, %: C 57.12; H 5.43; N 22.21.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
REFERENCES
1. Popova, E.A., Trifonov, R.E., and Ostrovskii, V.A., Russ.
Chem. Rev., 2019, vol. 88, no. 6, p. 644.
1-[(3-Phenylprop-2-yn-1-yl)amino]-1H-tetra-
zole-5-thiol (10). A solution of 0.5 g (1.6 mmol)
1-[(3-phenylprop-2-yn-1-yl)amino]-4-(tetrahydro-2H-
pyran-2-yl)-1H-tetrazole-5(4H)-thione 9 in a mixture
of 5 mL of methanol, 2 mL of water and catalytic
amounts of concentrated hydrochloric acid was boiled
for 4 h. Then 10 mL of cold water was added to the
reaction mixture. The resulting mixture was cooled.
Upon cooling, 1-[(3-phenylprop-2-yn-1-yl)amino]-1H-
tetrazole-5-thiol 10 was precipitated. The pale yellow
crystalline precipitate was filtered off and dried. Yield
0.19 g (54%), mp 133–134°С. IR spectrum, ν, cm–1: 1348
https://doi.org/10.1070/RCR4864
2. Eftekhar, M., Eshghi, H., Rahimizadeh, M.M.
Bakavoli, M., and Saberi, S., J. Chem. Res., 2014, vol. 38,
no. 6, p. 365.
https://doi.org/10.3184/174751914X14001496962946
3. Igei, M., Bakavoli, M., Shiri, A., Ebrahimpour, Z., Ba-
zizollahi, H., Beyzaei, H., and Moghaddam-Manesh, M.,
J. Chem. Res., 2016, vol. 40, no. 10, p. 628.
https://doi.org/10.3184/174751916X14742893137631
4. Eshghi, H., Rahimizadeh, M., Saberi, S., Ab-
nous, Kh., and Bakavoli, M., J. Chem. Res., 2013,
vol. 37, no. 9, p. 553.
https://doi.org/10.3184/174751913X13738978141695
5. Kulikov, A.S., Epishina, M.A., Fershtat, L.L., Ro-
manova, A.A., and Makhova, N.N., Tetrahe-
dron Lett., 2017, vol. 58, no. 48, p. 3998.
1
(N–C), 1529 (C6H5), 3215(NH). Н NMR spectrum, δ,
ppm: 4.26 s (2H, СH2), 7.32–7.44 m (5H, Ph), 7.77 s
(1H, NH). 13C NMR spectrum, δС, ppm: 39.13 (CH2),
85.18 (C≡C), 85.23 (C≡C), 122.41–131.68 (Ph), 162.69
(C–SH). Found, %: C 52.09; H 4.16; N 30.02. C10H9N5S.
Calculated, %: C 51.93; H 3.92; N 30.28.
https://doi.org/10.1016/j.tetlet.2017.09.014
6. Skryl’nikova, M.A., Khramchikhin, A.V., and
Krivchun, M.N., Russ. J. Gen. Chem., 2017, vol. 87,
no. 6, p. 1321.
Single crystal X-ray diffraction analysis of com-
pound 7 was carried out on an Oxford Diffraction Xcalibur
diffractometer equipped with an Atlas series CCD
detector with MoKα radiation (λ[MoKα] = 0.71073 Å).
The data were integrated in the CrysAlisPro software
package version 1.171.36.32 [10].Absorption correction
was introduced by a semiempirical method. The unit cell
parameters were refined by the least squares method based
on 2602 independent reflections, with 2θ in the range of
6.394°–59.998°. The structure was solved and refined
to R1 = 0.0296 (wR2 = 0.0720) for 2295 reflections with
I > 2σ(I) using the SHELX software package [11, 12]
included into the OLEX2 interface [13]. The studies were
carried out using the equipment of the Resource Center
“X-Ray Diffraction Research Methods” of the Science
Park of St. Petersburg State University.
https://doi.org/10.1134/S1070363217060329
7. Melnikova, Y.V., Roh, J., Kuneš, J., Artamonova, T.V,
and Zevatskii, Y.E., Tetrahedron Lett., 2017, vol. 58,
no. 40, p. 3842.
https://doi.org/10.1016/j.tetlet.2017.08.058
8. Myznikov, L.V., Melnikova, Yu.V., Baichurin, R.I.,
Artamonova, T.V., and Zevatskii, Yu.E., Russ. J.
Gen. Chem., 2018, vol. 88, no. 2, p. 216.
https://doi.org/10.1134/S1070363218020068
9. Wang, T., Miao, W., Wu, S., Bing, G., Zhang, X.,
Qin, Z., Yu, H., Qin, X., and Fang, J., Chin. J.
Chem., 2011, vol. 29, no. 5, p. 959.
https://doi.org/10.1002/cjoc.201190196
10. CrysAlisPro Software system, version 1.171.36.39.
Rigaku Oxford Diffraction, Oxford, UK, 2013.
11. Sheldrick, G.M., Acta Cryst. (A), 2015, vol. 71, p. 3.
https://doi.org/ 10.1107/S2053273314026370
12. Sheldrick, G.M., Acta Cryst. (C), 2015, vol. 71, p. 3.
https://doi.org/ 10.1107/S2053229614024218
13. Dolomanov, O.V., Bourhis, L.J., Gildea, R.J,
Howard, J.A.K., and Puschmann, H., J. Appl. Cryst.,
2009, vol. 42, no. 2, p. 339.
Crystals of 1-amino-4-(tetrahydro-2H-pyran-2-yl)-
1H-tetrazole-5(4H)-thione 7 are rhombic, C6H11N5OS,
M 201.26; crystal size 0.42 × 0.33 × 0.20 mm, space
group Pbca, Z = 8; unit cell parameters at 100(2) K:
a = 11.3057(4), b = 8.4579(3), c = 18.7915(5) Å, V =
https://doi.org/10.1107/S0021889808042726
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 7 2020