Effective synthesis of 7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines

Article abstract of DOI:10.1007/s10593-018-2325-8

[Figure not available: see fulltext.] A highly effective method for the preparation of 7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines was developed on the basis of condensation reaction between aryl(hetaryl) α-bromo ketones and commercially available thiocarbohydrazide, followed by treatment of the obtained 2-hydrazinyl-6H-1,3,4-thiadiazine hydrobromides with ortho esters in the presence of trifluoroacetic acid under mild conditions.

Full text of DOI:10.1007/s10593-018-2325-8

DOI 10.1007/s10593-018-2325-8
Chemistry of Heterocyclic Compounds 2018, 54(6), 669–672
Effective synthesis of 7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines
Alexander S. Kulikov1, Margarita A. Epishina1, Leonid L. Fershtat1, Nina N. Makhova1*
1 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky Ave., Moscow 119991, Russia; е-mail: mnn@ioc.ac.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(6), 669–672
Submitted May 10, 2018
Accepted June 22, 2018
A highly effective method for the preparation of 7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines was developed on the basis of condensation
reaction between aryl(hetaryl) α-bromo ketones and commercially available thiocarbohydrazide, followed by treatment of the obtained
2-hydrazinyl-6H-1,3,4-thiadiazine hydrobromides with ortho esters in the presence of trifluoroacetic acid under mild conditions.
Keywords: α-bromo ketones, hydrazinylthiadiazines, ortho esters, thiocarbohydrazide, 7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines,
condensation.
Fused nitrogenous heterocyclic systems exhibit a broad
range of pharmacological activity.1–4 Well-known examples
of this class of compounds include condensed ring
structures comprising of six-membered heterocycles and
1,2,4-triazole.5–8 In particular, pharmacologically active
compounds have been identified among 7H-1,2,4-triazolo-
[3,4-b][1,3,4]thiadiazines 1, which have revealed anti-
microbial,9,10 antiparasitic,11 and antiproliferative activity.12,13
The most frequently used methods for building the
molecular framework of compounds 1 start from the
synthesis of 5-substituted 1,2,4-triazoles 2 that contain
reactive vicinal amino and mercapto groups, followed by
annulation of thiadiazine ring by reacting triazoles 2 with
α-halo ketones 3.6,10,11 Synthesis of the starting 1,2,4-
triazoles 2 and their subsequent transformations are
performed with toxic reagents (СS2, N2H4·H2O) and at
elevated temperatures (Scheme 1).
available thiocarbohydrazide 5 at room temperature in
DMSO and nitrosation of the formed 2-hydrazinyl-1,3,4-
thiadiazine hydrobromide 6 by treatment with NaNO2 in
hydrochloric acid. The nitrosation product – azido
derivative 7 undergoes intramolecular cyclization as a
result of azide-tetrazole tautomerism, the equilibrium of
which is completely shifted toward the tetrazole form. All
of these reactions proceed under mild conditions and the
final products are obtained in high yields (Scheme 2).
The goal of this work was to study the possible
applications of an analogous approach for the preparation
of 7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 1 with aromatic
and heterocyclic substituents. The starting materials
selected for this purpose were 2-hydrazinyl-6Н-1,3,4-
thiadiazine hydrobromides 6, which were previously
synthesized by us for the preparation of 7H-tetrazolo[5,1-b]-
[1,3,4]thiadiazines 4.14 Generally, the annulation of 1,2,4-
triazole ring to six-membered azines starting from their
hydrazinyl derivatives 8 can be accomplished by any of the
following three methods: synthesis of hydrazones 9
followed by oxidative condensation,15,16 dehydration of
acylhydrazinyl derivative 10 by refluxing in POCl3,17 and
condensation with ortho esters. The third route can be
In contrast to that, we recently developed a generally
applicable, highly effective method for the synthesis of
7H-tetrazolo[5,1-b][1,3,4]thiadiazines 4, which relies on
the initial assembly of thiadiazine ring, followed by
annulation of the tetrazole ring.14 This method includes
condensation of α-bromo ketones 3 with the commercially
Scheme 1
0009-3122/18/54(6)-0669©2018 Springer Science+Business Media, LLC
669

Chemistry of Heterocyclic Compounds 2018, 54(6), 669–672
Scheme 2
Table 1. Optimization of reaction conditions for the preparation of
6-(4-bromophenyl)-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazine (1а)
from 5-(4-bromophenyl)-2-hydrazinyl-6Н-1,3,4-thiadiazine (6а)*
accomplished either by refluxing the hydrazinyl derivative
in mixture with an ortho ester18 or by performing the
reaction in the presence of trifluoroacetic acid19 (Scheme 3).
HC(OMe)3,
mmol
CF3CO2H,
mmol
Time,
h
Scheme 3
Entry
Yield, %
1
2
3
4
5
6
7
9
9
26
6.5
6.5
6.5
6.5
6.5
0
12
12
8
53
80
67
46
90
95
0
9
9
4
13.5
18
18
12
12
12
* Compound 6а (1 mmol), rt.
from the isolated amount of the product. The optimal
conditions were found when the reaction was performed at
the molar ratio 6а:HC(OMe)3:CF3CO2H = 1:18:6.5 at 20°С
for 12 h (Table 1, entry 6). The reaction did not proceed in
the absence of CF3CO2H (entry 7).
Initially, we chose to prepare the desired 7H-1,2,4-
triazolo[3,4-b][1,3,4]thiadiazines 1 according to the first
approach, based on oxidative condensation of hydrazones,
which does not require harsh reaction conditions. In the
role of model substrate we selected 4-nitrophenylhydrazone
11, which was synthesized by condensation of 5-(4-bromo-
phenyl)-2-hydrazinyl-6Н-1,3,4-thiadiazine hydrobromide 6а
with 4-nitrobenzaldehyde (Scheme 4). This oxidation
process was performed at room temperature, using such
oxidizing reagents as PhI(OAc)2 and (NH4)2Ce(NO3)6
in MeCN or Br2 in AcOH. However, TLC analysis
indicated that complex mixtures of products were formed
under all of the tested conditions, with significant
resinification occurring during the reaction. Therefore, we
favored the method based on room temperature
condensation of hydrazinyl derivatives with ortho esters in
the presence of trifluoroacetic acid.
For the optimization of reaction conditions, we selected
hydrobromide 6а as the model compound, which was used
in the reaction with HC(OMe)3. The reaction parameters
that were subjected to optimization included the amount of
HC(OMe)3, CF3CO2H and the duration of the process.
Since the starting compound was introduced into the
reaction as hydrobromide and the reaction was performed
in acidic medium, the conversion degree could not be
observed by TLC. Therefore, the yield of each experiment
using the particular reaction conditions was determined
The optimized conditions were further used for reacting
the rest of 2-hydrazinyl-1,3,4-thiadiazines 6b–f with
HC(OMe)3 and MeC(OEt)3, resulting in the formation of
7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 1b–i (Scheme 5).
This reaction was found to be generally applicable and
effective not only for 5-aryl-2-hydrazinyl-6Н-1,3,4-thia-
diazines 6b–d, which reacted with both HC(OMe)3
(compounds 1b–d) and MeC(OEt)3 (compounds 1e–g).
6-Hetaryl-2-hydrazinyl-1,3,4-thiadiazines 6e,f also reacted
with HC(OMe)3 under analogous conditions forming
6-hetaryl-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 1h,i.
All compounds were formed in high yields and compounds
1 in the majority of cases precipitated from the reaction
mixture in sufficiently pure form, without need for
additional purification.
The structure of the synthesized compounds was
1
confirmed by their spectral characteristics (IR, Н and 13С
NMR spectroscopy, high-resolution mass spectrometry).
Some of the compounds have been described in the
literature, but were previously obtained in lower yields and
characterized only by their melting points and elemental
analysis data. Therefore, we report the spectral data for all
synthesized compounds in the Experimental part of this
article.
Scheme 4
Br
Br
Br
HC(OMe)3
4-NO C6H4CHO
N
S
NO2
N
2
N
S
N
N
N
CF3CO2H
rt, 4–12 h
0–95%
MeCN, rt, 12 h
NHNH2·HBr
72%
N
N
N
H
S
6a
N
11
670

Chemistry of Heterocyclic Compounds 2018, 54(6), 669–672
Scheme 5
In conclusion, a general and highly effective method for
crystallization from EtOH. Compound 1i was additionally
the preparation of 6-aryl-(hetaryl)-7H-1,2,4-triazolo[3,4-b]-
[1,3,4]thiadiazines has been proposed. This method is
based on the synthesis of 2-hydrazinyl-6Н-1,3,4-thia-
diazines by condensation of aryl(hetaryl) α-bromo ketones
with commercially available thiocarbohydrazide, followed
by annulation of 1,2,4-triazole ring to the 2-hydrazinyl-6Н-
1,3,4-thiadiazine intermediates using room temperature
reactions with ortho esters in the presence of trifluoroacetic
acid.
crystallized from EtOH.
6-(4-Bromophenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazine (1а). Yield 0.56 g (95%), cream-colored
powder, mp 208–209°C (mp 206–208°С18), Rf 0.28
(EtOAc). IR spectrum, ν, cm–1: 3127, 1584, 1480, 1443,
1
1285, 1178, 1076, 1006, 943, 841, 811. H NMR spectrum,
3
δ, ppm (J, Hz): 4.44 (2H, s, CH2); 7.79 (2H, d, J = 8.4,
3
H Ar); 7.92 (2H, d, J = 8.4, H Ar); 9.15 (1H, s, CH).
13C NMR spectrum, δ, ppm: 23.5; 125.7; 129.3; 132.0; 132.5;
140.1; 143.1; 154.7. Found, m/z: 296.9630 [M(81Br)+H]+,
294.9651 [M(79Br)+H]+. C10H8BrN4S. Calculated, m/z:
296.9627 (81Br), 294.9648 (79Br).
Experimental
IR spectra were recorded on a Bruker Alpha instrument
over 400–4000 cm–1 range (resolution 2 cm–1) for KBr
pellets. 1H and 13C NMR spectra were acquired on a Bruker
AM-300 spectrometer (300 and 75 MHz, respectively) for
solutions in DMSO-d6. Residual solvent signals were used
as internal standards (2.50 ppm for 1H nuclei and 39.5 ppm
for 13C nuclei). High-resolution mass spectra were recorded
on a Bruker micrOTOF II instrument using electrospray
ionization. Elemental analysis was performed on a
EuroVector EA instrument. Melting points were
determined on a Stuart SMP20 digital melting point
apparatus. The reaction progress was controlled by thin-
layer chromatography on Merck 60 F254 plates with
visualization under UV light (254 nm wavelength).
6-(3-Nitrophenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thia-
diazine (1b). Yield 0.50 g (96%), yellow powder, mp 233–
235°С (mp 235°С20), Rf 0.36 (CHCl3–EtOAc, 3:2).
IR spectrum, ν, cm–1: 3124, 1526, 1475, 1350, 1281, 882,
732. 1H NMR spectrum, δ, ppm (J, Hz): 4.55 (2H, s, CH2);
3
7.88 (2H, t, J = 8.4, H Ar); 8.39–8.46 (2H, m, H Ar); 8.76
(1H, s, H Ar); 9.23 (1H, s, CH). 13C NMR spectrum,
δ, ppm: 23.7; 121.8; 126.1; 130.7; 133.6; 135.0; 140.1;
143.2; 148.2; 153.8. Found, m/z: 262.0391 [M+H]+.
C10H8N5O2S. Calculated, m/z: 262.0394.
6-(4-Nitrophenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thia-
diazine (1c). Yield 0.36 g (69%), light-brown powder,
mp 253–254°C (254–257°С21), Rf 0.36 (CHCl3–EtOAc,
3:2). IR spectrum, ν, cm–1: 3034, 1521, 1470, 1445, 1347,
1302, 735. 1H NMR spectrum, δ, ppm (J, Hz): 4.51 (2H, s,
Starting 2-hydrazinyl-6Н-1,3,4-thiadiazines 6a–i were
obtained according to a published procedure.14
3
3
Synthesis of compounds 1a–i (General method).
Trifluoroacetic acid (1 ml, 13 mmol) was added dropwise
to a suspension of the appropriate 2-hydrazinyl-6Н-1,3,4-
thiadiazine hydrobromide 6a–i (2 mmol) in trimethyl
orthoformate or triethyl orthoacetate (36 mmol), and the
mixture was stirred for 12 h at room temperature. The
obtained precipitate was filtered off, washed with Et2O
(2×7 ml), and air-dried. Compound 1d was isolated by
evaporation of the reaction mixture at reduced pressure,
followed by treatment with diethyl ether (10 ml) and
additional crystallization from EtOH. Compound 1h was
isolated by evaporation of the reaction mixture at reduced
pressure followed by treatment with water (10 ml) and
CH2); 8.20 (2H, d, J = 8.8, H Ar); 8.38 (2H, d, J = 8.8,
H Ar); 9.21 (1H, s, CH). 13C NMR spectrum, δ, ppm: 23.8;
124.0; 128.7; 139.2; 140.1; 143.2; 149.1; 153.9. Found, m/z:
262.0391 [M+H]+. C10H8N5O2S. Calculated, m/z: 262.0398.
6-Phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine
(1d). Yield 0.29 g (68%), beige powder, mp 120–121°С
(EtOH) (mp 122–124°С18), Rf 0.56 (CHCl3–EtOAc, 3:2).
IR spectrum, ν, cm–1: 3128, 3064, 1481, 1450, 1283, 1182,
939, 773. 1H NMR spectrum, δ, ppm (J, Hz): 4.44 (2H, s,
CH2); 7.53–7.61 (3H, m, H Ph); 7.97 (2H, d, 3J = 7.1, H Ph);
9.14 (1H, s, CH). 13C NMR spectrum, δ, ppm: 23.7; 127.3;
129.0; 131.9; 133.3; 140.2; 143.0; 155.5. Found, m/z:
217.0543 [M+H]+. C10H9N4S. Calculated, m/z: 217.0542.
671

Chemistry of Heterocyclic Compounds 2018, 54(6), 669–672
(72%), orange crystals, mp 236–237°С (EtOH), Rf 0.22
6-(4-Bromophenyl)-3-methyl-7H-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazine (1е). Yield 0.56 g (93%), cream-colored
powder, mp 228–229°С (mp 225–227°С18), Rf 0.16
(CHCl3). IR spectrum, ν, cm–1: 1584, 1400, 1189, 1129,
(CHCl3). IR spectrum, ν, cm–1: 2876, 1589, 1514, 1447,
1
1339, 1053, 999, 843. H NMR spectrum, δ, ppm (J, Hz):
4.00 (2H, s, CH2); 7.67 (2H, d, 3J = 7.1, H Ar); 7.77 (2H, d,
3J = 7.1, H Ar); 7.98 (2H, d, J = 8.2, H Ar); 8.27 (2H, d,
1
3
1076, 1005, 721. H NMR spectrum, δ, ppm (J, Hz): 2.49
3
(3H, s, CH3); 4.37 (2H, s, CH2); 7.80 (2H, d, J = 8.4,
3J = 8.2, H Ar); 8.46 (1H, s, CH); 11.86 (1H, s, NH).
13C NMR spectrum, δ, ppm: 27.5; 129.1; 129.9; 133.8; 137.6;
139.9; 147.2; 151.6; 153.5; 156.5; 169.5. Found, %:
С 46.16; H 2.80; N 16.59. С16H12BrN5O2S. Calculated, %:
С 45.95; H 2.89; N 16.74.
3
H Ar); 7.97 (2H, d, J = 8.4, H Ar). 13C NMR spectrum,
δ, ppm: 9.7; 22.7; 125.6; 129.3; 132.0; 132.6; 140.0; 150.5;
154.0. Found, m/z: 310.9793 [M(81Br)+H]+, 308.9804
[M(79Br)+H]+. C11H10BrN4S. Calculated, m/z: 310.9789
(81Br), 308.9809 (79Br).
A Supplementary information file containing 1Н and 13
С
3-Methyl-6-(3-nitrophenyl)-7H-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazine (1f). Yield 0.44 g (84%), yellow
powder, mp 208–209°С (mp 210–211°С22), Rf 0.13
(EtOAc). IR spectrum, ν, cm–1: 1518, 1476, 1453, 1348,
1150, 855. 1H NMR spectrum, δ, ppm (J, Hz): 2.51 (3H, s,
NMR spectra of all obtained compounds is available at the
journal website at http://link.springer.com/journal/10593.
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3
CH3); 4.48 (2H, s, CH2); 7.88 (1H, t, J = 7.7, H Ar); 8.50
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148.2; 150.6; 152.9. Found, m/z: 276.0551 [M+H]+.
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1302, 1004, 760. H NMR spectrum, δ, ppm: 2.48 (3H, s,
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beige powder, mp 158–159°С, Rf 0.38 (CHCl3–EtOAc,
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1
1046, 856. H NMR spectrum, δ, ppm: 2.39 (3H, s, CH3);
4.47 (2H, s, CH2); 9.25 (1H, s, CH). 13C NMR spectrum,
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1
1232, 1186, 1153, 992, 941, 911, 723. H NMR spectrum,
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2 mmol) in MeCN (10 ml), and the mixture was stirred at
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