Efficient and convenient protocol for the synthesis of novel 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines

Article abstract of DOI:10.1080/00397910903261387

The novel triazolothiadiazine analogs 5a-p were obtained via a multistep synthetic sequence beginning with 5-substituted 4-amino-1,2,4-triazole-3-thiols 1. Compound 1, in reaction with various aromatic aldehydes 2 in acetic acid, afforded Schiff bases 3a-

Full text of DOI:10.1080/00397910903261387

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Efficient and Convenient Protocol for the
Synthesis of Novel 1,2,4-Triazolo[3,4-b]
[1,3,4]Thiadiazines
Naser Foroughifar a b , Akbar Mobinikhaledi b & Sattar Ebrahimi b
a Faculty of Chemistry, Islamic Azad University, North Tehran Branch,
Tehran, Iran
b Department of Chemistry, Faculty of Sciences, Arak University,
Arak, Iran
Version of record first published: 26 Jul 2010.
To cite this article: Naser Foroughifar, Akbar Mobinikhaledi & Sattar Ebrahimi (2010): Efficient and
Convenient Protocol for the Synthesis of Novel 1,2,4-Triazolo[3,4-b][1,3,4]Thiadiazines, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:16, 2421-2428
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Synthetic Communications1, 40: 2421–2428, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903261387
EFFICIENT AND CONVENIENT PROTOCOL
FOR THE SYNTHESIS OF NOVEL
1,2,4-TRIAZOLO[3,4-b][1,3,4]THIADIAZINES
Naser Foroughifar,1,2 Akbar Mobinikhaledi,2 and
Sattar Ebrahimi2
1Faculty of Chemistry, Islamic Azad University, North Tehran Branch,
Tehran, Iran
2Department of Chemistry, Faculty of Sciences, Arak University, Arak, Iran
The novel triazolothiadiazine analogs 5a–p were obtained via a multistep synthetic sequence
beginning with 5-substituted 4-amino-1,2,4-triazole-3-thiols 1. Compound 1, in reaction
with various aromatic aldehydes 2 in acetic acid, afforded Schiff bases 3a–p. Cyclization
of 3a–p with ethyl chloroacetate 4 in the presence of sodium hydride at room temperature
gave triazolothiadiazines 5a–p in good yields.
Keywords: Schiff-base; 1,2,4-triazole; triazolothiadiazine
INTRODUCTION
Heterocyclic compounds are rich sources of diverse physical, chemical, and
biological properties.[1] They are commonly used as templates to design biologically
active agents[2,3] in medicinal chemistry. Moreover, in the past 20 years, the
drug-discovery process has undergone extraordinary changes, and high-throughput
biological screening of potential drug candidates has led to an ever-increasing
demand for novel drug-like compounds. In the past few decades, the chemistry of
1,2,4-triazoles and their fused heterocyclic derivatives have received considerable
attention as a result of their synthetic and effective biological importance. 1,2,4-Tria-
zole moieties have been incorporated into a wide variety of therapeutically interest-
ing drug candidates including anti-inflammatories, central nervous system
stimulants, sedatives, anti-anxiety compounds, and antimicrobial agents.[4–6] In
addition, some s-triazolo[3,4-b]-[1,3,4]thiadiazines are reported to have antidepres-
sant,[7] fungicidal, anticancer,[8] and antiviral[9] activities.
The triazole fused six-membered ring system also has diverse applications in
the field of medicine. The commonly known systems are triazoles fused with pyri-
dines,[10] pyridazines,[11] pyrazines,[12] imidazoles,[13] pyrimidines, and triazines.[14]
A literature survey reveals that there are not many examples of triazoles fused with
Received June 5, 2009.
Address correspondence to Naser Foroughifar, Faculty of Chemistry, Islamic Azad University,
North Tehran Branch, Tehran, Iran. E-mail: n_foroughifar@yahoo.com
2421

2422
N. FOROUGHIFAR, A. MOBINIKHALEDI, AND S. EBRAHIMI
thiadiazines. Those incorporating the N-C-S linkage as in the skeleton of
1,2,4-triazolo[3,4-b][1,3,4]thiadiazine exhibit a broad spectrum of biological activity.
Various methods are available for the construction of 1,2,4-triazolo[3,4-b]-
[1,3,4]thiadiazine. Recently, Vainilavicius et al. used ethyl chlroacetate and 5-substi-
tuted 4-amino-1,2,4-triazole-3-thione for the synthesis of triazolo thiadiazine.[15]
Some other routes have been also reported for the synthesis of triazolothiadiazines,
include the reactions of 5-substituted-4-amino-1,2,4-triazole-3-thione with (a)
phenacyl bromides,[16,17] (b) substituted a-bromo-2-propen-1-one,[18] and (c) oxalyl
chloride.[19] However, these methodologies suffer from one or more disadvantages
such as poor yield, lack of availability and difficult preparation of the starting
materials, and harsh reaction conditions.
RESULTS AND DISCUSSION
In continuation of our effort to develop the synthesis of new fused heterocyclic
derivatives,[20,21] we report herein a simple and efficient method for the synthesis of sub-
stituted triazolo[3,4-b][1,3,4]thiadiazines 5a–p for the first time. Our synthetic app-
roaches are depicted in Figures 1 and 2. The required 4-amino-5-aryl substituted-3-
mercapto-1,2,4-triazoles 1 were prepared in good yields through a multistep reaction
using the method of Reid and Heindel.[22] The synthesis of 4-(substituted-
benzylideneamino)-5-aryl-4H-1,2,4-triazole-3-thiols 3a–p were accomplished in a sin-
gle step by reacting 4-amino-5-aryl substituted-3-mercapto-1,2,4-triazoles with various
aromatic aldehydes in refluxing acetic acid initially (Figure 1). The reaction conditions
between Schiff base 3a and ethyl chloroacetate 4 in dried tetrahydrofuran (THF) was
examined (Figure 2). Reaction of compound 3a (1.0 equiv) with 1.0 equiv of compound
4 and 2.0 equiv of NaH in THF at room temperature gave the desired product 5a in
30% yield (Table 1, entry 1).
Optimization of the reaction conditions was carried out. Different ratios of
starting materials were compared, and the ratio 1:1.4 (3a/4) was favored (Table 1,
entry 4). With the optimized condition in hand, the scope of the reaction was inves-
tigated, and the typical results are summarized in Table 2.
Compounds 3a–p were used as key intermediates for the synthesis of novel tria-
zolothiadiazine derivatives. Sodium hydride was added to a solution of compounds
3a–p in dry THF. Salt formation was allowed to proceed, and the resulting salt was
Figure 1. Synthesis of 4-(substituted-benzylideneamino)-5-aryl-4H-1,2,4-triazole-3-thiols 3a–p.

SYNTHESIS OF TRIAZOLOTHIADIAZINES
2423
Figure 2. Synthesis of 5a–p.
Table 1. Optimization of conditions for the synthesis of triazolothia-diazine 5a
Entry
Base
3a=4
Yields (%)a
1
2
3
4
5
NaH
NaH
NaH
NaH
NaH
1:1
30
52
40
74
74
1:1.2
1:1.3
1:1.4
1:1.5
aIsolated yields.
Table 2. Synthesis of compounds 3a–p and 5a–p
Yields (%)a
Entry
Ar
X
3
5
a
b
c
d
e
f
4-Pyridyl
3-Pyridyl
4-Pyridyl
3-Pyridyl
4-Pyridyl
3-Pyridyl
4-Pyridyl
3-Pyridyl
4-Pyridyl
3-Pyridyl
4-Pyridyl
3-Pyridyl
4-Pyridyl
3-Pyridyl
4-Pyridyl
3-Pyridyl
H
70
60
71
65
68
65
58
64
60
50
75
75
85
80
85
83
74
70
68
70
75
75
65
70
65
60
70
75
78
81
81
80
H
4-Me
4-Me
4-OMe
4-OMe
3-Br
g
h
i
3-Br
2-Cl
j
2-Cl
4-Cl
k
l
4-Cl
m
n
o
P
2-NO2
2-NO2
4-NO2
4-NO2
aIsolated yields.

2424
N. FOROUGHIFAR, A. MOBINIKHALEDI, AND S. EBRAHIMI
reacted with ethyl chloroacetate at room temperature to give the triazolothiadiazines
5a–p as shown in Figure 2. The isolated compounds were obtained as cis-diastereo-
mers. The stereochemistry of the products was determined by the coupling constant
1
between two vicinal methine protons. In the H NMR spectra of compounds 5a–p,
the coupling constant (3JN-CH, CH-S ꢀ 4.3–7.0 Hz) is a typical for the cis configur-
ation. The purity of compounds was checked on thin-layer chromatography
(TLC) in the solvent system ethanol=n-hexane (1:2).
1
The H NMR spectra of the Schiff bases 3a–p showed a broad signal at the
=
region d ¼ 9.41–9.82 ppm attributed to the resonance of the CH N proton, which
was not present in the spectra of compounds 5a–p. The appearance of the infrared
(IR) absorptions and 1H NMR signals due to the NH group of synthesized
compounds 5a–p clearly confirmed the formation of triazolothiadiazines.
CONCLUSION
In conclusion, a novel and efficient methodology was reported for the synthesis
of triazolothiadiazines by reaction of Schiff bases and ethyl chloroacetate. In
addition to the efficiency and simplicity provided, this protocol describes good yields
of cyclization and simple purification for these products.
EXPERIMENTAL
General Procedures
1
All products were characterized using IR, H NMR, and 13C NMR spectra as
well as the elemental analysis data. All yields refer to isolated products. IR spectra
were prepared on a Galaxy series Fourier transform (FT)–IR 5000 spectrophoto-
meter using KBr discs. NMR spectra were recorded on a Brucker spectrophotometer
(300 MHZ) in dimethylsulfoxide (DMSO-d6) using tetramethylsilane (TMS) as an
internal standard. Elemental analyses were performed on a Vario EL III elemental
analyzer.
General Procedure for the Synthesis of Schiff Bases 3a–p
Aromatic aldehydes 2 (5.0 mmol) was added to a solution of aminotriazoles 1
(5.0 mmol) in glacial acetic acid (25 ml), and the mixture was refluxed for 3 h. After
cooling, the mixture was poured into ice-water (50 ml). The resulting precipitate was
filtered and recrystallized from an appropriate solvent to give the desired compounds
3a–p.
Selected Characterization Data
3-(4-Methylbenzylideneamino)-5-(pyridin-3-yl)-4H-1,2,4-triazole-3-thiol
=
(3d). IR (KBr) nmax: 3119 (CH N) 3064 (aromatic CH stretch.), 2712 (SH stretch.),
1602 (C N), 1508, 1419 (C C ring stretch.) cmꢁ1; 1H NMR (300 MHz, DMSO-d6)
=
=
=
d (ppm): 14.37 (s, 1H, SH), 9.71 (s, 1H, CH N), 9.03 (s, 1H, Harom.), 8.72 (s, 1H,
H
arom.), 8.25 (d, 1H, J ¼ 7.6 Hz, Harom.), 7.78 (d, 2H, J ¼ 5.6 Hz, Harom.), 7.58 (br,

SYNTHESIS OF TRIAZOLOTHIADIAZINES
2425
1H, Harom.), 7.38 (d, 2H, J ¼ 6.0 Hz, Harom.), 2.38 (s, 3H, CH3);13C NMR (75 MHz,
DMSO d6) d (ppm): 21.8, 122.5, 124.2, 129.2, 129.6, 130.3, 136.3, 143.9, 147.1, 149.1,
151.7, 162.9, 167.0. Calcd. for C15H13N5S 61.00: H, 4.44; N, 23.71; S, 10.86%.
Found: C, 59.85; H, 4.36; N, 23.53; S, 10.69%.
4-(4-Methoxybenzylideneamino)-5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiol
=
(3e). IR (KBr) nmax: 3124 (CH N) 3070 (aromatic CH stretch.), 2720 (SH stretch.),
=
=
1603 (C N), 1514, 1433 (C C ring stretch.), 1257 (Ph-O stretch.), 1165 (C-O
1
stretch.) cmꢁ1; H NMR (300 MHz, DMSO d6) d (ppm): 14.48 (s, 1H, SH), 9.53
=
(s, 1H, CH N), 8.74 (d, 2H, J ¼ 6.0 Hz, Harom.), 7.87 (br, 4H, Harom.), 7.12 (d,
2H, J ¼ 7.1 Hz, Harom.), 3.85 (s, 3H, OCH3);13C NMR (75 MHz, DMSO d6) d
(ppm): 56.1, 115.3, 122.1, 124.7, 131.4, 133.3, 146.8, 150.8, 163.4, 164.4, 167.4. Calcd.
for C15H13N5OS: C, 57.86; H, 4.21; N, 22.49; S, 10.30%. Found: C, 57.72; H, 4.13;
N, 22.24; S, 10.14%.
General Procedure for the Synthesis of Compounds 5a–p
Sodium hydride (2.0 mmol) was added to a solution of compounds 3a–p
(1.0 mmol) in dry THF (20 mL) at room temperature. Salt formation was allowed
to proceed at ambient temperature for 10 min. Ethyl chloroacetate (1.4 mmol) was
then added, and the solution was stirred for 8 h. The solvent was removed under
vacuum and extracted with ethyl acetate; the organic layer was washed with water
(3 ꢂ 10 mL), dried (Na2SO4), and evaporated under vacuum. The residue was crys-
tallized, from ethyl acetate and petroleum ether to give triazolothiadiazines 5a–p.
Selected Characterization Data
Ethyl-6-phenyl-3-(4-pyridyl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazine-7-carboxylate (5a). IR (KBr) nmax: 3248 (NH stretch.), 2978 (ali-
=
=
=
phatic CH stretch.) 1714 (C O), 1602 (C N), 1514, 1481 (C C ring stretch.),
1
1190 (C-O) cmꢁ1; H NMR (300 MHz, DMSO d6) d (ppm): 8.72 (d, 2H, J ¼ 5.0 Hz,
H
arom.), 8.03 (s, 2H, Harom.), 7.55 [s, 1H, NH, (D2O exchange)], 7.33–7.40 (m,
5H, Harom), 4.99 (d, 1H, J ¼ 4.3 Hz, CH), 4.90 (d, 1H, J ¼ 4.6 Hz, CH), 4.10 (q,
2H, J ¼ 5.9 Hz, OCH2), 1.09 (t, 3H, J ¼ 6.3 Hz, CH3,); 13C NMR (75 MHz, DMSO
d6) d (ppm): 14.1, 43.6, 59.2, 62.5, 121.3, 127.7, 128.8, 129.2, 133.7, 136.6, 143.7,
150.1, 150.7, 169.3. Calcd. for C18H17N5O2S: C, 58.84; H, 4.66; N, 19.06; S,
8.73%. Found: C, 58.61; H, 4.57; N, 18.91; S, 8.56%.
Ethyl-6-(4-methylphenyl-3-(4-pyridyl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazine-7-carboxylate (5c). IR (KBr) nmax: 3244 (NH stretch.), 3067
=
=
(aromatic CH stretch.), 2976 (aliphatic CH stretch.) 1726 (C O), 1601 (C N),
1
1530, 1475 (C C ring stretch.), 1185 (C-O) cmꢁ1; H NMR (300 MHz, DMSO d6)
=
d (ppm): 8.73 (d, 2H, J ¼ 4.1 Hz, Harom.), 8.03 (d, 2H, J ¼ 4.0 Hz, Harom.), 7.45 [s,
1H, NH, (D2O exchange)], 7.28 (d, 2H, J ¼ 7.6 Hz, Harom.), 7.15 (d, 2H, J ¼ 7.4 Hz,
H
arom.), 4.91 (d, 1H, J ¼ 7.1 Hz, CH), 4.86 (d, 1H, J ¼ 6.8 Hz, CH), 4.10 (q, 2H,
J ¼ 6.9 Hz, OCH2), 2.26 (s, 3H, CH3), 1.09 (t, 3H, J ¼ 7.0 Hz, CH3); 13C NMR
(75 MHz, DMSO d6) d (ppm): 14.2, 21.1, 43.6, 59.0, 62.5, 121.3, 127.6, 129.7,

2426
N. FOROUGHIFAR, A. MOBINIKHALEDI, AND S. EBRAHIMI
133.5, 138.2, 143.7, 150.1, 150.6, 169.2. Calcd. for C19H19N5O2S: C, 59.82; H, 5.02;
N, 18.36; S, 8.41. Found: C, 59.61; H, 4.94; N, 18.18; S, 8.14%.
Ethyl-6-(4-methylphenyl-3-(3-pyridyl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazine-7-carboxylate (5d). IR (KBr) nmax: 3243 (NH stretch.), 3070
=
=
(aromatic CH stretch.), 2974 aliphatic CH stretch.), 1716 (C O), 1600 (C N),
1
1530, 1481 (C C ring stretch.), 1184 (C-O) cmꢁ1; H NMR (300 MHz, DMSO d6)
=
d (ppm): 9.15 (s, 1H, Harom), 8.67 (s, 1H, Harom), 8.35 (d, 1H, J ¼ 6.4 Hz, Harom.),
7.55 (br, 1H, Harom.), 7.40 [br, 1H, NH, (D2O exchange)], 7.26 (d, 2H, J ¼ 6.5 Hz,
H
arom.), 7.16 (d, 2H, J ¼ 6.3 Hz, Harom.), 4.90 (d, 1H, J ¼ 6.8 Hz, CH), 4.85 (d,
1H, J ¼ 6.4 Hz, CH), 4.10 (q, 2H, J ¼ 7.1 Hz, OCH2), 2.25 (s, 3H, CH3) 1.10 (t,
3H, J ¼ 6.8 Hz, CH3); 13C NMR (75 MHz, DMSO d6) d (ppm): 14.2, 21.1, 43.8,
59.2, 62.4, 123.0, 124.2, 127.6, 129.7, 133.5, 135.2, 138.3, 142.9, 148.4, 150.3,
151.0, 169.2. Calcd. for C19H19N5O2S: C, 59.82; H, 5.02; N, 18.36; S, 8.41. Found:
C, 59.71; H, 4.95; N, 18.22; S, 8.20%.
Ethyl-6-(4-methoxyphenyl-3-(4-pyridyl)-6,7-dihydro-5H-[1,2,4]triazolo
[3,4-b][1,3,4]thiadiazine-7-carboxylate (5e). IR (KBr) nmax: 3246 (NH stretch.)
=
=
3067 (aromatic CH stretch.), 2978 aliphatic CH stretch.), 1720 (C O), 1597 (C N),
=
1531, 1475 (C C ring stretch.), 1190 (C-O) cmꢁ1; 1H NMR (300 MHz, DMSO d6) d
(ppm): 8.72 (d, 2H, J ¼ 4.0 Hz, Harom.), 8.02 (d, 2H, J ¼ 3.9 Hz, Harom.), 7.45 [s, 1H,
NH, (D2O exchange)], 7.34 (d, 2H, J ¼ 7.8 Hz, Harom.), 6.91 (d, 2H, J ¼ 7.4 Hz,
H
arom.), 4.91 (d, 1H, J ¼ 6.5 Hz, CH), 4.84 (d, 1H, J ¼ 6.6 Hz, CH), 4.10 (q, 2H,
J ¼ 6.0 Hz, OCH2), 3.79 (s, 3H, OCH3), 1.09 (t, 3H, J ¼ 5.9 Hz, CH3); 13C NMR
(75 MHz, DMSO d6) d (ppm): 14.2, 43.7, 55.6, 58.8, 62.4, 114.5, 121.3, 128.3,
129.0, 133.8, 143.7, 150.1, 150.7, 159.6, 169.2. Calcd. for C19H19N5O3S: C, 57.42;
H, 4.82; N, 17.62; S, 8.07%. Found: C, 57.21; H, 4.76; N, 17.46; S, 7.94%.
Ethyl-6-(4-chlorophenyl-3-(3-pyridyl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazine-7-carboxylate (5l). IR (KBr): nmax: 3230 (NH stretch.), 3084
=
=
(aromatic CH stretch.), 2980 aliphatic CH stretch.), 1730 (C O), 1606 (C N),
1
1516, 1450 (C C ring stretch.), 1195 (C-O) cmꢁ1; H NMR (300 MHz, DMSO d6)
=
d (ppm): 9.16 (s, 1H, Harom), 8.67 (s, 1H, Harom), 8.36 (d, 1H, J ¼ 7.4 Hz, Harom.),
7.58 [s, 1H, NH, (D2O exchange)], 7.56 (s, 1H, Harom), 7.43 (s, 4H, Harom.), 4.99
(d, 1H, J ¼ 6.8 Hz, CH), 4.92 (d, 1H, J ¼ 6.4 Hz, CH), 4.10 (q, 2H, J ¼ 6.9 Hz,
OCH2), 1.11 (t, 3H, J ¼ 6.9 Hz, CH3); 13C NMR (75 MHz, DMSO d6) d (ppm):
14.2, 43.6, 58.8, 62.4, 123.0, 124.2, 129.2, 129.7, 133.6, 135.2, 135.7, 142.8, 148.4,
150.3, 151.0, 169.1. Calcd. for C18H16ClN5O2S: C, 53.80; H, 4.01, N, 17.43; S,
7.98%. Found: C, 53.55; H, 3.92; N, 17.29; S, 7.81%.
Ethyl-6-(2-nitrophenyl-3-(4-pyridyl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazine-7-carboxylate (5m). IR (KBr) nmax: 3235 (NH stretch.), 3070
=
=
(aromatic CH stretch.), 2982 (aliphatic CH stretch.), 1732 (C O), 1604 (C N),
1
1531, 1359 (NO2), 1186 (C-O) cmꢁ1; H NMR (300 MHz, DMSO d6) d (ppm):
8.69 (d, 2H, Harom, J ¼ 5.4 Hz), 7.94 [s, 1H, NH, (D2O exchange)], 7.89 (d, 2H,
J ¼ 5.0 Hz, Harom), 7.74–7.66 (m, 4H, Harom.), 5.50 (d, 1H, J ¼ 6.8 Hz, CH), 5.05
(d, 1H, J ¼ 6.6 Hz, CH), 4.11 (q, 2H, J ¼ 6.7 Hz, OCH2), 1.11 (t, 3H, J ¼ 6.6 Hz,
CH3); 13C NMR (75 MHz, DMSO d6) d (ppm): 14.1, 43.5, 55.1, 62.8, 121.0, 125.6,
128.4 129.0, 130.6, 133.4, 134.0, 144.5, 149.1, 150.1, 150.6, 168.8. Calcd. for

SYNTHESIS OF TRIAZOLOTHIADIAZINES
2427
C18H16N6O4S: C, 52.42; H, 3.91; N, 20.38; S, 7.77%. Found: C, 52.21; H, 3.79; N,
20.20; S, 7.58%.
ACKNOWLEDGMENT
We gratefully acknowledge the financial support from the Research Council of
Arak University.
REFERENCES
1. Balaban, A. T.; Oniciu, D. C.; Katritzky, A. R. Aromaticity as a cornerstone of
heterocyclic chemistry. Chem. Rev. 2004, 104, 2777–2812.
2. Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Heterocycles in Life and Society;
John Wiley-VCH: New York, 1997.
3. Myong, J.; Soon, Y. C.; Moon, W. C. Synthesis and biological evaluation of novel
isonucleosides with 1,2,4-triazole-3-carboxamide. Synth. Commun. 2005, 35, 2653–2663.
4. Jagadeesh, D. P.; Mithun, A.; Prakash, K.; Boja, P.; Shivarama, B. H.; Sucheta, N. K.
Synthesis and antimicrobial activities of some new triazolothiadiazoles bearing
4-methylthiobenzyl moiety. Eur. J. Med. Chem. 2009, 44, 551–557.
5. Holla, B. S.; Kalluraya, B.; Sridhar, K. R.; Drake, E.; Thomas, L. M.; Bhandary, K. K.;
Levine, M. J. Synthesis, structural characterization, crystallographic analysis, and anti-
bacterial properties of some nitrofuryl triazolo[3,4-b]-1,3,4-thiadiazines. Eur. J. Med.
Chem. 1994, 29, 301–308.
6. Mathew, V.; Keshavayya, J.; Vidya, V. P. Heterocyclic system containing bridgehead
nitrogen atom: Synthesis and pharmacological activities of some substituted
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles. Eur. J. Med. Chem. 2006, 41, 1048–1058.
7. Brucato, A.; Coppola, A.; Gianguzza, S.; Provenzano, P. M. Triazolam: Characteristics of
its depressive action [Triazolam: caratteristiche dell’azione depressiva. Boll. Soc. Ital. Biol.
Sper. 1978, 54, 1051–1057.
8. Shivarama, H. B.; Sooryanarayana, R. B.; Sarojini, B. K.; Akberali, P. M.; Suchetha, K. N.
Synthesis and studies on some new fluorine containing triazolothiadiazines as possible anti-
bacterial, antifungal and anticancer agents. Eur. J. Med. Chem. 2006, 41, 657–663.
9. Shivarama, H. B.; Akberali, P. M.; Shivananda, M. K. Studies on nitrophenylfuran
derivatives, part XII: Synthesis, characterization, antibacterial and antiviral activities of
some nitrophenylfurfurylidene-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines. Farmaco 2001, 56,
919–927.
10. Sadana, A. K.; Mirza, Y.; Aneja, K. R.; Prakash, O. Hypervalent iodine–mediated
synthesis of 1-aryl=hetryl-1,2,4-triazolo[4,3-a] pyridines and 1-aryl=hetryl 5-methyl-
1,2,4-triazolo[4,3-a]quinolines as antibacterial agents. Eur. J. Med. Chem. 2003, 38,
533–538.
11. Bussolari, J. C.; Panzica, R. P. Synthesis and anti-HIV evaluation of 20,30-dideoxy
imidazo- and n-triazolo[4,5-d]pyridazine nucleosides. Bioorg. Med. Chem. 1999, 7,
2373–2379.
12. Yao, G.; Haque, S.; Sha, L.; Kumaravel, G.; Wang, J.; Engber, T. M.; Whalley, E. T.;
Conlon, P. R.; Chang, H.; Kiesman, W. F.; Petter, R C. Synthesis of alkyne derivatives
of a novel triazolopyrazine as A 2A adenosine receptor antagonists. Bioorg. Med. Chem.
Lett. 2005, 15, 511–515.
13. Neochoritis, C.; Tsoleridis, C. A.; Stephanidou, J. S. 1-Arylaminoimidazole-2-thiones as
intermediates in the synthesis of imidazo[2,1-b][1,3,4]thiadiazines. Tetrahedron 2008, 64,
3527–3533.

2428
N. FOROUGHIFAR, A. MOBINIKHALEDI, AND S. EBRAHIMI
14. Vu, C. B.; Shields, P.; Peng, B.; Kumaravel, G.; Jin, X.; Phadke, D.; Wang, J.; Engber, T.;
Ayyub, E.; Petter, R. Triamino derivatives of triazolotriazine and triazolopyrimidine as
adenosine A2a receptor antagonists C. Bioorg. Med. Chem. Lett. 2004, 14, 4835–838.
15. Vainilavicius, P.; Smicius, R.; Jakubkiene, V.; Tumkevicius, S. Synthesis of 5-(6-methyl-
2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-4-amino-1,2,4-triazole-3-thione and
its reactions with polyfunctional electrophiles. Monatsh. Chem. 2001, 132, 825–831.
16. Karegoudar, P.; Prasad, D. J.; Manjathuru, M.; Ashok, M.; Poojary, B.; Holla, B. S. Syn-
thesis, antimicrobial, and anti-inflammatory activities of some 1,2,4-triazolo[3,4-b][1,3,4]-
thiadiazoles and 1,2,4-triazolo [3,4-b][1,3,4]thiadiazines bearing trichlorophenyl moiety.
Eur. J. Med. Chem. 2008, 43, 808–815.
17. Kaplancıklı, Z. A.; Zitouni, G. T.; Ouzdemir, A.; Revial, G. New triazole and triazo-
lothiadiazine derivatives as possible antimicrobial agents. Eur. J. Med. Chem. 2008, 43,
155–159.
18. Holla, B. S.; Sarojini, B. K.; Rao, B. S.; Akberali, P. M.; Kumari, N. S.; Shetty, V. Syn-
thesis of some halogen-containing 1,2,4-triazolo-1,3,4-thiadiazines and their antibacterial
and anticancer screening studies. Farmaco 2001, 56, 565–570.
19. Ghorab, M. M.; El-Sharief, A. M. S.; Ammar, Y. A.; Mohamed, S. I. Synthesis and
radiation stability of novel biologically active sulfur compounds derived from
1,2-bis(4-amino-5-mercapto-s-triazol-3-yl)ethane. Farmaco 2000, 55, 354–361.
20. Foroughifar, N.; Mobinikhaledi, A.; Ebrahimi, S.; Moghanian, H.; Bodaghi Fard, M. A.;
Kalhor, M. Synthesis of a new class of azathia crown macrocycles containing two
1,2,4-triazole or 1,3,4-thiadiazole rings as subunits. Tetrahedron Lett. 2009, 50, 836–839.
21. Foroughifar, N.; Mobinikhaledi, A.; Ebrahimi, S. Synthesis of a novel class of aza crown
macrocycles and lariat crown ethers containing two 1,2,4-triazole rings as subunits.
Synthesis 2009, 15, 2557–2560.
22. Reid, R. J.; Heindel, D. N. Improved syntheses of 5-substituted-4-amino-
3-mercapto-(4H)-1,2,4-triazoles. J. Heterocycl. Chem. 1976, 13, 925–926.