Novel method for the synthesis of s -triazolo[3,4- b ][1,3,4]thiadiazines

Article abstract of DOI:10.1055/s-0030-1258153

The reaction of 4-amino-3-mercapto-5-phenyl-s-triazole with aromatic or aliphatic ketones containing active -hydrogens as a methyl or methylene group using an acidified acetic acid method afforded the corresponding s-triazolo[3,4-b][1,3,4]thiadiazines. In

Full text of DOI:10.1055/s-0030-1258153

2636
PAPER
Novel Method for the Synthesis of s-Triazolo[3,4-b][1,3,4]thiadiazines
N
ovel Synthesis of
a
s
-Triazolo
s
[3,4-
b
]
[1,
s
a
zine
s
n A. H. El-Sherief,* Zeniab A. Hozien, Ahmed F. M. El-Mahdy, Abdelwareth A. O. Sarhan
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
Fax +20(88)2342708; E-mail: dr_Hassanahmed@yahoo.com
Received 15 March 2010; revised 4 April 2010
ficult to obtain.29 The advantages of this method are short
reaction time, one-pot reaction, direct use of ketones with-
out the formation of highly toxic and irritating phenacyl
bromides, ease of handling, very inexpensive materials
Abstract: The reaction of 4-amino-3-mercapto-5-phenyl-s-triazole
with aromatic or aliphatic ketones containing active a-hydrogens as
a methyl or methylene group using an acidified acetic acid method
afforded the corresponding s-triazolo[3,4-b][1,3,4]thiadiazines. In a
similar way, applying the same reaction with cyclic ketones afford- and the ease of removal of the reaction waste by neutral-
ed the corresponding tricyclic compounds. Interaction of 4-amino-
3-mercapto-5-phenyl-s-triazole with chloroacetonitrile under the
same reaction conditions directly gave the cyclized 6-amino-s-tria-
and environmentally safe. In this work, we have tried to
zolo[3,4-b][1,3,4]thiadiazine derivative. On treatment of 4-amino-
3-mercapto-5-phenyl-s-triazole with acetonitrile or ethyl cyanoace-
ization of the liquor with ammonium hydroxide. We be-
lieve that this reaction can be considered a clean reaction
generalize this reaction to be much more effective and ap-
plicable for the synthesis of many substituted fused het-
erocycles which could not be obtained by other reported
methods.
tate under the same reaction conditions, an s-triazolo[3,4-
b][1,3,4]thiadiazole derivative was obtained; the reaction carried
out with malononitrile or cyanoacetamide gave an alternative s-tri-
azolo[3,4-b][1,3,4]thiadiazole derivative. The mechanism of the re-
actions was investigated and the structures of all new compounds
R3
R4
R1
R2
R2
R3
1
were elucidated using IR, H NMR, 13C NMR and mass spectro-
N
N
N
scopic data, and elemental analyses.
R1
S
S
N
N
Key words: a-hydrogens, ketones, nitriles, one-pot reaction, triaz-
olothiadiazines
1
2
Figure 1
The importance of s-triazolo[3,4-b][1,3,4]thiadiazines
lies in their possession of antibacterial and antifungal ac-
tivity.1–5 These compounds have shown analgesic,6 insec-
ticidal,7 antiviral,8,9 antiparasitic,10 diuretic,11 anti-
inflammatory,12 antitubercular,9 anticancer9,13,14 and
antioxidant15 activity. It has been reported that these com-
pounds have marked antidepressant,16 anthelmintic17 and
plant-growth-promoting effects.18 The synthesis of s-tria-
zolo[3,4-b][1,3,4]thiadiazines by reacting either 4-amino-
Interaction of 4-amino-3-mercapto-5-phenyl-s-triazole
(3) with aromatic or aliphatic ketones 4a–k containing an
active methyl or methylene group in boiling acetic acid in
the presence of sulfuric acid as a catalyst for 3 hours di-
rectly afforded an unexpected cyclized product which was
identified as the 3-phenyl-7H-s-triazolo[3,4-b][1,3,4]thia-
diazines 5a–k (Table 1). The reaction pathway is assumed
to involve S-alkylation to give a nonisolable intermediate,
followed by intramolecular cyclization to give 5a–k, or to
occur via the formation of imine followed by attack of
enamine on the disulfide intermediate.
3-mercapto-s-triazoles10,19–23
or
2-hydrazino-1,3,4-
thiadiazines24–26 as starting materials with a-halo carbonyl
compounds has been reported. The disadvantages of these
methods include the many steps, the long reaction times,
the use of highly toxic and irritating halo carbonyl com-
pounds, and the poor to moderate overall yields. Recently,
we have reported the synthesis of triazolo[1,3,5]thiadiaz-
ines via a double Mannich reaction.27,28 In the present
work we report a facile synthesis of s-triazolo[3,4-
b][1,3,4]thiadiazines, using our method that we previous-
ly applied for the synthesis of thiazoloimidazoles 1 and
thiazolotriazoles 2 (Figure 1),29–32 in short reaction time
and good reaction yields.
The structures of compounds 5a–k were assigned on the
1
basis of elemental analyses, and IR, H NMR, 13C NMR
and mass spectroscopic data. The IR spectra of com-
pounds 5a–k lacked NH2 and NH absorption bands, ex-
cept for 5f with bands at 3400 and 3200 (NH2) cm–1; all
compounds showed bands at 3074–3000 (C–H aromatic),
2997–2921 (C–H aliphatic) and 1695–1560 (C=N) cm–1,
as well as the aromatic skeleton bands at 1473–1418 cm–1.
Additionally, compounds 5g and 5j showed hydroxy and
carbonyl absorption bands at 3450 and 1707 cm–1, respec-
1
tively. The H NMR spectra of compounds 5a–i were
As we have previously described, an acidified acetic acid
method was generally applicable for the synthesis of var-
ious fused heterocyclic systems which had been found dif-
characterized by the appearance of a singlet signal at
d = 4.5–3.5 which is attributed to the methylene group,
while a signal which appeared at d = 4.2–3.8 for com-
pounds 5j and 5k is attributed to C–H, in addition to the
other protons at the expected chemical shifts. The 13C
NMR spectra of compounds 5g and 5i showed one signal
at d = 23.0 and 25.7, respectively, attributed to the meth-
SYNTHESIS 2010, No. 15, pp 2636–2642
x
x.
x
x
.
2
0
1
0
Advanced online publication: 07.07.2010
DOI: 10.1055/s-0030-1258153; Art ID: Z06710SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Table 1
Novel Method of s-Triazolo[3,4-b][1,3,4]thiadiazines
2637
It is noteworthy that the interaction of s-triazole 3 with
ethyl acetoacetate gave a product whose IR spectrum
lacked carbonyl group absorption bands, while its H
N
N
O
1
Ph
S
N
NMR spectrum showed aromatic protons at d = 7.45–8.1
(m, 5 H) and two singlet signals at d = 3.5 (s, 2 H, CH2)
and 2.25 (s, 3 H, CH3), but lacked the signals that are char-
acteristic for an ethyl group. The 13C NMR spectrum ex-
hibited signals at d = 156.4 (C6=N), 152.1 (C3), 141.4
(C9), 130.2 (CH-aromatic), 128.5 (2 CH-aromatic), 128.3
(CH-aromatic), 128.2 (CH-aromatic), 126.0 (C-aromatic),
25.7 (C7) and 23.9 (CH3). The mass spectrum showed the
molecular ion peak at m/z = 230 (100%). Based on the IR,
1H NMR and 13C NMR spectra, TLC, melting point and
mixed melting point with the product obtained from the
reaction of s-triazole 3 with acetone in boiling acidified
acetic acid, the reaction product 5i was identified as 6-me-
thyl-3-phenyl-7H-s-triazolo[3,4-b][1,3,4]thiadiazine.
This is explained as postulated in Scheme 1, via hydroly-
sis of the ester group followed by decarboxylation.
R2
NH2
R1
N
N
O
N
N
AcOH/H+
3 h
R2
Ph
+
S
N
N
R1
SH
Ph
N
R2
NH2
R1
5a–k
3
4a–k
N
N
N
N
N
N
SH
Ph
air
oxidation
R2
Ph
R2
S
S
Ph
N
N
N
HN
HN
HN
R2
R1
R1
R1
Furthermore, when alicyclic ketones such as cyclopen-
tanone, cyclohexanone, cycloheptanone and cyclooc-
tanone (6a–d) were allowed to react with s-triazole 3
under the same reaction conditions, the corresponding
fused tricyclic compounds 7a–d were obtained in high
yield (Scheme 2).
R1
R2
a
Ph
H
b
c
d
e
f
4-ClC6H4
4-BrC6H4
4-Tol
H
H
N
N
O
N
N
AcOH/H+
3 h
H
SH
Ph
+
Ph
N
S
N
4-MeOC6H4
4-H2NC6H4
4-HOC6H4
1-Naph
Me
H
NH2
n
N
3
6a–d
H
n
7a–d
g
h
i
H
a: n = 1; b: n = 2; c: n = 3; d: n = 4
H
Scheme 2
Ha
Ac
Me
The structures of tricyclic compounds 7a–d were con-
firmed on the basis of elemental analyses and spectro-
scopic data. The IR spectra of compounds 7a–d showed
bands at 3069–3020 (C–H aromatic), 2997–2850 (C–H al-
iphatic) and 1695–1612 (C=N) cm–1, along with the aro-
j
Me
k
Me
a For 4i, R2 = CO2Et.
1
matic skeleton bands at 1473–1456 cm–1. The H NMR
ylene group, in addition to the other carbons at the expect-
ed chemical shifts. The mass spectra of compounds 5c, 5g,
5h, 5i, 5j and 5k showed the expected molecular ion peaks
at m/z = 370, 308, 342, 230, 272 and 244, respectively,
each peak with 100% intensity. Further, the melting points
of the previously reported compounds10 were in agree-
ment with those obtained from the compounds using our
synthetic method.
spectra of these compounds were characterized by the ap-
pearance of a triplet signal at d = 4.0–3.85 which is attrib-
uted to the cyclic CH and multiple signals at d = 3.0–1.2
attributable to the cyclic CH2 groups, in addition to the
other protons at the expected chemical shifts. The 13C
NMR spectra of compounds 7a, 7c and 7d in CDCl3
showed signals at d = 39.49–36.68 attributed to the cyclic
N
N
N
N
N
N
N
N
Ph
Ph
hydrolysis
Ph
Ph
S
N
N
S
N
N
S
N
S
N
– H+
– AcOH
COOEt
– CO2
COOH
N
NH2
AcO
+
COOEt
5i
Scheme 1
Synthesis 2010, No. 15, 2636–2642 © Thieme Stuttgart · New York

2638
H. A. H. El-Sherief et al.
PAPER
CH and at d = 36.17–21.22 attributed to the cyclic CH2 uted to the amino group and at d = 3.9 attributed to the
groups, in addition to the other carbons at the expected methylene group, while the mass spectrum showed the ex-
chemical shifts. The mass spectra of compounds 7a–d pected molecular ion peak at m/z = 231 (54%). In addi-
showed the molecular ion peaks [M+], [M+ + 1] and [M+ + tion, the structure of 5l was in agreement with authentic
2].
compound prepared by an unequivocal method.22 The
overall yield of compound 5l using the reported method
was 25%, but the yield obtained using our method was
found to be 70%.
The mechanism of these reactions is still under investiga-
tion. The S-alkylation may proceed via formation of the
disulfide 8 followed by nucleophilic attack by a-aryl/
alkyl-a-hydroxymethylene carboxylates (formed by ester- Furthermore, treatment of s-triazole 3 with acetonitrile
ification of the enol forms) to give the carbonium ions 9, (11a) or ethyl cyanoacetate (11b) under the same reaction
which undergo intramolecular cyclization to directly pro- conditions gave the s-triazolo[3,4-b][1,3,4]thiadiazole de-
duce the cyclized compounds (Scheme 3).
rivative 12a, while on using malononitrile (11c) or
cyanoacetamide (11d), the s-triazolo[3,4-b][1,3,4]thiadia-
zole derivative 12b was isolated (Scheme 5).
H+
N
N
N
N
N
N
AcOH/H+
Ph
N
N
N N
SH
Ph
Ph
N
S
S
N
N
NH2
AcOH/H+
reflux, 3 h
NH2
3
Ph
SH
+
RCH2CN
Ph
NH2
N
N
S
8
NH2
N
O
H+
AcO
R1
CH2R
R2
3
11
a: R = H
b: R = CO2Et
c: R = CN
d: R = CONH2
12
a: R = H
b: R = CONH2
R1
R2
N
N
N
N
HN
N
– H+
Scheme 5
Ph
S
+
Ph
N
Ph
S
R2
N
N
S
N
NH2
AcO
+
NH2
R2
The structures of compounds 12a and 12b were confirmed
on the basis of elemental analyses, and IR, 1H NMR, 13
H
R1
..
AcO R1
3
C
..
9
H+
NMR and mass spectroscopic data. The IR spectra of
compounds 12a and 12b lacked a CN absorption band and
showed bands at 3050–3010 (C–H aromatic), 2920–2900
(C–H aliphatic) and 1600–1540 (C=N) cm–1, while com-
pound 12b additionally showed bands at 3400–3150 cm–1
attributed to the NH2 group and for the amidic carbonyl at
N
N
N
N
Ph
S
Ph
N
S
– AcOH
– H+
N
R2
N
R2
N
H
..
R1
1
1680 cm–1. The H NMR spectrum of compound 12a
Ac O+
R1
5a–k
7a–d
H
showed a singlet signal at d = 2.9 attributed to the methyl
group, while the spectrum of 12b showed two signals at
d = 7.9 (exchangeable with D2O) and 4.1 attributed to the
amino and methylene groups, respectively, in addition to
the aromatic protons for 12a and 12b at d = 7.2–8.3. The
13C NMR spectrum of compound 12b showed the follow-
ing signals: d = 168.60 (C=O), 166.30 (C6=N), 155.87
(C3), 142.12 (C8), 130.63 (CH-aromatic), 129.57 (2 CH-
aromatic), 126.16 (2 CH-aromatic), 126.03 (C-aromatic)
and 37.91 (CH2CO). The mass spectra of compounds 12a
and 12b showed the expected molecular ion peaks at m/z =
216 and 259, respectively. Further, the structure of com-
pound 12a was chemically confirmed by unequivocal
synthesis by the reaction of s-triazole 3 with acetyl chlo-
ride or acetic acid following the previously reported meth-
ods.33,34
Scheme 3
Reaction of s-triazole 3 with chloroacetonitrile (10) under
the same reaction conditions resulted in the 6-amino-s-tri-
azolo[3,4-b][1,3,4]thiadiazine derivative 5l in good yield
(Scheme 4).
N
N
N
N
Ph
AcOH/H+
reflux, 3 h
N
N
S
Ph
ClCH2CN
SH
+
N
10
NH2
NH2
5l
3
Scheme 4
The mechanism of the formation of compounds 12a,b
could be explained by nucleophilic attack of the amino
group in compound 3 onto the cyano group of compounds
11a–d to yield the uncyclized imine derivatives 13 which
undergo intramolecular cyclization with the loss of am-
monia to give the cyclized compounds 12a,b (Scheme 6).
The structure of compound 5l was confirmed by elemental
analysis and spectroscopic data. The IR spectrum of 5l
lacked a cyano group absorption band and showed, be-
sides other bands, two characteristic bands at 3400–3200
1
cm–1 due to the NH2 group. The H NMR spectrum
showed signals at d = 7.2 (exchangeable with D2O) attrib-
Synthesis 2010, No. 15, 2636–2642 © Thieme Stuttgart · New York

PAPER
Novel Method of s-Triazolo[3,4-b][1,3,4]thiadiazines
2639
N
N
N N
N
N
..
..
H+
AcOH/H+
SH
Ph
SH
Ph
N
N
Ph
N
S
NH
HN
CH2R
3
CH2R
..
HN
H
C
N
C
CH2R
11
NH3
NH
+
13
..
– NH3
N
N
Ph
N
S
N
CH2R
12a,b
Scheme 6
3,6-Diphenyl-7H-s-triazolo[3,4-b][1,3,4]thiadiazine (5a)
It is apparent that the ester group of compound 12
(R = CO2Et) derived from 11b undergoes hydrolysis
which is followed by decarboxylation to give derivative
12a (R = H), while the cyano group of compound 12
(R = CN) derived from 11c undergoes hydrolysis to pro-
vide the amide derivative 12b (R = CONH2).
Yield: 1.01 g (69%); colorless crystals (EtOH); mp 216–217 °C
(Lit.10 213–214 °C).
IR: 3059 (C–H arom.), 2997 (C–H aliph.), 1600 (C=N), 1473 (C=C)
cm–1.
1H NMR (90 MHz, DMSO-d6): d = 4.1 (s, 2 H, CH2), 7.5–8.1 (m,
10 H, H-arom.).
In this study, 4-amino-3-mercapto-5-phenyl-s-triazole (3)
was condensed with a variety of ketones containing an ac-
tive methyl or methylene group by refluxing in acetic acid
in the presence of sulfuric acid. Some of the resulting s-
triazolo[3,4-b][1,3,4]thiadiazines were synthesized as
new compounds with anticipated biological activity and
their structures were confirmed using spectroscopic data
and elemental analyses. The versatile, novel one-step syn-
thesis of these compounds derived in our laboratory has
the distinct advantage of dispensing with the use of highly
toxic and irritating halo carbonyl compounds which are
also not easy to obtain. Furthermore, the use of this meth-
od afforded a variety of substituents in the 6- and 7-posi-
Anal. Calcd for C16H12N4S (292.36): C, 65.73; H, 4.14; N, 19.16; S,
10.97. Found: C, 65.88; H, 4.34; N, 19.04; S, 10.80.
6-(4-Chlorophenyl)-3-phenyl-7H-s-triazolo[3,4-b][1,3,4]thiadi-
azine (5b)
Yield: 0.95 g (58%); colorless crystals (EtOH); mp 240–242 °C
(Lit.10 239–240 °C).
IR: 3034 (C–H arom.), 2990 (C–H aliph.), 1560 (C=N), 1463 (C=C)
cm–1.
1H NMR (90 MHz, DMSO-d6): d = 4.4 (s, 2 H, CH2), 7.55–8.0 (m,
9 H, H-arom.).
Anal. Calcd for C16H11ClN4S (326.80): C, 58.80; H, 3.39; N, 17.14;
S, 9.81. Found: C, 59.00; H, 3.45; N, 17.07; S, 9.55.
tions
of
the
s-triazolo[3,4-b][1,3,4]thiadiazines,
6-(4-Bromophenyl)-3-phenyl-7H-s-triazolo[3,4-b][1,3,4]thiadi-
azine (5c)
derivatives which could not be obtained using the classi-
cal methods.
Yield: 1.26 g (68%); colorless crystals (EtOH); mp 250–251 °C
(Lit.10 244–245 °C).
Melting points were determined using a Gallenkamp melting point
apparatus and are uncorrected. IR spectra were measured on a Shi-
madzu 470 spectrometer using KBr techniques. H NMR spectra
IR: 3031 (C–H arom.), 2993 (C–H aliph.), 1586 (C=N), 1463 (C=C)
cm–1.
1H NMR (90 MHz, DMSO-d6): d = 4.5 (s, 2 H, CH2), 7.5–8.0 (m, 9
H, H-arom.).
MS (EI, 70 eV): m/z (%) = 372.1 [M+ +2] (95), 370.1 [M+] (100),
197.0 (11), 181.1 (27), 147 (15), 121.1 (13), 115.1 (9), 104.1 (25),
102.1 (41), 91.1 (2), 76.1 (21), 63.9 (3), 51.2 (4).
1
were measured on a Varian EM-390 90-MHz spectrometer (Spec-
tral Unit, Assiut University, Egypt) or a Bruker DX 400-MHz spec-
trometer (Department of Physical Chemistry, Geneva) using CDCl3
or DMSO-d6 as the solvent and TMS as the internal standard. 13C
NMR spectra were measured on a Bruker DX 400-MHz spectrom-
eter. Mass spectra were recorded on a Jeol JMS-600H spectrometer
using a direct inlet system. Elemental analyses were performed us-
ing a Perkin-Elmer 240-C elemental analyzer.
Anal. Calcd for C16H11BrN4S (371.25): C, 51.76; H, 2.99; N, 15.09;
S, 8.64. Found: C, 51.61; H, 3.06; N, 15.08; S, 8.65.
3-Phenyl-6-(4-tolyl)-7H-s-triazolo[3,4-b][1,3,4]thiadiazine (5d)
Yield: 1.19 g (78%); colorless crystals (EtOH); mp 190–192 °C
(Lit.10 192–194 °C).
6-Substituted 3-Phenyl-7H-s-triazolo[3,4-b][1,3,4]thiadiazines
5a–k; General Procedure
A mixture of 4-amino-3-mercapto-5-phenyl-s-triazole (3; 0.96 g,
0.005 mol) and an aromatic or aliphatic ketone 4a–k (0.005 mol) in
glacial AcOH (25 mL) and a catalytic amount of concd H2SO4 was
refluxed for 3 h then, after cooling, was diluted with H2O (20 mL)
and neutralized with NH3 soln. The crude product thus obtained was
collected by filtration, washed with H2O and crystallized from the
appropriate solvent to give 5a–k as colorless crystals in 58–88%
yield.
IR: 3000 (C–H arom.), 2963 (C–H aliph.), 1616 (C=N), 1464 (C=C)
cm–1.
1H NMR (90 MHz, DMSO-d6): d = 2.3 (s, 3 H, CH3), 4.35 (s, 2 H,
CH2), 7.6–8.0 (m, 9 H, H-arom.).
Anal. Calcd for C17H14N4S (306.38): C, 66.64; H, 4.61; N, 18.29; S,
10.47. Found: C, 66.82; H, 4.64; N, 18.22; S, 10.35.
Synthesis 2010, No. 15, 2636–2642 © Thieme Stuttgart · New York

2640
H. A. H. El-Sherief et al.
PAPER
6-(4-Methoxyphenyl)-3-phenyl-7H-s-triazolo[3,4-b][1,3,4]thia-
diazine (5e)
13C NMR (100 MHz, CDCl3): d = 156.4 (C6=N), 152.1 (C3), 141.4
(C9), 130.2 (CH-arom.), 128.5 (2 CH-arom.), 128.3 (2 CH-arom.),
128.2 (CH-arom.), 126.0 (C-arom.), 25.7 (C7), 23.9 (CH3).
MS (EI, 70 eV): m/z (%) = 230.2 [M+] (100), 215 (18), 189.1 (3),
147.1 (4), 129.2 (57), 115.1 (17), 103.1 (82), 8.2 (7), 76.5 (33), 63.2
(9), 58.2 (99), 51.3 (15).
Yield: 1.18 g (73%); colorless crystals (EtOH); mp 198–200 °C
(Lit.10 216–217 °C).
IR: 3005 (C–H arom.), 2986 (C–H aliph.), 1604 (C=N), 1456 (C=C)
cm–1.
1H NMR (90 MHz, DMSO-d6): d = 3.9 (s, 3 H, OCH3), 4.3 (s, 2 H,
CH2), 7.0–8.1 (m, 9 H, H-arom.).
Anal. Calcd for C11H10N4S (230.29): C, 57.37; H, 4.38; N, 24.33; S,
13.92. Found: C, 57.23; H, 4.44; N, 24.12; S, 14.15.
Anal. Calcd for C17H14N4OS (322.38): C, 63.33; H, 4.38; N, 17.38;
S, 9.95. Found: C, 63.15; H, 4.32; N, 17.12; S, 10.13.
7-Acetyl-6-methyl-3-phenyl-7H-s-triazolo[3,4-b][1,3,4]thiadi-
azine (5j)
Yield: 1.15 g (84.5%); colorless crystals (benzene–n-hexane); mp
141–142 °C.
6-(4-Aminophenyl)-3-phenyl-7H-s-triazolo[3,4-b][1,3,4]thiadi-
azine (5f)
Yield: 0.92 g (60%); colorless crystals (DMF); mp 210–211 °C.
IR: 3074 (C–H arom.), 2921 (C–H aliph.), 1707 (C=O), 1629
(C=N), 1471 (C=C) cm–1.
1H NMR (90 MHz, CDCl3): d = 2.2 (s, 3 H, CH3), 2.23 (s, 3 H,
COCH3), 4.2 (s, 1 H, CH), 7.3–8.0 (m, 5 H, H-arom.).
MS (EI, 70 eV): m/z (%) = 272.1 [M+] (100), 259.1 (2), 230.1 (13),
217.1 (5), 185.1 (28), 178.1 (17), 165.9 (2), 146.1 (5), 119.1 (4),
102.9 (6), 92.9 (50), 75.1 (25), 66.1 (1), 57.1 (20), 50.9 (7).
IR: 3400–3200 (NH2), 3000 (C–H arom.), 2900 (C–H aliph.), 1695
(C=N), 1460 (C=C) cm–1.
1H NMR (90 MHz, DMSO-d6): d = 4.35 (s, 2 H, CH2), 7.6–8.1 (m,
9 H, H-arom.), 10.4 (s, 2 H, NH2).
Anal. Calcd for C16H13N5S (307.37): C, 62.52; H, 4.26; N, 22.78; S,
10.43. Found: C, 62.41; H, 4.41; N, 22.65; S, 10.50.
Anal. Calcd for C13H12N4OS (272.33): C, 57.34; H, 4.44; N, 20.57;
S, 11.77. Found: C, 57.03; H, 4.59; N, 20.44; S, 11.83.
6-(4-Hydroxyphenyl)-3-phenyl-7H-s-triazolo[3,4-b][1,3,4]thia-
diazine (5g)
Yield: 1.36 g (88%); colorless crystals (DMF); mp 296–298 °C.
6,7-Dimethyl-3-phenyl-7H-s-triazolo[3,4-b][1,3,4]thiadiazine
(5k)
IR: 3450 (OH), 3016 (C–H arom.), 2990 (C–H aliph.), 1691 (C=N),
1460 (C=C) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 4.2 (s, 2 H, CH2), 6.4 (d, J = 5
Hz, 2 H, H-arom.), 7.5 (m, 3 H, H-arom.), 7.9 (d, J = 5 Hz, 2 H, H-
arom.), 8.0 (d, J = 5 Hz, 2 H, H-arom.), 10.1 (s, 1 H, OH).
13C NMR (100 MHz, DMSO-d6): d = 161.4 (C6=N), 155.4 (COH),
151.7 (C3), 142.8 (C9), 130.2 (2 CH-arom.), 129.8 (CH-arom.),
128.8 (2 CH-arom.), 128.1 (2 CH-arom.), 126.6 (C-arom.), 124.1
(C-arom.), 116.2 (2 CH-arom.), 23.0 (C7).
MS (EI, 70 eV): m/z (%) = 307.8 [M+] (100), 276.8 (1), 255 (19),
214.7 (1), 191.6 (5), 189.1 (11), 176.7 (13), 146.9 (12), 132.9 (27),
120.9 (14), 118.9 (41), 102.9 (70), 90.9 (24), 88.9 (13), 76.9 (17),
64.8 (20), 51.7 (5).
Yield: 0.67 g (55%); colorless crystals (benzene–n-hexane); mp
120–121 °C.
IR: 3050 (C–H arom.), 2965 (C–H aliph.), 1654 (C=N), 1418 (C=C)
cm–1.
1H NMR (90 MHz, CDCl3): d = 1.25 (d, J = 6 Hz, 3 H, CHCH3), 2.2
(s, 3 H, CH3), 3.8 (q, J = 6 Hz, 1 H, CHCH3), 7.45–8.1 (m, 5 H, H-
arom.).
MS (EI, 70 eV): m/z (%) = 244.1 [M+] (100), 215.1 (2), 202.1 (17),
177.1 (6), 147.1 (12), 130.1 (2), 126.1 (2), 115.1 (13), 103.1 (97),
88.9 (5), 76.1 (23), 54.8 (37), 51.8 (7).
Anal. Calcd for C12H12N4S (244.32): C, 58.99; H, 4.95; N, 22.93; S,
13.12. Found: C, 58.80; H, 5.15; N, 22.87; S, 13.10.
Anal. Calcd for C16H12N4OS (308.36): C, 62.32; H, 3.92; N, 18.17;
S, 10.40. Found: C, 62.50; H, 4.07; N, 18.13; S, 10.45.
3-Phenylcycloalkano[e]-s-triazolo[3,4-b][1,3,4]thiadiazines 7a–
d; General Procedure
A mixture of 4-amino-3-mercapto-5-phenyl-s-triazole (3; 0.96 g,
0.005 mol) and a cyclic ketone 6a–d (0.005 mol) in glacial AcOH
(25 mL) and a catalytic amount of concd H2SO4 was refluxed for 3
h then, after cooling, was diluted with H2O (20 mL) and neutralized
with NH3 soln. The crude product thus obtained was collected by
filtration, washed with H2O and crystallized (benzene–n-hexane) to
give 7a–d as colorless crystals in 66–84% yield.
6-(1-Naphthyl)-3-phenyl-7H-s-triazolo[3,4-b][1,3,4]thiadiazine
(5h)
Yield: 1.37 g (80%); colorless crystals (EtOH); mp 210–211 °C.
IR: 3050 (C–H arom.), 2993 (C–H aliph.), 1656 (C=N), 1457 (C=C)
cm–1.
1H NMR (90 MHz, DMSO-d6): d = 4.30 (s, 2 H, CH2), 7.4–8.3 (m,
12 H, H-arom.).
MS (EI, 70 eV): m/z (%) = 342.5 [M+] (100), 309.6 (9), 280.7 (4),
209.7 (5), 198.8 (3), 177.7 (3), 166.8 (28), 151.8 (51), 146.8 (11),
126.8 (28), 114.8 (7), 102.9 (68), 87.9 (3), 76.9 (16), 63.7 (6), 57.7
(71), 51.7 (1).
3-Phenyl-6,7,8,8a-tetrahydrocyclopenta[e]-s-triazolo[3,4-
b][1,3,4]thiadiazine (7a)
Yield: 1.03 g (80%); colorless crystals (benzene–n-hexane); mp
180–182 °C.
IR: 3031 (C–H arom.), 2997–2902 (C–H aliph.), 1695 (C=N), 1459
(C=C) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.9–2.3 (m, 4 H, 2 CH2), 2.8–3.0
(m, 2 H, CH2), 3.9 (t, J = 5 Hz, 1 H, CH), 7.55–8.1 (m, 5 H, H-
arom.).
13C NMR (100 MHz, CDCl3): d = 169.41 (C6=N), 151.95 (C3=N),
142.20 (C9=N), 130.18 (CH-arom.), 128.52 (CH-arom.), 128.10
(CH-arom.), 127.61 (2 CH-arom.), 126.06 (C-arom.), 37.57 (CH-
cyclic), 31.62 (CH2-cyclic), 30.69 (CH2-cyclic), 23.68 (CH2-cy-
clic).
Anal. Calcd for C20H14N4S (342.42): C, 70.15; H, 4.12; N, 16.36; S,
9.36. Found: C, 70.20; H, 4.27; N, 16.30; S, 9.24.
6-Methyl-3-phenyl-7H-s-triazolo[3,4-b][1,3,4]thiadiazine (5i)
Yield: 1.10 g (87.5%); colorless crystals (benzene–n-hexane); mp
190–192 °C.
IR: 3010 (C–H arom.), 2978 (C–H aliph.), 1616 (C=N), 1464 (C=C)
cm–1.
1H NMR (400 MHz, CDCl3): d = 2.25 (s, 3 H, CH3), 3.5 (s, 2 H,
CH2), 7.45 (m, 3 H, H-arom.), 8.1 (d, J = 4 Hz, 2 H, H-arom.).
Synthesis 2010, No. 15, 2636–2642 © Thieme Stuttgart · New York

PAPER
Novel Method of s-Triazolo[3,4-b][1,3,4]thiadiazines
2641
MS (EI, 70 eV): m/z (%) = 258.3 [M+ + 2] (24), 257.2 [M+ + 1] (30),
256.2 [M+] (100), 216.9 (1), 190.9 (7), 185.1 (38), 177.9 (26), 167.9
(2), 149.0 (15), 130.9 (13), 103.9 (18), 76.9 (10), 74.9 (32), 60.9
(12), 56.9 (36), 50.9 (27).
6-Amino-3-phenyl-7H-s-triazolo[3,4-b][1,3,4]thiadiazine (5l)
A mixture of 4-amino-3-mercapto-5-phenyl-s-triazole (3; 0.96 g,
0.005 mol) and chloroacetonitrile (10; 0.38 g, 0.005 mol) in glacial
AcOH (25 mL) and a catalytic amount of concd H2SO4 was refluxed
for 3 h then, after cooling, was diluted with H2O (20 mL) and neu-
tralized with NH3 soln. The crude product thus obtained was col-
lected by filtration, washed with H2O and crystallized (EtOH) to
give 5l as colorless needles; yield: 0.81 g (70%); mp 246–248 °C
(Lit.22 246–247 °C).
Anal. Calcd for C13H12N4S (256.33): C, 60.19; H, 4.72; N, 21.86; S,
12.51. Found: C, 60.13; H, 4.84; N, 21.71; S, 12.67.
3-Phenyl-7,8,9,9a-tetrahydro-6H-cyclohexa[e]-s-triazolo[3,4-
b][1,3,4]thiadiazine (7b)
Yield: 0.93 g (68.5%); colorless crystals (benzene–n-hexane); mp
172–173 °C.
IR: 3400–3200 (NH2), 3005 (C–H arom.), 2910 (C–H aliph.), 1640
(C=N), 1450 (C=C) cm–1.
IR: 3021 (C–H arom.), 2919–2874 (C–H aliph.), 1660 (C=N), 1473
(C=C) cm–1.
1H NMR (90 MHz, DMSO-d6): d = 3.9 (s, 2 H, CH2), 7.2 (s, 2 H,
NH2), 7.2–8.1 (m, 5 H, H-arom.).
1H NMR (400 MHz, CDCl3): d = 1.2–2.5 (m, 6 H, 3 CH2), 2.8–3.0
(m, 2 H, CH2), 4.0 (t, J = 5 Hz, 1 H, CH), 7.5–8.1 (m, 5 H, H-arom.).
MS (EI, 70 eV): m/z (%) = 272.3 [M+ + 2] (27), 271.3 [M+ + 1] (23),
270.3 [M+] (100), 202.2 (13), 174.1 (3), 103.2 (21), 81.2 (9), 79.2
(4), 76.2 (4), 67.3 (2), 55.3 (3), 53.2 (5), 45.3 (2).
MS (EI, 70 eV): m/z (%) = 231.8 [M+] (54), 212.6 (2), 184.9 (49),
177.9 (14), 164.8 (7), 148.8 (34), 102.8 (11), 100.8 (10), 92.9 (100),
74.9 (70), 68.9 (12), 56.9 (56), 50.9 (16).
Anal. Calcd for C10H9N5S (231.28): C, 51.93; H, 3.92; N, 30.28; S,
13.86. Found: C, 51.85; H, 3.85; N, 30.45; S, 13.93.
Anal. Calcd for C14H14N4S (270.35): C, 62.20; H, 5.22; N, 20.72; S,
11.86. Found: C, 61.99; H, 5.36; N, 20.84; S, 11.80.
6-Substituted 3-Phenyl-s-triazolo[3,4-b][1,3,4]thiadiazoles
12a,b; General Procedure
A mixture of 4-amino-3-mercapto-5-phenyl-s-triazole (3; 0.96 g,
0.005 mol) and a cyano compound 11a–d (0.005 mol) in glacial
AcOH (25 mL) and a catalytic amount of concd H2SO4 was refluxed
for 3 h then, after cooling, was diluted with H2O (20 mL) and neu-
tralized with NH3 soln. The crude product thus obtained was col-
lected by filtration, washed with H2O and crystallized (EtOH) to
give 12a,b as colorless crystals in 50–81% yield.
3-Phenyl-6,7,8,9,10,10a-hexahydrocyclohepta[e]-s-triazolo[3,4-
b][1,3,4]thiadiazine (7c)
Yield: 0.93 g (66%); colorless crystals (benzene–n-hexane); mp
161–163 °C.
IR: 3020 (C–H arom.), 2950–2900 (C–H aliph.), 1665 (C=N), 1461
(C=C) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.2–2.1 (m, 8 H, 4 CH2), 2.8–2.9
(m, 2 H, CH2), 3.85 (t, J = 5 Hz, 1 H, CH), 7.5–8.1 (m, 5 H, H-
arom.).
13C NMR (100 MHz, CDCl3): d = 169.52 (C6=N), 151.45 (C3=N),
142.00 (C9=N), 130.15 (CH-arom.), 128.51 (2 CH-arom.), 128.11
(2 CH-arom.), 126.18 (C-arom.), 39.49 (CH-cyclic), 36.14 (CH2-
cyclic), 30.90 (CH2-cyclic), 28.70 (CH2-cyclic), 28.06 (CH2-cy-
clic), 26.38 (CH2-cyclic).
6-Methyl-3-phenyl-s-triazolo[3,4-b][1,3,4]thiadiazole (12a)
Yield: 0.88 g (81%); colorless crystals (EtOH); mp 186–187 °C
(Lit.33,34 186–187 °C).
IR: 3050 (C–H arom.), 2920 (C–H aliph.), 1540 (C=N), 1460 (C=C)
cm–1.
1H NMR (90 MHz, CDCl3): d = 2.9 (s, 3 H, CH3), 7.2–8.3 (m, 5 H,
H-arom.).
MS (EI, 70 eV): m/z (%) = 286.3 [M+ + 2] (24), 285.3 [M+ + 1] (71),
284.3 [M+] (55), 248.6 (4), 229.6 (14), 177.8 (20), 165.8 (16), 130.9
(12), 103.8 (23), 76.9 (33), 68.9 (50), 56.9 (75), 52.9 (25), 50.9
(100).
MS (EI, 70 eV): m/z (%) = 16.2 [M+] (100), 129.2 (17), 118.3 (4),
103.2 (54), 91.3 (1), 77.3 (10), 63.3 (1), 51.3 (6).
Anal. Calcd for C10H8N4S (216.26): C, 55.54; H, 3.73; N, 25.91; S,
14.83. Found: C, 55.35; H, 3.67; N, 26.02; S, 14.99.
Anal. Calcd for C15H16N4S (284.38): C, 63.35; H, 5.67; N, 19.70; S,
11.28. Found: C, 63.21; H, 5.69; N, 19.86; S, 11.32.
6-(Aminocarbonylmethyl)-3-phenyl-s-triazolo[3,4-b][1,3,4]thi-
adiazole (12b)
Yield: 0.65 g (50%); colorless crystals (EtOH); mp 240–241 °C.
3-Phenyl-7,8,9,10,11,11a-hexahydro-6H-cycloocta[e]-s-triazo-
lo[3,4-b][1,3,4]thiadiazine (7d)
Yield: 1.25 g (84%); colorless crystals (benzene–n-hexane); mp
166 °C.
IR: 3400–3150 (NH2), 3010 (C–H arom.), 2900 (C–H aliph.), 1680
(C=O), 1600 (C=N), 1480 (C=C) cm–1.
1H NMR (90 MHz, DMSO-d6): d = 4.1 (s, 2 H, CH2), 7.9 (s, 2 H,
NH2), 7.55–8.2 (m, 5 H, H-arom.).
13C NMR (100 MHz, DMSO-d6): d = 168.60 (C=O), 166.30
(C6=N), 155.87 (C3), 142.12 (C8), 130.63 (CH-arom.), 129.57 (2
CH-arom.), 126.16 (2 CH-arom.), 126.03 (C-arom.), 37.91
(CH2CO).
MS (EI, 70 eV): m/z (%) = 259.0 [M+] (100), 216.9 (14), 186.1 (8),
176.9 (6), 147.0 (21), 102.9 (79), 77.1 (13), 75.9 (19), 64.9 (4), 56.8
(11), 51.8 (4).
IR: 3069 (C–H arom.), 2928–2850 (C–H aliph.), 1612 (C=N), 1456
(C=C) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.2–1.9 (m, 10 H, 5 CH2), 2.8–2.9
(m, 2 H, CH2), 3.85 (t, J = 5 Hz, 1 H, CH), 7.5–8.1 (m, 5 H, H-
arom.).
13C NMR (100 MHz, CDCl3): d = 165.63 (C6=N), 151.73 (C3=N),
142.01 (C9=N), 130.13 (CH-arom.), 128.58 (2 CH-arom.), 127.94
(CH-arom.), 127.61 (CH-arom.), 126.24 (C-arom.), 36.68 (CH-cy-
clic), 36.17 (CH2-cyclic), 34.99 (CH2-cyclic), 28.04 (CH2-cyclic),
24.89 (CH2-cyclic), 23.74 (CH2-cyclic), 21.22 (CH2-cyclic).
MS (EI, 70 eV): m/z (%) = 300.1 [M+ + 2] (34.6), 299.1 [M+ + 1]
(80), 298.1 [M+] (100), 265.3 (1), 230.1 (2), 216.1 (2), 202.1 (6),
177.1 (5), 146.9 (6), 138.1 (2), 103.0 (37), 91.0 (2), 76.9 (7), 67.1
(11), 54.8 (11), 51.8 (2).
Anal. Calcd for C11H9N5OS (259.29): C, 50.95; H, 3.50; N, 27.01;
S, 12.37. Found: C, 50.85; H, 3.65; N, 26.91; S, 12.24.
Acknowledgment
The authors wish to extend grateful thanks to Assiut University
(Egypt) for supporting this work.
Anal. Calcd for C16H18N4S (298.41): C, 64.40; H, 6.08; N, 18.78; S,
10.75. Found: C, 64.36; H, 6.13; N, 18.81; S, 10.83.
Synthesis 2010, No. 15, 2636–2642 © Thieme Stuttgart · New York

2642
H. A. H. El-Sherief et al.
PAPER
(16) Albrecht, W. L.; Sweet, F. W. US 3954983, 1976; Chem.
References
Abstr. 1976, 85, 177510v.
(1) Mohan, J.; Gsranjaneyulu, G. S. R.; Kiran, R. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1988, 27, 128.
(2) Kidwai, M.; Goel, Y.; Kumar, P.; Kumar, K. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1997, 36, 782.
(3) Tag, M. Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem. 1983, 22, 270.
(4) Prakash, K.; Jagdeesh, P. D.; Mithun, A.; Manjathuru, M.;
Boja, P.; Shivarama, H. B. Eur. J. Med. Chem. 2008, 43,
808.
(5) Mithun, A.; Shivarama, H. B. Indian J. Pharm. Toxicol.
2007, 2, 256.
(6) Ravindra, K. C.; Vagdevi, H. M.; Vaidya, V. P. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2008, 47,
1271.
(17) Ramana, R. G.; Srinivasa, R. K. Indian Drugs 1989, 26, 220.
(18) Xiao-Xia, Y.; Jin, Z.; An-Jiang, Z.; Li-Xue, Z. J. Heterocycl.
Chem. 2008, 45, 987.
(19) Dash, B.; Dora, E. K.; Panda, C. S. Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 1981, 20, 369.
(20) Heravi, M. M.; Rahimzadeh, M.; Seyf, M.; Davoodnia, A.;
Ghassemzadeh, M. Phosphorus, Sulfur Silicon Relat. Elem.
2000, 167, 211.
(21) Chande, M. S.; Karnik, B. M. Indian J. Heterocycl. Chem.
1991, 1, 117.
(22) Ewiss, N. E.; Bahajaj, A. A. J. Heterocycl. Chem. 1987, 24,
1173.
(23) Pascal, J. C.; Pinhas, H. Ger. Offen. 2 818 395, 1978; Chem.
Abstr. 1979, 90, 152246f.
(24) Kawashima, Y.; Ishkawa, H.; Kide, S.; Tanaka, T.; Masuda,
K. JP Kokai Tokkyo Koho 61 260 085, 1982; Chem. Abstr.
1987, 106, 138475x.
(25) Tadashi, S.; Eiko, I.; Ikuo, S. J. Org. Chem. 1982, 47, 2757.
(26) Pfeiffer, W. D.; Erich, D.; Ehrenfried, B. Z. Chem. 1977, 17,
15.
(27) Hozien, Z. A.; Sarhan, A. A. O.; El-Sherief, H. A. H.;
Mahmoud, A. M. Z. Naturforsch., B 1997, 52, 1401.
(28) Mahmoud, A. M.; El-Sherief, H. A. H.; Habib, O. M. A.;
Sarhan, A. A. O. Phosphorus, Sulfur Silicon Relat. Elem.
2007, 182, 1757.
(7) Shivarama, H. B.; Prasanna, C. S.; Boja, P.; Rao, K. S.;
Shridhara, K. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 2006, 45, 2071.
(8) Farghaly, A.-R.; De Clercq, E.; El-Kashef, H. ARKIVOC
2006, (x), 137.
(9) Vijaya, K. P.; Rajeswar, R. V. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 2008, 47, 106.
(10) El-Dawy, M. A.; Omar, A. M.; Ismail, A. M.; Hazzaa, A. A.
B. J. Pharm. Sci. 1983, 72, 45.
(11) Tag, M. Chim. Acta Turc. 1988, 16, 91.
(12) Prasad, A. R.; Ramalingam, T.; Rao, A. B.; Diwan, P. V.;
Sattur, P. B. Eur. J. Med. Chem. 1989, 24, 199.
(13) Shivarama, H. B.; Sooryanarayana, R. B.; Sarojini, B. K.;
Akberali, P. M.; Suchetha, K. N. Eur. J. Med. Chem. 2006,
41, 657.
(14) Shivarama, H. B.; Sarojini, B. K.; Sooryanarayana, R. B.;
Akberali, P. M.; Suchetha, K. N.; Shetty, V. Farmaco 2001,
56, 565.
(29) Sarhan, A. A. O.; El-Sherief, H. A. H.; Mahmoud, A. M.
Tetrahedron 1996, 52, 10485.
(30) Hozien, Z. A.; Sarhan, A. A. O.; El-Sherief, H. A. H.;
Mahmoud, A. M. J. Heterocycl. Chem. 2000, 37, 943.
(31) Sarhan, A. A. O. Heteroat. Chem. 2000, 11, 399.
(32) El-Sherief, H. A. H.; Mahmoud, A. M.; Sarhan, A. A. O.;
Hozien, Z. A.; Habib, O. M. A. J. Sulfur Chem. 2006, 27, 65.
(33) Kanaoka, M. J. Pharm. Soc. Jpn. 1956, 76, 1133.
(34) Invidiata, F. P.; Furno, G.; Lampronti, I.; Simoni, D.
J. Heterocycl. Chem. 1997, 34, 1255.
(15) Demchenko, A. M.; Yanchenko, V. O.; Smolskii, O. S.;
Ageev, V. O.; Lozinskii, M. O. Farmatsevtichnii Zh. 2003,
6, 41; Chem. Abstr. 2004, 140, 231335t.
Synthesis 2010, No. 15, 2636–2642 © Thieme Stuttgart · New York