Efficient routes for the synthesis of novel bis(s-triazolo[3,4-b][1,3,4] thiadiazines)

Article abstract of DOI:10.1002/jhet.1854

Bis(triazolo[3,4-b]thiadiazine) 4 in which the fused system is linked directly to the benzene core can be synthesized in 75% yield by, firstly, preparation of bis(s-triazole) 2 followed by reaction with phenacyl bromide 3 in refluxing EtOH/DMF mixture containing piperidine. Bis(s-triazolo[3,4-b][1,3,4] thiadiazines) 8 and 11 in which the triazolothiadiazines are linked to benzene core via alkyl or ether linkage were synthesized in 70 and 72% yields, respectively, starting from dicarboxylic acids 5 and 9 upon treatment with two moles of thiocarbohydrazide 6 to give the corresponding bis(4-amino-5-mercapto- s-triazolo-3-y1) derivatives 7 and 10 and subsequent reaction with two equivalents of phenacyl bromide. Bis(6-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazines) 15a, 15b, 15c, 15d, 15e, 15f, which are linked to arene cores via sulfanylmethylene spacers, were prepared by the reaction of 4-amino-4H-1,2,4- triazole-3,5-dithiol 12 with the appropriate bis(bromomethyl)benzenes 13a, 13b, 13c, 13d, 13e, 13f to give bis(4-amino-5-mercapto-4H-3-sulfanylmethyl)arenes 14a, 14b, 14c, 14d, 14e, 14f and subsequent reaction with phenacyl bromide. Compounds 15a, 15b, 15c, 15d, 15e, 15f were alternatively obtained in 60-70% yields by twofold substitution of 13a, 13b, 13c, 13d, 13e, 13f with two equivalents of 6-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-3-thiol 16 in refluxing EtOH/DMF mixture containing KOH. Bis(triazolothiadiazine) 22 attached to the benzene core through the thiadiazine ring via an amine linkage was prepared in 70% yield starting from p-phenylenediamine 19 by, firstly, acylation with chloroacetyl chloride 18 followed by bis-alkylation with 1,2,4-triazole 20 and subsequent intramolecular ring closure upon treatment with phosphorus oxychloride.

Full text of DOI:10.1002/jhet.1854

E176
Efficient Routes for the Synthesis of Novel
Bis(s-triazolo[3,4-b][1,3,4]thiadiazines)
Vol 51
*
Radwan M. Sarhan, Mohamed A. Badawy, and Ahmed H. M. Elwahy
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
*
E-mail: aelwahy@hotmail.com
Received July 25, 2012
DOI 10.1002/jhet.1854
Published online 22 April 2014 0in Wiley Online Library (wileyonlinelibrary.com).
N
N
N
N
Y
Y
Arenes
S
S
N
N
N
N
Ph
Several Steps
Ph
Or
X
X
Arenes
S
N
S
Y
Y
Arenes
N
N
N
N
N
N
N
X = CO2Et, CH2COOH, OCH2COOH, NH2, CH2Br
Y = -, CH2, OCH2, SCH2, NH
Ph
Ph
Bis(triazolo[3,4-b]thiadiazine) 4 in which the fused system is linked directly to the benzene core can be
synthesized in 75% yield by, firstly, preparation of bis(s-triazole) 2 followed by reaction with phenacyl
bromide 3 in refluxing EtOH/DMF mixture containing piperidine. Bis(s-triazolo[3,4-b][1,3,4]thiadiazines)
8 and 11 in which the triazolothiadiazines are linked to benzene core via alkyl or ether linkage were synthesized
in 70 and 72% yields, respectively, starting from dicarboxylic acids 5 and 9 upon treatment with two moles of
thiocarbohydrazide 6 to give the corresponding bis(4-amino-5-mercapto-s-triazolo-3-y1) derivatives 7 and 10
and subsequent reaction with two equivalents of phenacyl bromide. Bis(6-phenyl-7H-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazines) 15, which are linked to arene cores via sulfanylmethylene spacers, were prepared by the
reaction of 4-amino-4H-1,2,4-triazole-3,5-dithiol 12 with the appropriate bis(bromomethyl)benzenes 13 to give
bis(4-amino-5-mercapto-4H-3-sulfanylmethyl)arenes 14 and subsequent reaction with phenacyl bromide.
Compounds 15 were alternatively obtained in 60–70% yields by twofold substitution of 13 with two equivalents
of 6-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-3-thiol 16 in refluxing EtOH/DMF mixture containing
KOH. Bis(triazolothiadiazine) 22 attached to the benzene core through the thiadiazine ring via an amine linkage
was prepared in 70% yield starting from p-phenylenediamine 19 by, firstly, acylation with chloroacetyl chloride
18 followed by bis-alkylation with 1,2,4-triazole 20 and subsequent intramolecular ring closure upon treatment
with phosphorus oxychloride.
J. Heterocyclic Chem., 51, E176 (2014).
INTRODUCTION
the triazolothiadiazines are linked to arene core either
directly or via alkyl, ether, thioether, or amine linkages.
In the last decades, a special attention was given to
1,2,4-triazole and their heterocyclic fused analogs,
especially, triazolothiadiazines, owing to their promi-
sing biological activities such as antimicrobial, anti-
inflammatory, hypoglycemic, anticancer, anti-HIV,
CNS stimulant, antifungal, antiviral, and analgesic
properties [1–23].
In addition, bis-heterocyclic compounds with a suitable
spacer constitute an important class of compounds, and
their various types of activities, especially, as antitumor
and as antimicrobial, have been studied. These activities,
which result in their pharmacological utility, have been
reported to be enhanced when different functionalities or
substitutions are present on the two heterocyclic moieties
in the bis-compound [24–37].
RESULTS AND DISCUSSION
The strategy used for the synthesis of the target bis-
compounds in which triazolothiadiazines are attached to
the arenes through the triazole ring depends mainly on the
initial formation of the appropriate bis(aminotriazolethiol)s.
The amino and mercapto groups in these compounds serve
thereby as readily accessible nucleophilic centers for the
preparation of N-bridged heterocycles.
Thus, bis(triazolo[3,4-b]thiadiazine) 4 in which the fused
system is linked directly to the benzene core can be synthe-
sized starting from the readily available diethyl phthalate (1)
as outlined in Scheme 1. Thus compound 1 was firstly con-
verted to the corresponding acid hydrazide upon treatment
with methanol and hydrazine hydrate. Subsequent reaction
of the hydrazide with carbon disulfide in ethanolic potassium
hydroxide, to form a potassium dithiocarbazinate intermedi-
ate, followed by a cyclocondensation with excess of
In connection with these findings and in continuation of
our interest in the synthesis of bis(hetrocycles) [38–46], we
describe herein simple and efficient routes for the synthesis
of novel bis(s-triazolo[3,4-b][1,3,4]thiadiazines) in which
© 2014 HeteroCorporation

August 2014
Efficient Routes for the Synthesis of Novel Bis(s-triazolo[3,4-b][1,3,4]thiadiazines)
E177
Scheme 1
N
N
N
N
N
N
N
N
N
N
(a)
(b)
O
O
N
N
S
S
N
HS
SH
N
EtO
OEt
NH2
H2N
1
2
4
a) NH2NH2/EtOH, CS2/KOH, NH2NH2
b) PhCOCH2Br (3), DMF/EtOH, piperidine
hydrazine hydrate produced the bis(s-triazole) 2 as a white
solid in good yield. Reaction of 2 with phenacyl bromide 3
in refluxing EtOH/DMF mixture containing piperidine
afforded the target compound 4 in 75% yield.
Bis(s-triazolo[3,4-b][1,3,4]thiadiazines) 8 and 11 in
which the triazolothiadiazines are linked to benzene core
via alkyl or ether linkage were synthesized as depicted in
Scheme 2. Thus, reaction of one mole of each of dicarboxylic
acids 5 and 9 with two moles of thiocarbohydrazide (6)
under fusion conditions afforded the corresponding bis
(4-amino-5-mercapto-s-triazolo-3-y1) derivatives 7 and
10 in 80 and 78% yields, respectively. Treatment of 7
and 10 with two equivalents of phenacyl bromide 3 in
refluxing EtOH/DMF mixture containing piperidine
afforded the corresponding bis(triazolothiadiazines)
8 and 11 in 70 and 72% yields, respectively.
Scheme 2
HOOC
COOH
O
O
COOH
HOOC
5
9
NH2NHCSNHNH2
NH2NHCSNHNH2
(a)
(a)
6
6
H2N
N
NH2
N
N
N
N
N
O
O
N
N
HS
SH
N
SH
N
N
N
NH2
HS
H2N
7
10
(b)
(b)
N
N
N
N
N
N
N
N
O
O
N
S
N
N
N
N
N
S
S
S
N
N
8
11
a) 180 0C, 10 min.
b) PhCOCH2Br (3), DMF/EtOH, piperidine
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E178
R. M. Sarhan, M. A. Badawy, and A. H. M. Elwahy
Vol 51
Scheme 3
Arenes
N
N
Br
N
N
Br
Arenes
N
N
13a-f
HS
SH
S
S
N
HS
SH
N
N
14a-f
NH2
KOH/EtOH
NH2
NH2
12
PhCOCH2Br
DMF/EtOH, Piperidine
3
DMF/EtOH, Piperidine
N
N
Arenes
Br
Br
HS
S
13a-f
N
N
15a-f
KOH/EtOH
Arene,
a =
b =
c =
16
d =
e =
f =
N
N
N
N
N
N
N
N
N
S
S
S
N
S
S
S
N
N
N
S
S
N
N
N
N
15a
15c
15b
N
N
N
N
N
N
N
N
S
S
S
S
S
S
S
N
S
N
N
N
N
N
N
N
N
15d
N
N
N
N
N
N
N
N
S
S
N
S
S
S
S
S
N
N
N
N
S
N
N
N
15e
15f
We also studied the synthesis of novel twofold branched
triazolothiadiazines 15a–f, which are linked to arene cores
via sulfanylmethylene spacers (Scheme 3).
The same methodology was extended to the preparation of
bis(triazolothiadiazine)s 15b–f . Thus, twofold substitution
of 13b–f with two equivalents of 12, and subsequent reaction
with phenacyl bromide 13 under similar conditions afforded
15d, 15e, and 15f in 67–70% yields, respectively.
The reaction proceeds via initial formation of bis(4-amino-
5-mercapto-4H-3-sulfanylmethyl)arenes 14 followed by reaction
with phenacyl bromide to give 15. The corresponding bis
(aminotriazole)s 14a, 14c, 14e, and 14f were isolated, thereby
providing strong evidence for the proposed mechanism. The
latter compounds underwent cyclocondensation with
Thus, bis(6-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine) 15a was prepared by the reaction of 4-amino-
4H-1,2,4-triazole-3,5-dithiol 12 with 1,2-bis(bromomethyl)
benzene 13a in refluxing EtOH/DMF mixture containing
KOH. After 2 h, phenacyl bromide 3 was added, and
heating under reflux was continued for additional 2 h.
wAfter workup, compound 15a was obtained as yellow
crystals in 62% yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

August 2014
Efficient Routes for the Synthesis of Novel Bis(s-triazolo[3,4-b][1,3,4]thiadiazines)
E179
Scheme 4
N
N
HS
Ph
N
O
O
O
O
NH2
N
20
N
N
CL
S
CL
N
N
S
N
N
H
H
H
H
N
KOH/EtOH
N
N
21
19
Ph
Ph
H2N
NH2
ClCOCH2Cl
POCl3
TEA
18
S
N
S
N
NH2
H2N
N
N
N
N
H
H
N
N
N
N
17
Ph
Ph
22
phenacyl bromide in refluxing EtOH/DMF containing few
drops of piperidine to give 15a, 15c, 15e, and 15f,
respectively.
closure reaction occurred. All other protons were seen at
the expected chemical shifts and integral values.
Compounds 15a–f were alternatively obtained in 60–70%
yields, respectively, by twofold substitution of 13a–f
with two equivalents of 6-phenyl-7H-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazine-3-thiol (16) in refluxing EtOH/DMF
mixture containing KOH.
CONCLUSIONS
We developed a simple method for the synthesis of bis
(triazolothiadiazinyl)arenes. The triazolothiadiazine moiety
in the novel compounds are linked to arene core either
directly or via alkyl, ether, thioether or amine linkages.
Full characterization of these compounds is reported.
The new synthesized compounds are interesting both in
their own right as unusual molecules and for their promising
pharmacological and biological activities. They offer an
advantage of their easy synthesis in a simple one step or
two steps procedure from inexpensive starting materials.
Compound 16 was obtained in 50% yield, upon treat-
ment of 12 with one equivalent of phenacyl bromide 3 in
refluxing EtOH/DMF mixture containing piperidine.
Bis(system) 22 in which triazolothiadiazines are attached
to the benzene core through the thiadiazine ring via amine
likage was prepared starting from p-phenylenediamine 17
by, firstly, acylation with chloroacetyl chloride 18 in basic
medium to give 1,4-phenylenedicarbamic chloride 19.
Reaction of 19 with two equivalents of 4-amino-5-phenyl-
4H-1,2,4-triazole-3-thiol (20) in ethanol in the presence of
potassium hydroxide gave N,N0-(1,4-phenylene)bis(2-(4-
amino-5-phenyl-4H-1,2,4-triazol-3-ylthio)acetamide) (21) in
80% yield. The latter underwent intramolecular ring closure
with the formation of N1,N4-bis(3-phenyl-7H-[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazin-6-yl)benzene-1,4-diamine 22
in 70% yields upon treatment with phosphorus oxychloride.
The reaction sequence is outlined in Scheme 4.
All compounds were characterized by their melting
points, elementary analysis, IR, 1H NMR, and mass spectra.
The spectral data agree with the proposed structures. Thus,
the disappearance of NH2 stretching bands in the IR spectra
of triazolothiadiazines 4, 8, 11, 15a–f, and 22, together with
the disappearance of the characteristic peaks belonging to
primary amine in their 1H NMR spectra, is an evidence for
the cyclocondensation of phenacyl bromide with the
corresponding bis-aminotriazoles. In addition, the presence
of SCH2 protons, resonated at d 4.35–5.28 ppm as singlet
signals integrating four protons, clearly indicated that ring
EXPERIMENTAL
Melting points were determined in open glass capillaries with a
Gallenkamp apparatus and were not corrected. The IR spectra
were recorded in potassium bromide disks on a Pye Unicam SP
3-300 and Shimadzu FTIR 8101 PC IR spectrophotometer. The
1H and 13C NMR spectra were determined on a Varian Mercury
VX 300-NMR spectrometer using TMS as an internal standard
and DMSO-d6 as a solvent. Mass spectra were measured on a
GCMS-QP1000 EX spectrometer at 70 eV. 4-Aminotriazol-
3-thione derivatives 12 [47], 20 [48], and dibromoarenes 13a–d [49]
were prepared as reported. Dibromoarenes 13e and 13f were used
as purchased from Aldrich.
Synthesis of 1,4-bis(4-amino-5-mercapto-1,2,4-triazole-3-thiol)
benzene (2). To a solution of diethyl phthalate 1 (10 mmol) in
methanol (20 mL), hydrazine hydrate (20 mmol) was added. The
reaction mixture was heated under reflux for 3 h, the solvent was
then removed in vacuo, and the remaining solid was diluted with
cold water (100 mL). The precipitated terephthalic dihydrazide was
collected and crystallized from methanol as colorless crystals. The
latter dihydrazide was then added in small portions and with
continuous stirring to a cold solution of KOH (3 mmol) in absolute
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E180
R. M. Sarhan, M. A. Badawy, and A. H. M. Elwahy
Vol 51
ethanol (25 mL). The reaction mixture was stirred for further 12 h at
RT. The precipitated potassium dithiocarbazinate was collected by
filtration, washed with cold ethanol (50 mL), and dried in vacuum.
The salt thus obtained was used in the next step without further
purification.
A suspension of potassium dithiocarbazinate (1 mmol) in water
(5 mL) and hydrazine hydrate (99%, 3 mmol) was heated for
18–20 h at 100ꢀC with occasional shaking. The color of the reaction
mixture changed to green with the evolution of hydrogen sulfide gas.
A homogeneous reaction mixture was obtained during the reaction
process. The reaction mixture was cooled to RT and diluted with
cold water (20 mL). On acidification with HCL, the required
triazole was precipitated out and recrystallized from DMF/H2O
mixture as colorless crystals (75%); mp 312–314ꢀC, (Lit. [50];
314ꢀC).
1,3-Bis(6-phenyl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazol-3-
ylmethoxy)benzene (11).
Colorless crystals (dioxan), yield:
1
72%; mp 230ꢀC; IR (cmꢁ1): 1593 (C═N); H NMR (DMSO): d
4.44 (s, 4H, SCH2), 5.36 (s, 4H, OCH2), 6.73–7.97 (m, 14H,
ArH0s); ms: m/z (%) 567 (M+, 0.1), 550 (0.2), 391 (0.1), 215
(0.7), 166 (7), 105 (0.7), 88 (97), 58 (100). Anal. Calcd for C28
H22N8O2S2 (566.67): C, 59.35; H, 3.91; N, 19.77. Found: C,
59.17; H, 3.77; N, 19.82.
Synthesis of bis(4-amino-5-mercapto-1,2,4-triazol-3-yl)
arenes (14a, 14c, 14e, 14f). General procedure: To a solution
of 12 (50 mmol) in ethanol (50 mL) containing KOH (25 mmol),
a solution of the appropriate dihaloarene 13a, 13c, 13e, 13f
[25 mmol in DMF(10 mL)] was added. The reaction mixture
was heated under reflux for 3 h. The solvent was then removed
in vacuo, and the remaining solid was collected and crystallized
from DMF/H2O to give compounds 14a, 14c, 14e, and 14f,
respectively.
Synthesis of bis(4-amino-5-mercapto-s-triazolo-3-yl)arenes
7 and 10.
A mixture of thiocarbazide (20 mmol) and the
appropriate dicarboxylic acid 5 or 9 was fused at 180ꢀC in
an oil bath for 10 min. After cooling, the reaction mixture
was triturated with ethanol, and the obtained solid was
crystallized from DMF/H2O to give compounds of 7 and 10,
respectively.
1,2-Bis(4-amino-5-mercapto-1,2,4-triazol-3-ylsulfanyl)benzene
(14a).
Colorless crystals (80%); mp 228–230ꢀC; IR (cmꢁ1):
1
3162, 3094 (NH2), 1298 (C═S); H NMR (DMSO): d 4.46 (s,
4H, SCH2), 5.64 (s, 4H, NH2), 7.23–7.42 (m, 4H, ArH0s), 13.75
(s, 2H, SH) ppm; ms: m/z (%) 398 (M+, 0.4), 390 (1), 384 (2), 293
(2), 177 (8), 129 (14.4), 95 (88), 57 (71), 55 (100). Anal. Calcd
for C12H14N8S4 (398.55): C, 36.16; H, 3.54; N, 28.11. Found: C,
36.05; H, 3.33; N, 28.01.
1,4-Bis(4-amino-5-mercapto-s-triazol-3-ylmethyl)benzene (7).
Yellow crystals (80%); mp 265ꢀC; IR (cmꢁ1): 3192 (NH2), 1301
(C═S); 1H NMR (DMSO): d 3.98 (s, 4H, CH2), 5.53 (s, 4H, NH2),
7.20 (s, 4H, ArH0s), 13.53 (s, 2H, SH) ppm; ms: m/z (%) 535 (M+,
0.4), 333 (2), 293 (1), 240 (1), 166 (7), 189 (1), 153 (3), 98 (12), 79
(100), 60 (21). Anal. Calcd for C12 H14N8S2 (334.43): C, 43.10; H,
4.22; N, 33.51. Found: C, 43.22; H, 4.34; N, 33.42.
1,3-Bis(4-amino-5-mercapto-s-triazol-3-ylmethoxy)benzene
(10). Yellow crystals (78%); mp 270ꢀC, (Lit.[51]; 110–112ꢀC);
IR (cmꢁ1): 3255, 3184 (NH2), 1297 (C═S); 1H NMR (DMSO): d
5.09 (s, 4H, CH2), 5.66 (s, 4H, NH2), 6.6–7.94 (m, 4H, ArH0s),
13.85 (s, 2H, SH) ppm; ms: m/z (%) 366 (M+, 2), 337 (1.7), 222
(2.5), 170 (1.5), 161 (4), 121 (2), 64 (100). Anal. Calcd for
C12H14N8O2S2 (366.43): C, 39.34; H, 3.85; N, 30.58. Found: C,
39.17; H, 3.75; N, 30.37.
1,4-Bis(4-amino-5-mercapto-1,2,4-triazol-3-ylsulfanyl)benzene
(14c). Colorless crystals (78%); mp 233ꢀC; IR (cmꢁ1): 3296,
3172 (NH2), 1299 (C═S); 1H NMR (DMSO): d 4.32 (s, 4H,
SCH2), 5.58 (s, 4H, NH2), 7.34 (s, 4H, ArH0s), 13.66 (s, 2H,
SH) ppm; ms: m/z (%) 398 (M+, 0.1), 340 (6), 313 (31.6), 262
(32), 123 (29), 81 (74.8), 69 (74.4), 55 (100). Anal. Calcd for
C12H14N8S4 (398.55): C, 36.16; H, 3.54; N, 28.11. Found: C,
36.02; H, 3.62; N, 28.23.
1,5-Bis(4-amino-5-mercapto-1,2,4-triazol-3-ylsulfanylmethyl)
naphthalene (14e). Colorless crystals (75%); mp 258–260ꢀC; IR
(cmꢁ1): 3297, 3160 (NH2), 1297 (C═S); 1H NMR (DMSO): d 4.48
(s, 4H, SCH2), 5.65 (s, 4H, NH2), 7.52–7.86 (m, 6H, ArH0s), 13.0
(s, 4H, SH) ppm; ms: m/z (%): 448 (M+, 0.2), 395 (4), 337 (11),
155 (62), 147 (24), 63 (100). Anal. Calcd for C16H16N8S4
(448.62): C, 42.84; H, 3.59; N, 24.98. Found: C, 42.96; H, 3.66;
N, 24.88.
9,10-Bis(4-amino-5-mercapto-1,2,4-triazol-3-ylsulfanylmethyl)
anthracene (14f). Colorless crystals (72%); mp 262–264ꢀC; IR
(cmꢁ1): 3299, 3084 (NH2), 1289 (C═S); 1H NMR (DMSO): d
5.38 (s, 4H, SCH2), 5.76 (s, 4H, NH2), 7.61–8.46 (m, 8H, ArH0s),
13.92 (s, 4H, SH) ppm; ms: m/z(%) 496 (M+, 0.5), 63 (67), 80
(65), 148 (8), 187 (3), 189 (17), 217 (100). Anal. Calcd for
C20H18N8S4 (498.68): C, 48.17; H, 3.64; N, 22.47. Found: C,
48.37; H, 3.44; N, 22.33.
Synthesis of bis(triazolothiadiazinyl)arenes (4, 8 and 11).
General procedure: To a solution of 1, 7, and 10 (10 mmol) in
ethanol/DMF (10:1) (50 mL) containing few drops of piperidine
was added phenacyl bromide 3 (20 mmol). The reaction mixture
was heated under reflux for 3 h. The solvent was then removed
in vacuo, and the remaining solid was diluted with cold
water (100 mL). The precipitate obtained was collected and
recrystallized from the proper solvent to give compounds 4, 8,
and 11, respectively.
1,4- Bis(6-phenyl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazol-3-yl)
benzene (4).
Colorless crystals (DMF), yield: 75%; mp
1
260ꢀC; IR (cmꢁ1): 1677 (C═N); H NMR (DMSO): d 5.18 (s,
4H, SCH2), 7.58–8.11 (m, 14H, ArH0s) ppm; ms: m/z (%)
506 (M+, 0.5), 500 (0.6), 452 (0.5), 351 (0.1), 138 (2), 95
(13), 82 (10), 81 (12), 79 (100). Anal. Calcd for
C26H18N8S2 (506.61): C, 61.64; H, 3.58; N, 22.21. Found:
Synthesis of bis(6-phenyl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazin-
3-ylsulfanyl)arenes (15a–15f).
Method A. General procedure: To a solution of 14a, c, e, f
(10 mmol) in EtOH/DMF [50 mL (30:20)] containing few drops of
piperidine, phenacyl bromide (20 mmol) was added. The reaction
mixture was heated under reflux for 3 h. The solvent was then
removed in vacuo, and the remaining solid was diluted with ice-
cold water (100 mL). The precipitate obtained was collected and
crystallized from the proper solvent to give compounds 15a, c, e, f.
C, 61.42; H, 3.38; N, 22.01.
1,4-Bis(6-phenyl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazol-
3-ylmethyl)benzene (8).
Colorless crystals (dioxan/H2O),
yield: 70%; mp 230ꢀC; IR (cmꢁ1): 1602 (C═N); 1H NMR
(DMSO): d 4.24 (s, 4H, CH2), 4.35 (s, 4H, SCH2), 7.22–7.95 (m,
14H, ArH0s)ppm; ms: m/z (%) 534 (M+, 0.4), 477 (0.1), 439
(0.4), 323 (0.7), 148 (100), 77 (15), 65 (41). Anal. Calcd for C28
H22N8S2 (534.67): C, 62.90; H, 4.15; N, 20.96. Found: C, 62.75;
H, 4.27; N, 20.78.
Method B.
General procedure: To a solution of 16
(50 mmol) in ethanol (50 mL) containing KOH (50 mmol) was
added the appropriate dibromo compounds 13a–f (25 mmol in
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

August 2014
Efficient Routes for the Synthesis of Novel Bis(s-triazolo[3,4-b][1,3,4]thiadiazines)
E181
10 mL DMF). The reaction mixture was heated under reflux for
3 h. The solvent was then removed in vacuo, and the remaining
solid was collected and crystallized from the proper solvent to
give compound of 15a–f.
Method C. General procedure: To a solution of 12 (50mmol)
in ethanol (50 mL) containing KOH (25 mmol), a solution of
the appropriate dihaloarenes 13a–f [25 mmol in DMF(10 mL)]
was added. The reaction mixture was heated under reflux for
3 h. Phenacyl bromide (50 mmol) was added, and the reaction
mixture was heated under reflux for further 3 h. The solvent
was then removed in vacuo, and the remaining solid was
collected and crystallized from the proper solvent to give
compound of 15a–f.
(s, 4H, SCH2), 5.28 (s, 4H, SCH2), 7.39–8.28 (m, 18H,
ArH0s) ppm; ms: m/z (%) 698 (M+, 0.5), 667 (0.4), 573 (0.4), 463
(1), 429 (2), 137 (12), 57 (100). Anal. Calcd for C36H26N8S4
(698.92): C, 61.87; H, 3.75; N, 16.03. Found: C, 61.77; H, 3.65;
N, 16.23.
Synthesis of 6-phenyl-5(1H)-thion-1,2,4 triazolo[3,4-b][1,3,4]
thiadiazin (16). To a solution of 12 (10mmol) in ethanol/DMF
(10:1) (50 mL) was added phenacyl bromide 3 (10 mmol). The
reaction mixture was heated under reflux for 3 h. The solvent
was then removed in vacuo, and the remaining solid was
diluted with cold water (100 mL). The precipitate obtained was
collected and crystallized from the acetic acid as colorless
crystals, yield: 50%; mp 245ꢀC; IR (cmꢁ1): 1275 (C═S), 1597
(C═N); 1H NMR (DMSO): d 4.40 (s, 2H, SCH2), 7.54–8.01
(m, 5H, ArH0s), 13.98 (s, 1H, SH) ppm; ms: m/z (%): 248
(M+, 16), 247 (100), 117 (59), 102 (26), 77 (72), 51 (33).
Anal. Calcd for C10H8N4S2 (248.33): C, 48.37; H, 3.25;
N, 22.56. Found: C, 48.12; H, 3.21; N, 22.33.
1,2-Bis(6-phenyl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazin-3-
ylsulfanylmethyl)benzene (15a).
Yellow crystals (butanol),
yield: 65% (method A), 60% (method B), 62% (method C); mp
170ꢀC; IR(cmꢁ1): 1449 (C═N); 1H NMR (DMSO): d 4.38 (s,
4H, SCH2), 4.64 (s, 4H, SCH2), 7.20–7.95 (m, 14H, ArH0s) ppm;
ms: m/z (%) 598 (M+, 3), 577 (21), 501 (2), 448 (1), 95 (73), 81
(84), 55 (100). Anal. Calcd for C28H22N8S4 (598.80): C, 56.16; H,
3.70; N, 18.71. Found: C, 56.03; H, 3.82; N, 18.68.
N,N0-(1,4-phenylene)bis(2-(4-amino-5-phenyl-4H-1,2,4-triazol-
3-ylthio)acetamide) (21). To solution of 20 (20 mmol) in EtOH
(50 mL) containing KOH (20 mmol), compound 19 (10 mmol) was
added. The reaction mixture was heated under reflux for 3 h. The
solvent was then removed in vacuo, and the remaining solid was
collected and crystallized from DMF to give pale yellow crystals,
yield: 80%; mp 265ꢀC; IR (cmꢁ1): 3294, 3185 (NH2), 1663
1,3-Bis
(6-phenyl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazin-3-
ylsulfanylmethyl)benzene (15b).
Yellow crystals (butanol),
yield: 65% (method B), 67% (method C); mp 168–170ꢀC; IR
1
(cmꢁ1): 1644 (C═N); H NMR (DMSO): d 4.40 (s, 4H, SCH2),
4.44 (s, 4H, SCH2), 7.23–7.96 (m, 14H, ArH0s) ppm; ms: m/z
(%) 598 (M+, 2), 105 (22), 130 (14), 159 (100), 190 (22), 271
(11), 302 (13), 348 (2), 436 (2), 506 (1). Anal. Calcd. for
C28H22N8S4 (598.80): C, 56.16; H, 3.70; N, 18.71. Found: C,
56.03; H, 3.56; N, 18.67.
1
(C═O); H NMR (DMSO): d 4.12 (s, 4H, SCH2), 6.18 (s, 4H,
NH2), 7.50–7.97 (m, 14H, ArH0s), 10.29 (s, 2H, NH) ppm. Anal.
Calcd for C26H24N10O2S2 (572.62): C, 59.53; H, 4.22; N, 24.46.
Found: C, 59.48; H, 4.13; N, 24.37.
N1,N4-bis(3-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-
6-yl)benzene-1,4-diamine (22). A solution of 21 in phosphorus
oxychloride (5 mL) was heated under reflux for 5 h. The excess of
phosphorus oxychloride was then removed in vacuo, and the
reaction mixture was poured over cursed ice (100 mL). The
solution was basified with 5% NaOH, and the remaining solid was
collected and crystallized from DMSO as pale yellow crystals
(70%); mp 253ꢀC; IR (cmꢁ1): 3289 (NH), 1569 (C═N); 1H NMR
(DMSO): d 4.00 (s, 4H, SCH2), 7.42–8.07 (m, 14H, ArH0s), 9.7
(br, 2H, NH) ppm; ms: m/z (%) 535 (M+, 30), 50 (72), 63 (70), 81
(100), 97 (23), 139 (34), 185 (30), 229 (12), 296 (3). Anal. Calcd
for C26H20N10S2 (534.64): C, 58.91; H, 3.76; N, 26.10. Found: C,
58.77; H, 3.66; N, 26.28.
1,4-Bis(6-phenyl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazin-3-
ylsulfanylmethyl)benzene (15c).
Yellow crystals (DMSO),
yield: 65% (method A), 60% (method B), 67% (method C); mp
1
268–270ꢀC; IR (cmꢁ1): 1682 (C═N); H NMR (DMSO): d 4.39
(s, 4H, SCH2), 4.45 (s, 4H, SCH2), 7.37–7.96 (m, 14H,
ArH0s)ppm; ms: m/z (%) 598 (M+, 5), 577 (17), 505 (1.8), 435
(1), 381 (1), 247 (81), 77 (56), 55 (100). Anal. Calcd for
C28H22N8S4 (598.80): C, 56.16; H, 3.70; N, 18.71. Found: C,
56.06; H, 3.04; N, 18.56.
1,3-Bis(6-phenyl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazin-3-
ylsulfanylmethyl)pyridine (15d).
Colorless crystals (dioxane),
yield: 60% (method B), 67% (method C); mp 210–212ꢀC; IR
(cmꢁ1): 1633 (C═N); 1H NMR (DMSO): d 4.41 (s, 4H,
SCH2), 4.54 (s, 4H, SCH2), 7.38–7.96 (m, 14H, ArH0s) ppm;
ms: m/z (%) 598 (M+, 3), 344 (5), 282 (4), 255 (3), 146 (10),
102 (19), 83 (7), 75 (14), 59 (100). Anal. Calcd for
C27H21N9S4 (599.78): C, 54.07; H, 3.53; N, 21.02. Found: C,
54.22; H, 3.48; N, 20.88.
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