Anodic formation of 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles and 2(3-aryl-5-methyl-1H-[1,2,4]triazol-1-yl)-5-aryl-1,3,4-thiadiazoles

Article abstract of DOI:10.1016/j.tet.2011.02.084

3,6-Disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles together with the unknown systems 2-(3-aryl-5-methyl-1H-[1,2,4]triazol-1-yl)-5-aryl-1,3,4- thiadiazoles were obtained by anodic oxidation, under aprotic conditions, of aryl aldehyde N-(5-aryl-1,3,

Full text of DOI:10.1016/j.tet.2011.02.084

Tetrahedron 67 (2011) 3076e3080
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Anodic formation of 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
and 2(3-aryl-5-methyl-1H-[1,2,4]triazol-1-yl)-5-aryl-1,3,4-thiadiazoles
*
Belen Batanero , Rebeca Saez, Fructuoso Barba
Department of Organic Chemistry, University of Alcala, Campus Universitario-Fac. Farmacia, N-II km. 33,6, 28871 Alcala de Henares, Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
3,6-Disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles together with the unknown systems 2-(3-aryl-
5-methyl-1H-[1,2,4]triazol-1-yl)-5-aryl-1,3,4-thiadiazoles were obtained by anodic oxidation, under
aprotic conditions, of aryl aldehyde N-(5-aryl-1,3,4-thiadiazol-2-yl) hydrazones. Mechanistic proposals
are given.
Received 23 February 2011
Accepted 28 February 2011
Available online 5 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Triazolo[3,4-b][1,3,4]thiadiazoles
Electrochemistry
Acetonitrile
Proposed mechanism
2-(1H-[1,2,4]Triazol-1-yl)-5-methyl-1,3,4-
thiadiazoles
1. Introduction
2. Results and discussion
1,2,4-Triazolo[3,4-b][1,3,4]thiadiazole ring system was first
made by Kanaoka.1
Because many of these 3,6-disubstituted derivatives possess in-
teresting and various biological activity (antibacterial, analgesic,
antiinflammatory, fungicidal, etc.)2 much attention has been devoted
to them.
Herein, we report the electrochemical synthesis of several 3,6-
disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles (2) together
with unknown 2-(3-aryl-5-methyl-1H-[1,2,4]triazol-1-yl)-5-aryl-
1,3,4-thiadiazoles (3), by anodic oxidation in acetonitrile of 2-ary-
lidene-1-(5-aryl-1,3,4-thiadiazol-2-yl)hydrazine (1) (Scheme 1), at
a platinum electrode.
There are two synthetic strategies for the preparation of these
interesting 3,6-disubstituted derivatives depending on the starting
material. In one case 5-substituted-4-amino-3-mercapto-1,2,4-tri-
azoles were used,3e7 while in the other case 5-substituted-2-
hydrazino-1,3,4-thiadiazoles3,8,9 were employed. The latter prepared
by condensation of carbonothioic dihydrazide with appropriated
aldehydes, followed by oxidative cyclization of the corresponding
bis-hydrazones with iron(III) chloride in ethanol8 or using silica-
supported dichlorophosphate as a recoverable dehydrant, under
microwave irradiations.10
To the best of our knowledge no reports have been published on
the electrosynthesis of 3,6-disubstituted 1,2,4-triazolo[3,4-b][1,3,4]
thiadiazole. However, electrochemical synthesis of 1,2,4-triazol-3-
thione derivatives has been performed by anodic oxidation of
N-thioamidohydrazones.11
Scheme 1.
The obtained yields of 2 and the unexpected 3 (not previously
described) are indicated in Table 1.
2-Arylidene-1-(5-aryl-1,3,4-thiadiazol-2-yl)hydrazine (1) were
experimentally prepared by oxidation with iron(III) chloride of the
corresponding bis-hydrazone, as already described by Shawali and
Sayed.8 However, together with the expected thiadiazoles (1),
4-(arylideneamino)-5-aryl-2H-1,2,4-triazole-3(4H)-thione (4) were
also obtained. The formation of 4 can be explained by donation, to
the benzyl cation, the electron pair from the nitrogen atom, instead
of the electron pair of the sulfur atom, as it is showed in Scheme 2
(Table 2). Heterocycles 1 and 4 were isolated and characterized by
* Corresponding author. Tel.: þ34 91 8852517; fax: þ34 91 8854686; e-mail
address: belen.batanero@uah.es (B. Batanero).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.084

B. Batanero et al. / Tetrahedron 67 (2011) 3076e3080
3077
Table 1
Yields of 2 and 3 in the anodic oxidation of 1
Ar
Yield of 2 (%)
Yield of 3 (%)
a: C6H5
60
58
54
55
64
62
22
31
12
11
16
30
b: 4-MeOeC6H4
c: 2-MeeC6H4
d: 4-MeeC6H4
e: 4-CleC6H4
f: 4-BreC6H4
S
N
H
N
Ar
iron(III) chloride/EtOH
-2e-/-1H+
N
H
a)
N
N
H
N
H
N
..
S
Ar
N
Scheme 4.
Ar
Ar
b)
a)
-H+
N
NH
b)
Finally, a direct anodic oxidation, starting from the initial bis-
hydrazones, obtained by condensation of carbonothioic dihy-
drazide with the appropriated aldehyde, led to a mixture of 1, 2, and
3, but in lower yields than the obtained in the anodic oxidation of 1.
Ar
N
N
-H+
S
Ar
N
N
N
Ar
N
H
S
4
1
Ar
3. Conclusion
Scheme 2.
We can conclude:
Table 2
Obtained yields of 1 and 4 in the oxidation of the corresponding bis-hydrazone with
iron(III) chloride
(a) Unexpected 4-(benzylideneamino)-5-phenyl-2H-1,2,4-triazo-
le-3(4H)-thione (4) together with expected 2-arylidene-1-(5-
aryl-1,3,4-thiadiazol-2-yl)hydrazine (1) were obtained in the
conventional oxidation of the corresponding bis-hydrazones
with iron(III) chloride.
Ar
Yield of 1 (%)
Yield of 4 (%)
a: C6H5
80
77
82
84
79
77
14
13
10
8
11
12
b: 4-MeOeC6H4
c: 2-MeeC6H4
d: 4-MeeC6H4
e: 4-CleC6H4
f: 4-BreC6H4
(b) The anodic oxidation of 1 or 4, afforded 3,6-disubstituted
1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles (2)
(c) A new family of 2-(3-aryl-5-methyl-1H-[1,2,4]triazol-1-yl)-
5-aryl-1,3,4-thiadiazoles (3) were electrochemically
obtained as secondary products when the reaction is carried
out under controlled potential conditions. However 3 is the
main product under galvanostatic conditions.
their spectroscopical data, summarized in the experimental section
of this paper.
Cyclic voltammetry of 1 in acetonitrile/LiClO4 as SSE (solvent-
supporting-electrolyte system) at a platinum anode showed an ir-
reversible anodic peak at þ2.75 V (vs Ag/Agþ). The anodic oxidation
of thiadiazoles 1 or triazoles 4 under potentiostatic conditions
(constant potential) led to the formation of same product 2,
through the proposed mechanism summarized in Scheme 3.
(d) The solvent, acetonitrile, plays an important roll in the
synthesis of the new compounds 3.
4. Experimental section
4.1. General
The electrolyses were carried out using an Amel potentiostat,
Model 552, connected with an electronic coulombimeter integrator
Amel, Model 721.
Mass spectra (EI, ionizing voltage 70 eV) were determined with
a HewlettePackard Model 5988A mass-selective detector equipped
with a HewlettePackard MS Chem Station. IR spectra were
obtained, as dispersions in KBr, on a PerkineElmer Model 583
spectrophotometer.
1H NMR and 13C NMR (300 MHz & 75.4 MHz, respectively)
spectra were recorded on a Varian Unity 300 apparatus with deu-
terochloroform as an internal standard. The chemical shifts are
given in parts per million.
Scheme 3.
Melting points were determined on a Reichert Thermovar
microhot stage apparatus, and are uncorrected. Elemental analyses
were performed on a Leco CHNS Model 932 analyzer.
However, the electrolysis of 1 produced, together with 2, the
new compounds 3, which formation involves an acetonitrile mol-
ecule. In this case, the oxidation of 1 to the benzyl cation is followed
by a Ritter reaction with the solvent, to give (after subsequent
intramolecular cyclization) the compound 3 (Scheme 4).
Surprisingly, when this reaction is performed under galvano-
static conditions (constant current of 200 mA) and at a graphite
anode, the yield of 3 was increased to 49e64% at expense on the
yield of 2.
4.2. General procedure
Treatment of carbonothioic dihydrazide with appropriated al-
dehydes gave rise to the corresponding bis-hydrazones quantita-
tively. 1,2,4-Triazolo[3,4-b][1,3,4]thiadiazole (1) was obtained by
conventional oxidation in EtOH of the bis-hydrazone with double

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B. Batanero et al. / Tetrahedron 67 (2011) 3076e3080
molecular amount of iron(III) chloride. After 30 min refluxing the
mixture, it was stirred overnight, removed the solvent by vacuum
and washed with water. Filtration of the crude product allowed the
isolation of 1, which was later crystallized in EtOH. The secondary
product 4 was obtained from the EtOH filtrate after being chro-
matographed on silica gel 60 (35e70mesh) in a (24ꢀ2.5 cm) col-
umn, using mixtures hexane/EtOAc (7:3) as eluent.
125.2, 128.5, 128.7, 129.0, 129.7, 130.8, 132.2, 132.7, 150.0, 162.7,
164.2. MS m/e (relative intensity) EI: 281 (Mþþ1, 23), 280 (Mþ, 12),
178 (100), 120 (12), 118 (13), 104 (16), 91 (8).
4.2.8. 4-(4-Methoxy-benzylideneamino)-5-(4-methoxyphenyl)-2H-
1,2,4-triazole-3(4H)-thione (4b). Compound 4b (13% yield). Mp
170e172 ꢁC. IR (KBr) (cmꢂ1): 3118, 2937, 1606, 1566, 1514, 1423,
n
1258, 1167, 1023, 827. 1H NMR (300 MHz, CDCl3)
d: 3.84 (s, 3H), 3.87
4.2.1. 2-Benzylidene-1-(5-phenyl-1,3,4-thiadiazol-2-yl)hydrazine
(s, 3H), 6.95 (d, 2H, J¼8.9 Hz), 6.97 (d, 2H, J¼8.5 Hz), 7.83 (d, 2H,
(1a). Compound 1a (80% yield). Mp 241e243 ꢁC [lit.10 242e244 ꢁC].
J¼8.9 Hz), 7.90 (d, 2H, J¼8.5 Hz), 9.75 (s, 1H). 13C NMR (75.4 MHz,
13C NMR (75.4 MHz, CDCl3)
d
: 126.9, 127.3, 128.5, 128.9, 129.2, 130.2,
CDCl3) d: 55.4, 55.5, 114.0, 114.5, 117.7, 124.7, 130.2, 130.9, 149.7,
130.4, 130.8, 133.6, 147.1, 171.4.
161.4, 162.5, 163.3, 164.4. MS m/e (relative intensity) EI: 341 (Mþþ1,
2), 340 (Mþ, 5), 207 (55), 148 (8), 135 (79), 133 (100), 103 (3). Anal.
Calcd for C17H16N4O2S: C, 60.00; H, 4.71; N, 16.47; S, 9.41. Found: C,
59.81; H, 4.99; N, 16.25; S, 9.70.
4.2.2. 2-(4-Methoxybenzylidene)-1-(5-(4-methoxyphenyl)-1,3,4-
thiadiazol-2-yl)hydrazine (1b). Compound 1b (77% yield). Mp
190e193 ꢁC [lit.10 182e184 ꢁC]. 1H NMR (300 MHz, CD3OD)
d: 3.75
(s, 3H), 3.77 (s, 3H), 6.82 (d, 2H, J¼8.6 Hz), 6.88 (d, 2H, J¼8.6 Hz),
4.2.9. 4-(2-Methyl-benzylideneamino)-5-(2-methylphenyl)-2H-
7.52 (d, 2H, J¼8.6 Hz), 7.64 (d, 2H, J¼8.6 Hz), 7.97 (s, 1H). 13C NMR
1,2,4-triazole-3(4H)-thione (4c). Compound 4c (10% yield). Mp
(75.4 MHz, CDCl3)
d
: 55.3, 55.4, 114.2, 114.5, 126.4, 128.3, 128.6,
194e196 ꢁC. IR (KBr) (cmꢂ1): 3101, 2937, 1594, 1508, 1355, 1281,
n
146.2, 161.3, 161.5, 170.0. MS m/e (relative intensity) EI: 341 (Mþþ1,
27), 340 (Mþ, 97), 253 (10), 207 (74), 152 (38), 133 (81), 121 (91), 91
(100).
969, 763. 1H NMR (300 MHz, CDCl3)
d: 2.28 (s, 3H), 2.40 (s, 3H),
7.10e7.39 (m, 7H), 7.68 (d, 1H, J¼7.6 Hz), 10.37 (s, 1H). 13C NMR
(75.4 MHz, CDCl3) d: 19.8, 20.3, 124.9, 125.7, 126.3, 127.6, 130.6,
130.9, 131.2, 132.2, 138.5, 139.9, 151.0, 161.7, 162.0. MS m/e (relative
intensity) EI: 309 (Mþþ1, 11), 308 (Mþ, 3), 233 (9), 192 (61), 158
(100), 131 (37), 116 (31), 90 (18). Anal. Calcd for C17H16N4S: C, 66.23;
H, 5.19; N, 18.18; S, 10.39. Found: C, 65.98; H, 4.95; N, 18.21; S, 10.23.
4.2.3. 2-(2-Methylbenzylidene)-1-(5-(2-methylphenyl)-1,3,4-thia-
diazol-2-yl)hydrazine (1c). Compound 1c (82% yield). Mp
210e212 ꢁC. IR (KBr) (cmꢂ1): 3187, 3057, 2780, 1600, 1583, 1442,
n
1069, 751, 711. 1H NMR (300 MHz, DMSO-d6)
3H), 7.20e7.40 (m, 6H), 7.6 (d, 1H, J¼6.8 Hz), 7.7 (d, 1H, J¼6.8 Hz),
8.38 (s, 1H), 12.4 (br s, 1H). 13C NMR (75.4 MHz, CDCl3)
: 19.1, 20.8,
d: 2.50 (s, 3H), 2.52 (s,
4.2.10. 4-(4-Methyl-benzylideneamino)-5-(4-methylphenyl)-2H-
d
1,2,4-triazole-3(4H)-thione (4d). Compound 4d (8% yield). Mp
22.1, 125.6, 125.7, 125.9, 128.7, 129.0, 129.1, 129.3, 130.4, 130.9, 131.4,
135.5, 135.6, 142.4, 169.3. MS m/e (relative intensity) EI: 309 (Mþþ1,
19), 308 (Mþ, 35), 190 (25), 150 (100), 148 (76), 118 (46), 91 (15).
Anal. Calcd for C17H16N4S: C, 66.23; H, 5.19; N,18.18; S,10.39. Found:
C, 65.99; H, 5.37; N, 17.88; S, 10.47.
230e231 ꢁC. IR (KBr) (cmꢂ1): 3120, 2925, 1602, 1508, 1274, 825,
n
812, 727, 667. 1H NMR (300 MHz, CDCl3)
7.20e7.40 (m, 4H), 7.60e7.80 (m, 4H), 10.3 (s, 1H). 13C NMR
(75.4 MHz, CDCl3) : 21.3, 127.6, 128.0, 128.6, 129.1, 129.5, 129.7,
d: 2.45 (s, 3H), 2.47 (s, 3H),
d
142.2, 143.0, 144.1, 149.0, 164.5. MS m/e (relative intensity) EI: 309
(Mþþ1, 19), 308 (Mþ, 19), 191 (100), 132 (39), 118 (71), 116 (19), 91
(47), 89 (22). Anal. Calcd for C17H16N4S: C, 66.23; H, 5.19; N, 18.18; S,
10.39. Found: C, 66.21; H, 4.89; N, 17.88; S, 10.47.
4.2.4. 2-(4-Methylbenzylidene)-1-(5-(4-methylphenyl)-1,3,4-thia-
diazol-2-yl)hydrazine (1d). Compound 1d (84% yield). Mp
247e249 ꢁC [lit.12 238e240 ꢁC]. 1H NMR (300 MHz, CD3OD)
d: 2.39
(s, 3H), 2.41 (s, 3H), 7.22 (d, 2H, J¼8.0 Hz), 7.27 (d, 2H, J¼8.0 Hz), 7.6
4.2.11. 4-(4-Chloro-benzylideneamino)-5-(4-chlorophenyl)-2H-1,2,4-
(d, 2H, J¼8.0 Hz), 7.75 (d, 2H, J¼8.0 Hz), 8.1 (s, 1H). 13C NMR
triazole-3(4H)-thione (4e). Compound 4e (11% yield). Mp
(75.4 MHz, CDCl3)
d
: 21.2, 21.3, 126.6, 126.7, 127.7, 129.3, 129.6, 131.1,
208e210 ꢁC. IR (KBr) (cmꢂ1): 3110, 2934, 1605, 1499, 1423, 1274,
n
140.0, 140.4, 145.1, 159.0, 170.4.
1093, 827, 717. 1H NMR (300 MHz, CDCl3)
d: 7.52e7.60 (m, 4H), 7.93
(d, 2H, J¼8.0 Hz), 8.00 (d, 2H, J¼8.0 Hz), 10.2 (s, 1H). 13C NMR
4.2.5. 2-(4-Chlorobenzylidene)-1-(5-(4-chlorophenyl)-1,3,4-thiadia-
(75.4 MHz, CDCl3) d: 127.8, 128.4, 129.1, 129.2, 129.9, 130.3, 135.4,
zol-2-yl)hydrazine (1e). Compound 1e (79% yield). Mp 222e224 ꢁC
137.3, 147.6, 161.4, 162.5. MS m/e (relative intensity) EI: 350 (Mþþ2,
6), 348 (Mþ, 8), 213 (37), 211 (100), 153 (34), 151 (77), 139 (31), 137
(65), 124 (18), 102 (19), 76 (20). Anal. Calcd for C15H10Cl2N4S: C,
51.57; H, 2.87; N, 16.04; S, 9.17. Found: C, 51.41; H, 3.03; N, 16.17; S,
8.96.
[lit.10 218e220 ꢁC]. 1H NMR (300 MHz, DMSO-d6)
d: 7.45 (d, 2H,
J¼7.7 Hz), 7.51 (d, 2H, J¼7.7 Hz), 7.64 (d, 2H, J¼7.7 Hz), 7.72 (d, 2H,
J¼7.7 Hz), 8.07 (s, 1H), 12.6 (br s, 1H). 13C NMR (75.4 MHz, CDCl3)
d:
127.6, 127.7, 128.4, 128.8, 132.5, 133.6, 134.1, 142.1, 156.0, 169.4.
4.2.6. 2-(4-Bromobenzylidene)-1-(5-(4-bromophenyl)-1,3,4-thiadia-
4.2.12. 4-(4-Bromo-benzylideneamino)-5-(4-bromophenyl)-2H-
zol-2-yl)hydrazine (1f). Compound 1f (77% yield). Mp 217e220 ꢁC.
1,2,4-triazole-3(4H)-thione (4f). Compound 4f (12% yield). Mp
IR (KBr)
1008, 816. 1H NMR (300 MHz, DMSO-d6)
1H), 12.4 (br s, 1H). 13C NMR (75.4 MHz, CDCl3)
n
(cmꢂ1): 3188, 3024, 2915, 1594, 1487, 1434, 1397, 1067,
214e216 ꢁC. IR (KBr) (cmꢂ1): 3104, 2930, 1590, 1497, 1421, 1272,
n
d
: 7.6e7.8 (m, 8H), 8.1 (s,
: 127.6, 127.7, 128.4,
1072, 1012, 822, 714. 1H NMR (300 MHz, DMSO-d6)
d: 7.70e7.80 (m,
d
4H), 7.80e7.87 (m, 4H), 9.87 (s, 1H). 13C NMR (75.4 MHz, DMSO-d6)
128.8, 132.5, 133.6, 134.1, 142.1, 156.0, 169.4. MS m/e (relative in-
tensity) EI: 440 (Mþþ4, 2), 438 (Mþþ2, 3), 436 (Mþ, 1), 367 (8), 257
(12), 186 (86), 184 (100), 120 (38), 102 (28), 89 (76), 74 (52). Anal.
Calcd for C15H10Br2N4S: C, 41.10; H, 2.28; N, 12.79; S, 7.31. Found: C,
40.84; H, 2.32; N, 12.67, S, 7.53.
d: 124.3, 126.5, 130.1, 130.3, 131.1, 131.6, 131.8, 132.0, 147.9, 162.5,
164.6. MS m/e (relative intensity) EI: 440 (Mþþ4, 3), 438 (Mþþ2, 6),
436 (Mþ, 3), 369 (10), 367 (18), 365 (10), 286 (10), 257 (100), 255
(72), 198 (22), 184 (60), 182 (60), 117 (22), 104 (50), 102 (75), 90 (31),
76 (36). Anal. Calcd for C15H10Br2N4S: C, 41.10; H, 2.28; N, 12.79; S,
7.31. Found: C, 40.89; H, 2.36; N, 12.82; S, 7.55.
4.2.7. 4-(Benzylideneamino)-5-phenyl-2H-1,2,4-triazole-3(4H)-thi-
one (4a). Compound 4a (14% yield). Mp 168e169 ꢁC [lit.13
4.3. General electrochemical procedure
168e172 ꢁC]. IR (KBr) (cmꢂ1): 3104, 2927, 1601, 1572, 1542, 1504,
n
1483, 1277, 759, 681. 1H NMR (300 MHz, CDCl3)
6H), 7.76e7.92 (m, 4H), 9.95 (s, 1H). 13C NMR (75.4 MHz, CDCl3)
d: 7.33e7.50 (m,
The electrochemical oxidation of 1 (1 mmol, 60 ml SSE) was
performed under potentiostatic conditions (a constant potential of
d:

B. Batanero et al. / Tetrahedron 67 (2011) 3076e3080
3079
þ2.7 V (vs Ag/Agþ) was applied), or under galvanostatic conditions
(constant current of 200 mA) in a concentric cell with two com-
partments separated by a low porosity (D4) glass frit diaphragm
and equipped with a magnetic stirrer. The temperature was
maintained constant at 20 ꢁC. A platinum plate electrode (or
a graphite electrode under galvanostatic conditions) was used as
the anode. A platinum plate electrode as the cathode and a Ag/AgCl
(sat) electrode as the reference. The SSE (solvent-supporting-elec-
trolyte system) was dry acetonitrile containing 0.1 M lithium per-
chlorate. The initial current of 180 mA decreased to 40 mA after
a charge consumption corresponding to a 2eꢂ/substrate molecule
process.
Once the reaction was finished the anodic solution was removed
under reduced pressure. The residue was extracted with ether/H2O.
The organic phase was dried over MgSO4 and concentrated by
evaporation. The resulting solid, containing 2 and 3, was chroma-
tographed on silica gel 60 (35e70 mesh) in a (28ꢀ2.5 cm) column,
using a mixture hexane/EtOAc (7:2) as eluent. The physical and
spectroscopical properties of the new obtained products are sum-
marized as follows:
C, 63.95; H, 4.07; N, 21.94; S, 10.03. Found: C, 64.37; H, 3.91; N,
21.77; S, 9.89.
4.3.8. 2-(5-Methyl-3-(4-methoxyphenyl)-1H-[1,2,4]triazol-1-yl)-5-
(4-methoxyphenyl)-1,3,4-thiadiazoles (3b). Compound 3b (31%
yield, 64% galvanost). Mp 172e174 ꢁC. IR (KBr) (cmꢂ1): 3040, 2925,
n
2853, 1606, 1505, 1384, 1252, 1175, 1030, 832, 753. 1H NMR
(300 MHz, CDCl3) d: 3.0 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 6.98e7.02
(m, 4H), 7.90 (d, 2H, J¼8.6 Hz), 8.07 (d, 2H, J¼8.6 Hz). 13C NMR
(75.4 MHz, CDCl3) d: 14.1, 55.3, 55.5, 114.1, 114.7, 121.9, 122.2, 128.3,
129.1, 155.0, 160.0, 161.2, 162.2, 166.7. MS m/e (relative intensity) EI:
380 (Mþþ1, 13), 379 (Mþ, 49), 338 (10), 246 (5), 177 (38), 159 (41),
151 (100), 133 (55), 108 (7), 103 (6). Anal. Calcd for C19 H17N5O2S: C,
60.16; H, 4.48; N, 18.47; S, 8.44. Found: C, 59.97; H, 4.62; N, 18.52; S,
8.65.
4.3.9. 2-(5-Methyl-3-(2-methylphenyl)-1H-[1,2,4]triazol-1-yl)-5-(2-
methylphenyl)-1,3,4-thiadiazoles (3c). Compound 3c (11% yield, 62%
galvanost). Mp 130e132 ꢁC. IR (KBr) (cmꢂ1): 3020, 2924, 2853,
n
1520, 1379, 1254, 1017, 765, 738. 1H NMR (300 MHz, CDCl3)
d: 2.60
(s, 3H), 2.62 (s, 3H), 3.0 (s, 3H), 7.20e7.40 (m, 6H), 7.65 (d, 1H,
4.3.1. 3,6-Diphenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (2a).
Compound 2a (60% yield). Mp 202e204 ꢁC [lit.4 204e205 ꢁC].
J¼8.0 Hz), 8.00 (d, 1H, J¼8.0 Hz). 13C NMR (75.4 MHz, CDCl3)
d: 15.0,
21.8, 22.1, 126.0, 126.5, 128.4, 128.5, 129.7, 129.8, 130.7, 130.8, 131.4,
131.9, 137.4, 137.6, 154.3, 161.4, 163.2, 166.6. MS m/e (relative in-
tensity) EI: 348 (Mþþ1, 26), 347 (Mþ, 34), 199 (100), 172 (13), 157
(47), 151 (34), 134 (17), 117 (38), 91 (26). Anal. Calcd for C19H17N5S:
C, 65.71; H, 4.90; N, 20.17; S, 9.22. Found: C, 65.88; H, 4.96; N, 20.41;
S, 9.41.
4.3.2. 3,6-Bis(4-methoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadia-
zole (2b). Compound 2b (58% yield). Mp 199e200 ꢁC [lit.8
200e201 ꢁC].
4.3.3. 3,6-Bis(2-methylphenyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadia-
zole (2c). Compound 2c (54% yield). Mp 116e118 ꢁC [lit.14
120e122 ꢁC].
4.3.10. 2-(5-Methyl-3-(4-methylphenyl)-1H-[1,2,4]triazol-1-yl)-5-
(4-methylphenyl)-1,3,4-thiadiazoles (3d). Compound 3d (11% yield,
49% galvanost). Mp 192e194 ꢁC. IR (KBr) (cmꢂ1): 3041, 2924, 2853,
n
4.3.4. 3,6-Bis(4-methylphenyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadia-
1505,1378,1265, 822, 746. 1H NMR (300 MHz, CDCl3)
d: 2.33 (s, 3H),
zole (2d). Compound 2d (55% yield). Mp 165e167 ꢁC. IR (KBr)
n
2.35 (s, 3H), 2.97 (s, 3H), 7.15e7.30 (m, 4H), 7.80 (d, 2H, J¼8.0 Hz),
(cmꢂ1): 3060, 2918, 1609, 1478, 1185, 969, 947, 816. 1H NMR
(300 MHz, CDCl3) : 2.44 (s, 6H), 7.27e7.37 (m, 4H), 7.72e7.82 (m,
2H), 8.22e8.30 (m, 2H). 13C NMR (75.4 MHz, CDCl3)
: 21.6, 21.7,
7.97 (d, 2H, J¼8.0 Hz). 13C NMR (75.4 MHz, CDCl3)
d: 15.1, 21.5, 22.7,
d
126.8, 127.5, 129.4, 130.1, 140.5, 142.2, 155.2, 160.4, 162.6, 167.2. MS
m/e (relative intensity) EI: 348 (Mþþ1, 13), 347 (Mþ, 42), 306 (10),
230 (13), 173 (13), 161 (24), 143 (34), 135 (100), 117 (33), 91 (21).
Anal. Calcd for C19H17N5S: C, 65.71; H, 4.90; N, 20.17; S, 9.22. Found:
C, 66.01; H, 4.87; N, 20.43; S, 9.24.
d
126.3, 127.0, 129.6, 130.1, 140.6, 142.2, 144.1, 143.7, 166.7. MS m/e
(relative intensity) EI: 307 (Mþþ1, 9), 306 (Mþ, 26), 162 (11), 136
(100), 118 (18), 89 (10). Anal. Calcd for C17H14N4S: C, 66.67; H,
4.58; N, 18.30; S, 10.46. Found: C, 66.77; H, 4.81; N, 18.09; S,
10.49.
4.3.11. 2-(5-Methyl-3-(4-chlorophenyl)-1H-[1,2,4]triazol-1-yl)-5-(4-
chlorophenyl)-1,3,4-thiadiazoles (3e). Compound 3e (16% yield, 57%
4.3.5. 3,6-Bis(4-chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
galvanost). Mp 230e233 ꢁC. IR (KBr) (cmꢂ1): 3089, 2922, 2852,
n
(2e). Compound 2e (64% yield). Mp 233e235 ꢁC [lit.15 235e236 ꢁC].
1524, 1499, 1409, 1374, 1260, 1114, 1088, 1012, 841, 832, 747. 1H NMR
(300 MHz, CDCl3)
d
: 3.1 (s, 3H), 7.49 (d, 2H, J¼8.6 Hz), 7.56 (d, 2H,
4.3.6. 3,6-Bis(4-bromophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
J¼8.6 Hz), 7.95 (d, 2H, J¼8.6 Hz), 8.13 (d, 2H, J¼8.6 Hz). 13C NMR
(2f). Compound 2f (62% yield). Mp 227e230 ꢁC. IR (KBr)
n
(cmꢂ1):
(75.4 MHz, CDCl3) d: 15.1, 127.8, 128.2, 128.8, 129.1, 129.4, 129.7,
3078,1589,1470,1397,1072,1010, 980, 959, 828. 1H NMR (300 MHz,
136.4, 137.9, 155.6, 160.7, 161.8, 166.0. MS m/e (relative intensity) EI:
391 (Mþþ4, 5), 389 (Mþþ2, 23), 387 (Mþ, 32), 348 (6), 346 (9), 252
(8), 250 (23), 183 (11), 181 (20), 165 (17), 163 (30), 157 (45), 155
(100), 139 (13), 138 (19), 102 (7). Anal. Calcd for C17H11Cl2N5S: C,
52.58; H, 2.83; N, 18.04; S, 8.25. Found: C, 52.77; H, 3.02; N, 18.23; S,
8.09.
CDCl3)
d
: 7.6e7.7 (m, 4H), 7.75 (d, 2H, J¼8.2 Hz), 8.20 (d, 2H,
J¼8.2 Hz). 13C NMR (75.4 MHz, CDCl3)
d: 124.5, 125.0, 127.8, 127.9,
128.1, 128.6, 132.3, 132.9, 144.1, 146.7, 166.2. MS m/e (relative in-
tensity) EI: 438 (Mþþ4, 12), 436 (Mþþ2, 24), 434 (Mþ, 11), 227 (12),
225 (12), 201 (100), 183 (88), 181 (86), 146 (19), 120 (46), 102 (55),
75 (37). Anal. Calcd for C15H8Br2N4S: C, 41.28; H, 1.83; N, 12.84; S,
7.34. Found: C, 41.51; H, 1.99; N, 12.81; S, 7.22.
4.3.12. 2-(5-Methyl-3-(4-bromophenyl)-1H-[1,2,4]triazol-1-yl)-5-(4-
bromophenyl)-1,3,4-thiadiazoles (3f). Compound 3f (30% yield, 60%
4.3.7. 2-(5-Methyl-3-phenyl-1H-[1,2,4]triazol-1-yl)-5-phenyl-1,3,4-
galvanost). Mp 238e240 ꢁC. IR (KBr) (cmꢂ1): 3060, 2924, 2853,
n
thiadiazoles (3a). Compound 3a (22% yield, 52% galvanost). Mp
1588, 1526, 1497, 1406, 1264, 1114, 1069, 1009, 835, 818, 745. 1H
180 ꢁC. IR (KBr)
n
(cmꢂ1): 3061, 2923, 1530, 1501, 1355, 1268, 761,
NMR (300 MHz, CDCl3)
d
: 3.1 (s, 3H), 7.68 (d, 2H, J¼8.6 Hz), 7.71 (d,
719, 688. 1H NMR (300 MHz, CDCl3)
3H), 7.44e7.50 (m, 3H), 7.88e7.94 (m, 2H), 8.07e8.12 (m, 2H). 13C
NMR (75.4 MHz, CDCl3) : 15.0, 126.9, 127.6, 128.8, 129.4, 129.2,
d: 3.0 (s, 3H), 7.38e7.44 (m,
2H, J¼8.6 Hz), 7.88 (d, 2H, J¼8.6 Hz), 8.06 (d, 2H, J¼8.6 Hz). 13C
NMR (75.4 MHz, CDCl3) d: 15.1, 124.8, 126.2, 128.1, 128.4, 128.9,
d
132.0, 132.6, 132.7, 155.6, 160.8, 162.0, 166.1. MS m/e (relative in-
tensity) EI: 479 (Mþþ4, 23), 477 (Mþþ2, 41), 475 (Mþ, 22), 436
(10), 296 (100), 294 (98), 209 (33), 207 (31), 201 (67), 199 (69), 183
(97), 146 (32), 120 (94), 102 (60), 75 (28). Anal. Calcd for
129.6, 130.4, 131.6, 155.4, 160.7, 162.5, 167.2. MS m/e (relative in-
tensity) EI: 320 (Mþþ1, 22), 319 (Mþ, 65), 278 (21), 216 (27), 158
(53), 146 (20), 121 (100),103 (12), 77 (11). Anal. Calcd for C17H13N5S:

3080
B. Batanero et al. / Tetrahedron 67 (2011) 3076e3080
3. Shaban, M. A. E.; Nasr, A. Z. Adv. Heterocycl. Chem. 1990, 49, 277e383.
4. Invidiata, F. P.; Furno, G.; Lampronti, I.; Simoni, D. J. Heterocycl. Chem. 1997, 34,
1255e1258.
C17H11Br2N5S: C, 42.77; H, 2.31; N, 14.67; S, 6.71. Found: C, 42.61;
H, 2.52; N, 14.44; S, 6.89.
5. Bai, Y.; Zhao, G.; Li, C.; Zhao, S.; Shi, Z. Synth. Commun. 2008, 38, 3311e3319.
6. Almajan, G. L.; Barbuceanu, S.-F.; Bancescu, G.; Saramet, I.; Saramet, G.; Dra-
ghici, C. Eur. J. Med. Chem. 2010, 45, 6139e6146.
Acknowledgements
7. Hu, L.-x; Li, D.-j. Heterocycl. Commun. 2010, 16, 73e77.
8. Shawali, A.; Sayed, A. R. J. Sulfur Chem. 2006, 27, 1e13.
9. Omar, A. M. M. E.; Aboul-Wafa, O. M. J. Heterocycl. Chem. 1986, 23, 1339e1341.
10. Li, Z.; Feng, X.; Zhao, Y. J. Heterocycl. Chem. 2008, 45, 1489e1492.
11. Chmekh, R.; Tapsoka, I.; Medini, H.; Maisonhaute, E.; Benkhoud, M. L.; Boujlel,
K. J. Electroanal. Chem. 2007, 599, 85e90.
This study was financed by the Spanish Ministry of Science and
Education CTQ2007-62612/BQU. B.B. thanks this Ministry for the I3
Program financial support.
References and notes
12. Hassan, A. A.; Mohamed, N. K.; Aly, A. A.; Mourad, A.-F. E. Monatsh. Chem. 1997,
128, 61e70.
13. Aliya. J. Indian Chem. Soc. 2008, 85, 926e929.
14. Li, Z.; Zhao, Y. Synth. Commun. 2009, 39, 3816e3824.
15. Eweiss, N. F.; Bahajaj, A. A. J. Heterocycl. Chem. 1987, 24, 1173e1182.
1. Kanaoka, M. Yakugaku Zasshi 1956, 76, 1133e1136.
2. Mathew, V.; Keshavayya, J.; Vaidya, V. P. Eur. J. Med. Chem. 2006, 41, 1048e1058
and references cited therein.