Synthesis of some novel 3-(4-Pyridinyl)-6-aryl-1,2,4-triazolo[3,4-b]-1,3,4- thiadiazoles

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Synthesis of Some Novel 3-(4-
Pyridinyl)-6-aryl- 1,2,4-triazolo[3,4-
b]-1,3,4-thiadiazoles
Akbar Mobinikhaledi a , Naser Foroughifar a & Mahsa Bayat a
a Department of Chemistry, University of Arak, Dr. Beheshti Ave,
Arak, 38156-8-8349, Iran
Version of record first published: 02 Aug 2011.
To cite this article: Akbar Mobinikhaledi, Naser Foroughifar & Mahsa Bayat (2011): Synthesis of
Some Novel 3-(4-Pyridinyl)-6-aryl- 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles, Organic Preparations and
Procedures International: The New Journal for Organic Synthesis, 43:4, 368-371
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Organic Preparations and Procedures International, 43:368–371, 2011
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2011.582011
Synthesis of Some Novel 3-(4-Pyridinyl)-6-aryl-
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles
Akbar Mobinikhaledi, Naser Foroughifar, and Mahsa Bayat
Department of Chemistry, University of Arak, Dr. Beheshti Ave, Arak
38156-8-8349, Iran
It is well known that the thiadiazole nucleus possesses interesting biological properties
such as antimicrobial,1–3 antiinflammatory,4–6 antituberculosis,7 antihypertensive,8,9 and
anticancer10 activities. Furthermore, the triazole nucleus11–13 and the pyridine14 unit have
attracted special attention from chemists due to their attractive biological activities. In-
corporating a pyridine ring into active compounds sometimes improves their biological or
physiological activities.15 Several heterocycles containing a thiadiazole or triazole moiety
have been reported;1–14 however, the synthesis of heterocyclic systems containing a thiadi-
azole nucleus fused to a pyridine-substituted triazole ring has rarely been reported.16–18 A
combination of these three rings may have a variety of structural and biological activities.
As a continuation of our studies on the synthesis of thiadiazoles,18 we now report the syn-
thesis of some novel 3-(4-pyridinyl)-6-aryl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles in good
yields and purity by a method that recommends itself for its simplicity and convenience.
Treatment of 4-pyridinecarboxylic acid hydrazide (1) with base and carbon disulfide
in ethanol gave potassium 4-pyridinyldithiocarbazate (2) in good yield. The carbazate was
then cyclized to triazole 3 by reaction with hydrazine hydrate under reflux. A variety of
aromatic carboxylic acids were subsequently treated with 3 (4:1 molar ratio) in the presence
of phosphorus oxychloride to produce the title compounds 4a-j as shown in Scheme 1.
The conversion of 3 to 4 proceeded without complication under simple reflux for 8–
10 h, and the products were readily isolated by pouring the reaction mixture onto crushed ice,
neutralization with bicarbonate and collection of the resulting solid (40–63% yields). One
recrystallization from ethanol-water was sufficient to obtain the analytical samples; with
aliphatic carboxylic acids only low yields (10–15%) were obtained. The elemental analyses
and spectrometric data for the compounds were consistent with the expected structures.
Notably, signals near 1600 cm−1 in the infrared spectra and δ 8.8 in the 1H-NMR spectra
indicated the presence of the pyridine moiety in all of the compounds prepared. Our method
suggests itself as a useful one for the further investigation of this uncommon combination
of heterocyclic units.
Submitted March 18, 2010.
Address correspondence to Akbar Mobinikhaledi, Department of Chemistry, University of Arak,
Dr. Beheshti Ave, Arak 38156-8-8349, Iran. E-mail: a-mobinikhaledi@araku.ac.ir
368

Novel 3-(4-Pyridinyl)-6-aryl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles
369
SH
N
CONHNHCSS-K+
NH2NH2
N
CONHNH2
N NH2
N
N
N
CS2/KOH
C2H5OH
ArCOOH
POCl3
N
OH-
N
S
N
N
N
1
2
4
3
Ar
Ar: a) C6H5, b) 2-MeC6H4, c) 3-MeC6H4, d) 4-ClC6H4, e) 2-ClC6H4, f) 4-BrC6H4,
g) 4-CH3OC6H4, h) 4-NO2C6H4, i) 3-NO2C6H4, j) 4-Cl-3-NO2C6H3
Scheme 1
Experimental Section
All chemicals used were obtained from Merck or Fluka Company. Melting points were
determined on an electrothermal digital melting point apparatus. The IR spectra were
1
acquired on a Unicom Galaxy series FT-IR 5000 spectrometer as KBr discs. H-NMR
spectra were recorded on a Brucker spectrophotometer (300 MHz) in DMSO-d6 using TMS
as an internal standard. Microanalyses were performed on an elemental analyzer (Elemental,
Vario EL III) at Arak University. Reactions were monitored by thin layer chromatography
using silica gel F254 aluminum sheets (Merck). Reactions involving evolution of H2S or use
of POCl3 must be carried out with due safety precautions in the hood.
Preparation of Potassium 4-Pyridinyldithiocarbazate (2)
4-Pyridinecarboxylic acid hydrazide (0.007 mol, 1 g) was treated with a solution of potas-
sium hydroxide (0.01 mol, 0.6 g) in ethanol (20 mL) at 0–5◦C with stirring. Carbon
disulfide (0.11 mol) was added slowly and the reaction mixture stirred overnight at room
temperature. The solution was concentrated on rotary evaporator to give a precipitate. The
yellow solid product was collected, washed with diethyl ether and air dried to yield 1.32 g
(75%) product. It was used directly for the next step without purification. FT-IR: 3348,
3362 (NH), 3041 (CH aromatic), 1610 (C = O) cm−1
.
3-(4-Pyridinyl)-4-amino-5-mercapto-1,2,4-triazole (3)
In an efficient hood, a suspension of potassium 4-pyridinyldithiocarbazate (0.02 mol, 0.5 g)
in water (4 mL) and 85% hydrazine hydrate (0.08 mol, 0.25 mL) was refluxed for 3 h. The
color of the reaction mixture changed to green with the evolution of the hydrogen sulfide
gas. The homogeneous reaction mixture was cooled to room temperature and diluted with
water (30 mL) and acidified to pH 7 with conc. hydrochloric acid. The white precipitate was
collected, washed with cold water (15–20 mL) and recrystallized from EtOH/H2O (1:1) to
yield 3.10 g (80%) of 3, mp. 250–251◦C [lit.19 mp. 259–261◦C]. FT-IR: 3491, 3528 (NH2),
1
2754 (SH) cm−1. H-NMR (DMSO-d6): δ 5.86 (s, 2H, NH2), 8.02 (m, 2H, H2), 8.75 (t,
J = 4.5 Hz, 2H, H1), 14.19 (s, 1H, SH) ppm.

370
Mobinikhaledi et al.
Table 1
Yields, mps, 1H NMR and Element Analysis for Compounds 4a-j.
Cmpda Yield
(%)
m.p.
(◦C)
1H NMRb
Combustion Analysis (Found)
(δ)
C
H
N
S
4a
53 246–247
7.68–8.84
(m, 9H, aromatic)
2.67
60.19 (60.25) 3.25 (3.50) 25.08 (25.15) 11.48 (11.39)
4b
54 183–185
61.41 (61.31) 3.79 (3.85) 23.88 (23.66) 10.93 (10.71)
(s, 3H, CH3),
7.48v8.83
(m, 8H, aromatic)
2.45
4c
58 228–229
61.41 (61.65) 3.79 (3.70) 23.88 (23.65) 10.93 (11.03)
(s, 3H, CH3),
7.53–8.86
(m, 8H, aromatic)
7.72–8.85
(m, 8H, aromatic)
7.60–8.82
(m, 8H, aromatic)
7.76–8.86
(m, 8H, aromatic)
3.85
4d
4e
4f
60 295–296
55 200–202
62 278–279
63 252–253
53.58 (53.81) 2.57 (2.51) 22.32 (22.53) 10.22 (10.14)
53.58 (53.41) 2.57 (2.71) 22.32 (22.54) 10.22 (10.11)
46.94 (46.66) 2.56 (2.63) 19.55 (19.49)
8.95 (8.98)
4g
58.23 (58.01) 3.59 (3.64) 22.64 (22.74) 10.37 (10.29)
(s, 3H, CH3),
7.11–8.82
(m, 8H, aromatic)
7.74–8.77
(m, 8H, aromatic)
7.74–8.87
(m, 8H, aromatic)
7.73–8.76
4h
4i
45 360–361
40 285–286
45 291–292
51.84 (51.69) 2.49 (2.54) 25.92 (25.70)
51.84 (52.05) 2.49 (2.70) 25.92 (25.74)
46.86 (46.59) 1.97 (2.02) 23.43 (23.51)
9.89 (9.98)
9.89 (9.81)
8.94 (9.07)
4j
(m, 7H, aromatic)
a
b
All compounds are white crystals except for 4f which is yellow. In DMSO-d6
General Preparation of 3-(4-Pyridinyl)-6-aryl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (4)
In an efficient hood, a mixture of 3-(4-pyridinyl)-4-amino-5-mercapto-1,2,4-triazole
(0.25 mol, 0.048 g), the corresponding carboxylic acid (1 mmol) in POCl3 (5 mL) was
refluxed for 8–10 h. The reaction mixture was poured slowly into crushed ice with stir-
ring and neutralized with solid potassium bicarbonate. The mixture was allowed to stand
overnight and the precipitate was collected and washed with cold water (10 mL). The crude
product was crystallized from ethanol-water. Physical and spectral data of compounds 4a-j
are shown in Table 1.
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