Highly efficient synthesis of 3,5-disubstituted 1,2,4-thiadiazoles using pentylpyridinium tribromide as a solvent/reagent ionic liquid

Article abstract of DOI:10.1080/17415993.2011.649757

In this paper, a facile and highly efficient synthesis of 3,5-disubstituted 1,2,4-thiadiazoles by oxidative dimerization of thioamides using pentylpyridinium tribromide is reported.

Full text of DOI:10.1080/17415993.2011.649757

Journal of Sulfur Chemistry
Vol. 33, No. 2, April 2012, 165–170
Highly efficient synthesis of 3,5-disubstituted 1,2,4-thiadiazoles
using pentylpyridinium tribromide as a solvent/reagent ionic
liquid
Hassan Zali-Boeinia, Arash Shokrolahib, Abbas Zalib* and Kamal Ghanib
aDepartment of Chemistry, University of Isfahan, PO Box 81746-73441, Isfahan, Islamic Republic of Iran;
bDepartment of Chemistry, Malek-Ashtar University of Technology, PO Box 83145-115, Shahin shahr,
Islamic Republic of Iran
(Received 25 October 2011; final version received 11 December 2011)
In this paper, a facile and highly efficient synthesis of 3,5-disubstituted 1,2,4-thiadiazoles by oxidative
dimerization of thioamides using pentylpyridinium tribromide is reported.
S
N
Ar
Ar
Ar
NH2
S
N
Br-
-
Br3
N
N
Br2
Keywords: 3,5-disubstituted 1,2,4-thiadiazoles; thiobenzamide; pentylpyridinium tribromide; oxidative
cyclization; ionic liquid
1. Introduction
1,2,4-Thiadazolesareimportantheterocycles, whichhavebeenthesubjectofgreatinterestbecause
of their biological activities (1). Very interesting therapeutic applications have been found in
*Corresponding author. Email: abbasazali@gmail.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2012 Taylor & Francis
http://dx.doi.org/10.1080/17415993.2011.649757
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166 H. Zali-Boeini et al.
the 1,2,4-thiadiazole system and its usefulness as a pharmacophore in medicinal chemistry has
prompted the advances in thechemistry of this system (2). A large number of 1,2,4-thiadiazoles
have been used and patented in the agricultural (3, 4) and medicinal industries (5–7). Also,
thiadiazole derivatives have shown good corrosion inhibitor effects in aggressive media (8–10).
The main synthetic route to obtain symmetrical 3,5-dialkyl/diaryl-1,2,4-thiadiazole deriva-
tives generally comprises an oxidation step of the thioamides followed by the cyclization to
the corresponding thiadiazole. Various oxidizing agents such as nitrous acid (11), hydrogen per-
oxide (12), thionyl chloride (13), a mixture of HCl–DMSO (14), pyridinium salt–DMSO (15),
polymer-supported diaryl selenoxide and telluroxide (16), organotellurium (17), p-toluenesulfinic
acid (18), phenyliodine (III) diacetate (19, 20), t-butyl hypochlorite (21), N-bromosuccinimide
(22), and o-iodoxybenzoic acid in the presence of tetraethylammonium bromide (23) have been
employed for this transformation. Although the above reagents provide efficient access to 1,2,4-
thiadiazoles, several drawbacks are associated with their utilization and many of these reagents are
poisonous or corrosive and can be difficult to manipulate on small scales. The formation of nitrile
and isothiocyanate by-products and tedious workup are also disadvantages of these protocols.
Room temperature ionic liquids (RTILs) are currently attracting considerable attention as poten-
tially benign solvents/reagents for organic transformations, and a large number of reactions have
been successfully performed using these solvents. They are non-volatile, have excellent chemical
and thermal solubility, and can solubilize a wide variety of substrates (24). Pentylpyridinium
tribromide is a non-volatile ionic liquid analog of bromine, which plays a dual role as a solvent
and a reagent and can be easily prepared from commercially available starting materials (25).
Herein, we report a rapid, mild, facile, and efficient method for the synthesis of symmetrical 3,5-
diaryl-1,2,4-thiadiazoles by oxidative dimerization of the corresponding thiobenzamides using
pentylpyridinium tribromide (Scheme 1).
S
N
Ar
Ar
Ar
NH2
S
N
Br-
-
Br3
N
N
Br2
Scheme 1. Oxidative dimerization of thioamides.
2. Results and discussion
As reported in Table 1, a variety of thiobenzamides successfully underwent oxidative dimerization
to form the corresponding 3,5-disubstituted 1,2,4-thiadiazoles using pentylpyridinium tribromide
as a non-volatile RTIL and as an alternative reagent to liquid bromine.All the reactions were clean
and smooth and proceeded without the formation of any tarry materials and were completed within
3–7 min, providing a high yield. The other advantage of the presented methodology lies in the fact
thatthereagentcanbereadilyrecoveredandreusedseveraltimes.Therecoveryandregenerationof
pentylpyridiniumtribromideinvolvedtheextractionoftheaqueouslayerfromthereactionmixture
withetherfollowedbytreatmentwithbromine.Then, theprecipitatedpentylpyridiniumtribromide

Journal of Sulfur Chemistry 167
Table 1. Rapid and efficient conversion of thioamides to 1,2,4-thiadiazole derivatives.
Entry
Ar
Time (min)
Yielda (%)
Reference
1
2
3
4
5
6
7
8
9
Ph
4
3
7
4
4
6
5
4
6
3
5
4
97
95
89
93
95
90
92
94
88
91
90
92
15
15
23
26
20
23
20
15
26
15
26
20
4-Me-C6H4
4-NO2-C6H4
3-Br-C6H4
4-Br-C6H4
2-Cl-C6H4
3-Cl-C6H4
4-Cl-C6H4
4-F-C6H4
10
11
12
4-MeO-C6H4
2,4-Cl2-C6H3
2-Furanyl
Note: aAll yields refer to isolated products.
was separated and washed twice with a small amount of water (10 ml) and dried under vacuum.
It is also remarkable that no bromination takes place at the aromatic rings during the reaction.
Weproposeaplausiblereactionpathway, asshowninScheme 2. Probably, thisreactionproceeds
viatheformationofN-bromothioamideandsubsequentdimerizationtogiveintermediateA, which
undergoes intermolecular cyclization to the corresponding 1,2,4-thiadiazole.
-
Br3
Br-
N
N
Br2
+
S
S
S
Ar
NH2
Br Br
Ar
NH2
Ar
Ar
NH Br
-HBr
-HBr
S
S
NH
Ar
N
NH
Ar
-H2S
A
N
S
Ar
Scheme 2. Proposed mechanism for the formation of 3,5-disubstituted 1,2,4-thiadiazoles.
3. Experimental
3.1. General experimental information
All the solvents were used as purchased from commercial sources. Thin-layer chromatography
(TLC) was performed using silica gel 60 F254 pre-coated plates (0.25 mm). All the products were
purified by crystallization to homogeneity by TLC analysis (single spot), using a UV lamp and/or
iodine and/or CAN or basic KMnO4 for detection purposes. NMR spectra were recorded on
500 MHz spectrometers. 1H and 13C NMR chemical shifts are reported as δ using residual solvent
as an internal standard.

168 H. Zali-Boeini et al.
3.2. General procedure for the preparation of pentylpyridinium tribromide
Bromine (64.48 g, 404.7 mmol) was added over 30 min to solid crushed pentylpyridinium bromide
(93.07 g, 404.4 mmol) under mechanical stirring and cooling in a water bath affording a deep red
liquid. After stirring for 2 h, the liquid was left in vacuo overnight (yield, 156 g (99%); melting
point, 0◦C).
3.3. General procedure for the preparation of thiobenzamides
Method A. In a round-bottomed flask, the benzamide derivative (5 mmol) was dissolved in dry
THF (20 ml) and then P2S5 (1.12 g, 5 mmol) was added and the mixture was heated at 65◦C for
3 h. Thereafter, the reaction mixture was cooled, poured in NaHCO3 (10%, 50 ml), and stirred
for 30 min. Then, the resulting yellow solid was filtered, dried, and recrystallized from EtOAc to
give thiobenzamide as light yellow prisms.
MethodB. Inaround-bottomedflask, amixtureofthebenzonitrilederivative(5 mmol), (NH4)2S
(20%, 5 ml), and an ammonia solution (32%, 2 ml) was dissolved (or suspended) in EtOH (5 ml)
and stirred at room temperature for 16 h. Thereafter, water (10 ml) was added to the mixture and
the precipitated compound was filtered. Then, the resulting crude thiobenzamide derivative was
recrystallized from EtOAc–hexane to obtain pure compounds as yellow prisms.
3.4. General procedure for the preparation of 3,5-diaryl-1,2,4-thiadiazole
Finely pulverized thiobenzamide (10 mmol) and pentylpyridinium tribromide (10 mmol, 3.90 g)
were mixed and the resulting orange syrup was stirred for the times given in Table 1. At the start
of the reaction, the reaction mixture was yellow and it turned to a pale yellow after completion
of the reaction. Thereafter, 20 ml water was added to the reaction mixture. Then, the precipitated
compound was filtered and crystallized in ethanol (or ethanol–chloroform) to obtain pure target
compounds as white to light yellow needles and in good to excellent yields.
It is worthwhile to note that the ionic liquid pentylpyridinium bromide was recycled from the
reaction mixture and the reagent was regenerated by the direct action of bromine. The effectiveness
of this recycling and regenerating process was tested and found effective for up to six cycles.
3.5. Spectroscopic data for compounds
3.5.1. 3,5-Diphenyl-1,2,4-thiadiazole (Entry 1)
1
White needles (EtOH), m.p. 91–93◦C; H NMR (500 MHz, CDCl3): 8.43 (d, J = 8.0 Hz, 2H),
8.10 (d, J = 7.5 Hz, 2H), 7.52–7.60 (m, 6H); 13C NMR (125 MHz, CDCl3): 185.8, 174.1, 132.6,
130.7, 130.3, 129.2, 128.7, 128.5, 127.5.
3.5.2. 3,5-Di-p-tolyl-1,2,4-thiadiazole (Entry 2)
White crystals (EtOH), m.p. 129–131◦C; 1H NMR (500 MHz, CDCl3): 8.31 (d, J = 8.1 Hz, 2H),
7.98 (d, J = 8.1 Hz, 2H), 7.34–7.37 (m, 4H), 2.51 (s, 3H), 2.48 (s, 3H); 13C NMR (125 MHz,
CDCl3): 180.2, 171.3, 140.6, 138.3, 137.8, 131.3, 129.4, 128.3, 127.5, 21.8, 21.6.
3.5.3. 3,5-Bis(4-nitrophenyl)-1,2,4-thiadiazole (Entry 3)
1
Light yellow needles (EtOH–CHCl3), m.p. 201–202◦C; H NMR (500 MHz, CDCl3): 8.63 (d,
J = 8.2 Hz, 2H), 8.45 (d, J = 8.2 Hz, 2H), 8.43 (d, J = 8.2 Hz, 2H), 8.30 (d, J = 8.2 Hz, 2H); 13
C
NMR (125 MHz, CDCl3): 187.4, 173.3, 148.2, 139.8, 128.9, 126.8, 126.4, 125.8, 123.5, 121.5.

Journal of Sulfur Chemistry 169
3.5.4. 3,5-Bis(3-bromophenyl)-1,2,4-thiadiazole (Entry 4)
White crystals (EtOH–CHCl3), m.p. 138–140◦C; 1H NMR (500 MHz, CDCl3): 8.51 (s, 1H), 8.32
(d, J = 8.7 Hz, 1H), 8.21 (s, 1H), 7.93 (dd, J = 8.7, 1.5 Hz, 1H), 7.60–7.68 (m, 2H), 7.35–7.42
(m, 2H); 13C NMR (125 MHz, CDCl3): 186.8, 172.4, 134.9, 134.5, 133.4, 130.8, 130.3, 126.9,
126.1, 123.4, 122.9. Anal. calcd for C14H8Br2N2S: C, 42.45; H, 2.04; N, 7.07; S, 8.10. Found: C,
42.28; H, 1.99; N, 7.15; S, 8.31.
3.5.5. 3,5-Bis(4-bromophenyl)-1,2,4-thiadiazole (Entry 5)
White crystals (EtOH–CHCl3), m.p. 167–169◦C; H NMR (500 MHz, CDCl3): 8.24 (d, J =
1
8.5 Hz, 2H), 790 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 6.9 Hz, 2H), 6.64 (d, J = 6.9 Hz, 2H); 13C
NMR (125 MHz, CDCl3): 187.2, 172.9, 132.8, 132.3, 131.6, 129.8, 129.5, 128.8, 126.6, 125.1.
Anal. calcd for C14H8Br2N2S: C, 42.45; H, 2.04; N, 7.07; S, 8.10. Found: C, 42.30; H, 2.01; N,
7.10; S, 8.25.
3.5.6. 3,5-Bis(2-chlorophenyl)-1,2,4-thiadiazole (Entry 6)
White crystals (EtOH), m.p. 93–95◦C; H NMR (500 MHz, CDCl3): 8.65 (td, J = 7.2, 2.1 Hz,
1
1H), 8.05 (td, J = 7.2, 2.2 Hz, 1H), 7.55–7.60 (m, 2H), 7.46–7.48 (m, 2H), 7.40–7.42 (m, 2H); 13
C
NMR (125 MHz, CDCl3): 183.1, 173.2, 133.8, 133.3, 132.3, 132.1, 130.9, 130.8, 130.7, 129.6,
127.5, 126.8. Anal. calcd for C14H8Cl2N2S: C, 54.74; H, 2.62; N, 9.12; S, 10.44. Found: C, 54.51;
H, 2.45; N, 9.05; S, 10.55.
3.5.7. 3,5-Bis(3-chlorophenyl)-1,2,4-thiadiazole (Entry 7)
White crystals (EtOH–CHCl3), m.p. 128–129◦C; 1H NMR (500 MHz, CDCl3): 8.39 (s, 1H), 8.27
(d, J = 7.0 Hz, 1H), 8.07 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.52–7.54 (m, 1H), 7.43–7.49 (m,
3H); 13C NMR (125 MHz, CDCl3): 186.9, 172.5, 135.5, 134.8, 134.3, 132.1, 132.0, 130.6, 130.0,
128.5, 127.3, 126.4, 125.7. Anal. calcd for C14H8Cl2N2S: C, 54.74; H, 2.62; N, 9.12; S, 10.44.
Found: C, 54.60; H, 2.51; N, 9.10; S, 10.61.
3.5.8. 3,5-Bis(4-chlorophenyl)-1,2,4-thiadiazole (Entry 8)
1
White crystals (EtOH–CHCl3), m.p. 162–164◦C; H NMR (500 MHz, CDCl3): 8.32 (d, J =
8.6 Hz, 2H), 8.99 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H); 13C
NMR (125 MHz, CDCl3): 187.0, 172.9, 135.7, 134.8, 131.3, 129.7, 129.4, 128.9, 127.7, 126.8.
3.5.9. 3,5-Bis(4-fluorophenyl)-1,2,4-thiadiazole (Entry 9)
White crystals (EtOH), m.p. 186–188◦C; 1H NMR (500 MHz, CDCl3): 8.38 (ddd, J = 12.2, 6.7,
3.3 Hz, 2H), 8.05 (ddd, J = 11.9, 5.2, 2.8 Hz, 2H), 7.16–7.24 (m, 4H); 13C NMR (125 MHz,
CDCl3): 187.0, 172.8, 166.0, 165.2, 163.9, 163.2, 130.4, 129.6, 116.5, 115.7. Anal. calcd for
C14H8F2N2S: C, 61.30; H, 2.94; N, 10.21; S, 11.69. Found: C, 61.21; H, 2.80; N, 10.02; S, 11.80.
3.5.10. 3,5-Bis(4-methoxyphenyl)-1,2,4-thiadiazole (Entry 10)
1
Pale yellow needles (EtOH–CHCl3), m.p. 138–139◦C; H NMR (500 MHz, CDCl3): 8.33 (dd,
J = 6.9, 2.0 Hz, 2H), 7.99 (dd, J = 6.8, 2.0 Hz, 2H), 7.00–7.03 (m, 4H), 3.90 (s, 3H), 3.89 (s,

170 H. Zali-Boeini et al.
3H); 13C NMR (125 MHz, CDCl3): 180.4, 171.6, 162.9, 136.7, 134.5, 133.5, 132.6, 126.9, 114.5,
113.1, 113.0, 57.7, 57.5.
3.5.11. 3,5-Bis(2,4-dichlorophenyl)-1,2,4-thiadiazole (Entry 11)
1
White needles (EtOH–CHCl3), m.p. 133–134◦C; H NMR (500 MHz, CDCl3): 8.57 (d, J =
8.7 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), (d, J = 2.1 Hz, 1H), (d, J = 2.1 Hz, 1H), (dd, J = 8.7,
2.1 Hz, 1H), (dd, J = 8.4, 2.1 Hz, 1H); 13C NMR (125 MHz, CDCl3): 182.3, 173.2, 138.0, 136.4,
136.3, 134.4, 134.2, 133.1, 131.4, 130.8, 130.3, 120.7, 128.1, 127.2.Anal. calcd for C14H6Cl4N2S:
C, 44.71; H, 1.61; Cl, 37.71; N, 7.45; S, 8.53. Found: C, 44.60; H, 1.54; N, 7.37; S, 8.74.
3.5.12. 3,5-Di(furan-2-yl)-1,2,4-thiadiazole (Entry 12)
White needles (EtOH), m.p. 104–106◦C; 1H NMR (500 MHz, CDCl3): 7.94 (d, J = 3.6 Hz, 1H),
7.70 (d, J = 3.7 Hz, 1H), 7.59 (d, J = 5.1 Hz, 1H), 7.46 (d, J = 5.0 Hz, 1H), 7.13–7.22 (m, 2H);
13C NMR (125 MHz, CDCl3): 185.4, 171.1, 158.9, 151.4, 151.0, 147.6, 116.9, 116.7, 112.3.
Acknowledgement
We are grateful to the research council Malek-Ashtar University of Technology for partial support of this work.
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