TCT-DMSO/[bmim]BF4: A novel promoter system for the synthesis of 3,5-diaryl-1,2,4-thiadiazoles at ambient temperature

Article abstract of DOI:10.1002/jhet.261

An efficient and practical procedure for direct synthesis of 3,5-diaryl-1,2,4-thiadiazoles by thioamides with 2,4,6-trichloro-1,3,5-triazine (TCT) and dimethylsulfoxide using 1-butyl-3-methylimidazolium tetrafluoroborate as an eco-friendly reaction medium

Full text of DOI:10.1002/jhet.261

226
TCT-DMSO/[bmim]BF4: A Novel Promoter System for the
Synthesis of 3,5-Diaryl-1,2,4-thiadiazoles at Ambient
Temperature
Vol 48
Ahmad R. Khosropour* and Jalil Noei
Catalysis Division, Department of Chemistry, University of Isfahan, Isfahan 81746-73441, Iran
*E-mail: khosropour@chem.ui.ac.ir
Received April 28, 2009
DOI 10.1002/jhet.261
Published online 6 October 2010 in Wiley Online Library (wileyonlinelibrary.com).
An efficient and practical procedure for direct synthesis of 3,5-diaryl-1,2,4-thiadiazoles by thioamides
with 2,4,6-trichloro-1,3,5-triazine (TCT) and dimethylsulfoxide using 1-butyl-3-methylimidazolium tet-
rafluoroborate as an eco-friendly reaction medium under ambient temperature is described. This protocol
can be considered as a new procedure for 3,5-diaryl-1,2,4-thiadiazoles synthesis.
J. Heterocyclic Chem., 48, 226 (2011).
INTRODUCTION
RESULTS AND DISCUSSION
1,2,4-Thiadiazole nucleus constitutes the core units of
many natural products [1]. Although, currently, the only
commercial 1,2,4-thiadiazole drug is the antibiotic cefo-
zopram [2], there are a number of synthetic products
related to this system with a broad range of biological
activities concerning central nervous system (CNS) [3],
G-protein coupled receptors [4], inflammation [5], cardi-
ovascular system [6], or antibiotic activity [7]. The anti-
oxidant and muscarinic receptor binding properties of a
family of 1,2,4-thiadiazole derivatives has also shown
acetylcholinesterase inhibitory activity [3]. A number of
derivatives were described as the first non-ATP competi-
tive glycogen synthase kinase 3b inhibitors [8]. Also,
the properties of 1,2,4-thiadiazoles as thiol trapping
agents have been recently reviewed [9].
In recent years, 2,4,6-trichloro-1,3,5-triazine (TCT)
has invoked enormous interest in various organic trans-
formations [12]. Moreover, ionic liquids (ILs) have
emerged extensively as a novel eco-friendly reaction
media for many organic syntheses [13]. In such perspec-
tive, in the combination with our recent lies on the
design of new synthetic methodologies [14] and devel-
opment of useful tactics and strategies for the synthesis
of heterocyclic compounds [15], especially in ILs [16],
we report, herein, a novel and efficient procedure using
of TCT-DMSO as a new promoter system in [bmim]BF4
for direct synthesis of 3,5-diaryl-1,2,4-thiadiazoles from
arylthioamids (Scheme 1).
To the best of our knowledge; there is no report on
the oxidative dimerization reaction with TCT-DMSO in
ionic liquid. At the onset of this work, to explore the
scope of this method, we used thiobenzamide as a
model, and the role of various conditions on the reaction
system was investigated (Table 1). We found that the
optima ratio of thioamide/TCT/DMSO is about 1:0.3:1
(Table 1, entry 5). Further investigations revealed that
reducing the loading of TCT to 0.25 equiv gave the
desired product in a lower yield of 79% (Table 1, entry
4). The use of 1 equiv of DMSO was also found to be
necessary for this transformation to proceed smoothly;
when DMSO was reduced to 0.9 equiv, a slightly lower
product yield of 81% was afforded (Table 1, entry 6).
To determine the most appropriate solvent, the reac-
tion was examined using different ILs and also using
Traditional methods for the synthesis of 3,5-diaryl-
1,2,4-thiadiazoles limited to the oxidative dimerization
reaction of thioamides with 1-methyl pyridinium chlo-
ride, benzoyl chloride, or acetyl chloride in chlorinated
organic solvents [10]. Recently, these compounds have
also been prepared by stoichiometric amount of
PhI(OAC)2 at 70ꢀC [11]. However, these methods are
not quite satisfactory in view of using large excess of
reagents, long reaction times, harsh reaction conditions,
and also involvement of toxic solvents such as acetoni-
trile or dichloromethane. Hence, there is a need to de-
velop a convenient, simple, rapid, and environmentally
friendly method for the synthesis of these important
heterocyclic compounds.
C
V
2010 HeteroCorporation

January 2011
TCT-DMSO/[bmim]BF4: A Novel Promoter System for the Synthesis
of 3,5-Diaryl-1,2,4-thiadiazoles at Ambient Temperature
227
Scheme 1
Table 2
Synthesis of 3,5-diphenyl-1,2,4-thiadiazoles through oxidation
condensation reaction promoted with TCT-DMSO in [bmim]BF4 as a
room temperature ionic liquid.
Entry
Ar
Time (min)
Yield (%)a
a
b
c
d
e
f
C6H5
4-FC6H4
10
10
10
10
10
10
10
10
10
10
12
96
94
95
93
93
92
94
90
93
90
91
traditional solvents such as ethanol, acetonitrile, and
chloroform. The results are summarized in Table 1.
Choosing an appropriate solvent is of crucial importance
for successful synthesis. [bmim]BF4 and [bmim]OTf
were the best solvents in terms of yields (Table 1,
entries 5 and 7). However, [bmim]BF4 was favored
as water could be used for the work-up. Interestingly,
we observed that combination of TCT-DMSO in
[bmim]BF4 is essential for this transformation that
attempts to carry out the reactions, in the absence of
each of these almost did not yield the product. Another
important factor was the reaction temperature.
4-ClC6H4
4-BrC6H4
3-BrC6H4
2,4-Cl2C6H3
3-ClC6H4
2-ClC6H4
4-CH3OC6H4
4-BnOC6H4
2-furyl
g
h
i
j
k
a Yields refer to isolated pure products.
yields. Acid sensitive thioamides such as 2-furylthioa-
mide also formed the corresponding thiadiazole quanti-
tatively (Table 2, entry k).
The experiments were run from 0 to 40ꢀC. We found
that those conducted at room temperature (23–25ꢀC)
afforded almost quantitative yields, whereas at 40ꢀC
some by-products were observed. The experimental pro-
cedure for this transformation is remarkably straightfor-
ward and does not require the use of toxic organic sol-
vents or inert atmospheres. The structures of the prod-
Based on the earlier experimental results and the liter-
ature [10], we propose a plausible reaction pathway, as
shown in Scheme 2.
Addition of DMSO to TCT in [bmim]BF4 causes the
oxidation of thioamide to N-chlorothioamide. Nucleo-
philic attack by sulfur of another molecule of thioamide
to N-chlorothioamide gives the intermediate (A) that on
further rapid oxidation gives the product.
1
ucts were established by H NMR, 13C NMR, IR, and
mass spectrum. The use of these optimal experimental
conditions to the reactions of different arylthioamides
containing both electron-donating and electron-with-
drawing groups in the aromatic rings was found to
undergo the conversion smoothly (Table 2, entries a–j).
The reaction proceeded at room temperature, and the
products were formed within 10–12 min in excellent
In conclusion, we have presented a new, mild, effi-
cient, and convenient method for the preparation of 3,5-
diaryl-1,2,4-thiadiazoles through oxidative dimerization
using combination of TCT and DMSO in ionic liquid.
Moreover, in comparison to the previous methods, this
protocol design a unique rut for the efficient synthesis
of 3,5-diphenyl-1,2,4-thiadiazoles at room temperature
using a novel promoter system. Also, we have shown
Table 1
Optimization of conditions in the synthesis of
3,5-diphenyl-1,2,4-thiadiazole.
TCT:DMSO
equiv
Time
(min)
Yield
(%)b
Scheme 2
Entry
Solventa
1
2
0.1:1
0.15:1
0.2:1
0.25:1
0.3:1
0.3:0.9
0.3:1
0.3:1
0.3:1
0.3:0
0.3:1
0.3:1
0.3:1
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]OTf
[bmim]PF6
PYRTFSIc
[bmim]BF4
CH3CN
10
10
10
10
10
10
10
10
10
60
60
60
60
18
54
75
79
96
81
95
42
60
0
3
4
5
6
7
8
9
10
11
12
13
65
50
45
EtOH
CHCl3
a 2 mL.
b Isolated yield.
c N-butyl-N-methylpyrrolidinium bi(trifluoromethanesulfonyl)imide.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

228
A. R. Khosropour and J. Noei
Vol 48
H, 2.62; N, 9.12; S, 10.44. Found: C, 54.60; H, 2.59; N, 9.04;
S, 10.29.
3,5-Bis(3-chlorophenyl)[1,2,4]thiadiazole. Solid, mp 123–
that the method is tolerant to a variety of functional
groups. By using this protocol, we synthesized target
molecules in excellent yields. The details of synthetic
applications of this methodology are being further stud-
ied in our laboratory.
1
125ꢀC; H NMR (500 MHz, CDCl3) d 8.39 (d, J ¼ 1.6 Hz, 1
H), 8.27 (dd, J ¼ 6.9 Hz, 1 H), 8.07 (d, J ¼ 1.7 Hz, 1 H),
7.89 (d, J ¼ 7.6 Hz, 1 H), 7.54–7.42 (m, 4 H). 13C NMR (125
MHz, CDCl3) d 186.9, 172.5, 135.5, 134.8, 134.2, 132.0,
131.9, 130.6, 130.5, 130.0, 128.5, 127.3, 126.4, 125.6. Anal.
Calcd. For C14H8Cl2N2S: C, 54.74; H, 2.62; N, 9.12; S, 10.44.
Found: C, 54.51; H, 2.62; N, 9.15; S, 10.25.
EXPERIMENTAL
General procedure for the synthesis of 3,5-diaryl-1,2,4-
thiadiazoles by thioamides promoted with TCT and dime-
thylsulfoxide in [bmim]BF4. To a stirred solution of arylth-
ioamide (1 mmol) in [bmim]BF4 (2 mL) at r.t. was added TCT
(0.0554 g, 0.3 mmol) and DMSO (0.078 g, 1 mmol). The reac-
tion mixture was stirred magnetically at room temperature for
the specified time (see Table 2) until arylthioamide was com-
pletely disappeared (the progress of the reaction was followed
by TLC). When the reaction was completed, quenched with
ice water (10 mL) and stirred at room temperature for 10 min.
The above mixture was extracted with ethyl acetate (3 ꢁ 5
mL), and the organic layers were combined and washed with
brine. After dryness and concentration in vacuo, the residue
was chromatographied on silica gel (n-heptane/ethyl acetate as
eluent) to afford the pure product in 90–96% yield.
3,5-Diphenyl-[1,2,4]thiadiazole. Solid, mp 81–83ꢀC; 1H
NMR (500 MHz, CDCl3) d 8.41 (br s, 2 H), 8.07 (br s, 2 H),
7.54–7.50 (m, 6 H). 13C NMR (125 MHz, CDCl3) d 182.1,
174.5, 133.5, 130.9, 130.9, 130.6, 131.1, 129.2, 129.2, 128.7,
127.5, 127.5, 129.2, 129.2. Anal. Calcd. For C14H10N2S: C,
70.56; H, 4.23; N, 11.76; S, 13.46. Found: C, 70.60; H, 4.20;
N, 11.77; S, 13.43.
3,5-Bis(2-chlorophenyl)[1,2,4]thiadiazole. Solid, mp 85–
1
86ꢀC; H NMR (500 MHz, CDCl3) d 8.65 (m, 1 H), 8.05 (m,
1 H), 7.60–7.55 (m, 2 H), 7.48–7.46 (m, 2 H), 7.42–7.40 (m, 2
H); 13C NMR (125 MHz, CDCl3) d 183.0, 173.2, 133.8, 133.3,
132.2, 132.1, 132.0, 130.9, 130.7, 130.6, 130.4, 129.6, 127.4,
126.7. Anal. Calcd. For C14H8Cl2N2S: C, 54.74; H, 2.62; N,
9.12; S, 10.44. Found: C, 54.42; H, 2.82; N, 9.35; S, 10.51.
3,5-Bis(2,4-dichlorophenyl)[1,2,4]thiadiazole. Solid; mp 132–
134ꢀC.1H NMR (500 MHz, CDCl3): d ¼ 7.39 (1 H, dd, J ¼
8.2 Hz), 7.46 (1 H, dd, J ¼ 8.4 Hz), 7.58 (1 H, d, J ¼ 2.1
Hz), 7.63 (1 H, d, J ¼ 2.1 Hz), 8.04 (1 H, d, J ¼ 8.4 Hz,),
8.57 (1 H, d, J ¼ 8.6 Hz).13C NMR (125 MHz, CDCl3): d ¼
127.1, 128.1, 129.7, 130.2, 130.8, 131.4, 133.1, 134.1, 134.3,
136.3, 136.4, 137.9, 173.2, 182.2. Anal. Calcd. For
C14H6Cl4N2S: C, 44.71; H, 1.61; N, 7.45; S, 8.52. Found: C,
44.36; H, 1.82; N, 7.33; S, 8.75.
3,5-Bis(4-bromophenyl)[1,2,4]thiadiazole. Solid, mp 149–
1
154ꢀC; H NMR (500 MHz, CDCl3) d 8.24 (d, J ¼ 8.5 Hz, 2
H), 7.90 (dd, J ¼ 6.6 Hz, 2 H), 7.66 (dd, J ¼ 6.7 Hz, 2 H),
7.63 (dd, J ¼ 6.7 Hz, 2 H); 13C NMR (125 MHz, CDCl3) d
187.1, 173.2, 132.8, 132.5, 132.3, 132.2, 131.9, 131.6, 129.8,
129.4, 128.8, 126.6, 125.0. Anal. Calcd. For C14H8Br2N2S: C,
42.45; H, 2.04; N, 7.07; S, 8.10. Found: C, 42.27; H, 2.03; N,
7.17; S, 8.31.
3,5-Bis(4-methoxyphenyl)[1,2,4]thiadiazole. Solid, mp 128–
1
130ꢀC; H NMR (500 MHz, CDCl3) d 8.32 (d, J ¼ 8.8 Hz, 2
H), 7.99 (d, J ¼ 8.8 Hz, 2 H), 7.01 (m, 4 H), 3.90 (s, 3 H),
3.89 (s, 3 H). 13C NMR (125 MHz, CDCl3) d 180.1, 171.5,
162.8, 160.1, 140.3, 140.4, 138.2, 138.3, 128.3, 127.6, 114.6,
114.4, 111.8, 111.6, 59.7, 59.6. Anal. Calcd. For
C16H16N2O2S: C, 63.98; H, 5.37; N, 9.33; S, 10.67. Found: C,
63.91; H, 5.39; N, 9.30; S, 10.71.
3,5-Bis(3-bromophenyl)[1,2,4]thiadiazole. Solid, mp 137–
1
140ꢀC; H NMR (500 MHz, CDCl3) d 8.55 (s, 1 H), 8.32 (m,
1 H), 8.21 (s, 1 H) 7.93–7.91 (m, 1 H), 7.68–7.60 (m, 2 H),
7.42-7.35 (m, 2 H); 13C NMR (125 MHz, CDCl3) d 186.7,
172.3, 134.8, 134.4, 133.4, 132.2, 131.4, 130.7, 130.3, 130.2,
126.8, 126.1, 123.4, 122.8. Anal. Calcd. For C14H8Br2N2S: C,
42.45; H, 2.04; N, 7.07; S, 8.10. Found: C, 42.52; H, 2.15; N,
7.01; S, 8.02.
3,5-Bis(4-benzyloxyphenyl)[1,2,4]thiadiazole. Solid, mp 154–
1
157ꢀC; H NMR (500 MHz, CDCl3) d 7.59 (d, J ¼ 8.6 Hz, 4
H), 7.42–7.36 (m, 10 H), 7.02 (d, J ¼ 8.7 Hz, 4 H), 5.12 (s, 4
H). 13C NMR (125 MHz, CDCl3) d 180.2, 171.6, 162.1, 162.1,
162.0, 162.0, 134.2, 134.1, 133.4, 133.4, 133.3, 133.2, 132.2,
132.1, 131.6, 128.7, 126.8, 126.8, 123.9, 123.9, 123.8, 123.8,
123.0, 123.0, 122.9, 129.9. Anal. Calcd. For C26H18N2O2S: C,
73.92; H, 4.29; N, 6.63; S, 7.59. Found: C, 73.89; H, 4.31; N,
6.65; S, 7.57.
3,5-Bis(4-fluoroophenyl)[1,2,4]thiadiazole. Solid, mp 185–
1
188ꢀC; H NMR (500 MHz, CDCl3) d 8.37 (m, 2 H), 8.05 (m,
2 H), 7.24–7.16 (m, 4 H); 13C NMR (125 MHz, CDCl3) d
186.9, 172.8, 165.9, 165.2, 163.9, 163.2, 130.4, 130.3, 129.6,
129.5, 116.6, 116.4, 115.8, 115.6. Anal. Calcd. For
C14H8F2N2S: C, 61.30; H, 2.94; N, 10.21; S, 11.69. Found: C,
61.24; H, 2.92; N, 10.17; S, 11.49.
3,5-Di(2-furyl)-[1,2,4]thiadiazole. Solid, mp 88–90ꢀC; 1H
NMR (500 MHz, CDCl3) d 7.93 (d, J ¼ 3.5 Hz, 1 H), 7.70
(d, J ¼ 3.7 Hz, 1 H), 7.58 (d, J ¼ 5.1 Hz, 1 H), 7.45 (d, J ¼
5 Hz, 1 H), 7.18–7.13 (m, 2 H). 13C NMR (125 MHz, CDCl3)
d 185.1, 170.4, 159.0, 151.3, 151.1, 147.9, 117.1, 117.0, 117.0,
112.1. Anal. Calcd. For C10H6N2O2S: C, 55.03; H, 2.77; N,
12.84; S, 17.71. Found: C, 55.32; H, 2.41; N, 12.65; S, 17.62.
3,5-Bis(4-chlorophenyl)[1,2,4]thiadiazole. Solid, mp 146–
Acknowledgments. The authors are grateful to the Center of
Excellence of Chemistry of University of Isfahan (CECUI) and
also the Research Council of the University of Isfahan for finan-
cial support of this work.
REFERENCES AND NOTES
1
148ꢀC; H NMR (500 MHz, CDCl3) d 8.32 (d, J ¼ 8.5 Hz, 2
H), 7.99 (d, J ¼ 8.5 Hz, 2 H), 7.51 (d, J ¼ 8.5 Hz, 2 H), 7.48
(d, J ¼ 8.5 Hz, 2 H). 13C NMR (125 MHz, CDCl3) d 187.0,
173.1, 133.3, 133.0, 132.7, 132.5, 132.1, 132.0, 129.8, 129.4,
128.8, 126.6, 125.0. Anal. Calcd. For C14H8Cl2N2S: C, 54.74;
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DOI 10.1002/jhet

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TCT-DMSO/[bmim]BF4: A Novel Promoter System for the Synthesis
of 3,5-Diaryl-1,2,4-thiadiazoles at Ambient Temperature
229
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