Solvent-free synthesis of 3,5-di(hetero)aryl-1,2,4-thiadiazoles by grinding of thioamides under oxidative conditions

Article abstract of DOI:10.3184/030823410X12677120188989

An efficient and facile synthesis of 3,5-di(hetero)aryl-1,2,4-thiadiazoles by oxidative dimerisation of thioamides by grinding with NBS under solvent-free conditions at room temperature has been developed. The efficiency of this reaction was demonstrated by the compatibility with trifluoromethyl, methyl, methoxy, chloro, pyridyl and thienyl groups. This method has notable advantages in terms of short reaction times, high yields and is a more practical alternative to the existing methods to access these compounds.

Full text of DOI:10.3184/030823410X12677120188989

JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 151
MARCH, 151–153
Solvent-free synthesis of 3,5-di(hetero)aryl-1,2,4-thiadiazoles by grinding
of thioamides under oxidative conditions
Yali Xua, Jiuxi Chena, Wenxia Gaoa, Huile Jina, Jinchang Dinga,b and Huayue Wua*
aCollege of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. China
bWenzhou Vocational andTechnical College, Wenzhou, 325035, P. R. China
An efficient and facile synthesis of 3,5-di(hetero)aryl-1,2,4-thiadiazoles by oxidative dimerisation of thioamides by
grinding with NBS under solvent-free conditions at room temperature has been developed. The efficiency of this
reaction was demonstrated by the compatibility with trifluoromethyl, methyl, methoxy, chloro, pyridyl and thienyl
groups. This method has notable advantages in terms of short reaction times, high yields and is a more practical
alternative to the existing methods to access these compounds.
Keywords: thioamides, thiadiazoles, grinding, solvent-free synthesis
Thiadiazoles play a important part in the synthesis of many
bioactive molecules belonging to various therapeutic catego-
ries, such as bactericides,1 fungicides,2 herbicides3 and antibi-
otics.4 Various approaches toward the synthesis of thiadiazoles
derivatives have been explored during the past years. One
of the most common methods for the synthesis of 1,2,4-
thiadiazoles involves the oxidative dimerisation of thioamides
in the presence of various promoting agents, such as nitrous
acid,5 tertiary butyl hypochlorite,6 DMSO/electrophilic regent,7
polystyrene-bound diaryl selenoxide and telluroxide,8 organo-
tellurium,9 p-toluenesulfinic acid,10 polystyrene-supported
iodobenzene diacetate (PIBD)11 and PIBD/ionic liquids.12
Recently,Akamanchi and co-worker reported that IBX/TEAB–
mediated oxidative dimerisation of thioamides for the synthe-
sis of 3,5-disubstituted 1,2,4-thiadiazoles in acetonitrile.13
Some other methods include intramolecular cyclisation14–16
and intermolecular cyclisation.17–19 Although these methods
are suitable for certain synthetic conditions, many of these
procedures are associated with one or more disadvantages
such as long reaction time, use of hazardous organic solvents
and harsh reaction conditions, which leaves scope for further
development of new environmentally clean syntheses.
Table 1 Effect of reaction condition on synthesis of
3,5-disubstituted 1,2,4-thiadiazolesa
Entry
NBS/equiv
Media
Time/min
Yield/%b
1
2
3
4
5
6
7
1.2
1.2
1.2
–
1.05
1.05
1.05
Silica gel
15
15
15
15
5
15
5
77
Neutral Al2O3
Basic Al O
Basic Al22O33
Silica gel
78
93
Trace
73
Basic Al O
92
Basic Al22O33
92 (93)c
a Reactions conditions: thiobenzamide 1a (0.5 mmol) and
media (0.5g) in the presence of NBS on grinding at room
temperature under solvent-free conditions.
b Isolated yields.
c Thiobenzamide 1a (0.686 g, 5 mmol), NBS (0.935 g, 5.25 mmol)
and basic Al2O3 (5 g).
On the basis of the above results, to extend the scope and
generality of this method, a variety of aromatic and heteroaro-
matic thioamides were subjected to oxidative dimerisation to
give various 3,5-disubstituted 1,2,4-thiadiazoles by grinding
with NBS and the results are summarised in Table 2.
As shown in Table 2, a series of aromatic thioamides were
investigated. Thioamides containing electron-donating groups,
such as 4-methylthiobenzamide 1b and 3-methylthiobenza-
mide 1d afforded the corresponding thiadiazoles 2b and 2d
in 94% and 96%, respectively (Table 2, entries 2 and 4). Simi-
larly, thioamides containing electron-withdrawing groups,
such as 4-(trifluoromethyl) thiobenzamide afforded the corre-
sponding thiadiazole 2i in 91% (Table 2, entry 9), and showed
no deleterious electronic effect.
Next, we examined the steric effect of phenyl-ring sub-
stituents on the reactions. Good yields were obtained when the
sizes of the ortho-substituent groups were small, such as
2-methylthiobenzamide 1b, 2-methoxythiobenzamide 1c and
2-chlorothiobenzamide 1h (Table 2, entries 3, 5, 8). However,
it was found that yields were significantly decreased when the
sizes of the ortho-substituent groups were large. For example,
2-ethoxybenzothioamide was found to be less active and gave
the corresponding thiadiazole 2f in moderate yield even after
30 min (Table 2, entry 6).
In recent years, significant articles have appeared reporting
solid-state reactions by grinding.20–24 Most of these reactions
are carried out at room temperature in a completely solvent-
free environment using only a mortar and pestle, and therefore
the common merit of these processes is that they are efficient,
economical, and environmentally friendly.
In continuation of our interest in green chemistry,24–34 we
here describe a green, simple and practical method for the syn-
thesis of 3,5-diaryl-1,2,4-thiadiazole by oxidative dimerisation
of thioamides under solvent-free conditions.
To optimise the reaction conditions, initial studies were
concentrated on treatment of thiobenzamide 1a with NBS (N-
bromosuccinimide) as a model reaction. Different reaction
media were tested to find the optimal conditions. As shown in
Table 1, basic Al2O was determined to be the more suitable
medium, which affo3rded the desired product 2a with excellent
yield (Table 1, entry 3). When the amount of NBS was
decreased to 1.05 equiv, the reaction proceeded smoothly
within just 5 min without decreasing the yields (Table 1, entries
5–7).
Furthermore, the present route to 3,5-diphenyl-1,2,4-
thiadiazole 2a was successfully applied to a large-scale
reaction. For instance, the oxidative dimerisation reaction of
thiobenzamide 1a (5 mmol) using basic Al2O3 (5 g) as reaction
medium in the presence of NBS (5.25 mmol, 1.05 equiv.)
provided the desired product 2a in 93% (Table 1, entry 7).
Finally, we also examined the reactivity of heterocyclic
thioamides, such as pyridine-3-carbothioamide 1j and thio-
phene-2-carbothioamide 1k using the present protocol. It
was found that the desired products 2j and 2k were obtained
in 92% and 99% yields, respectively (Table 2, entries 10
and 11).
* Correspondent. E-mail: huayuewu@wzu.edu.cn

152 JOURNAL OF CHEMICAL RESEARCH 2010
Table 2 Synthesis of 3,5-disubstituted 1,2,4-thiadiazolesa
Entry
Substrate (1)
Product (2)
Time/min
5
Yield/%b
92
1
2
3
5
5
94
93
4
5
96
5
5
91
6
15
10
5
57 (62)c
7
94
8
90
9
5
91
10
11
15
5
92
99
a Reactions were carried out on a 0.5-mmol scale with NBS (1.05 equiv) by grinding at room temperature under solvent-free
conditions.
b Isolated yields.
c For 30 min.
using CDCl3 as the solvent with tetramethylsilane (TMS) as an inter-
nal standard at room temperature. Chemical shifts are given in δ
units relative to TMS, the coupling constants J = are given in Hz.
Mass spectra (MS) were measured with a Thermo Finnigan LCQ-
Advantage. Elemental analyses were carried out using a Carlo-Erba
EA1112 instrument. Column chromatography was performed using
EM Silica gel 60 (300–400 mesh).
In conclusion, we have developed a highly effcient and
facile method for the synthesis of 3,5-di(hetero)aryl-1,2,4-
thiadiazoles on grinding under solvent-free conditions. Good
yields, short reaction times and neat conditions are the notable
advantages of this method. We believe that this method has
provided better scope for the synthesis of 3,5-di(hetero)aryl-
1,2,4-thiadiazoles and will be a more practical alternative to
the existing methods for accessing these compounds.
Typical procedure for preparation of thiobenzamides
A three-necked and round-bottomed flask is fitted with a rubber
septum, thermometer, magnetic stirring bar, and reflux condenser
equipped with a nitrogen bubbler. The flask is charged with thiophene-
2-carboxamide (1.02 g 8 mmol) and Lawesson’s reagent (1.62 g
4 mmol) and then the reaction mixture is purged with N2, whereupon
Experimental
Chemicals were purchased and used without further purification.
All the melting points were uncorrected. NMR spectroscopy was
performed on a Bruker-300 spectrometer or Bruker-500 spectrometer

JOURNAL OF CHEMICAL RESEARCH 2010 153
the temperature of the reaction mixture increased to 95 °C. After
10 min dry toluene (15 mL) was added by syringe. The mixture was
stirred for 14 h. and then cooled to room temperature. The toluene is
removed with the aid of a rotary evaporator and the resulting yellow
mixture was separated by silica gel column chromatography to pro-
vide 0.584 g (51%) of thiophene-2-carbothioamide as a yellow solid,
m.p. 106–107 °C. Other thiobenzamide compounds were synthesised
by a similar method.
3,5-Bis(3-pyridyl)-1,2,4-thiadiazole (2j): Solid, m.p. 128–129 °C,
(lit.13 133–135 °C). 1H NMR (300 MHz, CDCl3): δ 7.38–7.48 (m, 2H),
8.28–8.31 (m, 1H), 8.56–8.59 (m, 1H), 8.68–8.75 (m, 2H), 9.21
(s, 1H), 9.55 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 123.5, 124.0,
126.5, 128.3, 134.4, 135.4, 148.4, 149.6, 151.2, 152.7, 171.5, 185.4.
3,5-Bis(2-thienyl)-1,2,4-thiadiazole (2k): Solid, m.p. 87–89 °C,
(lit.35 84–86 °C).1H NMR (300 MHz, CDCl3): δ 7.03–7.06 (m, 2H),
7.34–7.36 (m, 1H), 7.45–7.47 (m, 1H), 7.56–7.58 (m, 1H), 7.82–7.84
(m, 1H); 13C NMR (125 MHz, CDCl3): δ 127.8, 128.4, 128.8, 129.2,
129.8, 130.5, 133.0, 136.2, 168.3, 180.6. ESI-MS: m/z (%): 251
([M+H]+, 100). Anal. Calcd for C10H6N2S3: C, 47.97; H, 2.42;
N, 11.19. Found: C, 47.91; H, 2.37; N, 11.25%.
Typical procedure for preparation of 1,2,4-thiadiazoles
The following components were added to the glass mortar:
basic Al O3 (200–300mesh, 500 mg), thiobenzamide 1a (68.6 mg,
0.5 mmo2l) and NBS (93.5 mg, 0.525 mmol). The mixture was then
ground at room temperature with a glass pestle in the glass mortar.
When the mixture became pale yellow, a sample was dissolved in
ethyl acetate to monitor the progress of the reaction using TLC. After
completion of the reaction, the mixture was washed with ethyl acetate.
The combined washings were removed under vacuum. The pure
product was obtained by silica gel column chromatography. The
physical and spectral data of compounds 2a–k are as follows.
3,5-Diphenyl-1,2,4-thiadiazole (2a): Solid, m.p. 88–89 °C, (lit.13
90–92 °C). 1H NMR (300 MHz, CDCl3): δ 7.49–7.56 (m, 6H), 8.04–
8.08 (m, 2H), 8.38–8.41 (m, 2H); 13C NMR (125 MHz, CDCl3):
δ 127.4, 128.3, 128.6, 129.1, 130.3, 130.6, 131.8, 173.7, 188.0.
3,5-Bis(4-methylphenyl)-1,2,4-thiadiazole (2b): Solid, m.p. 119–
We are grateful to the National Key Technology R&D Program
(No. 2007BAI34B00) and the Natural Science Foundation of
Zhejiang Province (No. Y4080107) for financial support.
Received 16 December 2009; accepted 5 February 2010
Paper 090916 doi: 10.3184/030823410X12677120188989
Published online: 23 March 2010
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