Highly efficient synthesis of 3,5-diaryl-1,2,4-thiadiazoles in water-wet paste conditions

Article abstract of DOI:10.1080/00397911.2010.515368

1,3-Dibromo-5,5-diphenylimidazolidine-2,4-dione (N,N'-dibromo phenytoin) was efficiently used for the rapid conversion of thiobenzamides to the corresponding 3,5-diaryl-1,2,4-thiadiazoles in water-wet paste conditions. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.515368

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Highly Efficient Synthesis of 3,5-
Diaryl-1,2,4-thiadiazoles in Water–Wet
Paste Conditions
Hassan Zali Boeini a
a Department of Chemistry , University of Isfahan , Isfahan , Iran
Published online: 29 Jun 2011.
To cite this article: Hassan Zali Boeini (2011) Highly Efficient Synthesis of 3,5-Diaryl-1,2,4-
thiadiazoles in Water–Wet Paste Conditions, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 41:19, 2932-2938, DOI:
10.1080/00397911.2010.515368
To link to this article: http://dx.doi.org/10.1080/00397911.2010.515368
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Synthetic Communications1, 41: 2932–2938, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515368
HIGHLY EFFICIENT SYNTHESIS OF 3,5-DIARYL-
1,2,4-THIADIAZOLES IN WATER–WET PASTE
CONDITIONS
Hassan Zali Boeini
Department of Chemistry, University of Isfahan, Isfahan, Iran
GRAPHICAL ABSTRACT
Abstract 1,3-Dibromo-5,5-diphenylimidazolidine-2,4-dione (N,N’-dibromo phenytoin) was
efficiently used for the rapid conversion of thiobenzamides to the corresponding 3,5-diaryl-
1,2,4-thiadiazoles in water–wet paste conditions.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Green chemistry; solvent-free; thiadiazole; thioamide
INTRODUCTION
Immense efforts to develop efficient strategies for the synthesis of thiadiazoles
have been put forth because of their considerable applications in medicinal chemistry
for treatment of human leukemia[1] and as antibiotics.[2] Moreover, some of them
show anticonvulsant[3] and intense muscarinic activity.[4] They have been widely used
as insecticidal, herbicidal, and fungicidal agents in agriculture[5] and as corrosion
inhibitors of mild steel in acidic media.[6]
Undoubtedly, thioamides are very important building blocks in organic syn-
thesis and especially in construction of heterocyclic compounds.[7] They have been
used as versatile synthons in the synthesis of five, and six-membered heterocycles[8].
Among them, primary thioamides are good substrates for the synthesis of wide vari-
eties of thiazole[9] and thiadiazole derivatives. A large number of oxidants such as
nitrous acid,[10] hydrogen peroxide,[11] thionyl chloride,[12] HCl–dimethyl sulf-
oxide (DMSO),[13] and pyridinium salt–DMSO,[14] bis(acyloxyiodo) arenas,[15] and
Received June 9, 2010.
Address correspondence to Hassan Zali Boeini, Department of Chemistry, University of Isfahan,
81746-73441, Isfahan, Iran. E-mail: h.zali@chem.ui.ac.ir
2932

3,5-DIARYL-1,2,4-THIADIAZOLES
2933
Scheme 1.
polymer-supported iodobenzene diacetate[16] have been successfully employed for
the conversion of thiobenzamide derivatives to the corresponding 1,2,4-thiadiazoles.
In continuation of our attempts to develop novel synthetic routes for the
preparation of sulfur heterocycles using thioamides,[17] herein an efficient and mild
method for the rapid conversion of thiobenzamides to the corresponding
3,5-diaryl-1,2,4-thiadiazoles using 1,3-dibromo-5,5-diphenylimidazolidine-2,4-dione
(N,N0-dibromo phenytoin) and a water–wet paste method is reported (Scheme 1).
To the best of our knowledge, this is the first report of the application of this reagent
for the oxidative cyclization of thiobenzamides to the corresponding thiadiazoles.
RESULTS AND DISCUSSION
Phenytoin sodium is commonly used as an anticonvulsant in the treatment of
epilepsy. In this study, a different application for this compound is reported.
Although there are a lot of reports evidencing the feasibility of application of
1,3-dibromo-5,5-dimethyl hydantoin as brominating or oxidizing agent,[18] to our
knowledge, 1,3-dibromo-5,5-diphenyl hydantoin has not been applied for oxidative
dimerization of thioamides to the corresponding thiadiazoles so far. Phenytoin has
been efficiently converted to its N,N’-dibromo derivative by the action of a mixture
of NaOH=Br2 in water.[19] It is well known that N-bromo imides are very good bro-
minating as well as oxidizing agents.[20] Because of these properties, we decided to
investigate the solid-state reaction of N-bromoimides with thiobenzamides. It was
found the solid–solid reaction of N-bromosuccinimide with 2 equivalents of thioben-
zamide 1a provided 3,5-diphenyl-1,2,4-thiadiazole in moderate yield (55%). In con-
trast, N,N’-dibromophenytoin and 4 equivalents of thiobenzamide reacted under
similar conditions to produce compound 3a in good yield (78%).
It was found that the grinding process takes place with difficulty because of the
formation of a gummy mixture. Interestingly, in the presence of a small amount of
water, the reaction course undergoes drastic, favorable changes. In a typical pro-
cedure, a blend of N,N’-dibromo phenytoin 2 (1 mmol) and 4 equivalents thiobenza-
mide 1a was soaked with a small amount of water (0.4 ml), and the resulting paste
was stirred for 7 min at room temperature. After addition of ethanolic sodium
hydroxide solution to the reaction mixture, the corresponding thiadiazole was preci-
pitated, filtered, and crystallized to obtain pure product 3a in almost quantitative
yield (99%). The reaction of 12 different thiobenzamides was investigated to evaluate

2934
H. Z. BOEINI
Table 1. Wet solid–solid method for the preparation of 3,5-diaryl-1,2,4-thiadiazoles
Entry
1
1
Ar
Time (min)
Product 3a
Yieldb (%)
a
Ph
5
99
2
b
4-tolyl
5
99
3
4
5
c
d
e
4-NO2-Ph
3-Br-Ph
4-Br-Ph
7
6
5
91
93
95
6
7
f
2-Cl-Ph
3-Cl-Ph
6
6
94
95
g
8
9
h
4-Cl-Ph
4-F-Ph
5
7
5
97
88
i
10
j
4-MeO-Ph
92
(Continued )

3,5-DIARYL-1,2,4-THIADIAZOLES
2935
Table 1. Continued
Entry
11
1
Ar
Time (min)
Product 3a
Yieldb (%)
k
2,4-di-Cl-Ph
6
93
12
l
2-furyl
5
96
aAll products were characterized by 1H NMR, 13C NMR, and elemental analysis.
bAll yields refer to pure isolated products.
the generality of this new synthetic approach, and the results are summarized in
Table 1.
It is worthwhile to note that the reaction was carried out easily and cleanly
without the formation of tarry materials. Another advantage of the presented meth-
odology is the possibility of the regeneration of reagent. After the conventional
workup, the aqueous ethanolic layer of the reaction mixture was separated and
washed with ether, and the aqueous solution was adjusted to pH 1 using concen-
trated HCl. The resulting phenytoin precipitated and was filtered (95% yield), from
which the brominated reagent could be regenerated. It is also remarkable that no
bromination takes place at the aromatic rings even in the cases of electron-rich
entries (compounds 3j and 3l).
CONCLUSIONS
In summary, a rapid conversion of thiobenzamides to the corresponding thia-
diazoles that proceeded in excellent yield in an aqueous paste is described. This reac-
tion can readily be performed on a large scale (up to 100-mmol scale), and the
workup and isolation of the product is very simple, allowing facile recovery of the
hydantoin. Meanwhile, the presented method also seems to be one of the simplest
and fastest routes for the preparation of these compounds developed so far.
EXPERIMENTAL
All solvents were used as purchased from commercial sources. Thin-layer
chromatography (TLC) was performed using silica gel 60 F254 precoated plates
(0.25 mm). All products were purified by crystallization to homogeneity by TLC
analysis (single spot), using an ultraviolet lamp and=or iodine or basic KMnO4
for detection purposes. NMR spectra were recorded on a Brucker DRX 500-MHz
spectrometer at 500(1H) and 125(13C) MHz at 298 K. Chemical shifts are reported
in d (ppm) relative to the solvent residual peak with CDCl3 as internal standard.
Elemental analyses were carried out on a Leco-932 model CHNS analyzer.

2936
H. Z. BOEINI
General Procedure for the Preparation of 3,5-Diaryl-1,2,4-thiadiazoles
in Wet Solid–Solid Conditions
Finely pulverized thiobenzamide (10 mmol) and N,N0-dibromo phenytoin
(2.7 mmol, 1.10 g) were mixed and wetted with water (2 ml). The resulting pasty mix-
ture was stirred using a mechanical stirrer for the times noted in Table 1. Thereafter,
a solution of ethanolic sodium hydroxide (EtOH=H2O=NaOH, 80:15:5, 30 ml) was
added to the reaction mixture. Then the precipitated compound was filtered and
crystallized in ethanol (or ethanol–chloroform) to obtain the pure target compounds
as white to pale yellow needles in good to excellent yields.
For the full experimental procedure and 1H NMR and 13C NMR spectral data
(including their copies) for compounds see the supplementary data (available online).
Selected Data
3,5-Diphenyl-1,2,4-thiadiazole 3a. White needles; 1H NMR (500 MHz,
CDCl3) 8.43 (d, J ¼ 8.0 Hz, 2H), 8.10 (d, J ¼ 7.5 Hz, 2H), 7.52–7.60 (m, 6H).
3,5-Di-p-tolyl-1,2,4-thiadiazole 3b. White crystals; 1H NMR (500 MHz,
CDCl3) 8.31 (d, J ¼ 8.1 Hz, 2H), 7.98 (d, J ¼ 8.1 Hz, 2H), 7.34–7.37 (m, 4H), 2.51
(s, 3H), 2.48 (s, 3H).
3,5-Bis(4-nitrophenyl)-1,2,4-thiadiazole 3c. Light yellow needles; 1H
NMR (500 MHz, CDCl3) 8.63 (d, J ¼ 8.2 Hz, 2H), 8.45 (d, J ¼ 8.2 Hz, 2H), 8.43
(d, J ¼ 8.2 Hz, 2H), 8.30 (d, J ¼ 8.2 Hz, 2H).
3,5-Bis(3-bromophenyl)-1,2,4-thiadiazole 3d. White crystals; 1H NMR
(500 MHz, CDCl3) 8.51 (s, 1H), 8.32 (d, J ¼ 8.7 Hz, 1H), 8.21 (s, 1H), 7.93 (dd,
J ¼ 8.7, 1.5 Hz, 1H), 7.68 (ddd, J ¼ 8.1, 1.8, 0.8 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-Bis(4-bromophenyl)-1,2,4-thiadiazole 3e. White crystals; 1H NMR
(500 MHz, CDCl3) 8.24 (d, J ¼ 8.5 Hz, 2H), 790 (d, J ¼ 6.9 Hz, 2H), 7.66 (d,
J ¼ 6.9 Hz, 2H), 6.64 (d, J ¼ 8.5 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-Bis(2-chlorophenyl)-1,2,4-thiadiazole 3f. White crystals; 1H NMR
(500 MHz, CDCl3) 8.65 (td, J ¼ 7.2, 2.1 Hz, 1H), 8.05 (td, J ¼ 7.2, 2.2 Hz, 1H),
7.55–7.60 (m, 2H), 7.46–7.48 (m, 2H), 7.40–7.42 (m, 2H); 13C 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-Bis(3-chlorophenyl)-1,2,4-thiadiazole 3g. White crystals; 1H NMR
(500 MHz, CDCl3) 8.39 (s, 1H), 8.27 (d, J ¼ 7.0 Hz, 1H), 8.07 (s, 1H), 7.90 (d,
J ¼ 7.6 Hz, 1H), 7.52–7.54 (m, 1H), 7.43–7.49 (m, 3H); 13C NMR (125 MHz, CDCl3)

3,5-DIARYL-1,2,4-THIADIAZOLES
2937
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-Bis(4-chlorophenyl)-1,2,4-thiadiazole 3h. White crystals; 1H NMR
(500 MHz, CDCl3) 8.32 (d, J ¼ 8.6 Hz, 2H), 8.99 (d, J ¼ 8.5 Hz, 2H), 7.51 (d,
J ¼ 8.5 Hz, 2H), 7.48 (d, J ¼ 8.6 Hz, 2H).
3,5-Bis(4-fluorophenyl)-1,2,4-thiadiazole 3i. White crystals; 1H NMR
(500 MHz, CDCl3) 8.38 (dd, J ¼ 12.2, 6.7 Hz, 2H), 8.05 (dd, J ¼ 12.2, 6.7 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-Bis(4-methoxyphenyl)-1,2,4-thiadiazole 3j. Pale yellow needles; 1H
NMR (500 MHz, CDCl3) 8.33 (d, J ¼ 6.9 Hz, 2H), 7.99 (d, J ¼ 6.9 Hz, 2H),
7.00–7.03 (m, 4H), 3.90 (s, 3H), 3.89 (s, 3H).
3,5-Bis(2,4-dichlorophenyl)-1,2,4-thiadiazole 3k. White needles; 1H NMR
(500 MHz, CDCl3) 8.57 (d, J ¼ 8.7 Hz, 1H), 8.04 (d, J ¼ 8.4 Hz, 1H), (d, J ¼ 2.1 Hz,
1H), (d, J ¼ 2.1 Hz, 1H), (dd, J ¼ 8.7, 2.1 Hz, 1H), (dd, J ¼ 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 .
1
3,5-Di(furan-2-yl)-1,2,4-thiadiazole 3l. White needles; H NMR (500 MHz,
CDCl3) 7.94 (d, J ¼ 3.6 Hz, 1H), 7.70 (d, J ¼ 3.7 Hz, 1H), 7.59 (d, J ¼ 5.1 Hz, 1H),
7.46 (d, J ¼ 5.0 Hz, 1H), 7.13–7.22 (m, 2H).
ACKNOWLEDGMENT
We are grateful to the University of Isfahan Research Council for financial
support of this work.
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