An unexpected synthesis of 3,5-diaryl-1,2,4-thiadiazoles from thiobenzamides and methyl bromocyanoacetate

Article abstract of DOI:10.1016/j.tetlet.2011.07.068

Aryl thioamides undergo very rapid condensation in the presence of methyl bromocyanoacetate to provide quantitative yields of 3,5-diaryl-1,2,4- thiadiazoles with an easy work-up and a high degree of product purity. The method can be scaled up with no loss in efficiency.

Full text of DOI:10.1016/j.tetlet.2011.07.068

Tetrahedron Letters 52 (2011) 4941–4943
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An unexpected synthesis of 3,5-diaryl-1,2,4-thiadiazoles
from thiobenzamides and methyl bromocyanoacetate
⇑
Abdelrahman S. Mayhoub , Evgeny Kiselev, Mark Cushman
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue University Center for Cancer Research,
Purdue University, West Lafayette, IN 47907, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Aryl thioamides undergo very rapid condensation in the presence of methyl bromocyanoacetate to
provide quantitative yields of 3,5-diaryl-1,2,4-thiadiazoles with an easy work-up and a high degree of
product purity. The method can be scaled up with no loss in efficiency.
Received 10 June 2011
Revised 11 July 2011
Accepted 14 July 2011
Available online 22 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
1,2,4-Thiadiazoles
Methyl bromocyanoacetate
Thioamides
Condensation
Introduction
The goal of the present study was to determine the scope of the
reaction of aryl thioamides 2 with methyl bromocyanoacetate (4)
A number of methyl 2-aryl-4-methylthiazole-5-carboxylates 3
and their derivatives were previously prepared by the condensa-
to determine if it could constitute a general method for the synthe-
sis of 3,5-diaryl-1,2,4-thiadiazoles.
tion of methyl
a-chloroacetoacetate (1) with thiobenzamides 2
(Scheme 1).1 In order to further study the potential of the aryl-
thiazole class of compounds as antiviral agents, the preparation
of methyl 4-amino-2-(4-chlorophenyl)thiazole-5-carboxylate (6)
was attempted (Scheme 2).
Results and discussion
First, to determine the solvent effects on the yield of compound
5a, methyl bromocyanoacetate (4) was allowed to react with the
thiobenzamide 2a using different solvents (methanol, ethanol,
dioxane, and dichloromethane). Thiadiazole 5a was obtained with-
out any significant differences in the reaction time or yield.
Methanol was generally used as the solvent throughout this work
as mentioned in the Supplementary data.
Next, a variety of commercially available aryl thioamides 2
were allowed to react with methyl bromocyanoacetate (4) at room
temperature (Scheme 4). Among the 1,2,4-thiadiazoles reported in
the chemical literature, the ortho-substituted derivatives have
been more difficult to prepare and there are fewer examples of
them.3 Therefore, in this study more attention was given to the
synthesis of products containing substituents in the ortho posi-
tions of the phenyl rings and six ortho substituted derivatives 5c,
5d, 5h, 5i, 5j and 5k were prepared. The reaction of ortho-substi-
tuted thiobenzamides 2c, 2h, 2i, 2j, and 2k proceeded in quantita-
tive yields; however, the o-trifluoromethyl derivative 5d was
obtained in a low yield (10%). Most of the other meta, para, and
disubstituted thiobenzamide derivatives afforded the correspond-
ing 1,2,4-thiadiazoles in essentially quantitative isolated yields of
pure products regardless of differences in the electronic and steric
Compound 6 was originally intended to be obtained by the
condensation of methyl bromocyanoacetate (4) with thiobenza-
mide 2a (Scheme 2). Compound 4, prepared by bromination of
the commercially available methyl cyanoacetate with N-bromo-
succinimide (NBS), was allowed to react with thiobenzamide 2a,
but instead of the expected 4-amino-2-arylthiazole 6, the diaryl-
thiadiazole 5a formed instantaneously and was isolated simply
by filtration in a near quantitative yield. A mechanism for the
expected conversion of 2a and 4 into 6 is outlined in Scheme 3.
The structure of 5a was confirmed by the spectral data (see Supple-
mentary data). To the best of our knowledge, this reaction has
never been reported before. However, bromocyanoacetate 4,
together with other a-halocarbonyl compounds, has been reported
as a mild oxidizing agent in the conversion of thiols into disufides.2
⇑
Corresponding author. Tel.: +1 765 494 1465; fax: +1 765 494 6790.
E-mail addresses: cushman@purdue.edu, cushman@pharmacy.purdue.edu (M.
Cushman).
On leave from Al-Azhar University, Collage of Pharmacy, Cairo, Egypt.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.068

4942
A. S. Mayhoub et al. / Tetrahedron Letters 52 (2011) 4941–4943
O
O
S
OMe
S
N
N
NC
R
O
O
S
O
R
NH2
2b-i
+
R
S
Br
N
OMe
Ar
NH2
+
5b-i
4
Cl
Ar
1
2
3
b, R = C6H5
c, R = 2-IC6H4
d, R = 2-CF3C6H4
e, R = 3-BrC6H4
f, R = 3-IC6H4
l, R = 3,4-Cl2C6H3
m, R = 4-CNC6H4
n, R = 4-CH3C6H4
o, R = 4-tBuC6H4
p, R = 4-nBuC6H4
q, R = 4-NO2C6H4
r, R = 4-HOC6H4
s, R = 4-CH3OC6H4
t, R = 3-pyridyl
Scheme 1. Preparation of thiazoles.
g, R = 3-FC6H4
S
O
h, R = 2,3-Cl2C6H3
i, R = 2,5-Cl2C6H3
j, R = 2-Br-p-tolyl
k, R = 5-Cl-o-tolyl
NH2
NC
O
+
u, R = 4-pyridyl
Cl
Br
2a
4
Scheme 4. Condensation of aryl thioamides with methyl bromocyanoacetate.
Cl
O
O
S
NC
H2N
OCH3
O
S
S
Br
Br
S
S
Ar
H2N
N
N
N
H2N
Ar
Ar
H2N
Ar
2
9
Br
S
N
S
S
Cl
H2N
Ar
Cl
Ar
N
H
H2N
H
Ar
5a
6
10
11
O
SBr
Scheme 2. Condensation of thiobenzamide 2a with methyl bromocyanoacetate.
NC
O
N
Br
Ar
S
NH
Br
S
NH2
O
N
Ar
Ar
N
Ar
NC
O
13
12
O
N
4
Br
S
Ar
O
N
HN
S
H2N
S
Ar
5
Scheme 5. Mechanism for formation of 5.
Cl
Cl
2a
5-diaryl-1,2,4-thiadiazoles did not work when 2,6-disubstituted
thiobenzamides were used. To date, there are no efficient methods
reported for the synthesis of 3,5-bis(2,6-dichlorophenyl)-1,2,4-
thiadiazole, although it has been obtained as a by-product from
the reaction of thioamides with nitrous acid.4 Moreover, oxi-
dation of 2,6-dichlorothiobenzamide was reported to yield the
corresponding isothiocyanate.5 We are unaware of any efficient
methods reported for the preparation of 3,5-di(2-pyridyl)-1,2,4-
thiadiazole or any 3,5-[(2,6-disubstituted)aryl]-1,2,4-thiadiazole,
including the presently reported method. Thioacetamide was tried
as an example of an aliphatic thioamide and it was unsuccessful.
To investigate the applicability of this method for large-scale
synthesis, four grams of thiobenzamides 2a and 2g was allowed
to react with a slight excess (1.3 equiv) of methyl bromocyanoace-
tate (4). The reaction mixtures were stirred vigorously for 2–3 min
to ensure the consumption of all of the starting materials, and the
corresponding thiadiazoles 5a and 5g were isolated in a high
degree of purity in 95% and 97% yields, respectively.
7
O
O
HN
OCH3
H2N
OCH3
H
N
S
N
S
Cl
Cl
6
8
Scheme 3. Mechanism for expected formation of 6.
properties of the substituent(s). The 3- and 4-pyridyl derivatives
5t and 5u were obtained in moderate yields (65–69%). However,
the corresponding 2-pyridyl derivative could not be obtained in
any yield and the starting materials decomposed under the
reaction conditions. The condensation reaction to produce 3,
Several literature precedents suggest a mechanism for the
condensation of two molecules of the aryl thioamides 2 to form
3,5-diaryl-1,2,4-thiodiazoles 5 in the presence of 4 (Scheme 5).
The question of S–Br versus S–C bond formation resulting from

A. S. Mayhoub et al. / Tetrahedron Letters 52 (2011) 4941–4943
4943
the reaction of thiols with
a
-bromo esters has been studied before,
methyl bromocyanoacetate (4), which can be prepared easily in
one step. This method was found to be applicable with sensitive
groups such as the hydroxyl group, ortho derivatives, and on
gram-scale reactions with easy work-up, high yield, very short
reaction times, and a very high degree of product purity. These
features compare favorably with many of the other methods of
3,5-diaryl-1,2,4-thiadiazoles synthesis.
with S–Br bond formation being documented in cases in which the
anion is more highly resonance stabilized (e.g., diethyl bromomal-
onate).2 This suggests the initial bromination of the sulfur of the
thioamide with methyl bromocyanoacetate to form the intermedi-
ate 9. Treatment of thioamides with alkylating agents that form
stable carbocations was reported to afford the more thermody-
namically stable N-alkylated product instead of the less stable
S-analogue.6 Therefore, the formation of intermediate 10 from
the stable carbocation 9 is suggested. Elimination of HSBr will
afford aminoarylmethylenethioamide 12. Oxidation of the sulfur
of thioamides is reported to facilitate N–S bond formation,7 which,
in this case, could be achieved by a second bromocyanoacetate
molecule. Therefore, S-bromination of 12 followed by tautomeriza-
tion and elimination of HBr would provide diarylthiadiazole 5. The
reaction stoichiometry supports this mechanism. When thiobenza-
mide 2a was allowed to react with 0.5 M equiv of 4, the thiadiazole
product 5a was obtained in about 50% yield and approximately
50% of the thiobenzamide starting material was left unchanged
in the reaction mixture as estimated by the NMR. Using of
1.2 equiv of 4 results in complete conversion of the thiobenza-
mides 2 to the final products.
Acknowledgments
This research was supported by a fellowship to A.S.M. from the
Egyptian government and by National Institutes of Health (NIH)
Research Grant UO1 CA89566.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.068.
References and notes
1. Ze, L.; Khaliq, M.; Zhou, Z.; Post, C. B.; Kuhn, R. J.; Cushman, M. J. Med. Chem.
2008, 51, 4660–4671.
The reported methods for the preparation of 3,5-diaryl-1,2,4-
thiadiazoles from the corresponding thioamides include using
different oxidants such as hypervalent iodine,3 dimethyl sulfoxide
(DMSO)/2-chloro-1,3-dimethylimidazolinium chloride (DMC),8
DMSO/haloiminium salt,9 DMSO/HCl,7 methanesulfonic acid deriv-
ative with benzenetellurinic acid,10 and telluroxide or selenox-
ide.11 Other more complicated methods are also reported: from
the corresponding oxathiazolone,12 benzenecarboximidamide and
diethyl azodicarboxylate,13 or from 1,2,4-oxathiazoles and Lewis
acid.14 The thermal cycloreversion of 6H-1,3,5-oxathiazine S-oxi-
des followed by ring closure of the resulting intermediates is also
reported to yield 1,2,4-thiadiazoles.15 More recently, Khosropour
and Noei described the preparation of 1,2,4-thiadiazoles using
2,4,6-trichloro-1,3,5-triazine, DMSO and polyethylene glycol
400.16 Many of the reported methods that provide high yields
(>80%) require specific alkaline or acidic reagents that might be
incompatible with some sensitive groups, tedious work up and
longer reaction times than the presently reported method, or
cannot be applied for larger-scale reactions.
2. Kato, E.; Oya, M.; Iso, T.; Iwao, J. Chem. Pharm. Bull. 1986, 34, 485–486. and
references cited within.
3. (a) Shah, A. A.; Khan, Z. A.; Choudhary, N.; Loholter, C.; Schafer, S.; Marie, G. P.
L.; Farooq, U.; Witulski, B.; Wirth, T. Org. Lett. 2009, 11, 3578–3581; (b) Cheng,
D.; Chen, Z. Synth. Commun. 2002, 32, 2155–2159; (c) Yan, M.; Chen, Z.; Zheng,
Q. J. Chem. Res. (S) 2003, 618–619; (d) Patil, P. C.; Bhalerao, D. S.; Dangate, P. S.;
Akamanchi, K. G. Tetrahedron Lett. 2009, 50, 5820–5822.
4. Yusuf, I.; Harun, P. Chemiker-Zeitung 1980, 104, 365–367.
5. Bahadir, M.; Nitz, S.; Parlar, H.; Korte, F. Z. Naturforsch., B: Anorg. Chem., Org.
Chem. 1979, 5, 768–769.
6. Katritzky, A. R.; Drevniak, M. Tetrahedron Lett. 1988, 29, 1755–1758.
7. Forlani, L.; Lugli, A.; Boga, C.; Corradi, A. B.; Sgarabotto, P. J. Heterocycl. Chem.
2000, 37, 63–69.
8. Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6989–6992.
9. Isobe, T. Jpn. Kokai Tokkyo Koho, Heisei, 06128243, 1994.
10. Fukumoto, T.; Matsuki, T.; Hu, N. X.; Aso, Y.; Otsubo, T.; Ogura, F. Chem. Lett.
1990, 2269–2272.
11. (a) Hu, N. X.; Aso, Y.; Otsubo, T.; Ogura, F. Bull. Chem. Soc. Jpn. 1986, 59, 879–
884; (b) Hu, N. X.; Aso, Y.; Otsubo, T.; Ogura, F. Chem. Lett. 1985, 603–606.
12. (a) Howe, R. K.; Shelton, B. R. J. Org. Chem. 1981, 46, 771–775; (b) Hojo, M.;
Masuda, R. J. Org. Chem. 1975, 40, 963–965.
13. Kihara, Y.; Kabashima, S.; Uno, K.; Okawara, T.; Yamasaki, T.; Furukawa, M.
Synthesis 1990, 1020–1023.
14. Rafiqul-Islam, M.; Shimada, K.; Aoyagi, S.; Takikawa, Y.; Kabuto, C. Heteroat.
Chem. 2004, 15, 175–186.
15. Shimada, K.; Rafiqul-Islam, M.; Sato, M.; Aoyagi, S.; Takikawa, Y. Tetrahedron
Lett. 2003, 44, 2517–2519.
16. Khosropour, A. R.; Noei, J. Monatsh. Chem. 2010, 141, 649–651.
Conclusion
In conclusion, a new and an efficient method for the synthesis of
the 3,5-diaryl-1,2,4-thiadiazole system was investigated using