Tribromo Phloroglucinol as a Novel and Highly Efficient Reagent for the Conversion of Benzothioamides to the Corresponding 1,2,4-Thiadiazoles

Article abstract of DOI:10.1080/00397911.2015.1040512

(Chemical Equation Presented) 2,4,6-Tribromo-1,3,5-trihydroxybenzene (TBTHB) as a reagent was efficiently reacted with 6 molar equivalents of benzothioamides in dimethyl sulfoxide (DMSO), and the corresponding 3,5-diaryl-1,2,4-thiadiazoles were obtained in almost quantitative yields (91-98%) and in short times (15-20 min) with the formation of hexahydroxybenzene as a rather valuable by-product. 2015

Full text of DOI:10.1080/00397911.2015.1040512

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Tribromo Phloroglucinol as a Novel
and Highly Efficient Reagent for the
Conversion of Benzothioamides to the
Corresponding 1,2,4-Thiadiazoles
Hassan Zali-Boeinia & Seyed Gholamhossein Mansouria
a Department of Chemistry, University of Isfahan, Isfahan, Iran
Accepted author version posted online: 22 Apr 2015.Published
online: 22 Apr 2015.
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To cite this article: Hassan Zali-Boeini & Seyed Gholamhossein Mansouri (2015): Tribromo
Phloroglucinol as a Novel and Highly Efficient Reagent for the Conversion of Benzothioamides to the
Corresponding 1,2,4-Thiadiazoles, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2015.1040512
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Synthetic Communications1, 0: 1–7, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1040512
TRIBROMO PHLOROGLUCINOL AS A NOVEL AND
HIGHLY EFFICIENT REAGENT FOR THE CONVERSION
OF BENZOTHIOAMIDES TO THE CORRESPONDING
1,2,4-THIADIAZOLES
Hassan Zali-Boeini and Seyed Gholamhossein Mansouri
Department of Chemistry, University of Isfahan, Isfahan, Iran
GRAPHICAL ABSTRACT
Abstract 2,4,6-Tribromo-1,3,5-trihydroxybenzene (TBTHB) as a reagent was efficiently
reacted with 6 molar equivalents of benzothioamides in dimethyl sulfoxide (DMSO),
and the corresponding 3,5-diaryl-1,2,4-thiadiazoles were obtained in almost quantitative
yields (91–98%) and in short times (15–20 min) with the formation of
hexahydroxybenzene as a rather valuable by-product.
Keywords Heterocycles; thiadiazole; thioamide
INTRODUCTION
Undoubtedly, thioamides are very important building blocks in organic
synthesis and especially in construction of heterocyclic compounds.[1] They have
been used as multipurpose synthons in the synthesis of five- and six-membered
heterocycles.[2] Among them, benzothioamides are good substrates for the synthesis
of the wide varieties of thiazole[3] and thiadiazole derivatives. Various types of
oxidants have been employed for the C-S coupling of benzothioamide derivatives
to the corresponding thiadiazoles such as halogens[4] [12], nitrous acid,[5] hydrogen
peroxide,[6] thionyl chloride,[7] a mixture of HCl–dimethylsulfoxide (DMSO),[8]
Received January 21, 2015.
Address correspondence to Hassan Zali-Boeini, Department of Chemistry, University of Isfahan,
81746-73441 Isfahan, Iran. E-mail: h.zali@chem.ui.ac.ir
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
1

2
H. ZALI-BOEINI AND S. G. MANSOURI
Scheme 1.
and pyridinium salt–DMSO.[9] Meanwhile, the reaction of 1-monosubstituted
thioureas with bis(acyloxyiodo)arene derivatives has been utilized as a synthetic
procedure to obtain 3,5-bis-(phenylamino)-1,2,4-thiadiazoles.[10] Thiadiazoles are
interesting building blocks in medicinal chemistry[11–13] and industrial chemical[14]
that are easy to access.
In continuation of our attempts to develop novel synthetic routes for the
preparation of sulfur heterocycles and sulfur-containing organic compounds using
thioamides,[15] an unexpected result in the reaction of benzothioamides with 2,4,6-
tribromo-1,3,5-trihydroxy benzene (TBTHB) in DMSO is reported. When a mixture
of TBTHB and 6 molar equivalents of a benzothioamide derivative in DMSO was
heated to 80 °C, complete conversion of starting materials was observed and the
corresponding 3,5-diaryl-1,2,4-thiadiazole was obtained in excellent yields (91–98%)
and very short times (15–20 min, Scheme 1).
RESULTS AND DISCUSSION
The initial study examined the reaction of benzothioamide as a test substrate
with tribromophloroglucinol in DMSO. Fortunately, the course of the reaction could
even be pursued visually. At the outset of the reaction, a light yellow color is visible in
the reaction mixture due to presence of the benzothioamide in the solution. After
10 min of heating at 80 °C, the reaction mixture turned orange in color and then chan-
ged to red after a further 5 min of heating at the same temperature. Finally, a rapid
and exothermic reaction occurred during the final minutes alongside the evolution
of Me2S and H2S gases, leading to the corresponding 3,5-diphenyl-1,2,4-thiadiazole
3a in almost quantitative yield (98%). The reaction temperature was found to be very
effective on the reaction time and the product yields of the reaction. The full results of
the temperature and time optimization for this reaction is outlined in Table 1.
Although oxidative cyclization reactions of benzothioamides to the correspond-
ing 1,2,4-thiadiazoles using various oxidative agents are known and there is a reason-
able mechanism to explain the course of those reactions,[9] in Scheme 2 we offer a
mechanism to explain the unusual stoichiometric ratio of the reactants, one to six,
in our novel method.
It seems that bromodimethylsulfonium ion 5 formed via the reaction of
dimethyl sulfoxide and TBTHB 1 is the active intermediate in the reaction. Mean-
while, benzothioamide 2a undergoes an S-bromination with this reactive intermediate
to produce species 6, which after subsequent reaction with another benzothioamide
molecule transforms to N-(imino(phenyl)methylthio) benzothioamide 7. Eventually,
this intermediate cyclizes to the corresponding 3,5-diphenyl-1,2,4-thiadiazole 3a
alongside with the elimination of H2S.

RAPID SYNTHESIS OF 1,2,4-THIADIAZOLES
3
Table 1. Temperature screening in the synthesis of thiadiazoles
Entry
Temperature (°C)
Time (min)
Yield (%)a
1
2
3
4
5
6
rt
40
60
80
100
120
120
60
40
15
10
6
40
58
81
98
98b
96b
aPure isolated yields.
bFormation of some dark-colored impurities were observed.
Scheme 2.

4
H. ZALI-BOEINI AND S. G. MANSOURI
Table 2. TBTHB as a novel reagent for the preparation of 1,2,4-thiadiazolesa
Entry
1
Ar
Time
15
Product
Yield (%)b
C6H5
98
2
3
4
4-MeC6H4
3-BrC6H4
4-BrC6H4
15
18
15
98
92
94
5
6
2-ClC6H4
3-ClC6H4
18
17
93
94
7
4-ClC6H4
15
96
(Continued)

RAPID SYNTHESIS OF 1,2,4-THIADIAZOLES
5
Table 2. Continued
Entry
Ar
Time
17
Product
Yield (%)b
8
4-FC6H4
91
97
9
4-MeOC6H4
15
10
11
2,4-Cl2C6H4
20
15
91
94
2-furyl
aReaction conditions: Benzothioamide derivative (3 mmol), TBTHB (0.5 mmol), and DMSO (1 mL).
bIsolated yields.
As is clear from the proposed mechanism, DMSO has a dual function in the
course of the reaction because it plays both the role of the reagent as well as the
solvent. Formation of hexahydroxybenzene by-product 4 was proven by comparison
of its thin-layer chromatographic (TLC), physical, and spectral data with the
authentic sample prepared by the known method.[16] Ten different benzothioamide
derivatives were probed in the course of reaction to evaluate the generality of this
new reagent and the results are summarized in Table 2. Unfortunately, only aromatic
and heteroaromatic thioamides (except pyridyl thioamides) work well in this method
and our attempts to obtain 3,5-dialkyl-1,2,4-thiadiazoles by the presented method
were not successful.
Significant values of the presented reagent and the method lie in very high
reaction yield, short reaction times, and simplicity involved in the isolation of the
products. After completion of the reaction and cooling, the thiadiazole product
was precipitated as fine crystals. Also, hexahydroxybenzene as a rather valuable
by-product was produced during the reaction and found to be freely soluble in the
reaction media as well as in water. Therefore, the reaction mixture was poured
in a mixture of MeOH–water (50:50) to achieve complete isolation of the pure
thiadiazole product.

6
H. ZALI-BOEINI AND S. G. MANSOURI
The hexahydroxybenzene is a very simple to remove and rather valuable by-
product. The presented method could also find application in other reaction classes
such as the Pfitzner–Moffatt oxidation.[17]
CONCLUSIONS
In summary, a novel reagent for the rapid and extremely efficient conversion of
benzothioamide derivatives to the corresponding thiadiazoles has been developed.
To our knowledge, the method also seems to be one of the simplest and fastest routes
for the preparation of 3,5-diaryl-1,2,4-thiadiazoles so far developed.
EXPERIMENTAL
General Procedure for the Preparation of 3,5-Diaryl-1,2,4-
thiadiazoles
Benzothioamide derivatives (3 mmol) and 2,4,6-tribromo-1,3,5-trihydroxy
benzene (TBTHB, 0.5 mmol, 182 mg) was dissolved in DMSO (1 mL) and heated
at 80 °C for 15–20 min. After completion of the reaction (TLC) and cooling to
ambient temperature, MeOH–water (1:1, 5 mL) was added to the reaction mixture
and the resulting crystals of the product were filtered, washed with MeOH–water
(1:1, 2 × 5 mL), and dried to obtain the pure compound as white crystals.
ACKNOWLEDGMENT
The authors warmly acknowledge University of Isfahan Research Council for
providing the facilities for this research.
SUPPLEMENTAL MATERIAL
1
Full experimental details and H and 13C NMR spectra for this article can be
accessed on the publisher’s website.
REFERENCES
1. Jagodzinski, S. T. Chem. Rev. 2003, 103, 197.
2. (a) Orazio, A. A.; De Crescentini, L.; Foresti, E.; Galarini, R.; Santeusanio, S.; Serra-
Zanetti, F. Synthesis 1995, 1397; (b) Lorente, A.; Garcia Navio, J. L.; Fuentes, L.; Soto,
J. L. Synthesis 1985, 86; (c) Bogdanowicz-Szwed, K.; Grochowski, J.; Obara, A.; Rys, B.;
Serda, P. J. Org. Chem. 2001, 66, 7205.
3. (a) Katritzky, A. R.; Fan, W.-Q. J. Heterocycl. Chem. 1993, 30, 1679; (b) Gasteiger, J.;
Herzig, J. Tetrahedron 1981, 37, 2607.
4. Hofmann, A. W.; Gabriel, S. Ber. 1892, 25, 1578.
5. Cronyn, M. W.; Nakagawa, T. W. J. Am. Chem. Soc. 1952, 74, 3693.
6. Cashman, J. R.; Hanzlik, R. P. J. Org. Chem. 1982, 47, 4645.
7. Castro, A.; Castano, T.; Encinas, A.; Porcal, W.; Gil, C. Bioorg. Med. Chem. 2006, 14,
1644.
8. Miotti, U. J. Chem. Soc., Perkin Trans. 2, 1991, 617.

RAPID SYNTHESIS OF 1,2,4-THIADIAZOLES
7
9. Takikawa, Y.; Shimada, K.; Sato, K.; Sato, S. Bull. Chem. Soc. Jpn. 1985, 58, 995.
10. Mamaeva, E. A.; Bakibaev, A. A. Tetrahedron 2003, 59, 7521.
11. Leung-Toung, R.; Tam, T. F.; Wodzinska, J. M.; Zhao, Y.; Lowrie, J.; Simpson, C. D.;
Karimian, K.; Spino, M. J. Med. Chem. 2005, 48, 2266.
12. Unangst, P. C.; Shrum, G. P.; Connor, D. T.; Dyer, R. D.; Schrier, D. J. J. Med. Chem.
1992, 35, 3691.
13. Macleod, A. M.; Baker, R.; Freedman, S. B.; Patel, S.; Merchant, K. J.; Roe, M.;
Saunders, J. J. Med. Chem. 1990, 33, 2052.
14. Leung-Toung, R.; Tam, T. F.; Zhao, Y.; Simpson, C. D.; Li, W.; Desilets, D.; Karimian,
K. J. Org. Chem. 2005, 70, 6230.
15. (a) Hajibabaei, K.; Zali-Boeini, H. Synlett 2014, 2044; (b) Zali-Boeini, H.; Pourjafarian, F.
J. Sulfur Chem. 2012, 33, 639; (c) Zali-Boeini, H.; Pourjafarian, F. Helv. Chim. Acta 2012,
95, 1164; (d) Zali-Boeini, H.; Shokrolahi, A.; Zali, A.; Ghani, K. J. Sulfur Chem. 2012, 33,
165; (e) Zali-Boeini, H.; Mobin, M. Helv. Chim. Acta 2011, 94, 2039; (f) Zali-Boeini, H.
Synth. Commun. 2011, 41, 2932; (g) Zali-Boeini, H., Haji Babaei Najafabadi, K. Eur. J.
Org. Chem., 2009, 4926; (h) Zali-Boeini, H. Helv. Chim. Acta 2009, 92, 1268; (i) Zali-
Boeini, H. J. Iran Chem. Soc. 2009, 6, 547; (j) Matloubi Moghaddam, F.; Zali Boeini,
H. Synlett 2005, 1612; (k) Matloubi Moghaddam, F.; Zali Boeini, H. Tetrahedron 2004,
60, 6085; (l) Matloubi Moghaddam, F.; Zali Boeini, H. Tetrahedron Lett. 2003, 44, 6253.
16. Fatiadi, A. J.; Sager, W. F. Org. Synth. Coll. 1973, 5, 595.
17. Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1963, 85, 3027.