A convenient strategy for the synthesis of 3,5-diaryl-1,2,4-thiadiazoles: Oxidative dimerization of arylthioamides using CC-DMSO in PEG-400

Article abstract of DOI:10.1007/s00706-010-0295-3

An inexpensive and effective preparative protocol for the highly efficient synthesis of structurally diverse 3,5-diaryl-1,2,4-thiadiazoles at ambient temperature with 2,4,6-trichloro-1,3,5-triazine (CC) and DMSO in polyethylene glycol 400 (PEG-400) as sol

Full text of DOI:10.1007/s00706-010-0295-3

Monatsh Chem (2010) 141:649–651
DOI 10.1007/s00706-010-0295-3
ORIGINAL PAPER
A convenient strategy for the synthesis of 3,5-diaryl-1,2,4-
thiadiazoles: oxidative dimerization of arylthioamides
using CC–DMSO in PEG-400
•
Ahmad Reza Khosropour Jalil Noei
Received: 23 July 2009 / Accepted: 15 March 2010 / Published online: 16 April 2010
Ó Springer-Verlag 2010
Abstract An inexpensive and effective preparative pro-
tocol for the highly efficient synthesis of structurally
diverse 3,5-diaryl-1,2,4-thiadiazoles at ambient tempera-
ture with 2,4,6-trichloro-1,3,5-triazine (CC) and DMSO in
polyethylene glycol 400 (PEG-400) as solvent is described.
with 1-methylpyridinium chloride, benzoyl chloride, or
acetyl chloride in chlorinated organic solvents [10]; or by
using a stoichiometric amount of PhI(OAc)2 at 70 °C [11].
Nonetheless, the preparation of these substituted 1,2,4-
thiadiazoles remains a challenge. All of the reported pro-
cedures require drastic reaction conditions due to low
yields, expensive or not readily available reagents, or
tedious workup. Some of these reactions also require high
temperatures.
Keywords Thioamides Á 2,4,6-Trichloro-1,3,5-triazine Á
Dimethyl sulfoxide Á Polyethylene glycol Á
Room temperature
In our opinion, it is still possible and desirable to devise
new preparative procedures which would be easy, inex-
pensive, safe, and effective for this transformation. We
hope that the new method reported in this paper may fulfill,
at least in part, these expectations.
Introduction
The 1,2,4-thiadiazole scaffold represents an important class
of core structures in pharmaceutical molecules and prod-
ucts possessing a variety of biological activities [1, 2].
Also, the properties of 1,2,4-thiadiazoles as thiol trapping
agents have been recently reviewed [3]. Although currently
the only commercial 1,2,4-thiadiazole drug is the antibiotic
cefozopram [4], there are a number of synthetic products
related to this system with a broad range of biological
activities, e.g., anti-inflammatory [5], cardiovascular [6, 7],
or antibiotic activity [8, 9].
Results and discussion
As a part of our interest in finding synthetic applications of
2,4,6-trichloro-1,3,5-triazine (CC) [12] and designing new
eco-friendly transformations in organic synthesis [13–16],
we envisaged the use of CC–DMSO in polyethylene glycol
400 (PEG-400) for the transformation of arylthioamides into
the corresponding 3,5-diaryl-1,2,4-thiadiazoles (Scheme 1).
In preliminary investigations, thiobenzamide (1 mmol)
was used as a model substrate for optimization of reaction
conditions. The influence of solvents on the reaction yields
was examined first. The reaction was carried out at 25 °C
for 10 min with CC (30 mol%) and DMSO (1 mmol) in
2 cm3 of various solvents and we found that PEG-400 was
the best solvent in terms of yield and reaction time (Fig. 1).
Further studies showed that the optimal ratio of thio-
amide/CC/DMSO is about 1:0.3:1; reducing the loading of
CC or DMSO led to a dramatic decline in yields. More-
over, in the absence of CC or DMSO no oxidative reaction
Despite their wide range of pharmacological activity and
synthetic applications, only a few methodologies have been
reported in the literature for the synthesis of 3,5-diaryl-
1,2,4-thiadiazoles. The synthesis of these compounds is
limited to the oxidative dimerization reaction of thioamides
A. R. Khosropour (&) Á J. Noei
Catalysis Division, Department of Chemistry,
Faculty of Science, University of Isfahan,
81746-73441 Isfahan, Iran
e-mail: khosropour@chem.ui.ac.ir
123

650
A. R. Khosropour, J. Noei
Cl
N
CC,DMSO
PEG-400
ArCSNHCl
ArCSNH2
Ar
N
N
S
N
Ar
Ar
Cl
Cl
S
2 ArCNH2
Ar
S
S N
-HCl
N
(CH3)2SO
S +
HNC Ar
Cl
NH
Ar
PEG-400, r.t.
8-15 min
O
H2N
1a-1k
2a-2k
A
Scheme 1
Ar
N
N
Ar
S
Scheme 2
excellent yields of the desired products. Electron-donating
and electron-withdrawing substituents on the aromatic ring
did not profoundly affect the efficiency of the reactions.
Acid-sensitive groups such as methoxy or furyl were
retained, showing the mildness of the present reaction
conditions.
Although the mechanism is not clear, this reaction pre-
sumably proceeds via the formation of N-chlorothioamide
and subsequent dimerization to give intermediate A which
undergoes intramolecular cyclization to the corresponding
thiadiazole (Scheme 2).
Fig. 1 Effect of solvents on the synthesis of 3,5-diaryl-1,2,4-
thiadiazoles with CC–DMSO
was observed. Having determined the optimum reaction
conditions, in order to demonstrate the generality and
applicability of the present process, we performed the
reaction on a variety of arylthioamides with CC–DMSO at
25 °C in PEG-400. The results are summarized in Table 1.
In all cases, the use of 0.3 equivalent of CC and 1
equivalent of DMSO was sufficient to achieve high to
The recycling performance of PEG-400 was also
investigated in the synthesis of 3,5-diphenyl-1,2,4-thiadi-
azole as a model. The data showed that PEG-400 could be
reused at least five times.
In conclusion, we have found that combination of CC
and DMSO in PEG-400 as a green medium makes an
inexpensive and highly efficient promoter system for the
elaboration of substituted 3,5-diaryl-1,2,4-thiadiazoles with
high to excellent yields in very short reaction times. In
addition to its efficiency and simplicity, this study provides
an alternative procedure for the synthesis of biologically
active 3,5-diaryl-1,2,4-thiadiazoles.
Table 1 Synthesis of 3,5-diaryl-1,2,4-thiadiazoles 2a–2k with CC–
DMSO in PEG-400
Entry
Ar
Product
Time
(min)
Isolated
yield (%)
Reference
1
Ph
2a
2b
2c
2d
2e
2f
10
10
10
15
8
95
92
91
89
93
94
88
90
93
94
96
[17]
[17]
[10]
[17]
[17]
[10]
[17]
[10]
[10]
[10]
[10]
2
4-OMe-Ph
4-OBn-Ph
2-Furyl
4-Cl-Ph
3-Cl-Ph
2-Cl-Ph
2,4-Cl2-Ph
4-Br-Ph
3-Br-Ph
4-F-Ph
Experimental
3
4
PEG-400, 2,4,6-trichloro-1,3,5-triazine (CC), DMSO, and
other chemicals were purchased from Merck Chemical Co.
and used without further purification. Arylthioamides were
prepared as described in [16]. Melting points were mea-
sured on a Stuart Scientific SMP2 apparatus. Elemental
analyses for C, H, N, and S were performed by using a
Leco CHNS-932 analyzer, and the results agreed favorably
5
6
8
7
2g
2h
2i
12
8
8
9
8
10
11
2j
8
1
with the calculated values. H and 13C NMR spectra were
2k
8
1
The products were characterized by H NMR, 13C NMR, and CHNS
analysis and data were compared with those in the literature
measured in CDCl3 solution with a Bruker DRX-500
Avance spectrometer at 500.1 and 125.7 MHz.
123

Synthesis of 3,5-diaryl-1,2,4-thiadiazoles by oxidative dimerization
651
2. Leung-Toung R, Wodzinska J, Li W, Lowrie J, Kukreja R,
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General experimental procedure for the synthesis
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Mini Rev Med Chem 5:367
To 1.0 mmol thioamide dissolved in 2 cm3 PEG-400,
0.055 g 2,4,6-trichloro-1,3,5-triazine (0.3 mmol) and
0.078 g DMSO (1 mmol) were added at 25 °C. The reac-
tion mixture was vigorously stirred at room temperature
until thioamide had completely disappeared (the progress
of the reaction was followed by TLC). When the reaction
was completed, it was quenched with 10 cm3 ice water and
stirred at room temperature for 10 min. The stirring was
stopped and the mixture was filtered. The filtrate was
extracted with ethyl acetate (3 9 5 cm3) and dried over
anhydrous MgSO4. After the removal of the solvent the
residue was purified by flash column chromatography on
silica gel (30% ethyl acetate in n-heptane as eluent) to
afford the pure product.
4. Iizawa Y, Okonogi K, Hayashi R, Iwahi T, Yamazaki T, Imada A
(1993) Antimicrob Agents Chemother 37:100
5. Song YT, Connor DT, Sercel AD, Sorenson RJ, Doubleday R,
Unangst PC, Roth BD, Beylin VG, Gilbertsen RB, Chan K,
Schrier DJ, Guglietta A, Bornemeier DA, Dyer RD (1999) J Med
Chem 42:1161
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J Med Chem 39:5228
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P, Xu JZ, Yang M, Zhu P, Zhou L, Reuman M, Hu Z, Russell R,
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Med Chem 50:3954
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Pharmacol 60:339
Procedure for determining the recyclability
of PEG-400
10. Forlani L, Boga C (2002) J Chem Soc Perkin Trans 2: 768
(references therein)
11. Yan M, Chen Z-C, Zheng Q-G (2003) J Chem Res 618
12. Khosropour AR, Mohammadpoor-Baltork I, Khodaei MM,
Jowkar M (2006) Heterocycles 68:1551
13. Khosropour AR, Khodaei MM, Beygzadeh M (2007) Heteroatom
Chem 18:684
14. Khosropour AR, Khodaei MM, Hoseini Jomor S (2008) J Het-
erocycl Chem 45:683
15. Khosropour AR (2008) Ultrason Sonochem 15:659
16. Noei J, Khosropour AR (2008) Tetrahedron Lett 49:6969 and
references therein
Recyclability of the solvent was studied by using the
reaction of 0.137 g thiobenzamide (1.0 mmol) as a model.
We found that after the reaction was over and washed with
ice water, the aqueous layer can be dried at 80 °C for 12 h
and reused in at least five runs with insignificant changes in
yields.
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 financial
support.
17. Patil PC, Bhalerao DS, Dangate PS, Akamanchi KG (2009)
Tetrahedron Lett 50:5820
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123