Highly efficient oxidative dimerization of thioamides to 3,5-Disubstituted 1,2,4-thiadiazoles mediated by DDQ

Article abstract of DOI:10.1080/00397911.2010.551287

A highly efficient oxidative dimerization of thioamides by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) is reported. The reaction is carried out in ClCH₂CH₂Cl at room temperature. The corresponding 3,5-disubstituted 1,2,4-thiadiazoles are obtained in good to excellent yields.

Full text of DOI:10.1080/00397911.2010.551287

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Highly Efficient Oxidative Dimerization
of Thioamides to 3,5-Disubstituted
1,2,4-Thiadiazoles Mediated by DDQ
Dongping Cheng a , Ruiwen Luo a , Wen Zheng a & Jizhong Yan a
a College of Pharmaceutical Science, Zhejiang University of
Technology, Hangzhou, China
Accepted author version posted online: 27 Oct 2011.Version of
record first published: 26 Mar 2012.
To cite this article: Dongping Cheng , Ruiwen Luo , Wen Zheng & Jizhong Yan (2012): Highly Efficient
Oxidative Dimerization of Thioamides to 3,5-Disubstituted 1,2,4-Thiadiazoles Mediated by DDQ,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:13, 2007-2013
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Synthetic Communications1, 42: 2007–2013, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.551287
HIGHLY EFFICIENT OXIDATIVE DIMERIZATION
OF THIOAMIDES TO 3,5-DISUBSTITUTED
1,2,4-THIADIAZOLES MEDIATED BY DDQ
Dongping Cheng, Ruiwen Luo, Wen Zheng, and Jizhong Yan
College of Pharmaceutical Science, Zhejiang University of Technology,
Hangzhou, China
GRAPHICAL ABSTRACT
Abstract A highly efficient oxidative dimerization of thioamides by 2,3-dichloro-5,6-dicya-
nobenzoquinone (DDQ) is reported. The reaction is carried out in ClCH2CH2Cl at room
temperature. The corresponding 3,5-disubstituted 1,2,4-thiadiazoles are obtained in good to
excellent yields.
Keywords DDQ; oxidative dimerization; thiadiazoles; thioamides
INTRODUCTION
2,3-Dicyano-5,6-dichloro-1,4-benzoquinone (DDQ) is a well-known oxidant in
organic synthesis. It has been mainly used as a dehydrogenating oxidant in the dehy-
drogenation of steroids and lactones[1] and the aromatization of dihydrobenzene
derivatives.[2] Recently, DDQ has been successfully applied in cross-
dehydrogenative-coupling (CDC) reactions.[3] For example, Zhang and Li reported
first that DDQ mediated the direct CDC reaction between benzyl ethers and simple
ketones.[3a] Then, we and others studied a series of oxidative coupling reactions using
DDQ.[3b-3i] In our research, 1,3-diarylpropene reacted with some different substances
containing active hydrogen, such as active methyenelic compounds, indoles, alco-
hols, thiols, and oximes. With our interest in the application of DDQ in organic
Received November 26, 2010.
Address correspondence to Jizhong Yan, College of Pharmaceutical Science, Zhejiang University
of Technology, Hangzhou 310028, China. E-mail: yjz@zjut.edu.cn
2007

2008
D. CHENG ET AL.
Scheme 1. Synthesis of 1,2,4-thiadiazole mediated by DDQ.
chemistry, more recently we have tried the reaction between 1,3-diphenylpropene
and phenylthioamide in CH2Cl2 at room temperature. However, in this experiment,
we observed that a pale yellow solid (sulfur) precipitated quickly. Unexpectedly,
3,5-diphenyl-1,2,4-thiadiazole was obtained in good yield, not the desired coupling
product (Scheme 1).
1,2,4-Thiadiazoles have occupied an important position in chemical and
medicial technology as an effective agricultural fungicide, as pesticides, and as inter-
mediates in other processes.[4] Among the existing methods for the preparation of
1,2,4-thiadiazole derivatives, the oxidative dimerization of thioamides is obviously
a simpler one.[5] According to the literature, the oxidants used in the dimerization
are hypervalent iodine,[5a-5c] dimethyl sulfoxide electrophilic reagent,[5g] polymer-
supported diaryl selenoxide and telluroxide,[5f] and organotellurium,[5e] To the best
of our knowledge, there are few reports about the self-coupling reaction using
DDQ as an oxidant.[6] In 2007, Bose and Idrees reported the synthesis of benzothia-
zole by intramolecular cyclization of thioformanilides by DDQ.[6a] However, in their
research, no example was mentioned of the oxidative dimerization of thioamides,
which gives a different product, 1,2,4-thiadiazoles. Herein, we report that DDQ
mediates a highly efficient oxidative dimerization of thioamides to 3,5-disubstituted
1,2,4-thiadiazoles at room temperature.
RESULTS AND DISCUSSION
To begin our study, we chose phenylthioamide with DDQ as a model reaction
to search for the best reaction conditions (Table 1). Initially, several solvents were
screened. The reaction could proceed in all the solvents tested (Table 1, entries
1–6). When the reaction was performed in ClCH2CH2Cl, it gave the product with
95% yield. Then an analogous quinine oxidant, 1,4-benzoquinone (BQ), was
surveyed. The reaction was comparatively sluggish, and the yields were very poor.
Obviously, it is not as efficient as DDQ in this dimerization (Table 1, entries 7 and
8). As for the dosage of DDQ, it was found that using the amount of 1 equiv. could
also give the product with 95% yield in a few minutes (Table 1, entry 9).
With the optimized reaction conditions established, various thioamides were
subjected to oxidative dimerization (Table 2). All the arylthioamides bearing an
electron-donating or electron-withdrawing group on the aromatic ring reacted
rapidly, and 88–99% yields were obtained (Table 2, entries 1–11). No obvious elec-
tronic effect of the substituent on the aromatic ring was observed. Heteroaryl species
such as thienyl are also suitable substrates and excellent results was achieved

OXIDATIVE DIMERIZATION OF THIOAMIDES
2009
Table 1. Optimization of the reaction conditionsa
Entry
Reagent (mol equiv.)
Solventb
Time (min)
Yield (%)c
1
2
3
4
5
6
7
8
9
DDQ (1.1)
DDQ (1.1)
DDQ (1.1)
DDQ (1.1)
DDQ (1.1)
DDQ (1.1)
BQ (1.1)
CH3CN
ClCH2CH2Cl
CH2Cl2
5
<5
10
89
95
87
92
83
67
33
27
95
CH3NO2
Toluene
H2O
<5
10
30
60
ClCH2CH2Cl
CH3NO2
ClCH2CH2Cl
BQ (1.1)
DDQ (1.0)
60
<5
aReactions were carried out on a 0.5-mmol scale at rt.
b1 mL.
cIsolated yields.
(Table 2, entry 12). It is worth mentioning that benzylthioamide was compatible with
the present procedure, but the product was unstable (Table 2, entry 13).
In summary, we have developed a highly efficient oxidative dimerization of
thioamides by DDQ. A series of 3,5-disubstituted 1,2,4-thiadiazoles are synthesized
efficiently and concisely. It is a valuable addition to the existing methods available
for the oxidative dimerization of thioamides.
General Procedure for the Synthesis of 3,5-Disubstituted-
1,2,4-thiadiazoles
DDQ (0.5 mmol) was added at room temperature to a stirred suspension of
substrate[7] (0.5 mmol) in 1,2-dichloroethane (1 mL). The mixture was stirred for
the time indicated in Table 2. After completion of the reaction, 1,2-dichloroethane
was removed under reduced pressure, and the residue obtained was purified through
silica gel using petroleum ether=ethyl acetate (10:1) as developer.
Spectral Data for the 3,5-Disubstituted-1,2,4-thiadiazoles
3,5-Diphenyl-1,2,4-thiadiazole (2a). Solid, mp 89–90 ꢀC (lit.[5g] 91–91.5 ꢀC).
1H NMR (500 MHz, CDCl3): d 8.41–8.39 (m, 2H), 8.06–8.05 (m, 2H), 7.55–7.48 (m,
6H) ppm. IR (KBr): 2924, 1510, 1476, 1439, 1330, 760, 707, 682 cmꢁ1
.
3,5-Bis(4-fluorophenyl)-1,2,4-thiadiazole (2b). Solid, mp 185–186 ꢀC
1
(lit.[8a] 185–186). H NMR (500 MHz, CDCl3): d 8.39–8.36 (m, 2H), 8.07–8.04 (m,
2H), 7.24–7.17 (m, 4H) ppm. IR (KBr): 2963, 1598, 1475, 1410, 1261, 1097, 804,
743 cmꢁ1
.
3,5-Bis(4-chlorophenyl)-1,2,4-thiadiazole (2c). Solid, mp 161–162 ꢀC
1
(lit.[5g] 161.5–162 ꢀC). H NMR (500 MHz, CDCl3): d 8.33–8.31 (m, 2H), 8.00–7.97
(m, 2H), 7.52–7.46 (m, 4H) ppm. IR (KBr): 1595, 1468, 1401, 1385, 1091, 828,
739 cmꢁ1
.

2010
D. CHENG ET AL.
Table 2. Oxidative dimerization of thioamides to 3,5-disubstituted 1,2,4-thiadiazolesa
Entry
1
Substrate (1)
Product (2)
Time (min)
Yield (%)b
<5
95
2
3
4
<5
<5
<5
93
93
99
5
6
<5
<5
90
96
7
8
<5
<5
<5
<5
<5
97
88
92
90
9
10
11
94
(Continued )

OXIDATIVE DIMERIZATION OF THIOAMIDES
2011
Table 2. Continued
Entry
12
Substrate (1)
Product (2)
Time (min)
Yield (%)b
<5
<5
94
13
77
aReactions were carried out on a 0.5-mmol scale at rt.
bIsolated yields.
3,5-Bis(4-methoxyphenyl)-1,2,4-thiadiazole (2d). Solid, mp 139–140 ꢀC
1
(lit.[5g] 139–139.5 ꢀC). H NMR (500 MHz, CDCl3): d 8.33–8.31 (m, 2H), 8.00–7.98
(m, 2H), 7.02–7.00 (m, 4H), 3.90 (s, 3H), 3.89 (s, 3H) ppm. IR (KBr): 1609, 1477,
1421, 1253, 1169, 1029, 835, 747 cmꢁ1
.
3,5-Bis(4-nitrophenyl)-1,2,4-thiadiazole (2e). Solid, mp 198–199 ꢀC (lit.[5a]
200–202 ꢀC). 1H NMR (500 MHz, CDCl3): d 8.60–8.58 (m, 2H), 8.43–8.38 (m,
4H), 8.27–8.25 (m, 2H) ppm. IR (KBr): 2924, 2853, 1536, 1470, 1351, 851,
716 cmꢁ1
.
3,5-Bis(4-methylphenyl)-1,2,4-thiadiazole (2f). Solid, mp 130–131 ꢀC
(lit.[5g] 130.5–131 ꢀC). 1H NMR (500 MHz, CDCl3): d 8.27 (d, J ¼ 8.5 Hz, 2H),
7.94 (d, J ¼ 8.0 Hz, 2H) 7.30 (t, J ¼ 8.3 Hz, 4H), 2.44 (s, 3H), 2.43 (s, 3H) ppm. IR
(KBr): 2923, 1475, 1405, 1321, 815, 737 cmꢁ1
.
3,5-Bis(3-methylphenyl)-1,2,4-thiadiazole (2g). Solid, mp 56–58 ꢀC (lit.[8b]
55–57 ꢀC). 1H NMR (500 MHz, CDCl3): d 8.22 (s, 1H), 8.19 (d, J ¼ 8.0 Hz, 1H), 7.88
(s, 1H), 7.84 (d, J ¼ 7.5 Hz, 1H), 7.41–7.36 (m, 3H), 7.31 (s, 1H), 2.47 (s, 6H) ppm. IR
(KBr): 2918, 1480, 1436, 1309, 800, 731, 686 cmꢁ1
.
3,5-Bis(2-nitrophenyl)-1,2,4-thiadiazole (2h). Solid, mp 158–160 ꢀC (lit.[9]
159–160 ꢀC). 1H NMR (500 MHz, CDCl3): d 8.12–8.10 (m, 1H), 8.06–8.04 (m,
2H), 7.85–7.83 (m, 1H), 7.81–7.78 (m, 1H), 7.74–7.69 (m, 2H), 7.65–7.61 (m, 1H)
ppm. IR (KBr): 1535, 1479, 1372, 779, 700 cmꢁ1
.
3,5-Bis(3-nitrophenyl)-1,2,4-thiadiazole (2i). Solid, mp 184–185 ꢀC (lit.[9]
190–191 ꢀC). 1H NMR (500 MHz, CDCl3): d 9.26 (m, 1H), 8.91 (m, 1H),
8.741–8.737 (m, 1H), 8.46–8.36 (m, 3H), 7.79 (t, J ¼ 8.0 Hz, 1H), 7.73 (t, J ¼ 8.0 Hz,
Hz, 1H) ppm. IR (KBr): 3092, 1525, 1493, 1352, 718, 672 cmꢁ1
.
3,5-Bis(3-fluoro-4-bromophenyl)-1,2,4-thiadiazole (2j). Solid, mp 180–
182 ꢀC. 1H NMR (500 MHz, CDCl3): d 8.14–8.12 (m, 1H), 8.06–8.04 (m, 1H),
7.85–7.83 (m, 1H), 7.74–7.66 (m, 3H) ppm. 13C NMR (125 MHz, CDCl3): 186.3,
171.9, 160.5, 160.3, 158.5, 158.3, 134.7, 134.0, 133.65, 133.59, 131.33, 131.27,
124.99, 124.97, 124.2, 124.1, 116.4, 116.2, 115.2, 115.0, 113.6, 113.4, 111.9, 111.7.

2012
D. CHENG ET AL.
IR (KBr): 2926, 1504, 1461, 1433, 1384, 841, 739 cmꢁ1. MS (EI) m=z: 433 (Mþ þ 4,
11), 431 (Mþ þ 2, 22), 429 (Mþ, 11), 232 (97), 230 (100), 152 (32), 120 (24), 94 (11).
Anal. calc. for C14H6Br2F2N2S: C, 38.92; H, 1.40; N, 6.48. Found: C, 38.66; H, 1.66;
N, 6.32%.
3,5-Bis(3-chlorophenyl)-1,2,4-thiadiazole (2k). Solid, mp 130–131 ꢀC
1
(lit.[10] 128–128.5 ꢀC). H NMR (500 MHz, CDCl3): d 8.39 (s, 1H), 8.28–8.26 (m,
1H), 8.07 (s, 1H), 7.91–7.89 (m, 1H), 7.54–7.52 (m, 1H), 7.49–7.43 (m, 3H) ppm.
IR (KBr): 1573, 1473, 1386, 787, 730, 676 cmꢁ1
.
3,5-Bis(2-thiophene)-1,2,4-thiadiazole (2l). Solid, mp 94–96 ꢀC (lit.[11]
1
84–86 ꢀC). H NMR (500 MHz, CDCl3): d 7.94–7.93 (m, 1H), 7.71–7.70 (m, 1H),
7.60–7.58 (m, 1H), 7.46–7.45 (m, 1H), 7.18–7.14 (m, 1H) ppm. IR (KBr): 3097,
1540, 1466, 1415, 1312, 840, 710 cmꢁ1
.
3,5-Bis(4-nitrobenzyl)-1,2,4-thiadiazole (2m). Solid, mp 73–75 ꢀC. 1H
NMR (500 MHz, CDCl3): d 8.23 (d, J ¼ 8.5 Hz, 2H), 8.19 (d, J ¼ 8.5 Hz, 2H),
7.52–7.49 (m, 4H), 4.49 (s, 2H), 4.41 (s, 2H) ppm. 13C NMR (125 MHz, CDCl3):
189.5, 174.2, 147.5, 147.0, 144.3, 143.0, 130.0, 129.97, 124.2, 123.8, 38.9, 37.1 ppm.
IR (KBr): 2925, 1524, 1481, 1347, 843, 716 cmꢁ1. MS (EI) m=z: 356 (Mþ, 9),
220(12), 194 (100), 164 (25), 148 (43), 89 (24). Anal. calc. for C16H12N4O4S: C,
53.93; H, 3.39; N, 15.72. Found: C, 53.75; H, 3.48; N, 15.65%.
ACKNOWLEDGMENT
This work was financially supported by the Research Fund of Zhejiang Univer-
sity of Technology (1001116044408).
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