A novel copper-catalyzed, one-pot synthesis of symmetric organic disulfides from alkyl and aryl halides: Potassium 5-methyl-1,3,4-oxadiazole-2-thiolate as a novel sulfur transfer reagent

Article abstract of DOI:10.1016/j.tetlet.2012.10.016

A new method is reported for the synthesis of symmetric diaryl and dialkyl disulfides from aryl and alkyl halides in the presence of copper using potassium 5-methyl-1,3,4-oxadiazole-2-thiolate as the base, ligand, and sulfur-transfer reagent.

Full text of DOI:10.1016/j.tetlet.2012.10.016

Tetrahedron Letters 53 (2012) 7028–7030
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Tetrahedron Letters
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A novel copper-catalyzed, one-pot synthesis of symmetric organic disulfides
from alkyl and aryl halides: potassium 5-methyl-1,3,4-oxadiazole-2-thiolate
as a novel sulfur transfer reagent
⇑
Mohammad Soleiman-Beigi , Fariba Mohammadi
Department of Chemistry, Ilam University, PO Box 69315-516, Ilam, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method is reported for the synthesis of symmetric diaryl and dialkyl disulfides from aryl and alkyl
halides in the presence of copper using potassium 5-methyl-1,3,4-oxadiazole-2-thiolate as the base,
ligand, and sulfur-transfer reagent.
Received 9 August 2012
Revised 24 September 2012
Accepted 4 October 2012
Available online 12 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Copper-catalyzed
One-pot
Disulfides
1
,3,4-Oxadiazole
Sulfur transfer reagents
Organic disulfides are of importance in synthetic chemistry,
biochemistry, and industry.1 They are commonly used to prepare
many kinds of reactive intermediates, and participate in chemical
substitution or addition reactions.2 Many biologically active com-
In continuation of our efforts on the synthesis of organosulfur
compounds, we report a method for the direct synthesis of sym-
11
metric diaryl and dialkyl disulfides from aryl and alkyl halides.
12
Thus, potassium 5-methyl-1,3,4-oxadiazole-2-thiolate (2, Fig. 1)
3
pounds such as proteins, peptides, and prodrugs, and industrial
was utilized as a new heterocyclic sulfur donor with basic proper-
ties and for the chelation of copper.
4
vulcanizing agents, have disulfide linkages.
The oxidation of thiols to the corresponding disulfides is the pri-
mary method for preparing these compounds. However, the use of
The reaction of iodobenzene (1) with potassium 5-methyl-
1,3,4-oxadiazole-2-thiolate (2) was studied under normal atmo-
spheric conditions in order to optimize the reaction conditions in
terms of temperature, amount of reagent, and the type of copper
source (Scheme 1).
According to the results shown in Table 1, it was found that the
temperature significantly affected both the rate of the reaction and
the amount of the main product 3 formed. The reaction yield and
rate increased with temperature, whereas formation of the by-
product (4, diphenyl sulfide) was reduced.
5
toxic, odorous, and volatile thiols is considered a disadvantage of
this method. To overcome this disadvantage, attention has been di-
rected toward the synthesis of symmetric disulfides from alkyl ha-
lides in the presence of reagents such as thiourea and thiouronium
6
7
salts, sulfated borohydride exchange resin, and sulfur/sodium
8
sulfide. These methods are useful and effective for the synthesis
of only symmetric dialkyl disulfides.
To reduce the costs and the environmental risks of chemical
processes, syntheses employing one-pot, domino, and direct con-
versions are beneficial to reducing the number of reaction steps,
The copper salts tested in this investigation all catalyzed the
reaction well and had similar effects on the reaction progress
(Table 2). Furthermore, the progress of the reaction depended on
the amount of potassium 5-methyl-1,3,4-oxadiazole-2-thiolate
9
and minimizing the use of dangerous reagents. In this regard, sul-
fur-transfer reagents such as thiourea, potassium thiocyanate, thi-
osemicarbazide, and sodium sulfide are used instead of thiols, for
the direct synthesis of organic sulfides and disulfides from alkyl
6
–8,10
(
aryl) halides.
N
N
CH3
S K
O
⇑
Corresponding author. Tel./fax: +98 841 2227022.
E-mail address: SoleimanBeigi@yahoo.com (M. Soleiman-Beigi).
Figure 1. Structure of potassium 5-methyl-1,3,4-oxadiazole-2-thiolate (2).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.016

M. Soleiman-Beigi, F. Mohammadi / Tetrahedron Letters 53 (2012) 7028–7030
7029
Cu-source, S-source (2)
Table 3
PhI
PhS-SPh
+
PhSPh
Direct synthesis of symmetrical disulfides from aryl (alkyl) halides
DMF, Temp.
Entry
1
R-X
Producta
Time (h)
7.0
Yieldb (%)
1
3
4
Scheme 1.
I
6a
98
I
2
3
6b
6c
5.5
7.0
98c
Me
Table 1
Optimization of the reaction temperature
a
I
93
Entry
Temp (°C)
Time (h)
Yieldb (%)
Mpc (°C)
MeO
Disulfide 3
Sulfide 4
4
5
MeO
NH2
I
6d
6e
5.0
7.0
90
94
1
2
3
4
5
6
7
25
40
65
24
24
7
7
7
—
10
25
58
67
97
89
—
—
Oil
Oil
37–40
40–41
54–55
48–50
58
56
38
30
Trace
9
I
80
6
7
8
9
6f
6.0
6.0
7.0
74
55
68
I
S
110
130
140
7
7
Br
I
6g
6h
a
Model reaction conditions: PhI (2.0 mmol), DMF (4 mL), CuCl (0.6 mmol),
potassium 5-methyl-1,3,4-oxadiazole-2-thiolate (2) (3.0 mmol), air.
S
Br
32c
47
b
O N
Br
Br
Br
6i
6j
7.0
7.0
Determined by GC.
2
c
Melting points refer to a purified mixture of diphenyl disulfide 3 and diphenyl
1
0
1
Me
F
sulfide 4.
1
6k
6l
5.0
6.0
72c
96c
F
I
Table 2
a
Optimization of the copper source and amount of sulfur source
12
Entry
Temp (°C)
Sulfur
Copper salt
Yieldb (%)
source 2
Disulfide 3
Sulfide 4
(mmol)
Cl
1
3
4
6m
6n
0.5
1.0
86
88
1
2
3
4
5
6
7
8
9
110
110
110
130
130
130
130
130
130
130
1
2
3
1
2
3
4
3
3
3
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuI
33
55
67
50
75
97
98
98
95
96
40
36
30
28
Br
(CH ) Br
1
2
3
17
15
6o
1.0
84
Trace
Trace
Trace
Trace
Trace
a
All the products are known compounds and were characterized by comparison
5,6
of NMR spectral data and melting points with those reported in the literature.
2
Cu O
b
Isolated yield.
1
0
CuBr
c
A small amount of the corresponding diaryl sulfide derivative was formed as
a
by-product (7–16%).
Model reaction conditions: PhI (2.0 mmol), DMF (4 mL), copper salt (0.6 mmol),
air, 7 h.
b
Determined by GC.
also synthesized in good to excellent yields. The GC yields and
NMR data show that the diaryl (dialkyl) disulfide was often the
only reaction product, although 7–16% yields of the diaryl sulfide
were formed in some cases (Table 3, entries 2, 9, 11, and 12).
Although we cannot clearly determine the catalytic reaction
pathway for the synthesis of diaryl (alkyl) disulfides from aryl (al-
kyl) halides and potassium 5-methyl-1,3,4-oxadiazole-2-thiolate
(
3
2); the reaction was found to go into completion in the presence of
equiv of this reagent (Table 2).
A large number of symmetrical diaryl (alkyl) disulfides 6a–6o
was synthesized in the presence of copper chloride using 3 equiv
of potassium 5-methyl-1,3,4-oxadiazole-2-thiolate (2) at 130 °C
under normal atmospheric conditions (Scheme 2, Table 3). 2-
Alkylthio-5-methyl-1,3,4-oxadiazole was the main product of the
reaction in the absence of a copper catalyst and if the temperature
1
3
(2), it is possible that this reaction proceeds by the in situ genera-
tion of a thiolate radical via an SRN1 (Unimolecular Radical Nucle-
ophilic Substitution) type mechanism, followed by S–S coupling.
Aryl (alkyl) halides are activated via a Cu(I)/ Cu(II) redox couple
1
2b,14
was below 100 °C.
The reaction efficiency for the synthesis of diaryl disulfides from
various aryl halides was examined. As can be seen, aryl bromides
were useful, but not as reactive as aryl iodides, with yields of
1
5
SET (Single Electron Transfer).
This work reports a new and effective method for the synthesis
of symmetric diaryl (dialkyl) disulfides from aryl and alkyl halides,
which is more economic, more comprehensive, and more environ-
mentally friendly than previous methods. The use of potassium 5-
methyl-1,3,4-oxadiazole-2-thiolate (2), which was the ligand, base,
and the source of sulfur is another notable advantage of this
process.
3
2–72% (Table 3, entries 8–11). Symmetric diaryl disulfides with
different functional groups, such as CH
3
, NH
2
, OH, Br, and F were
CuCl, DMF
30 °C
2
R-X
+
3 (2)
RS-SR
Acknowledgement
1
5
6
We gratefully acknowledge financial support from the Iranian
National Science Foundation (INSF, Grant No. 89003646).
Scheme 2.

7
030
M. Soleiman-Beigi, F. Mohammadi / Tetrahedron Letters 53 (2012) 7028–7030
(a) Sonavane, S. U.; Chidambaram, M.; Almog, J.; Sasson, Y. Tetrahedron Lett.
8.
Supplementary data
2007, 48, 6048; (b) Wang, J.-X.; Gao, L.; Huang, D. Synth. Commun. 2002, 32,
963.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
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2
2
H
2
O (3 Â 10 mL). The organic layer was dried over anhydrous Na
2
4
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.
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5
j,k
1
mp = 41–43 °C (42–43 °C lit. ); H NMR (CDCl
3
, 400 MHz): d 3.82 (s, 6H),
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3
6
5
5
.87 (d, J = 8.8 Hz, 4H), 7.32 (d, J = 8.8 Hz, 4H); C NMR (CDCl
5.4, 114.7, 127.4, 132.8, 159.0 ppm; 6f (Table 3, entry 6): mp = 53–54 °C (54–
3
, 100 MHz): d
4
5l,6a
1
6 °C lit.
3
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13
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,100 MHz): d 127.5, 129.7, 132.8,
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, 400Mz): d 6.98–7.03 (m,
H), 7.25 (dd, J = 8.4, 2.8 Hz, 2H), 7.45 (dd, J = 8.6, 5.2 Hz, 2H); C NMR (CDCl
1
2
1
1
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6