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NOWROUZI ET AL.
3
aryl bromides bearing electron‐withdrawing and electron‐
donating groups were also utilized for the synthesis of sym-
metric diaryl sulfides, generating high yields (Table 2, entries
8–13). It is important to note that unprotected amino group in
aryl halides did not hinder the reaction and no N‐arylating
product was detected in these cases (Table 2, entries 4 and
10). We also studied the applicability of the method for the
reaction of aryl chlorides. To this end, the reaction of 4‐
chlorobenzonitrile with the catalytic system at 120°C was
studied. The results showed that the reaction did not proceed
and starting material was isolated intact after the appropriate
reaction time (Table 2, entry 14). Therefore, it can be said
that this catalytic system is not efficient for chloroarenes.
This protocol could also be applied to heterocyclic aryl
halides (Table 2, entry 15). Formation of disulfide side prod-
uct is one of the major limiting factors in this area through the
facile oxidation of thiols. Here, the NMR data showed that
diaryl sulfide was the only reaction product, and diaryl disul-
fide was not formed in any of the cases.
After successful thiolation of aryl halides using CuI/thio-
urea in wet PEG, the applicability of the system was investi-
gated for synthesis of diaryl disulfides. Organic disulfides
(disulfanes) are of importance in organic chemistry, biochem-
istry, industry and materials science.[14] They are commonly
used to prepare many kinds of reactive intermediates, and
participate in chemical substitution or addition reactions.[15]
Besides, many biologically active compounds have disulfide
linkages.[16] Because of the wide applicability of organic
disulfides in different branches of science, the protocols lead-
ing to disulfides that are practical, cheap and efficient have
attracted a great deal of attention. The oxidative coupling of
thiols is the most common method for diaryl disulfide forma-
tion.[17] Because of the difficulties of using free thiols, in the
recent past, various catalytic systems have been introduced
for disulfide formation in the presence of sulfur transfer
reagents.[18] According to the above results, the oxidation of
in situ‐generated thiophenols from the reaction of aryl halides
with thiourea in the presence of CuI as catalyst can provide
diaryl disulfides. Therefore, we decided to choose a suitable
oxidant and carry out this transformation. Due to the high
oxidation capability of thiourea[19] and thiol over‐oxidation
in alkaline conditions, the outcome of the couplings critically
depends on the proper choice of oxidant. We also believe that
degradation of copper(I) iodide can take place by employ-
ment of inappropriate oxidants. On the other hand, to achieve
disulfides without contamination with thioether, the oxida-
tion of the thiolate intermediate should be quite facile. Thus,
proper choice of the oxidant is an important factor for devel-
oping this strategy. In this way, the effect of various oxidants
such as C2Cl6, H2O2, oxone, Na2S2O8, KIO4 (potassium
periodate) and NaClO (sodium hypochlorite) was studied in
the reaction of iodobenzene and thiourea using CuI under
the optimized conditions developed earlier for the formation
of sulfides. Among the various oxidants tested, hexachloro-
ethane (C2Cl6) was the only suitable oxidant for the reaction.
As expected, in the presence of other oxidants, the reactions
did not progress at all and iodobenzene remained unreacted
in the reaction mixture after a long period of time (24 h).
We believe that thiourea could be completely destroyed in
the presence of these oxidants. With these results in hand,
C2Cl6 was selected as the oxidizing agent for the preparation
of diaryl disulfides from aryl halides in wet PEG at 120°C.
With the optimized reaction conditions in hand, we then
examined a series of aryl halides to establish the scope of
substrates and find the limits of the catalytic system. As sum-
marized in Table 3, some functional groups such as methyl,
methoxy, amino, nitro and cyano could be introduced into
aryl iodides and bromides to generate the corresponding
disulfides in excellent yields. However, when aryl halides
containing electron donor groups, such as methyl, methoxy
and amino groups, were used, longer reaction times were
required to obtain the respective disulfides. The lower reac-
tivity of the electron donor aryl iodides in this system is prob-
ably associated with the difficulty of insertion of copper into
carbon–iodine bond compared to electron‐deficient ones.[20]
Aryl chlorides were unreactive under the developed catalytic
conditions (Table 3, entry 14). Using this catalytic system, 2‐
iodothiophene as a heterocyclic aryl halide was reacted effi-
ciently and produced the corresponding product in excellent
yield (Table 3, entry 15).
The thiol intermediate was not observed during the reac-
tion leading to the conclusion that the oxidation of thiol must
be very fast. Due to rapid oxidation, diaryl sulfide was not
TABLE 3 Synthesis of diaryl disulfides from aryl halides in the presence of
thiourea and C2Cl6 catalysed by CuIa
Entry
1
X
I
Z
Time (h)
12
Yield (%)b
95[18]
93[18]
88[18]
80[18]
90[18]
91[18]
—
93[18]
93[18]
85[18]
88[18]
90[17]
87[18]
—
H
2
I
p‐Me
p‐OMe
p‐NH2
m‐Me
p‐NO2
o‐Me
H
14
3
I
14
4
I
16
5
I
12.5
11
6
I
7
I
48
8
Br
Br
Br
Br
Br
Br
Cl
15
9
p‐Me
p‐NH2
m‐OMe
p‐CN
p‐NO2
p‐CN
17
10
11
12
13
14
15
18
16
13
13
48
12
87[18]
2‐iodothiophene
aReaction conditions: aryl halide (2.0 mmol), thiourea (2.6 mmol), Na2CO3
(3.5 mmol), CuI (20 mol%), C2Cl6 (1.2 mmol), PEG‐200 (2 ml), 120°C.
bIsolated yield.