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Chemistry Letters Vol.33, No.12 (2004)
1
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CsOH H2O-Promoted Synthesis of Aryl Sulfides via Direct Coupling of Aryl Halides and Thiols
Ravi Varala, E. Ramu, M. Mujahid Alam, and Srinivas R. AdapaÃ
Inorganic Division, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(Received August 16, 2004; CL-040967)
We report here our observation that, using appropriate reac-
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of the crude product using silica gel flash chromatography
(Table 1, Entry 1). As a control experiment, the same reaction
tion conditions, CsOH H2O-promoted coupling of aryl halides
with thiols can be performed in moderate to good yields without
a transition metal catalyst.
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was carried out in the absence of CsOH H2O at 120 C, when
no cross-coupled product was observed even after heating for
a longer period of time. The optimum yield of the product is ob-
tained when a ratio of aryl halide to thiol of 1:1.2 is used. Of the
solvents tested for this reaction (DMSO-THF, H2O/TBAB,
NMP, and DMSO), DMSO was found to be the most efficient,
perhaps because thiolate anions are more reactive in aprotic sol-
vents such as DMSO than in protic solvents. In the absence of
DMSO, no product could be isolated from the crude reaction
mixture, thus solvent plays a vital role in this reaction.
Lately, both the scope and application of organosulfur
chemistry have received considerable attention in synthetic or-
ganic chemistry because sulfur-containing moieties serve as an
important auxiliary function in synthetic sequences in organic
chemistry. In addition, aryl sulfides are very useful intermediates
in organic synthesis.2 Furthermore, aryl sulfides also find impor-
tant applications as pharmaceuticals as many aryl sulfide con-
taining compounds show significant pharmacological activity.3
After early reports by Murahashi4 and Migita,5 only a few
new synthetic methods of carbon-sulfur bond-forming reactions
have appeared in the literature. The conversion of unactivated
aryl halides or triflates to aryl sulfides has been realized by using
stoichiometric amounts of copper salts6 and using palladium
complexes as catalysts.7 Guy et al. has developed an elegant syn-
thesis of aryl sulfides through copper-mediated cross-coupling of
aryl boronic acids and thiols.8 Buchwald et al.9 has reported cop-
per(I)-catalyzed coupling of aryl iodides and thiols using K2CO3
as a base and ethylene glycol as an additive in 2-propanol at
80 ꢀC. Recently, there is a report of coupling of aryl halides
and thiols by using copper catalysts under microwave condi-
tions.10 Even though these reported methods are very efficient
and provide good conversion for the synthesis of aryl sulfides,
these synthetic methodologies require use of transition metal
complexes, and suffer from long reaction times, and have a
relatively narrow application scope for substrates. Furthermore,
use of transition metal complexes leads to the generation of
hazardous waste, which has a number of environmental health
problems associated with it.11 Very recently, a convenient
one-pot synthesis of alkyl aryl sulfides from thiols and alkyl
halides using cesium carbonate, tetrabutyl ammonium iodide,
and DMF is reported.12 Thus, development of improved synthet-
ic methods for the synthesis of aryl sulfides still remains an
active research area.
SH
Br
S
CsOH.H2O
DMSO,1200C
+
Scheme 1.
With optimized experimental conditions for thiophenol in
hand, we then investigated the direct cross-coupling reactions
of a wide range of substituted aryl halides and thiols. The results
from this study are shown in Table 1. It is clear from Table 1 that
most substrates underwent direct coupling reactions to afford the
corresponding sulfides in moderate to good yields. Reaction time
is also very short (5–20 min) for most of the substrates. Howev-
er, the reaction of benzylmercaptan with 1-bromo-4-nitroben-
zene required no heating at all, as the reaction takes place at
room temperature in about 3 h in excellent yield, similarly, 4-
methylthiophenol coupled with 1-bromo-4-nitrobenzene gave
72% yield (Entry 4). In general, benzyl mercaptans gave excel-
lent yields compared to thiophenols. In general, electron donat-
ing groups like methyl, amino groups on the aryl halide gave
poor yields than those of reactions carried out with electron with-
drawing groups on aryl halides. For example, 4-bromotoluene
and 4-bromoaniline on reacting with thiophenol gave 62, 57%
in yields respectively (Entries 6 and 8). However, aryl halides
that contain p-hydroxy and p-methoxy substituents do not under-
go adduct formation at all under our experimental conditions.
However, when methoxy substituents were present in the aro-
matic thiol fragments, no inhibition for direct coupling reactions
were observed. As seen in Entry 11, 1-bromo-4-cyanobenzene
and 4-methoxybenzenethiol gave coupled products in good
yields. In a similar fashion, thiophenols containing amino groups
do not inhibit the reaction as well. The coupling of 1-bromo-
naphthalene and 4-aminobenzenethiol gave coupled product in
moderate yield 68% (Entry 12). In general, the use of aryl io-
dides for the coupling reactions gave higher yields of the desired
sulfides than those of reactions involving corresponding bro-
mides (Entries 2, 5, 7, and 9). This observation is consistent with
earlier observation that aryl iodides are more reactive than cor-
responding bromo analogues.15 Aliphatic thiols react readily
with aryl halides to form corresponding sulfides in moderate
.
In the last few years, CsOH H2O-promoted synthetic proto-
cols have been widely applied to the formation of a variety of
carbon–hetero atom and carbon–carbon bond.13 Herein, we pres-
ent our preliminary findings in the development of transition
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metal-free coupling of aryl halides and thiols using CsOH H2O
as efficient base for various structurally divergent benzene thiols
and aryl halides.
First, we evaluated the feasibility of direct cross-coupling of
bromobenzene (1.0 mmol) and thiophenol (1.2 mmol) in DMSO
14
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using 2 mmol of CsOH H2O in a sealed tube (Scheme 1). At
ambient temperatures, no reaction between the coupling partners
was observed, but heating the reaction mixture to 120 ꢀC for
10 min afforded diphenyl sulfide in 64% yield after purification
Copyright Ó 2004 The Chemical Society of Japan