Ligand-free palladium-catalyzed C-S coupling reactions using water as solvent and microwaves

Article abstract of DOI:10.1055/s-0030-1258815

Herein we demonstrate for the first time a rapid and efficient method for the synthesis of aryl sulfides by the direct substitution reaction of aromatic thiols with aryl halides using water as solvent under microwave irradiation. This procedure offers a high yield in shorter reaction time as compared to conventional methods.

Full text of DOI:10.1055/s-0030-1258815

LETTER
2733
Ligand-Free Palladium-Catalyzed C–S Coupling Reactions Using Water as
Solvent and Microwaves
C
–S Coupling
i
R
eacti
v
ons an Velmathi,*a,b Reena Vijayaraghavan,a Ch. Amarendar,a Ravindra P. Pal,b Ajayan Vinub
a
Organic and Polymer Synthesis Laboratory, Department of Chemistry, National Institute of Technology, Tiruchirappalli 620 015, India
b
International Center for Materials Nanoarchitectonics, World Premier International (WPI) Research Initiative,
National Institute for Materials Science, Tsukuba, Ibaraki 305-0044, Japan
Fax +91(431)2500133; E-mail: velmathis@nitt.edu
Received 26 July 2010
(TBAB) as a catalyst. The same group also reported the
copper-catalyzed C–S cross-coupling in water.21 Howev-
er, both reactions require at least 10–19 hours to obtain the
desired product. Recently, a copper-catalyzed Ullmann
Abstract: Herein we demonstrate for the first time a rapid and effi-
cient method for the synthesis of aryl sulfides by the direct substitu-
tion reaction of aromatic thiols with aryl halides using water as
solvent under microwave irradiation. This procedure offers a high
yield in shorter reaction time as compared to conventional methods. coupling reaction under ligand- and additive-free condi-
tions was also reported wherein the reaction requires 22
hours of refluxing in toluene with 10 mol% of CuI,
TBAB, and sodium hydroxide as base.22,23
Key words: C–S coupling, aryl halides, thiols, microwave, palladi-
um acetate
As most of the reported coupling reactions require extend-
ed reaction times and high reaction temperatures, it is
highly imperative to find an alternative way for the con-
ducting the C–S coupling reaction. Very recently Bagley
et al. reported the synthesis of aryl sulfides using CuI,
trans-cyclohexane-1,2-diol as ligand, and K2CO3 as base
under microwave conditions.24 It has been found that the
use of the microwaves in this reaction significantly reduc-
es the reaction time, requires just 3 hours for completion,
and it is well established that microwave heating improves
the preparative efficiency as well and reducing the reac-
tion time for several different types of organic transforma-
tions.25,26 Microwave-assisted protocols have also been
widely applied to the formation of a variety of carbon–
heteroatom and carbon–carbon bonds.27–29 As a part of our
ongoing research in the area of microwave-assisted organ-
ic synthesis.30–32 we report herein our preliminary investi-
gation on microwave-assisted C–S bond-formation
reactions in the absence of ligand under aqueous condi-
tions, which constitutes one of the most efficient and rapid
syntheses of aryl sulfides.
Formation of the C–S bond is an important reaction in or-
ganic synthesis.1 Sulfides and their derivatives are attrac-
tive building blocks in the synthesis of biologically active
compounds2 and sulfur-containing functional monomers.3
Consequently, numerous synthetic methods for the syn-
thesis of sulfides have been developed. Sulfide formation
is generally carried out by the condensation of activated
alkyl halides with alkali-metal thiolates4 or by the reduc-
tion of sulfones or sulfoxides using strong reducing agents
such as DIBAL-H or LiAlH4.5 However, many of these
classical methods are limited by their moderate yields,
harsh reaction conditions, or tedious workup. Thus, meth-
ods for the introduction of a carbon–sulfur bond with the
use of transition-metal catalysts have been recently devel-
oped. The transition-metal-catalyzed coupling reactions
of sulfur nucleophiles with aryl halides is an important re-
action in organic synthesis for synthesizing aryl sulfides.
Migita et al.6 first reported palladium-catalyzed coupling
of iodo and bromo arenes with thiols and, since then,
many ligands have been tested and found successful for
this reaction. It has been well documented in the literature
that transition metals such as Fe,7 Co,8 Ni,9 and Cu10,11 cat-
alyze C–S bond formation. In addition these transition-
metal-catalyzed reactions are promoted by the addition of
chelating ligands such as BINAP, Tol-BINAP, DPPF,
Pd2(dba)3, or phosphine-based ligands.12–19
Recently we published the microwave-assisted synthesis
of b-arylalkenyl nitriles using Pd(OAc)2 as catalyst and
water as solvent.32 As a starting point for the development
of our microwave-mediated methodology, we initially
chose to study the reaction of 4-aminothiophenol with 4-
iodoacetophenone using the same conditions tried for the
arylalkenyl nitrile synthesis. Results of the optimization
reactions are given in Table 1. It was found that the reac-
tion was significantly influenced by the base employed
and the temperature. Sodium carbonate which has proved
to be an efficient base in organic solvents did not yield any
of the coupling products in water. Thus, we studied a
number of other bases and found that NaF was able to cat-
alyze the reaction and furnish the desired product in 78%
yield (entries 1–3). Keeping the amount of base constant
and increasing the reaction time from 10 to 30 minutes did
not increase the product yield (entries 4 and 5). Increased
Copper catalyzed C–S bond formation requires the use of
copper salts in more than stoichiometric quantities, polar
solvents, and high reaction temperatures (above 200 °C)
or long reaction times. Recently Punniamurthy et al.20 re-
ported the synthesis of ligand-free aryl sulfides in excel-
lent yield using NiCl2 in tetrabutylammonium bromide
SYNLETT 2010, No. 18, pp 2733–2736
x
x
.x
x
.2
0
1
0
Advanced online publication: 08.10.2010
DOI: 10.1055/s-0030-1258815; Art ID: D20310ST
© Georg Thieme Verlag Stuttgart · New York

2734
S. Velmathi et al.
LETTER
Table 1 Optimization of Reaction Conditions for C–S Coupling Reactiona
Entry
ArX
X
Thiol R3
Base
Solvent
Time (min) Temp (°C) Yield (%)b
R2, R1
1
2
I
H, COMe
H, COMe
H, COMe
H, COMe
H, COMe
H, COMe
H, COMe
H, COMe
H, COMe
H, COMe
H, COMe
H, COMe
H, OMe
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
H
Na2CO3
K2CO3
NaF
NaF
NaF
NaF
NaF
NaF
NaF
NaF
NaF
NaF
NaF
NaF
NaF
NaF
NaF
DMF
20
20
20
10
30
20
20
20
20
20
20
20
20
20
20
30
20
150
150
150
150
150
170
150
150
150
150
150
150
150
150
150
150
170
21
19
32
trace
12
15
–
I
DMF
3
I
DMF
4
I
DMF
5
I
DMF
6
I
DMF
7
I
H2O–EtOH
H2O
8
I
–
9
I
H2O–TBAB
H2O–TBAB
H2O–TBAB
H2O–TBAB
H2O–TBAB
H2O–TBAB
H2O–TBAB
H2O–TBAB
H2O–TBAB
78
–
10c
11
11
12
13
14
15
16
I
I
NH2
H
–
Br
I
–
H
–
Br
Br
Br
I
H, OMe
H
–
H, H
H
–
H, NO2
H
–
H, COMe
H
–
a Aryl halide (1 mmol), aryl thiol (1mmol), Pd(OAc)2 (5 mol%) were used for entries 1–9.
b Isolated yield.
c For entries 10–16 reactions were done in the absence of Pd(OAc)2.
reaction temperatures were also not favorable as the reac- NaF (1 mmol), TBAB (1 mmol), Pd(OAc)2 (5 mol%), wa-
tant materials started to decompose when the reaction ter (15 mL), heating to 150 °C, for 20 minutes (Table 1,
temperature was increased from 150 to 170 °C (entry 6). entry 9) (Scheme 1).33
We also tried eliminating TBAB from the reaction or re-
In a few cases disulfides were formed in 6–20% yields.
placing it with ethanol as a co-solvent but both of these
This may be due to the presence of oxygen in the water
modifications resulted in a very poor conversion (entries
used since only distilled water was used for the coupling
7, 8). In the absence of palladium acetate the reactions did
reaction. Other than that, the C–S coupled products were
not go to completion (entries 10–16). Both electron-
obtained in good yields of 80–90%. Both electron-defi-
releasing- and electron-withdrawing-substituted aryl ha-
cient and electron-rich aryl bromides and iodides under-
lides were tried under these conditions, and we observed
went the coupling reactions. The reactivity of aryl halides
the same result. This could imply that the reactions are
was greatly improved by electron-withdrawing substitu-
largely proceeding under palladium catalysis. Both aryl
ents. A series of aryl halides was screened and results are
iodides and bromides were unreactive in the absence of
shown in Table 2. A number of aryl iodides can be con-
palladium acetate. After a series of experiments with dif-
verted to the corresponding aryl sulfides in good yields
ferent reaction conditions, we found the following condi-
(Table 2, entries 1–5, 9 and 10 and 12–14, and 16). Inter-
tions to be the best, affording the desired product in
estingly however, those substrates bearing a substituent in
excellent yield. Optimum reaction conditions for the C–S
the ortho position could not be converted into the aryl sul-
fides efficiently (Table 2, entry 5). The scope of aryl bro-
coupling reaction are as follows: aryl halide (1 mmol),
R2
R1
R2
X
S
Pd(OAc)2, NaF, TBAB
+
HS
R3
H2O, MW, 150 °C, 20 min
R1
R3
Scheme 1 Palladium-catalyzed coupling reaction of aryl halides with aryl thiols
Synlett 2010, No. 18, 2733–2736 © Thieme Stuttgart · New York

LETTER
C–S Coupling Reactions
2735
Table 3 1H NMR Data of the Aryl Sulfides Synthesized
mides is limited to those bearing electron-withdrawing
groups (Table 2, entries 6, 7, 11, and 15). Finally, aryl
chlorides were poor coupling reagents (Table 2, entry 8).
Both thiophenol and substituted thiophenols were found
to give the coupled products in good yield. Products were
characterized by comparison of NMR data with those in
the literature. 1H NMR data of the compounds synthesized
are given in Table 3.
Entry Product
1H NMR (400 MHz, CDCl3): d
(ppm)
S
5.85 (s, 4 H), 6.50 (m, 4 H),
6.90 (m, 4 H)34
1
H2N
NH2
NH2
3.70 (s, 3 H), 5.50 (s, 2 H),
6.40 (m, 2 H), 6.90 (m, 2 H),
7.00 (m, 2 H), 7.20 (m, 2 H)35
S
2
Table 2 The Reaction of Various Aryl Halides with Aryl Thiolsa
MeO
Entry ArX
X
Thiol R2 Yield (%)b
Aryl sulfide Disulfidec
S
S
2.57 (s, 3 H), 4.50 (br s, 2 H),
6.50 (m, 2 H), 7.20 (m, 2 H),
NH2 7.60 (m, 2 H), 7.80 (d, 2 H)
R2, R1
3
1
2
I
H, COMe
H, OMe
H, NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
H
78
75
70
89
65
70
70
0
10
12
12
0
O
I
2.57 (s, 3 H), 7.20 (m, 1 H),
7.30 (m, 2 H), 7.40 (m, 2 H),
7.50 (m, 2 H), 7.80 (d, 2 H)36
4
3
I
4
I
H, Ph
O
3.70 (s, 3 H), 6.60 (m, 2 H),
7.00 (m, 2 H), 7.20 (m, 1 H),
7.40–7.50 (m, 4 H)21
S
S
5
I
OMe, H
H, OMe
H, COMe
H, COMe
H, COMe
H, OMe
H, COMe
H, NH2
17
12
20
0
5
6
Br
Br
Cl
I
MeO
5.80 (s, 2 H), 6.50 (m, 2 H),
7.00 (m, 2 H), 7.20 (m, 1 H),
7.40–7.60 (m, 4 H)36
7
6
8
H2N
3.79 (s, 3 H), 5.50 (s, 2 H),
6.60 (m, 2 H), 6.90 (m, 2 H),
7.00–7.30 (m, 3 H), 7.50 (m, 1
H)
9
88
82
79
80
83
78
81
74
5
S
7
8
NH2
10
11
12
13
14
15
16
I
H
8
OMe
Br
I
H
8
5.70 (s, 2 H), 6.50 (m, 2 H),
6.90 (m, 2 H), 7.20 (d, 1 H),
7.40 (m, 1 H) 7.60 (m, 2 H),
7.70–7.90 (m, 2 H), 8.10 (m, 1
H)
H
8
S
I
H, OMe
H, COMe
H, COMe
H, NH2
Me
Me
Me
Me
7
NH2
I
11
6
2.20 (s, 3 H), 3.70 (s, 3 H),
S
S
Br
I
9
6.60 (m, 2 H), 7.00–7.20 (m, 4
H), 7.40–7.50 (m, 2 H)37
12
MeO
Me
a Reaction conditions: aryl halide (1 mmol), aryl thiol (1 mmol), NaF
(1 mmol), TBAB (1 mmol), Pd(OAc)2 (5 mol%), H2O (15 mL), under
MW irradiation 150 °C, reaction time of 20 min.
b Isolated yield.
2.00 (s, 3 H), 2.57 (s, 3 H),
6.50 (m, 2 H), 7.20 (m, 2 H),
7.60 (m, 2 H), 7.80 (d, 2 H)37
10
O
c Determined by GC-MS.
S
2.30 (s, 3 H), 5.50 (s, 2 H),
6.60 (m, 2 H), 7.00 (m, 2 H),
7.20 (m, 2 H), 7.40 (m, 2 H)38
11
The reaction may proceed via a mechanism similar to that
of palladium-catalyzed coupling reactions involving oxi-
dative addition of aryl halide 2 to the palladium(0) com-
plex to give 3 and a base-induced transfer of the R2S group
4 to 3 to form 5 and a reductive elimination of 6 from 5
leads to C–S bond formation (Scheme 2).
H2N
Acknowledgment
One of the authors (S.V.) gratefully acknowledges the support and
funding from Dr. M. Chidambaram, the Director of NITT. We also
wish to thank Dr. S. Perumal from Madurai Kamaraj University, for
extending the microwave reactor facility for carrying out some of
these reactions. This work was also partially supported by the Mini-
stry of Education, Culture, Sports, Science and Technology
(MEXT) under the Strategic Program for Building an Asian Science
and Technology Community Scheme and World Premier Interna-
tional Research Center (WPI) Initiative on Materials Nanoarchitec-
tonics, MEXT, Japan. Authors wish to thank the referees for
constructive suggestions in improving the quality of the work.
In conclusion, we have developed a rapid and efficient
method for the synthesis of aryl sulfides by the direct sub-
stitution reaction of thiols with aryl halides using water as
solvent under microwave irradiation. Particularly, the
methodology presented here is attractive because of its
shorter reaction time, higher yields, and the experimental
simplicity.
Synlett 2010, No. 18, 2733–2736 © Thieme Stuttgart · New York

2736
S. Velmathi et al.
LETTER
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