An efficient iron-catalyzed S-arylation of aryl and alkylthiols with aryl halides in the presence of water under aerobic conditions

Article abstract of DOI:10.1016/j.tetlet.2015.06.087

Abstract In this study, an environmentally benign FeCl₃·6H₂O/l-proline catalytic system in the presence of TBAB was employed as a catalyst for the coupling reactions of aryl halides with aryl and alkyl thiols in water under aerobic conditions. The versatility, low cost, and environmental friendliness, in combination with high yields, makes the procedure noteworthy. This protocol offers a simple and efficient thioetherification method for aryl halides.

Full text of DOI:10.1016/j.tetlet.2015.06.087

Tetrahedron Letters 56 (2015) 4923–4926
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient iron-catalyzed S-arylation of aryl and alkylthiols with
aryl halides in the presence of water under aerobic conditions
⇑
K. S. Sindhu, Amrutha P. Thankachan, Anns Maria Thomas, Gopinathan Anilkumar
School of Chemical Sciences, Mahatma Gandhi University, PD Hills PO, Kottayam 686 560, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, an environmentally benign FeCl3ꢀ6H2O/
L-proline catalytic system in the presence of TBAB
was employed as a catalyst for the coupling reactions of aryl halides with aryl and alkyl thiols in water
under aerobic conditions. The versatility, low cost, and environmental friendliness, in combination
Received 5 June 2015
Revised 25 June 2015
Accepted 26 June 2015
Available online 2 July 2015
with high yields, makes the procedure noteworthy. This protocol offers
thioetherification method for aryl halides.
a simple and efficient
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
C–S coupling
Iron catalysis
Green chemistry
Thioetherification
Cross coupling
Introduction
Moreover, in most cases, the catalytic systems comprised of
expensive catalysts, phosphine-based ligands, moisture sensitive
bases, and organic solvents.13
Transition metal catalyzed carbon–heteroatom cross-coupling
reactions have found widespread popularity in synthetic
chemistry, as several biologically active compounds with wide
ranges of activity contain carbon–heteroatom bonds.1 Whereas
many C–N and C–O cross-coupling reactions are reported over
the years, C–S bond formation leading to diaryl thioethers has
received comparatively less attention, despite of the prevalence
of these bonds in many molecules which are widely used for
biological, pharmaceutical, and material science applications.2 In
1978, Migita and co-workers reported the first C–S cross-coupling
of aryl halides with thiols using tetrakis(triphenylphosphine)-
palladium as catalyst.3 Later, several transition metal catalysts in
which palladium,4 nickel,5 cobalt,6 copper,7 rhodium,8 indium,9
and zinc10 serve as the metal sources in combination with appro-
priate ligands have been developed. Out of these transition metals,
iron is more attractive over other metals, owing to its cheap price,
less toxicity, and environmentally benign properties. In 2008, Bolm
et al. reported the first iron-catalyzed thioetherification of aryl
thiols with aryl iodides using FeCl3/DMEDA as the catalyst and
NaOtBu as the base in toluene under argon atmosphere.11
On the other hand, in recent years the design of green chemistry
approaches for the thiol S-arylation reactions has received much
attention. The use of water as a solvent for organic reactions is of
high practical value, since water is cheap, non-toxic, safe, and
environmentally benign as compared to organic solvents.14
Furthermore, the catalyst-containing aqueous solution can be
easily separated from the organic products.
Although several methods are available for the formation of aryl
sulfides, those employing green chemistry approaches are very
limited for iron-catalyzed C–S coupling reactions and confined to
a report by Tsai et al. which utilizes a cationic 2,20-bipyridyl system
as the catalyst. Therefore, it is highly desirable to develop a cheap
and greener methodology for the iron-catalyzed C–S cross-
coupling reactions with wide range of substrate scope. Herein,
we present a green, efficient, and versatile protocol for the synthe-
sis of thioethers based on FeCl3 and L-proline as catalyst system by
the coupling of aryl halides including bromides and chlorides with
aryl and alkyl thiols in water under air.
Thereafter, only
a few reports appeared on iron-catalyzed
Result and discussion
thioetherification reactions. However, most of these approaches
were limited to systems with aryl iodides and aryl thiols and were
ineffective for aryl bromides, aryl chlorides, and alkyl thiols.12
In this study, we wish to report an efficient FeCl3-catalyzed
S-arylation of aryl halides with thiols using
in water under aerobic conditions. Compared to phosphine-
based ligands, -proline is very cheap, non-toxic, and readily
L-proline as the ligand
L
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetlet.2015.06.087
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

4924
K. S. Sindhu et al. / Tetrahedron Letters 56 (2015) 4923–4926
available. It is proven that in the absence of the catalyst and ligand,
the C–S coupling product was obtained in lesser amounts, and
diphenyl disulfide, which arises from an iron-catalyzed oxidation
reaction of the thiol, was the main product. When our present proto-
col for the formation of C–S bond is compared with other existing
methods, the following features are worth mentioning: (i) the
methodology makes use of an environmentally benign and inexpen-
sive catalytic system that is a combination of readily available iron
salt and a universal ligand; (ii) in this approach, a broader scope of
substrates, various substituted aryl halides including bromides
and chlorides as well as both aryl and alkyl thiols can be applied
(iii) the most important aspect is that the most environmentally
friendly and cheapest reagent, water, is used as the solvent for the
reaction.
higher yields of the desired product were detected (Table 1, entries
6 and 7). At 130 °C, formation of the disulfide ceased and the
desired product was isolated in 95% yield (Table 1, entry 6).
Further experiments revealed that the thioetherification of 1a
with 2a has a significant dependence on the nature of the base.
Table 2
Iron-catalyzed carbon–sulfur bond formation of arene thiols and aryl halidesa
FeCl3.6H2O(10 mol %)
L-Proline (20 mol %)
KOH (2 equiv.)
S
3
I
HS
+
R2
R2
TBAB (1 equiv.)
water (3 ml),
130 oC, 24 h
R1
R1
1
2
Initially, we carried out a set of experiments using 4-iodoace-
tophenone (1.2 equiv) and thiophenol (1 equiv) as model sub-
strates in water under air using FeCl3 as the catalyst and L-
Entry Aryl halide 1 Thiol 2
Product 3
Yieldb
(%)
I
HS
HS
HS
HS
HS
HS
S
3a
proline as the ligand for optimizing the reaction conditions, and
the results are summarized in Table 1. As indicated in Table 1
(entries 1–3), in pure water, only low yields of the desired product
were obtained. More than half of the reactants were recovered
from the reaction mixture which indicated the poor solubility of
organic reagents especially aryl halides in water. It is presumed
that the reaction occurred through small portions of dissolved
solutes in the aqueous–organic interface. Therefore, we added
the phase transfer reagent tetrabutylammonium bromide (TBAB).
At first we added only 0.2 equiv of TBAB; but no considerable
increase in the yield was observed (not shown in table). To our
delight, addition of 1 equiv of TBAB to the reaction mixture led
to a sharp increase in the conversion rate (Table 1, entries 4 and 5).
In most of the cases, the formation of the undesired phenyl
disulfide was observed as a side product. To circumvent this, we
used thiol as the limiting reagent. The disulfide formation was pre-
dominant at lower temperatures and as the temperature increased,
1
2
3
4
5
95
O
O
O
O
O
O
O
O
O
O
Br
Cl
I
S
61
36
86
55
3a
S
3a
S
3b
I
S
OCH3
F
OCH3
F
3c
I
S
6
7
82
89
3d
O
O
I
Br
I
HS
HS
HS
HS
S
Table 1
Iron-catalyzed coupling reaction of thiophenol and 4-iodo acetophenone in watera
NC
NC
3e
S
catalyst (10 mol %)
8
58
74
86
79
81
76
65
L-Proline (20 mol %)
Base (2 equiv.),
NC
NC
S
HS
3e
I
S
+
TBAB (1 equiv.)
water (3 ml)
9
NC
OCH3
NC
OCH3
2a
O
3a
O
1a
3f
Temp. oC, 24 h
I
S
10
11
12
13
14
Yieldb (%)
O2N
O2N
Entry
Catalyst
Base
Additive
Temp (°c)
3g
S
I
I
I
HS
HS
HS
1
2
3
4
5
6
7
8
FeCl3
FeCl3
K2CO3
KOH
KOH
KOH
KOH
KOH
KOH
K2CO3
K3PO4
Cs2CO3
NaOH
KOH
KOH
KOH
KOH
—
—
—
—
120
120
120
120
120
130
110
130
130
130
130
130
130
130
130
130
38
50
53
85
88
95
62
65
19
36
57
64
69
36e
21e
13e
O2N
O2N
O2N
OCH3
O2N
O2N
O2N
OCH3
3h
S
FeCl3ꢀ6H2O
FeCl3
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
FeCl3ꢀ6H2O
FeCl3ꢀ6H2O
FeCl3ꢀ6H2O
FeCl3ꢀ6H2O
FeCl3ꢀ6H2O
FeCl3ꢀ6H2O
FeCl3ꢀ6H2O
FeCl3ꢀ6H2O
FeCl3ꢀ6H2O
—
3i
S
F
F
9
3j
10
11
12c
13d
14
15f
16
I
HS
HS
S
H3CO
H3CO
3k
I
I
S
S
15
16
60
64
FeCl3ꢀ6H2O
OCH3
OCH3
OCH3
FeCl3ꢀ6H2O
3k
3l
HS
a
Reaction conditions: aryl iodide (1.2 mmol), thiophenol (1 mmol), base
(2 equiv), catalyst (10 mol %), L-proline (20 mol %), TBAB (1 equiv), water (3 ml),
OCH3
130 °C, 24 h.
CF3
CF3
b
Isolated yield.
1.5 equiv of KOH.
c
a
Reaction conditions: aryl halide (1.2 mmol), thiol (1 mmol), KOH (2 equiv),
d
Use of 5 mol % FeCl3ꢀ6H2O and 10 mol % of
L
-proline.
GCMS showed the presence of a large peak corresponding to the disulfide.
Absence of -proline.
FeCl3ꢀ6H2O (10 mol %), L-proline (20 mol %), TBAB (1 equiv), water (3 ml), 130 °C,
e
f
24 h.
b
L
Isolated yield.

K. S. Sindhu et al. / Tetrahedron Letters 56 (2015) 4923–4926
4925
After screening several bases, we observed that weak bases such
as K2CO3, K3PO4, and Cs2CO3 did not show satisfactory results
(Table 1, entries 8–10); even though NaOH was active for this
transformation, KOH gave the best result. Thus, the optimal
reaction conditions for the S-arylation of thiophenol with
4-iodoacetophenone involved the use of 10 mol % of FeCl3ꢀ6H2O,
(Table 2, entries 4–6). When methoxy thiophenol was used, the
coupled product was formed in 55% yield with a considerable
amount (15%) of the disulfide (Table 2, entry 5). The aryl thiols
coupled successfully with electron-rich and electron-deficient aryl
iodides in good to excellent yields. 1-Iodo-4-nitrobenzene and
4-iodobenzonitrile underwent coupling reaction with aryl thiols
efficiently affording the corresponding products in high yields
(Table 2, entries 7–13). Electron-rich 4-iodoanisole also coupled
with thiol, affording the corresponding thioether in 65% yield
(Table 2, entry 14).
Next, we tried to extend this protocol for the coupling of alkyl
thiols with aryl iodides. To our delight, alkyl thiols also successfully
coupled with aryl iodides under the optimized reaction condition.
When benzyl, n-butyl, and isopropyl thiols were used as the
substrates, the products were obtained in very good yields
(Table 3, entries 1–7).
20 mol % of L-proline, and 2 equiv of KOH in water under air at
130 °C. The use of 5 mol % of the iron source also furnished the
product, but in low yields (Table 1, entry 13).
As part of control experiments, the reaction was performed at
optimized conditions in the absence of base, ligand, and catalyst,
which resulted in lower yield of the desired product along with
the formation of disulfide as the major product (Table 1, entries
14–16).
To explore the scope of the coupling reaction, we applied this
protocol to a range of commercially available aryl halides and
thiophenols. The methodology proved suitable for the synthesis
of the corresponding diaryl sulfides in good to excellent yields as
shown in Table 2.
Conclusion
Contrary to previous reports on iron-catalyzed S-arylation
reactions, the present iron-catalytic system is suitable for aryl
bromides and aryl chlorides as well. The coupling reaction of
thiophenol with 4-iodoacetophenone, 4-bromoacetophenone, and
4-chloroacetophenone demonstrates the higher reactivity of aryl
iodides over bromides and chlorides affording the products in
95%, 61%, and 36% yields respectively (Table 2, entries 1–3).
It is observed that the catalytic system is efficient in the cou-
pling of thiols bearing methyl, methoxy, and fluoro substituents
In summary, we have developed a greener and promising
protocol for the S-arylation of aryl and alkyl thiols with differently
substituted aryl halides including bromides and chlorides in water
under aerobic conditions. The reaction is efficiently promoted by a
catalyst system consisting of a combination of a cheap and
environment-friendly FeCl3ꢀ6H2O along with the universal ligand
L
-proline. The versatility, low cost, and environmental friendliness
of this method, in addition to the high yields it provides, makes it
viable for use in synthetic organic chemistry. Currently, we are
exploring the substrate scope, mechanistic aspects, and applica-
tions of the current iron-catalyzed S-arylation in our laboratory.
Table 3
Iron-catalyzed carbon–sulfur bond formation of alkyl thiolsa
Experimental procedure
FeCl3.6H2O(10 mol %)
I
S
L-Proline (20 mol %)
R2
Experimental procedure for the synthesis of 1-(4-phenyl-
sulfanyl-phenyl)-ethanone (3a)
HS
2
+
R2
KOH (2 equiv.) TBAB (1 equiv.)
water (3 ml),130 oC, 24 h
R1
1
R1
3
A
sealed tube was charged with 1.2 mmol (295 mg) of
4-iodoacetophenone, 20 mol % of -proline (23 mg), and 2 equiv
L
Entry
Aryl iodide 1
Alkyl thiol 2
Product 3
Yieldb (%)
75
of KOH (112 mg). To the above mixture, 10 mol % of FeCl3ꢀ6H2O
(27 mg), 1 equiv of TBAB (322 mg), and 3 ml of distilled water were
added followed by the addition of 1 mmol of thiophenol
(0.101 ml). The sealed tube was heated in an oil bath which was
preheated to 130 °C and the reaction mixture was stirred under
the same conditions for 24 h. The reaction mixture was then
cooled, extracted with ethyl acetate (3 ꢁ 15 ml), and the ethyl
acetate layer was washed with saturated aqueous NaCl solution.
The organic layer was dried over anhydrous Na2SO4 and the sol-
vent was removed under reduced pressure in a rotary evaporator.
The crude residue was purified by column chromatography using
EtOAc–hexane (2:98) as the eluent to get 217 mg (95%) of the pro-
duct as a colorless solid. Mp: 67 °C (from Hexane); 1H NMR
(400 MHz, CDCl3): d 7.83 (d, J = 8.8 Hz, 2H), 7.51–7.49 (m, 2H),
7.41–7.39 (m, 3H), 7.22 (d, J = 8.8 Hz, 2H), 2.55 (s, 3H); 13C NMR
I
HS
S
1
2
O
3m
O
I
HS
HS
HS
S
NC
81
NC
3n
I
S
3
4
O2N
76
93
O2N
3o
S
I
3p
O
O
(100 MHz, CDCl3):
d 197.11, 144.92, 134.52, 133.87, 132.13,
I
S
HS
HS
129.69, 128.90, 128.79, 127.49, 26.46; IR (neat): 3045, 1668,
1555, 1201, 819, 614 cmꢂ1; HRMS (QToF): [M+H]+ calculated for
C14H12OS is 229.0687; found 229.0675.
5
6
91
94
NC
NC
3q
S
I
3r
O2N
O2N
Acknowledgments
I
S
HS
7
93
G.A. thanks the Kerala State Council for Science, Technology and
3s
Environment (KSCSTE), Trivandrum
341/2013/KSCSTE dated 15.03.2013) for financial support. S.K.S.
and A.P.T. thank the UGC, New Delhi India and KSCSTE,
Trivandrum for junior research fellowships. A.M.T. thanks the
–
India (Order no.
O
O
a
Reaction conditions: aryl halide (1.2 mmol), thiol (1 mmol), KOH (2 equiv),
–
FeCl3ꢀ6H2O (10 mol %),
L
-proline (20 mol %), TBAB (1 equiv), water (3 ml), 130 °C.
b
Isolated yield.

4926
K. S. Sindhu et al. / Tetrahedron Letters 56 (2015) 4923–4926
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.06.
087.
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