A reusable FeCl3·6H2O/cationic 2,2′-bipyridyl catalytic system for the coupling of aryl iodides with thiols in water under aerobic conditions

Article abstract of DOI:10.1039/b820790a

In this study, an FeCl₃·6H₂O/cationic 2,2′-bipyridyl system was employed as a catalyst in the coupling of aryl iodides with thiols to form an aryl-sulfur bond in refluxed water under aerobic conditions. The residual aqueous solution after extraction could be reused for several cycles without a significant decrease in activity.

Full text of DOI:10.1039/b820790a

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A reusable FeCl3·6H2O/cationic 2,2¢-bipyridyl catalytic system for the
coupling of aryl iodides with thiols in water under aerobic conditions†
Wei-Yi Wu, Jui-Chan Wang and Fu-Yu Tsai*
Received 20th November 2008, Accepted 14th January 2009
First published as an Advance Article on the web 22nd January 2009
DOI: 10.1039/b820790a
In this study, an FeCl3·6H2O/cationic 2,2¢-bipyridyl system
was employed as a catalyst in the coupling of aryl iodides
with thiols to form an aryl–sulfur bond in refluxed water
under aerobic conditions. The residual aqueous solution
after extraction could be reused for several cycles without a
significant decrease in activity.
We have recently prepared a water-soluble cationic 2,2¢-
bipyridyl ligand 1 and used it to bring palladium and rhodium
complexes into aqueous phases in order to develop green and
reusable catalytic systems for carbon–carbon bond-forming
reactions9 and phenylacetylene polymerizations in water.10
Herein, we report that the combination of 1 and FeCl3·6H2O
was an efficient catalytic system for the cross-coupling of aryl
iodides with thiols in neat water under air. This operationally-
simple reaction enabled easy separation of the catalyst from the
organic phase, and the residual aqueous solution could be reused
for further reactions without any treatment (Scheme 1).
Introduction
Transition-metal-catalyzed cross-coupling of aryl halides with
thiols is a powerful method for the formation of carbon–sulfur
bonds and is widely used in biological, pharmaceutical, and
material science applications.1 Since Migita and co-workers first
reported the cross-coupling of aryl halides with thiols catalyzed
by Pd(PPh3)4,2 transition-metal-catalyzed formation of sulfur–
carbon bonds has been widely employed by synthetic chemists.
Several transition-metal catalysts, such as those based on
palladium,3 nickel,4 copper,5 and cobalt,6 have been developed
for use in this cross-coupling reaction. Recently, Bolm’s group
successfully developed a novel catalytic procedure for the
S-arylation of aryl iodides with thiols, which uses anhydrous
FeCl3/DMEDA as a catalyst and NaOtBu as a base in toluene
under an Ar atmosphere.7 The benefits of this procedure are
that iron salt is inexpensive and is less toxic to people and the
environment than other transition metals. However, moisture-
sensitive NaOtBu is employed as a base, so the use of a dried
organic solvent under an inert atmosphere is required, leading
to difficulties in recycling the catalyst.
On the other hand, the catalysis of organic reactions by water-
soluble transition-metal complexes using water as a solvent
has received much attention in recent years due to this green
solvent being cheap, nontoxic, safe, and environmentally benign,
as compared with organic solvents.8 Furthermore, the easy
separation of the catalyst-containing aqueous solution from
the organic products enables reuse of the catalyst. Despite the
reporting of iron-catalyzed S-arylation by Bolm’s group, this
cross-coupling reaction catalyzed by iron in water under air has
yet to be developed, and the design of a greener and reusable
iron-containing catalytic system for S-arylation is considered of
high practical value.
Scheme 1
Results and discussion
At the outset, 1-iodo-4-nitrobenzene and thiophenol were se-
lected as representative reactants for optimization of the reaction
conditions. The influence of bases, ligands, and the oxidation
state of iron in the cross-coupling reaction was investigated, and
the screening of reaction conditions is summarized in Table 1.
The reaction gave the desired product, 4a, in a 92% isolated yield
when the reaction mixture, 1-iodo-4-nitrobenzene (3 mmol) and
thiophenol (2 mmol), was stirred in refluxed water (5 mL) under
aerobic conditions in the presence of FeCl3·6H2O/1 (10 mol%)
and 4 mmol KOH for 24 h (Entry 1). Although it is known
that iron catalysts can promote the homocoupling of thiols to
produce disulfides,11 in this reaction, the formation of such by-
products was diminished by using thiol as the limiting reagent.
A ligand-free system afforded the cross-coupling reaction less
successfully, the product being afforded in a 55% isolated yield
(Entry 2). When FeCl2·4H2O was used as the catalyst, 60 and
48% product yields were obtained in the presence and absence
of ligand 1, respectively, under the same conditions (Entries 3
and 4). We found that increasing the amount of ligand or KOH
did not improve the yield for the formation of 4a (Entries 5–7).
Several common inorganic bases were employed in this reaction
and their effects on the reaction studied: K3PO4 provided the
arylated product in a 77% yield (Entry 8), whereas the other
Institute of Organic and Polymeric Materials, National Taipei University
of Technology, Taipei, 106, Taiwan. E-mail: fuyutsai@ntut.edu.tw;
Fax: +886 2 2731 7174
† Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic characterization data of cross-coupling prod-
ucts, and copies of 1H and 13C NMR of compound 4d. See DOI:
10.1039/b820790a
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Table 1 Optimization studies for the Fe-catalyzed coupling of 1-iodo-
4-nitrobenzene (2a) with thiophenol (3a) in watera
facilitate the reaction in neat water. It should be noted that
the use of this water-soluble cationic 2,2¢-bipyridyl/FeCl3·6H2O
catalytic system enabled easy separation of the catalyst from
the organic phase and the use of a simple reaction procedure
under air.
Entry
Iron source
Base (mmol)
Yield (%)b
1
2c
3
FeCl3·6H2O
FeCl3·6H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (6)
KOH (8)
K3PO4 (4)
K2CO3 (4)
KF (4)
92
55
60
48
81
48
40
77
41
22
trace
54
trace
In order to clarify whether the gradual loss of activity from
the fourth cycle onwards in the presence of 1 was due to the
successive extraction or deactivation of the catalyst, a successive
addition experiment was performed. After completion of the
first run (24 h), a fresh portion of 1-iodo-4-nitrobenzene, thio-
phenol, KOH, and water was added directly to the unseparated
reaction mixture and the second cycle was executed under
conditions identical to those of the first run; this procedure
was repeated until the completion of the sixth cycle. We found
that the overall isolated yield of 4a was 558%, corresponding to
an average of 93% yield for each cycle. This result excludes the
possibility of deactivation of the catalyst during the reactions
and indicates that the successive extraction in the previous
recycling studies led to the decrease in the catalyst concentration
in each cycle.
4c
5d
6
7
8
9
10
11
12
13
CsF (4)
Cs2CO3 (4)
KOAc (4)
a Reaction conditions: 2a (3 mmol), 3a (2 mmol), [Fe] (10 mol%), 1
(10 mol%), base, H2O (5 mL), refluxed for 24 h. b Isolated yields. c In the
absence of 1. d 20 mol% of 1 was used.
bases gave only trace amounts or moderate yields of the product
(Entries 9–13).
To explore the scope of this cross-coupling reaction catalyzed
by our system, the reactions of a variety of aryl iodides and
thiols were examined and the amount of disulfides formed
was also analyzed (Table 2). 1-Iodo-4-nitrobenzene coupled
with various aryl thiols efficiently to give the corresponding
products 4b–d in high yields (Entries 1–3), and the employment
of 1-iodo-3-nitrobenzene resulted in the formation of 4e–h in
good yields. Although a slower cross-coupling rate led to the
formation of a small amount of disulfide, it could be separated
easily upon purification (Entries 4–7). Cross-coupling reactions
with 1-chloro-4-iodobenzene proceeded exclusively at the
C–I group, affording chloro-substituted thioethers (Entries
8–10). Entries 11–19 illustrate that iodobenzene and electron-
rich iodotoluene were also effectively coupled with thiols,
affording the corresponding thioethers in 64–96% yields. When
4-iodobenzonitrile and ethyl-4-iodobenzoate were used as the
substrates, the hydrolyzed product 4r was the sole cross-coupling
product, obtained in high yields under such reaction conditions
(Entries 20 and 21). Contrary to the first reported iron-catalyzed
S-arylation system,7 aliphatic thiols such as benzyl mercaptan
coupled with aryl iodides in our system to give 4s and 4t in 25
and 22% yields along with 11 and 12% of disulfides, respectively
(Entries 22 and 23).
The reusability of the aqueous catalytic system is very
important from the practical and economic viewpoints. We
chose the conditions of the presence and absence of ligand
1 for comparison (Table 1, Entry 1 and 2). For the reaction
in the presence of 1, after completion of the cross-coupling
reaction of 1-iodo-4-nitrobenzene with thiophenol, the reaction
mixture was extracted with hexane and the product was purified
by column chromatography. The remaining aqueous solution
was then charged with 1-iodo-4-nitrobenzene, thiophenol and
base for the second-run reaction. As shown in Fig. 1, it was
possible to use the catalyst-containing aqueous solution at least
six times with only a slight decrease in activity. On the contrary,
the activity of the iron catalyst was drastically decreased in each
cycle and approached zero in the fifth cycle when the system
lacked ligand 1. Ligand 1 was therefore revealed to be important,
not only through its stabilization of the iron salt in the aqueous
phase, enabling the reuse of the catalytic system, but also because
the ionic parts of the ligand may play a surfactant role and
Experimental
General procedure for the iron-catalyzed carbon–sulfur bond
formation reaction
A 20 mL reactor equipped with a condenser was charged with
FeCl3·6H2O (54 mg, 0.2 mmol), ligand 1 (92 mg, 0.2 mmol)
◦
and H2O (5 mL). After stirring at 50 C for 0.5 h, aryl iodide
2 (3.0 mmol), thiol 3 (2.0 mmol) and KOH (4.0 mmol) were
added to the solution, and the reaction mixture was then stirred
under reflux conditions in air for 24 h. After cooling of the
reaction mixture to room temperature, the aqueous solution was
extracted with hexane; the organic layer was dried over MgSO4
and the solvent was then removed under vacuum. Column
chromatography on silica gel afforded the desired product.
Fig. 1 Recyclability of FeCl3·6H2O/1 (ꢀ) versus FeCl3·6H2O (ꢁ)
for the coupling of 1-iodo-4-nitrobenzene with thiophenol. Reaction
conditions: 1-iodo-4-nitrobenzene (3 mmol), thiophenol (2 mmol), KOH
(4 mmol), and catalyst (10 mol%) under refluxed H2O (5 mL) for 24 h
for each cycle.
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Table 2 Results of FeCl3 · 6H2O/1-catalyzed coupling of aryl iodides (2) with thiols (3) in watera
Yield (%)b
Entry
1
Aryl iodide (2)
Thiol (3)
ArSR (4)
RSSR (5)
4b, 80
4c, 99
4d, 86
0
2
3
4
0
0
4e, 68
10
5
6
7
4f, 56
4g, 77
15
8
4h, 83
0
8
9
4i, 99
0
0
4j, 81
10
11
12
4k, 87
0
0
0
4l, 89
4m, 96
13
14
15
16
4i, 94
0
13
0
4n, 70
4o, 92
4m, 82
0
17
18
19
20
4j, 74
4p, 87
4q, 64
4r, 92
9
0
12
0
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Table 2 (Contd.)
Yield (%)b
Entry
21
Aryl iodide (2)
Thiol (3)
ArSR (4)
RSSR (5)
4r, 87
0
22
23
4s, 25
11
12
4t, 22
a Reaction conditions: 2 (3 mmol), 3 (2 mmol), FeCl3·6H2O (10 mol%), 1 (10 mol%), KOH (4 mmol), H2O (5 mL), refluxed for 24 h. b Isolated yields.
S. Perrio and P. Beslin, Tetrahedron, 2005, 61, 5253; M. A. Ferna´ndez-
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Rodr´ıguez, Q. Shen and J. F. Hartwig, J. Am. Chem. Soc., 2006, 128,
2180.
In this paper, we have developed a green and reusable catalytic
system for the coupling of aryl iodides with thiols using
environmentally-friendly and cheap FeCl3·6H2O as a catalyst
in the greenest solvent, water. This method avoids the use of air-
sensitive reagents and the reaction can therefore be performed
under air, rendering the experimental procedure very simple. In
addition, the catalytic system can be reused at least six times
with only a slight decrease in activity, indicating its potential for
use in industrial applications. Further mechanistic studies on
this reaction and the applicability of this green system in other
organic syntheses are now under investigation in our group.
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This research was financially supported by the National Science
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