Nano indium oxide as a recyclable catalyst for C-S cross-coupling of thiols with aryl halides under ligand free conditions

Article abstract of DOI:10.1021/ol900009a

An efficient ligand-free C-S cross-coupling of aryl halides with aromatic/alkyl thiols has been developed using a catalytic amount of nanocrystalline indium oxide as a recyclable catalyst with KOH as the base in DMSO at 135 °C. A variety of aryl sulfides can be synthesized in excellent yields utilizing this protocol.

Full text of DOI:10.1021/ol900009a

ORGANIC
LETTERS
2
009
Vol. 11, No. 8
697-1700
Nano Indium Oxide as a Recyclable
Catalyst for C-S Cross-Coupling of
Thiols with Aryl Halides under Ligand
Free conditions
1
Vutukuri Prakash Reddy, Akkilagunta Vijay Kumar, Kokkirala Swapna, and
Kakulapati Rama Rao*
Organic Chemistry DiVision-I, Indian Institute of Chemical Technology,
Hyderabad-500 007, India
kakulapatirama@gmail.com
Received February 4, 2009
ABSTRACT
An efficient ligand-free C-S cross-coupling of aryl halides with aromatic/alkyl thiols has been developed using a catalytic amount of
nanocrystalline indium oxide as a recyclable catalyst with KOH as the base in DMSO at 135 °C. A variety of aryl sulfides can be synthesized
in excellent yields utilizing this protocol.
Transition-metal-catalyzed C-S bond formation has been a
subject of intense study over the past decade due to the
importance of aryl sulfides and their derivatives in numerous
However, the transition-metal-catalyzed C-S cross-
coupling reaction is much less studied than the corresponding
C-N and C-O bonds, due to deactivation of the metal
catalysts by the organosulfur compounds because of their
1
biological and pharmaceutically active compounds. Indeed,
5
a number of drugs in therapeutic areas such as diabetes,
strong coordinating properties. This limitation led to in-
2
3
4
creased interest in the field of transition metal-catalyzed
organosulfur chemistry, bringing important progress in the
field.
inflammatory, Alzheimer’s, Parkinson’s, cancer, and HIV
diseases contain the aryl sulfide functional group.
The traditional methods for C-S bond formation were of
limited use due to their harsh reaction conditions. For
example, the coupling of copper thiolates with aryl halides
takes place in polar solvents, such as HMPA and at elevated
temperatures around 200 °C. The reduction of sulfones or
(
1) (a) Liu, L.; Stelmach, J. E.; Natarajan, S. R.; Chen, M.-H.; Singh,
S. B.; Schwartz, C. D.; Fitzgerald, C. E.; O’Keefe, S. J.; Zaller, D. M.;
Schmatz, D. M.; Doherty, J. B. Bioorg. Med. Chem. Lett. 2003, 13, 3979.
b) Kaldor, S. W.; Kalish, V. J.; Davies, J. F., II; Shetty, B. V.; Fritz, J. E.;
(
Appelt, K.; Burgess, J. A.; Campanale, K. M.; Chirgadze, N. Y.; Clawson,
D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D. A.; Kosa, M. B.;
Lubbehusen, P. P.; Muesing, M. A.; Patick, A. K.; Reich, S. H.; Su, K. S.;
Tatlock, J. H. J. Med. Chem. 1997, 40, 3979.
sulfoxides requires strong reducing agents, such as DIBAL-H
6
or LiAlH
4
. To overcome these difficulties, transition metal-
(2) (a) Liu, G.; Huth, J. R.; Olejniczak, E. T.; Mendoza, F.; Fesik, S. W.;
7
von Geldern, T. W. J. Med. Chem. 2001, 44, 1202. (b) Nielsen, S. F.;
Nielsen, E. Ø.; Olsen, G. M.; Liljefors, T.; Peters, D. J. Med. Chem. 2000,
catalyzed coupling systems involving the use of palladium,
8
9
10
nickel, copper, and iron based catalytic systems have been
studied. A cobalt-catalyzed reaction in the presence of a
4
3, 2217.
(3) De Martino, G.; Edler, M. C.; La Regina, G.; Cosuccia, A.; Barbera,
M. C.; Barrow, D.; Nicholson, R. I.; Chiosis, G.; Brancale, A.; Hamel, E.;
Artico, M.; Silvestri, R. J. Med. Chem. 2006, 49, 947.
(
4) Kadlor, S. W.; Kalish, V. J.; Davies, J. F.; Shetty, B. V.; Fritz, J. E.;
(5) Kondo, T.; Mitsudo, T.-A. Chem. ReV. 2000, 100, 3205.
(6) (a) Lindley, J. Tetrahedron 1984, 40, 1433. (b) Yamamoto, T.;
Sekine, Y. Can. J. Chem. 1984, 62, 1544. (c) Hickman, R. J. S.; Christie,
B. J.; Guy, R. W.; White, T. J. Aust. J. Chem. 1985, 38, 899. (d) Bierbeek,
A. V.; Gingras, M. Tetrahedron Lett. 1998, 39, 6283.
Appelt, K.; Burgess, J. A.; Campanale, K. M.; Chirgadze, N. Y.; Clawson,
D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D. A.; Kosa, M. B.;
Lubbehusen, P. P.; Muesing, M. A.; Patick, A. K.; Reich, S. H.; Su, K. S.;
Tatlock, J. H. J. Med. Chem. 1997, 40, 3979.
10.1021/ol900009a CCC: $40.75
Published on Web 03/20/2009
 2009 American Chemical Society

a
Table 1. Cross-Coupling of Thiophenol with Aryl Iodide
Table 2. Indium Oxide Amount Screening for the C-S
a
Coupling
b
entry
base
solvent
temp (°C)
yield (%)
b
entry
In
O
2 3
(mol %)
yield (%)
1
2
3
4
5
6
7
8
9
K
Cs
KO Bu
KOH
KOH
KOH
NaOMe
K
Cs
KO Bu
KOH
KOH
Cs
KOH
none
3
PO
4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
PhMe
PhMe
PhMe
DMF
135
135
135
135
80
trace
69
trace
97
CO
3
1
2
3
4
5
1.0
67
80
88
97
97
2
t
2.0
2.5
3.0
3.5
78
rt
0
135
135
135
135
135
135
135
135
135
trace
0
a
Reaction conditions: Iodobenzene (1.1 mmol), benzenethiol (1.0 mmol),
b
3
PO
4
In
2
O
3
(mol%), KOH (2.0 equiv), DMSO (2.0 mL), 135 °C, 24 h. Isolated
c
yield. Sulfur source (0.5 mmol).
2
CO
3
0
0
t
10
11
12
13
14
15
trace
trace
trace
0
Over the past decades, Pd, Cu, Ni, and Fe based catalysts
were explored for cross-coupling reactions. However until
now there has been no report on indium catalyzed cross-
coupling reaction. We attempted C-S cross-coupling with
indium. Recently, nanoparticles have been employed as
heterogeneous catalysts for various organic transforma-
2
CO
3
DMF
Water
DMSO
0
a
Reaction conditions: Iodobenzene (1.1 mmol), benzenethiol (1.0 mmol)
3
(3.0 mol %), base (2.0 equiv), solvent (2.0 mL), 24 h, under a nitrogen
In
2
O
b
atmosphere. Isolated yield.
9
k,13
tions.
This inspired us to focus on the aspect of indium
11
ligand, CoI
2
(dppe), and Zn has also been reported recently.
oxide nanoparticle catalysis for the formation of aryl-sulfur
bonds. The heterogeneous catalysts are also attractive both
from economic and industrial points of view as compared
to homogeneous catalysts. In general, nanoscale heteroge-
neous catalysts offer higher surface area and lower-
coordinating sites, which are responsible for the higher
However, almost all of these methods involve ligands or
well-defined catalysts and these protocols have common
problems such as metal toxicity, low turnover numbers,
excess reagents and nonrecyclability of these catalysts, thus
increasing the cost and limiting the scope of the reaction.
Recently Koten and co-workers reported copper-catalyzed
C-S coupling of aryl iodides and thiols under ligand free
conditions. However, this protocol reports a lone example
of aliphatic thiol, butanethiol, in lower yields (54%) and also
14
catalytic activity. However, until now, the investigation of
nanoparticles as catalysts has been scarce.
12
the catalyst cannot be recycled. In this regard we envisaged
the application of readily available and inexpensive nano-
particles as catalysts.
2 3
Table 3. Nano In O Catalyzed C-S Cross-Coupling of
a
Iodobenzene with Different Sulfur Sources
(
7) (a) Mispelaere-Canivet, C.; Spindler, J.-F.; Perrio, S.; Beslin, P.
Tetrahedron 2005, 61, 5253. (b) Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587.
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0, 7397. (e) Schopfer, U.; Schlapbach, A. Tetrahedron 2001, 57, 3069.
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Bellato, C. R.; Dias, A. K. C.; Massabni, A. C. Catal. Lett. 2006, 109, 171.
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(
6
(
(
Tetrahedron 1991, 47, 8621. (i) Ishiyama, T.; Mori, M.; Suzuki, A.;
Miyaura, N. J. Organomet. Chem. 1996, 525, 225. (j) Zheng, N.;
McWilliams, J. C.; Fleitz, F. J.; Armstrong, J. D.; Volante, R. P. J. Org.
Chem. 1998, 63, 9606. (k) Mann, G.; Baranano, D.; Hartwig, J. F.;
Rheingold, A. L.; Guzei, I. A. J. Am. Chem. Soc. 1998, 120, 9205.
(
8) (a) Cristau, H. J.; Chabaud, B.; Chene, A.; Christol, H. Synthesis
a
1
981, 892. (b) Millois, C.; Diaz, P. Org. Lett. 2000, 2, 1705. (c) Percec,
Reaction conditions: Iodobenzene (1.1 mmol), sulfur source (1.0
V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60, 6895. (d) Takagi, K.
Chem. Lett. 1987, 2221.
mmol), In O (3.0 mol %), KOH (2.0 equiv), DMSO (2.0 mL), 135 °C,
2
3
b
c
24 h. Isolated yield. Phenyl disulfide (0.5 mmol).
(
9) (a) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002,
4
, 2803. (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517. (c)
Wu, Y.-J.; He, H. Synlett. 2003, 1789. (d) Bates, C. G.; Saejueng, P.;
Doherty, M. Q.; Venkataraman, D. Org. Lett. 2004, 6, 5005. (e) Palomo,
C.; Oiarbide, M.; Lopez, R.; Gomez- Bengoa, E. Tetrahedron Lett. 2000,
Initially, the reaction between iodobenzene and ben-
zenethiol was selected as a model reaction, and various
41, 1283. (f) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2002, 4,
4309. (g) Herradura, P. S.; Pendola, K. A; Guy, R. K. Org. Lett. 2000, 2,
2019. (h) Chen, Y.-J.; Chen, H.-H. Org. Lett. 2006, 8, 5609. (i) Ranu, B. C.;
Saha, A.; Jana, R. AdV. Synth. Catal. 2007, 349, 2690. (j) Ley, S. V.;
Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (k) Rout, L.; Sen,
T. K.; Punniyamurthy, T. Angew. Chem., Int. Ed. 2007, 46, 5583.
(13) (a) Choudary, B. M.; Kantam, M. L.; Ranganath, K. V. S.;
Mahender, K.; Sreedhar, B. J. Am. Chem. Soc. 2004, 126, 3396. (b)
Choudary, B. M.; Ranganath, K. V. S.; Pal, U.; Kantam, M. L.; Sreedhar,
(
10) Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47,
B. J. Am. Chem. Soc. 2005, 127, 13167.
2
880.
(14) (a) Pacchioni, G. Surf. ReV. Lett. 2000, 7, 277. (b) Knight, W. D.;
Clemenger, K.; de Heer, W. A.; Saunders, W. A. M.; Chou, Y.; Cohen,
M. L. Phys. ReV. Lett. 1984, 52, 2141. (c) Kaldor, A.; Cox, D.; Zakin,
M. R. AdV. Chem. Phys. 1988, 70, 211.
(
11) Wong, Y.-C.; Jayanth, T. T.; Cheng, C.-H. Org. Lett. 2006, 8, 5613.
(
12) Sperotto, E.; Klink, G. P. M. V.; De Vries, J. G.; Koten, G. V. J.
Org. Chem. 2008, 73, 5625.
698
1
Org. Lett., Vol. 11, No. 8, 2009

Table 4. Evaluation of Different Catalysts for the Formation of
Aryl Sulfides
Table 6. C-S Cross-Coupling of Aryl Halides with Alkyl
a
a
Thiols
a
Reaction conditions: Iodobenzene (1.1 mmol), benzenethiol (1.0 mmol)
catalyst (3.0 mol %), KOH (2.0 equiv), DMSO (2.0 mL), 135 °C, 24 h,
b
under a nitrogen atmosphere. Isolated yield.
parameters were optimized to develop the scope of this
reaction further. First we tried the significant dependence of
the S-arylation on the nature of the base and solvents (Table
1
). The solvents DMF and toluene were less effective than
DMSO. A variety of bases were screened in which Cs CO
2
3
and KOH provided the arylated compound in moderate to
Table 5. C-S Cross-Coupling of Aryl Halides with Aromatic
a
Thiols
a
Reaction conditions: Iodobenzene (1.1 mmol), alkyl thiols (1.0 mmol),
In O (3.0 mol %), KOH (2.0 equiv), DMSO (2.0 mL), 135 °C, 24 h, under
2 3
b
a nitrogen atmosphere Isolated yield.
excellent yields (Table 1, entries 2, 4). Other bases such as
t
K
3
PO
4
, KO Bu, and NaOMe gave trace amounts of diaryl
sulfide (Table 1, entries 1, 3, 7).
The influence of the amount of In
2
3
O catalyst was also
evaluated. As shown in Table 2, The amount of catalyst
loading had an impact on the yield. The yield was highly
dependent upon the reaction temperature, base, solvent and
catalyst. The optimum reaction conditions for the desired
C-S cross-coupling were found to be 3.0 mol % of In
.0 equiv of KOH, 135 °C temperature with DMSO (2.0
mL) as the solvent to obtain 97% of the diphenyl sulfide
2 3
O ,
2
(Table 1, entry 4).
We have also made a study of C-S cross-coupling with
various sulfur nucleophiles under these conditions (Table 3).
It is surprising to observe the cleavage of S-S and S-N
bonds of diphenyl disulfide and N-(phenylthio) phthalimide
to provide the corresponding cross-coupling products in 60%
and 88% yields respectively. Among these reagents ben-
zenethiol is inexpensive, and therefore we preferred ben-
zenethiols for the C-S cross-coupling reaction.
a
Reaction conditions: aryl halides (1.1 mmol), benzenethiols (1.0 mmol),
Next, we studied the effect of various metal nanoparticles
on the aryl sulfide formation with KOH in DMSO at 135
In O (3.0 mol %), KOH (2.0 equiv), DMSO (2.0 mL), 135 °C, 24 h, under
2 3
b
a nitrogen atmosphere. Isolated yield.
°
C (Table 4). Among these metal nanoparticle In
2
O
3
was
Org. Lett., Vol. 11, No. 8, 2009
1699

found to be a very effective catalyst for C-S coupling
reaction. The coupling reaction did not occur in the absence
of the catalyst (Table 4, entry 6).
Furthermore, iodobenzene was found to be a more reactive
substrate than chloro and bromobenzenes (Table 5, entries
2 3
Table 7. Recycling of In 0 Nanoparticles
recycles
yield (%)
catalyst recovery (%)
1
2
3
4
97
95
92
92
95
92
90
90
1
, 2, 3).
To explore the scope of the reaction, various aryl halides
were reacted with different substituted aromatic thiols (Table
, entries 1-15). In general, all reactions were very clean
5
and the diaryl sulfide derivatives were obtained in high yields
under the optimized conditions. It is observed that the
electron donating substituents in thiols increased the yields
of the products (Table 5, entries 6, 7 and 8). Utilizing these
conditions, various alkyl thiols were reacted with different
substituted aryl halides (Table 6, entries 1-12). It is observed
that an increase in the size of the alkyl chain led to a slight
decrease in the yield of the aryl sulfides. However the
coupling of heterocyclic thiol (Table 5, entry 15) and benzyl
thiol (Table 6, entry 12) with aryl iodide was not successful.
These reactions resulted in the formation of only disulfides
with the recovery of the starting iodobenzene.
To check the recyclability of the catalyst, it was separated
from the reaction mixture by ultra centrifugation, washed
with water, dried under vacuum and reused for further
catalytic reactions. The catalyst maintained its high level of
activity even after being recycled four times as shown in
Table 7.
2 3
In conclusion, In O as nanoparticle has been shown to
be an active, stable, inexpensive and nontoxic catalyst for
carbon-sulfur bond formation of both aromatic and aliphatic
thiols under ligand free conditions in excellent yields. This
method precludes the use of ligands and provides in most
cases the desired sulfide in high yields. The catalyst can be
easily recovered and reused. We are in the process of
expanding the substrate scope of these reactions.
Acknowledgment. V.P.R. thanks CSIR, and A.V.K. and
K.S. thank UGC, New Delhi, for the award of fellowships.
Supporting Information Available: Detailed experimen-
tal procedures and copies of analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL900009A
1700
Org. Lett., Vol. 11, No. 8, 2009