Indium-catalyzed C-S cross-coupling of aryl halides with thiols

Article abstract of DOI:10.1021/jo802731j

Indium-catalyzed C-S cross-coupling of aromatic and alkane thiols with aryl halides proceeds smoothly in the presence of In(OTf)₃ (10 mol %), TMEDA (20 mol %), and KOH as a base in DMSO at 135 °C. When this protocol was utilized, a variety of thiols could be cross-coupled with aryl halides to afford the corresponding aryl sulfides in good to excellent yields.

Full text of DOI:10.1021/jo802731j

TABLE 1. Indium-Catalyzed C-S Cross-Coupling of Thiophenol
Indium-Catalyzed C-S Cross-Coupling of Aryl
with Iodobenzenea
Halides with Thiols
V. Prakash Reddy, K. Swapna, A. Vijay Kumar, and
K. Rama Rao*
Organic Chemistry DiVision I, Indian Institute of Chemical
entry
base
solvent
yieldb (%)
Technology, Hyderabad 500 007, India
1
2
3
4
5
6
Cs2CO3
K3PO4
NaOMe
KOH
KOH
KOH
DMSO
DMSO
DMSO
DMSO
toluene
DMF
72
trace
0
96
trace
trace
kakulapatirama@gmail.com
ReceiVed December 13, 2008
a Reaction conditions: thiophenol (1.0 mmol), iodobenzene (1.1
mmol), In(OTf)3 (10 mol %)/ligand (20 mol %), base (2.0 equiv),
solvent (2.0 mL), 135 °C, 24 h. b Yield of isolated product after flash
chromatography.
C-S cross-coupling;7 however, this protocol was ineffective
when using aliphatic thiols for C-S coupling. Therefore, the
iron-catalyzed C-S cross-coupling reaction needs to be modified
to expand the scope of these methodologies and to employ more
universal ligands.
In this study, we report an efficient indium-catalyzed C-S
cross-coupling of aryl halides with various aliphatic and aromatic
thiols using N,N,N′,N′-tetramethylethylenediamine (TMEDA)
as the ligand. In the first instance, we have studied the cross-
coupling of iodobenzene (1) with thiophenol (2) as the model
reaction in the presence of In(OTf)3 (10 mol %)/TMEDA (20
mol %) and KOH in DMSO at 135 °C for 24 h, and the
corresponding aryl sulfide (3) was obtained in 96% yield (Table
1, entry 4). To the best of our knowledge, this is the first
In(OTf)3-catalyzed cross-coupling of aryl halides with thiols to
form aryl sulfides.
To optimize the reaction conditions, we have made a study
about the effect of different solvents and bases on the C-S
cross-coupling reaction catalyzed by In(OTf)3. The results
are shown in Table 1 (entries 1-6). Among these solvents,
DMSO was found to be most efficient. In a comparison of
the efficiency of the base, KOH was found to act as an
excellent base, whereas Cs2CO3 was effective to some extent
and other bases, such as K3PO4 and NaOMe, were not at all
effective.
Indium-catalyzed C-S cross-coupling of aromatic and alkane
thiols with aryl halides proceeds smoothly in the presence
of In(OTf)3 (10 mol %), TMEDA (20 mol %), and KOH as
a base in DMSO at 135 °C. When this protocol was utilized,
a variety of thiols could be cross-coupled with aryl halides
to afford the corresponding aryl sulfides in good to excellent
yields.
Aryl sulfides are an important class of organic compounds
found in numerous pharmaceutically active compounds1 as well
as in a number of drugs in therapeutic areas, such as diabetes,
inflammatory, immune, Alzheimer’s, and Parkinson’s diseases.2
In the past decade, palladium-,3 nickel-,4 copper-,5 and cobalt-
based6 catalytic systems have been studied for this purpose.
Recently, Bolm et al. reported the first genuine iron-catalyzed
(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.
Next, we investigated the effect of different combinations
of Lewis acids and a series of ligands on the course of the
reaction, and the results are shown in Table 2 (entries 1-16).
(2) Liu, G.; Huth, J. R.; Olejniczak, E. T.; Mendoza, R.; DeVries, P.; Leitza,
S.; Reilly, E. B.; Okasinski, G. F.; Fesik, S. W.; von Geldern, T. W. J. Med.
Chem. 2001, 44, 1202.
(3) (a) Mispelaere-Canivet, C.; Spindler, J.-F.; Perrio, S.; Beslin, P. Tetra-
hedron 2005, 61, 5253. (b) Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587. (c)
Ferna´ndez Rodrı´guez, M. A.; Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006,
128, 2180. (d) Murata, M.; Buchwald, S. L. Tetrahedron 2004, 60, 7397. (e)
Schopfer, U.; Schlapbach, A. Tetrahedron 2001, 57, 3069. (f) Li, G. Y. Angew.
Chem. 2001, 113, 1561; Angew. Chem., Int. Ed. 2001, 40, 1513. (g) BarbiKri,
R. S.; Bellato, C. R.; Dias, A. K. C.; Massabni, A. C. Catal. Lett. 2006, 109,
171. (h) Dickens, M. J.; Gilday, J. P.; Mowlem, T. J.; Widdowson, D. A.
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.
(5) (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) Deng, W.; Zou, Y.; Wang, Y.-
F.; Liu, L.; Guo, Q.-X. Synlett 2004, 1254. (f) Palomo, C.; Oiarbide, M.; Lopez,
R.; Gomez-Bengoa, E. Tetrahedron Lett. 2000, 41, 1283. (g) Savarin, C.; Srogl,
J.; Liebeskind, L. S. Org. Lett. 2002, 4, 4309. (h) Herradura, P. S.; Pendola,
K. A.; Guy, R. K. Org. Lett. 2000, 2, 2019. (i) Chen, Y.-J.; Chen, H.-H. Org.
Lett. 2006, 8, 5609. (j) Zhu, D.; Xu, L.; Wu, F.; Wan, B. S. Tetrahedron Lett.
2006, 47, 5781. (k) Ley, S. V.; Thomas, A. W. Angew. Chem. 2003, 115, 5558;
Angew. Chem., Int. Ed. 2003, 42, 5400. (l) Sperotto, E.; Klink, G. P. M. V.; De
Vries, J. G.; Koten, G. V. J. Org. Chem. 2008, 73, 5625. (m) She, J.; Jiang, Z.;
Wang, Y. Tetrahedron Lett. 2009, 50, 593.
(4) (a) Cristau, H. J.; Chabaud, B.; Chene, A.; Christol, H. Synthesis 1981,
892. (b) Millois, C.; Diaz, P. Org. Lett. 2000, 2, 1705. (c) Percec, V.; Bae,
J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60, 6895. (d) Takagi, K. Chem. Lett.
1987, 2221.
(6) Wong, Y.-C.; Jayanth, T. T.; Cheng, C.-H. Org. Lett. 2006, 8, 5613.
(7) Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 2880.
10.1021/jo802731j CCC: $40.75
Published on Web 03/18/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3189–3191 3189

TABLE 2. Indium-Catalyzed C-S Cross-Coupling of Thiophenol
TABLE 3. C-S Cross-Coupling of Aryl Halides with Thiolsa
with Iodobenzenea
entry
catalyst
In
InCl3
InBr3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
Bi(OTf)3
La(OTf)3
Sc(OTf)3
Zn(OTf)2
In(OTf)3
ligand
yieldb (%)
1
2
3
4
5
6
7
8
L2
L2
L2
L1
L2
L3
L4
L5
L6
L2
L2
L2
L2
trace
85
91
84
96
59
73
89
78
80
82
90
90
35c
26d
0e
9
10
11
12
13
14
15
16
L2
a Reaction conditions: thiophenol (1.0 mmol), iodobenzene (1.1
mmol), catalyst (10 mol %)/ligand (20 mol %), base (2.0 equiv), solvent
(2.0 mL), 135 °C, 24 h. b Yield of isolated product after flash
chromatography. c In the absence of ligand. d In the absence of catalyst.
e In the presence of base only.
It was found that In(OTf)3 has shown the best activity
compared to other Lewis acids such as InCl3 (85%), InBr3
(91%), Bi(OTf)3 (80%), La(OTf)3 (82%), Sc(OTf)3 (90%), and
Zn(OTf)2 (90%) with the combination of TMEDA (L2), which
proved to be the best choice compared with the other ligands
(L1 and L3-L6). In the absence of any supporting ligand, the
desired cross-coupling product was obtained in low yields (Table
2, entry 14). Similarly, low yields were obtained in the absence
of catalyst (Table 2, entry 15). The importance of the catalyst
and ligand was revealed by a reaction carried out in the presence
of base alone that gave no C-S coupling product and only
diphenyl disulfide (Table 2, entry 16).
To explore the scope of the reaction, various aryl halides were
reacted with different substituted aromatic thiols and aliphatic
thiols (Table 3). In general, all reactions were very clean and
the diaryl sulfide derivatives were obtained in high yields under
optimized conditions. The results have shown that substitution
played a major role in governing the reactivity of the substrate.
With electron-donating substituents in the aryl iodide, decreased
yields of products were observed (Table 3, entries 4-6). For
example, the coupling of p-methoxyiodobenzene with ben-
zenethiol gave only a trace amount of the product. However,
the effect was reversed when the electron-donating groups were
present in thiols, and the corresponding aryl sulfides were
obtained in excellent yields (Table 3, entries 7-9). Electron-
withdrawing groups (e.g., CF3, F, NO2) in the aryl iodide favored
the coupling reaction with aryl thiols, affording the correspond-
ing thioethers in high yields (Table 3, entries 11-13). Under
the same reaction conditions, 4-iodophenol and 4-iodoaniline
also reacted well to give the corresponding aryl sulfides in
excellent yields (Table 3, entries 14 and 15). Another important
a Reaction conditions: thiophenol (1.0 mmol), iodobenzene (1.1
mmol), 0.1 equiv of In(OTf)3, 0.2 equiv of TMEDA, 2.0 equiv of KOH,
DMSO (2.0 mL), 135 °C, 24 h, nitrogen atmosphere. b The products
were characterized by IR, 1H and 13C NMR, and mass spectroscopy.
c Yield of isolated product after flash chromatography.
aspect of the cross-coupling is the successful reaction of
3-iodopyridine and 3-bromopyridine with benzenethiol to give
3190 J. Org. Chem. Vol. 74, No. 8, 2009

good yields of the heterocyclic aryl sulfide (Table 3, entry 17).8
In the reaction of substrates with alkyl thiols, increasing the
size of the alkyl chain led to a slight decrease in the yield of
the aryl sulfides (Table 3, entries 19-22). Unfortunately, all
attempts to couple benzyl thiols and heteroaromatic thiols with
iodobenzene have failed.8
In conclusion, we have developed a novel indium-catalyzed
C-S cross-coupling. The cross-coupling of aliphatic and
aromatic thiols with aryl iodides and aryl bromides generates
the corresponding coupling products in good to excellent yields.
under a nitrogen atmosphere. The reaction mixture was then stirred
at 135 °C for 24 h. The progress of the reaction was monitored by
TLC. The mixture was allowed to cool to room temperature. Diethyl
ether (5 mL) was added, and the organic phase was separated, dried
over anhydrous Na2SO4, and purified by chromatography on silica
gel to afford the corresponding coupling product (3) in 96% yield:
colorless oil, 1H NMR (200 MHz, CDCl3, TMS) δ 7.34-7.14 (m,
10H);13C NMR (100 MHz, CDCl3, TMS) δ 135.7, 131.0, 129.1,
127.0. The spectral data are consistent with those reported in the
literature.6
Acknowledgment. V.P.R. thanks CSIR and K.S. and A.V.K.
thank UGC, New Delhi, India, for the award of fellowships.
Experimental Section
Supporting Information Available: Detailed experimental
procedures and compound characterization data for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
General Procedure. To a stirred solution of 1 (1.1 mmol) and
In(OTf)3 (10 mol %) in dry DMSO (2.0 mL) was added 2 (1.0
mmol) followed by TMEDA (20 mol %) and KOH (2.0 equiv)
(8) See the Supporting Information.
JO802731J
J. Org. Chem. Vol. 74, No. 8, 2009 3191