An efficient copper-catalyzed carbon-sulfur bond formation protocol in water

Article abstract of DOI:10.1021/ol102784c

An efficient protocol of copper-catalyzed C-S bond formation between aryl halides and potassium thiocyanate leading to diaryl sulfides is reported. A variety of diaryl sulfides can be synthesized in good to excellent yields up to 94%.

Full text of DOI:10.1021/ol102784c

ORGANIC
LETTERS
2011
Vol. 13, No. 3
454-457
An Efficient Copper-Catalyzed
Carbon-Sulfur Bond Formation
Protocol in Water
Fang Ke, Yanyang Qu, Zhaoqiong Jiang, Zhengkai Li, Di Wu, and Xiangge Zhou*
Institute of Homogeneous Catalysis, College of Chemistry, Sichuan UniVersity,
Chengdu 610041, China
zhouxiangge@scu.edu.cn
Received November 17, 2010
ABSTRACT
An efficient protocol of copper-catalyzed C-S bond formation between aryl halides and potassium thiocyanate leading to diaryl sulfides is
reported. A variety of diaryl sulfides can be synthesized in good to excellent yields up to 94%.
The development of new, efficient, and environmentally
benign synthetic methodologies for the construction of
complex molecules is an important target in modern organic
synthesis.1 Diaryl sulfide functionalities have been found in
numerous drugs with a broad spectrum of therapeutic
activities such as antidiabetes, anti-inflammatory, anti-
Alzheimer’s, anti-Parkinson’s, anticancer, and anti-HIV.2
However, the related C-S bond formation reactions are less
studied compared with C-N and C-O processes, which is
partially caused by the fact that organic sulfur compounds
have a tendency to bind to metals, acting as metal deactiva-
tors.3 Originally, the traditional methods for the formation
of C-S bonds take place in polar solvents, such as HMPA,
and at elevated temperatures around 200 °C.4 To overcome
these drawbacks, transition-metal-catalyzed coupling systems
have been explored. Migita et al. first reported cross-coupling
reactions of aryl halides with thiols in the presence of
Pd(PPh3)4 in their seminal work in 1980.5 Recently, nickel,6
palladium,7 iron,8 and cobalt9 catalysts have emerged as
appealing catalysts for this reaction.
Copper salts have also been used as alternative and
promising catalysts for many organic transformations includ-
ing C-S bond forming reaction.10
On the other hand, the common methods for the assembly
of diaryl sulfides are based on the condensation of aryl halides
with thiols or metal sulfides. Less common synthetic strategies
involve the transformation of thiourea or disulfides.11 Still and
Toste reported that direct preparation of diaryl sulfides could
be achieved Via the reaction of samarium thiolates with aryl
(5) Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.; Kato, Y.; Kosugi,
M. Bull. Chem. Soc. Jpn. 1980, 53, 1385.
(6) (a) Percec, V.; Bas, J. Y.; Hill, D. H. J. Org. Chem. 1995, 60, 6895.
(b) Beletskaya, I. P.; Ananikov, V. P. Eur. J. Org. Chem. 2007, 3431. (c)
Zhang, Y.; Ngeow, K. C.; Ying, J. Y. Org. Lett. 2007, 9, 3495.
(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.
(c) Fernandez Rodr´ıguez, 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., Int. Ed. 2001, 40, 1513. (g) Zheng, N.;
McWilliams, J. C.; Fleitz, F. J.; Armstrong, J. D., III; Volante, R. P. J.
Org. Chem. 1998, 63, 9606. (h) Mann, G.; Baranano, D.; Hartwig, J. F.;
Rheingold, A. L.; Guzei, I. A. J. Am. Chem. Soc. 1998, 120, 9205. (i)
Eichman, C. C.; Stambuli, J. P. J. Org. Chem. 2009, 74, 4005. (j) Jiang,
Z.; She, J.; Lin, X. AdV. Synth. Catal. 2009, 351, 2558.
(1) (a) Jones, D. N. ComprehensiVe Organic Chemistry; Barton, D. H.,
Ollis, D. W., Eds.; Pergamon: New York, 1979. (b) Tiecco, M. Synthesis
1988, 749. (c) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. ReV. 2002, 102, 1359. (d) Beletskaya, I. P.; Cheprakov, A. V.
Coord. Chem. ReV. 2004, 248, 2337. (e) Ley, S. V.; Thoma, A. W. Angew.
Chem., Int. Ed. 2003, 42, 5400. (f) Herradura, P. S.; Pendola, K. A.; Guy,
R. K. Org. Lett. 2000, 2, 2019.
(2) (a) Liu, G.; Huth, J. R.; Olejniczak, E. T.; Mendoza, F.; Fesik, S. W.;
Von Genldern, 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,
43, 2217.
(8) (a) Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed. 2008,
47, 2880. (b) Wu, W.-Y.; Wang, J.-C.; Tsai, F.-Y. Green Chem. 2009, 11,
326.
(3) Kondo, T.; Mitsudo, T. Chem. ReV. 2000, 100, 3205.
(4) Lindley, J. Tetrahedron 1984, 40, 1433.
(9) Wong, Y. C.; Jayanth, T. T.; Cheng, C. H. Org. Lett. 2006, 8, 5613.
10.1021/ol102784c  2011 American Chemical Society
Published on Web 12/21/2010

halides in THF.12 Moreover, thiocyanate is more stable than
the above-mentioned sulfur sources and has usually been used
as a sulfur transfer reagent in organic transformation.13 Inspired
by these encouraging results, we considered the application of
metal thiocyanates in the coupling reaction.
Furthermore, the use of water as solvent in organic
reactions has attracted much attention in recent years due to
the low cost, nontoxicity, safety, and environmental friendli-
ness compared with organic solvents.14 As part of our
endeavors to develop aqueous catalysis,15 herein is reported
the efficient C-S bond formation between potassium thio-
cyanate and aryl halides by a copper catalyst in water.
Initially, iodobenzene and potassium thiocyanate were
selected as model substrates during the optimization of
reaction conditions. As shown in Table 1, among the different
K2CO3, K3PO4, NaOH, and Na2CO3 were screened, and
Cs2CO3 gave the best result (Table 1, entries 10-14). Further
studies revealed the optimal reaction temperature to be 130
°C and reaction time to be around 48 h (Table 1, entries
15-19). Meanwhile, control experiments proved the essential
presence of metal and PTC ((nBu)4NF) (Table 1, entries
20-21). Therefore, the optimal catalytic system involved the
use of CuCl2·2H2O (10 mol %), L2 (10 mol %), (nBu)4NF (20
mol %), and Cs2CO3 (2 equiv) in water at 130 °C for 48 h.
Then, a number of aryl iodides were examined to explore
the scope of substrates. As shown in Table 2, different aryl
Table 2. Copper-Catalyzed C-S Coupling of Different Aryl
Iodides with Potassium Thiocyanatea
Table 1. Optimization of Reaction Conditions in the
Copper-Catalyzed Coupling of Iodobenzene and Potassium
Thiocyanatea
entry [Cu] source ligand
base
t(h) temp(°C) yield(%)b
1
2
3
4
5
6
7
8
CuI
L1
L2
L3
L4
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
Cs2CO3 48
Cs2CO3 48
Cs2CO3 48
Cs2CO3 48
Cs2CO3 48
Cs2CO3 48
Cs2CO3 48
Cs2CO3 48
Cs2CO3 48
130
130
130
130
130
130
130
130
130
130
130
130
130
130
120
140
130
130
130
130
130
52
92
33
45
39
42
94
20
17
60
26
58
63
44
83
90
60
86
89
9
Cu(OAc)2·H2O
CuSO4·5H2O
CuCl2·2H2O
CuO
Cu2O
CuCl2·2H2O
9
10
11
12
13
14
15
16
17
18
19
20c
21
NaOH
48
a Reactions were carried out using aryl iodide (1.0 mmol), KSCN (1.5
mmol), CuCl2·2H2O (0.1 mmol), L2 (0.1 mmol), Cs2CO3 (2.0 mmol), and
(nBu)4NF (0.2 mmol) in water (5 mL) at 130 °C for 48 h. b Isolated yield
after chromatography.
Na2CO3 48
KOH
K2CO3
K3PO4
48
48
48
Cs2CO3 48
Cs2CO3 48
Cs2CO3 24
Cs2CO3 36
Cs2CO3 60
Cs2CO3 60
Cs2CO3 60
iodides were transformed into the corresponding diaryl sulfides
in moderate to excellent yields ranging from 69% to 94%. Steric
hindrance seemed to have an effect on the results. For example,
p-iodotoluene and p-nitroiodobenzene gave the desired products
in 90% yields, while 83% and 85% yields were obtained in the
case of o-iodotoluene and o-nitroiodobenzene as substrates
(Table 2, entries 2-5). Moreover, 78% and 79% yields obtained
trace
a Reactions were carried out using iodobenzene (1.0 mmol), KSCN (1.5
mmol), Cu source (0.1 mmol), ligand (0.1 mmol), base (2.0 mmol), and
(nBu)4NF (0.2 mmol) in water (5 mL). b Determined by GC using 1,4-
dichlorobenzene as internal standard. c Without addition of (nBu)4NF.
(10) (a) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517. (b)
Bates, C. G.; Saejueng, P.; Doherty, M. Q.; Venkataraman, D. Org. Lett.
2004, 6, 5005. (c) Taniguchi, N. Synlett 2005, 1687. (d) Chen, Y. J.; Chen,
H. H. Org. Lett. 2006, 8, 5609. (e) Rout, L.; Sen, T. K.; Punniyamurthy, T.
Angew. Chem., Int. Ed. 2007, 46, 5583. (f) Ma, D.; Cai, Q. Acc. Chem.
Res. 2008, 41, 1450. (g) Ku, X.; Huang, H.; Jiang, H.; Liu, H. J. Comb.
Chem. 2009, 11, 338. (h) Bhadra, S.; Sreedhar, B.; Ranu, B. C. AdV. Synth.
Catal. 2009, 351, 2369. (i) Wang, H.; Jiang, L.; Chen, T.; Li, Y. Eur. J.
Org. Chem. 2010, 2324. (j) Kabir, M. S.; Lorenz, M.; Van Linn, M. L.;
Namjoshi, O. A.; Ara, S.; Cook, J. M. J. Org. Chem. 2010, 75, 3626.
ligands L1-L4, L2 (1,10-phenanthroline) exhibited the
highest catalytic activity in 92% yield (Table 1, entries 1-4).
Comparison of different copper sources indicated that
CuCl2·2H2O and CuI were superior to others including
Cu(OAc)2·H2O, CuSO4·5H2O, CuO, and Cu2O (Table 1,
entries 5-9). A range of bases including Cs2CO3, KOH,
Org. Lett., Vol. 13, No. 3, 2011
455

in the case of p-chloroiodobenzene and p-bromoiodobenzene
implied that there was good chemoselectivity between iodide,
bromide, and chloride functional groups (Table 2, entries 6, 7).
Furthermore, the catalytic system could well tolerate a variety
of functional groups, including ketone, and hydroxymethyl
groups (Table 2, entries 8, 9). A heterocyclic compound, such
as 3-iodopyridine, could also afford the corresponding product
in 69% yield (Table 2, entry 10).
Table 4. Cross-Coupling of Aryl Iodides Catalyzed by Cua
entry
1a
1b 2a yield(%)b 3a yield(%)c 3b yield(%)d
Aryl bromides could also react with potassium thiocyanate
under the same reaction conditions albeit in slightly lower yields
than aryl iodides, and the results were listed in Table 3. Another
1
2
3
1.0 1.0
1.0 3.0
1.0 5.0
37
58
74
52
25
8
41
57
64
a Reactions were carried out using KSCN (3.0 mmol), CuCl2·2H2O (0.1
mmol), L2 (0.1 mmol), Cs2CO3 (2.0 mmol), and (nBu)4NF (0.2 mmol) in
water (5 mL) at 130 °C for 48 h. b Isolated yields based on 1.0 mmol of
reactant. c Yields based on 1a. d Yields based on 1b.
Table 3. Copper-Catalyzed C-S Coupling of Different Aryl
Bromides with Potassium Thiocyanatea
the symmetric products were found to be the main side product
as expected (Table 4, entry 1). To improve the results, the ratio
of substrates was increased to 1:3 and 1:5, and the corresponding
yields resulted in 58% and 74% respectively (Table 4, entry
2-3). The catalytic system was then extended to other substrates
and afforded moderate to good yields (Table 5) (see the
Supporting Information).
Table 5. Copper-Catalyzed Cross-Coupling Reaction of
Different Aryl Iodidesa
a Reactions were carried out using aryl halide (5 mmol), iodobenzene
(1 mmol), KSCN (3.0 mmol), CuCl2•2H2O (0.1 mmol), L2 (0.1 mmol),
Cs2CO3 (2.0 mmol), and (nBu)4NF (0.2 mmol) in water (5 mL) at 130 °C
for 48 h. b Isolated yields based on 1.0 mmol of reactant.
At last, this catalytic system was extended to the synthesis
of 2-phenylsulfanylbenzamide, which was reported to exhibit
SIRT1 (an NAD+-dependent protein deacetylase) inhibitory
activity.16 As shown in Scheme 1, the product could be
a Reactions were carried out using aryl bromide (1.0 mmol), KSCN
(1.5 mmol), CuCl2·2H2O (0.1 mmol), L2 (0.1 mmol), Cs2CO3 (2.0 mmol),
and (nBu)4NF (0.2 mmol) in water (5 mL) at 130 °C for 48 h. b Isolated
yield after chromatography.
(11) (a) Wu, J. R.; Lin, C. H.; Lee, C. F. Chem. Commun. 2009, 4450.
(b) Jammi, S.; Sakthivel, S.; Rout, L.; Mukherjee, T.; Mandal, S.; Mitra,
R.; Saha, P.; Punniyamurthy, T. J. Org. Chem. 2009, 74, 1971. (c) Chen,
C. K.; Chen, Y. W.; Lin, C. H.; Lin, H. P.; Lee, C. F. Chem. Commun.
2010, 46, 282. (d) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org.
Lett. 2002, 4, 2803. (e) Ma, D.; Xie, S.; Xue, P.; Zhang, X.; Dong, J.;
Jiang, Y. Angew. Chem., Int. Ed. 2009, 48, 4222. (f) Zhang, S.; Qian, P.;
Zhang, M.; Hu, M.; Cheng, J. J. Org. Chem. 2010, 75, 6732. (g) Firouzabadi,
H.; Iranpoor, N.; Gholinejad, M. AdV. Synth. Catal. 2010, 352, 119. (h)
Kumar, S.; Engman, L. J. Org. Chem. 2006, 71, 5400. (i) Taniguchi, N. J.
Org. Chem. 2004, 69, 6904. (j) Baldovino-Pantaleon, O.; Hernandez-Ortega,
S.; Morales-Morales, D. AdV. Synth. Catal. 2006, 348, 236.
reaction by using chlorobenzene as a substrate gave only 5%
product under the same conditions, which proved the inactivity
of the C-Cl bond in this catalysis.
Next, we tried the possibility of applying this catalytic system
in the cross-coupling reaction between two different aryl halides
by using iodobenzene and 4-methoxyiodobenzene as model
substrates. As shown in Table 4, when the ratio of two substrates
was 1:1, only 37% cross-coupling product was obtained, while
456
Org. Lett., Vol. 13, No. 3, 2011

Scheme 1
.
Synthesis of 2-Phenylsulfanylbenzamide in Water
Scheme 3. Proposed Catalytic Pathway for the C-S Formation
by a Cu(II) complex, leading to the formation of aryl
thiocyanate. Then, aryl thiocyanate is hydrolyzed to generate
a thiolate ion, which reacts with the aryl halide to afford the
C-S coupling product, and CN- is hydrolyzed by a base
under the reaction conditions.17,18
In conclusion, we have developed an effective copper
catalytic system for the reaction of aryl halides and potassium
thiocyanate in neat water without inert reaction conditions.
A variety of aryl halides could be reacted with potassium
thiocyanate to give the desired products in high yields up to
94%. 2-Phenylsulfanylbenzamide derivatives could be ef-
ficiently synthesized by this method. Further applications to
the synthesis of biologically important molecules and mech-
anism studies are in progress.
conveniently obtained from the reaction of 2-iodobenzoic
acid or 2-bromobenzoic acid with iodobenzene, followed by
treatment with EDCI and HOBt in ∼70% total yield. This
two-step reaction contributed an alternative way to access
2-phenylsulfanylbenzamide derivatives.
Furthermore, during our investigation of the catalytic path-
way, the presence of H2O was found to be essential for the
catalysis, while only a trace of product could be obtained by
using organic solvents including DMSO or THF either with or
without PTC. The existence of thiophenol and phenyl thiocy-
anate detected by GC/MS during reaction suggested the
dissociation of PhSCN during the catalysis. Control experiments
between thiophenol and PhSCN with iodobenzene afforded the
coupling product in 98% and 97% yields respectively under
the optimal catalytic conditions (Scheme 2). Based on these
Acknowledgment. We appreciate the Natural Science
Foundation of China (Nos. 20771076, 20901052, 21072132),
Sichuan Provincial Foundation (08ZQ026-041), and Ministry
of Education (NCET-10-0581) for financial support and the
Analytical & Testing Centre of Sichuan University for NMR
analysis.
Supporting Information Available: Detailed procedure
and spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
Scheme 2
.
Reaction of Iodobenzenes with Thiophenol and
Phenyl Thiocyanate
OL102784C
(14) (a) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb,
H. C.; Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275. (b) Li,
C.-J. Chem. ReV. 2005, 105, 3095. (c) Dallinger, D.; Kappe, C. O. Chem.
ReV. 2007, 107, 2563. (d) Chanda, A.; Fokin, V. V. Chem. ReV. 2009, 109,
725.
(15) (a) Liang, L.; Li, Z.; Zhou, X. Org. Lett. 2009, 11, 3294. (b) Wang,
Y.; Wu, Z.; Wang, L.; Li, Z.; Zhou, X. Chem.sEur. J. 2009, 15, 8971.
(16) Beletskaya, I. P.; Sigeev, A. S.; Peregudov, A. S.; Petrovskii, P. V.
MendeleeV Commun. 2006, 16, 250.
results and literature,13a,16 the reaction pathway is assumed
as shown in Scheme 3. First, an aromatic halide is activated
(17) (a) Siegel, J. R.; Rosenblatt, D. H. J. Am. Chem. Soc. 1958, 80,
1753. (b) Tarbell, D. S.; Harnish, D. P. Chem. ReV. 1951, 49, 1. (c)
(12) Still, I. W. J.; Toste, F. D. J. Org. Chem. 1996, 61, 7677.
(13) (a) Clark, J. H.; Jones, C. W.; Duke, C. V. A.; Miller, J. M. J. Chem.
Soc., Chem. Commun. 1989, 81. (b) Suzuki, H.; Abe, H. Synth. Commun.
1996, 26, 3413. (c) Sayyahi, S. Synlett 2009, 12, 2035.
Hoggarth, E.; Sexton, W. A. J. Chem. Soc. 1947, 815.
(18) (a) Rout, L.; Saha, P.; Jammi, S.; Punniyamurthy, T. Eur. J. Org.
Chem. 2008, 640. (b) Jiang, Y.; Qin, Y.; Xie, S.; Zhang, X.; Dong, J.; Ma,
D. Org. Lett. 2009, 11, 5250
.
Org. Lett., Vol. 13, No. 3, 2011
457