The first N-heterocyclic carbene-based nickel catalyst for C-S coupling

Article abstract of DOI:10.1021/ol071248x

We have developed the first N-heterocyclic carbene (NHC)-based transition metal catalysts for C-S coupling reactions. Ni-NHC catalysts showed good to excellent activities toward various aryl halides in C-S coupling reactions. The catalytic activities were greatly affected by the electronic and steric properties of the NHC ligands. The new catalysts were inexpensive, easy to synthesize, and environmentally friendly. They could be excellent candidates to replace Pd-organophosphanes for C-S coupling catalysis.

Full text of DOI:10.1021/ol071248x

ORGANIC
LETTERS
2
007
Vol. 9, No. 18
495-3498
The First N-Heterocyclic Carbene-Based
Nickel Catalyst for C S Coupling
3
−
Yugen Zhang,* Kao Chin Ngeow, and Jackie Y. Ying*
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos,
Singapore 138669, Singapore
jyying@ibn.a-star.edu.sg; ygzhang@ibn.a-star.edu.sg
Received May 28, 2007
ABSTRACT
We have developed the first N-heterocyclic carbene (NHC)-based transition metal catalysts for C−S coupling reactions. Ni−NHC catalysts
showed good to excellent activities toward various aryl halides in C
−S coupling reactions. The catalytic activities were greatly affected by the
electronic and steric properties of the NHC ligands. The new catalysts were inexpensive, easy to synthesize, and environmentally friendly.
They could be excellent candidates to replace Pd-organophosphanes for C−S coupling catalysis.
N-heterocyclic carbenes (NHCs) have emerged as an ex-
tremely useful class of ligands for transition-metal catalysis.
The striking similarity of electron-rich organophosphanes
reactions. However, it is surprising that no NHC-based metal
catalyst has been developed for C-S coupling reactions.
Organosulfur chemistry has been receiving increasing atten-
tion since sulfur-containing groups serve an important
1
3
(PR ) and NHCs, and NHCs’ excellent σ-donating properties
8
make them ligands of choice for transition metals. NHC-
auxiliary function in organic synthetic sequences. Aryl
metal complexes have been successfully used in many
sulfides are also a common functional group in numerous
pharmaceutically active compounds. However, synthesis of
the aryl-sulfur bond has been a challenge until the recent
2
9
processes, such as olefin metathesis, C-C or C-N cross-
3
4
coupling, olefin hydrogenation, transfer hydrogenation of
5
6
7
ketones, and also symmetric or asymmetric hydrosilylation
series of palladium organophosphane (Pd-PR
3
) catalysts
were developed by Migita, Buchwald, Hartwig,12 and
1
0
11
1
3
(
1) (a) Bourissou, D.; Guerret, O.; Gabbar, F. P.; Bertrand, G. Chem.
ReV. 2000, 100, 39. (b) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41,
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f) Hahn, F. E. Angew. Chem., Int. Ed. 2006, 45, 1384. (g) Kantchev, E. A.
3
others. The Pd-PR catalysts suffered from some limita-
1
(
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Tinant, B.; Declercq, J. Science 2002, 298, 204. (b) Diez-Gonzalez, S.;
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Chemistry; Jones, D. N., Ed.; Pergamon Press: Oxford, 1979; Vol. 3.
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S. F.; Nielsen, E. O.; Olsen, G. M.; Liljefors, T.; Peters, D. J. Med. Chem.
2000, 43, 2217.
(
B.; O’Brien, J.; Organ, M. G. Angew. Chem., Int. Ed. 2007, 46, 2768. (h)
Diez-Gonzalez, S.; Nolan, S. P. Top. Organomet. Chem. 2007, 21, 47. (i)
Diez-Gonzalez, S.; Nolan, S. P. Coord. Chem. ReV. 2007, 251, 874.
(2) (a) Scholl, M.; Trnka, T.; Morgan, J. P.; Grubbs, R. H. Tetrahedron
Lett. 1999, 40, 2247. (b) Huang, J. K.; Stevens, E. D.; Nolan, S. P. J. Am.
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B.; Buchmeiser, M. R. Angew. Chem., Int. Ed. 2001, 40, 3839.
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(c) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642. (d) Marion,
N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan, S. P. J. Am.
Chem. Soc. 2006, 128, 4101.
(10) Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.; Kato, Y.; Kosugi,
M. Bull. Chem. Soc. Jpn. 1980, 53, 1385.
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Rodriguez, M. A.; Shen, Q.; Hartwig, J. F. Chem.sEur. J. 2006, 12, 7782.
(
4) (a) Lee, H. M.; Jiang, T.; Stevens, E. D.; Nolan, S. P. Organometallics
001, 20, 1255. (b) Perry, M. C.; Cui, X. H.; Powell, M. T.; Hou, D. R.;
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2
(
1
0.1021/ol071248x CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/04/2007

tions, including low turnover number,10,11,13 high cost, and
12
bonds to the metal center than phosphanes.19 It was also
known that the steric hindrance and strong electron-donating
the use of environmentally unfriendly PR ligands. Several
3
other transition-metal organophosphane-based catalysts have
ligands could create more active catalysts for the Pd-PR
3
been developed,1
4-16
but they also exhibit low activities and
system.
12,20
Thus, we have investigated different types of
some other problems. For instance, the cobalt organophos-
phane catalyst needs excess zinc as reagent for catalyst
reduction.16 Herein we present the first NHC-ligated nickel
catalyst for C-S coupling reaction. This Pd-free and PR -
3
free catalyst showed excellent activities for a wide range of
substrates.
NHC ligands and different NHC/Ni ratios in the coupling
of 4-bromotoluene with thiophenol. The different types of
Ni-NHC catalysts studied were all active in this coupling
reaction. Strong electron-donating NHC generated from 3
showed the highest activity among NHCs 1-5 (Table 1).
Recently, Ni-NHC complexes have demonstrated that
they can provide for efficient C-F and C-C bond activa-
tion.17 It is also known that nickel complexes can catalyze
C-S coupling, but good activities were only achieved with
aryl iodides. Ni-NHC catalyzed hydrothiolation of alkynes
has also been reported.18 With this in mind, Ni-NHC was
examined as the catalyst for the coupling of thiols with aryl
halides since NHCs share similar properties as organophos-
phanes. Thermochemical and computational studies on NHC
complexes of nickel have shown that NHCs form stronger
Table 1. C-S Coupling Reactions over Ni-NHC Catalystsa
15
ligand
ligand/Ni ratio)
ligand
(ligand/Ni ratio)
(
% yieldb
% yieldb
54
1 (1)
3 (1)
(3)
5 (2)
7 (1)
(1) + 3 (1)
14
56
34
2 (2)
3 (2)
4 (2)
6 (1)
8 (1)
9 (1)
c
89 (56 )
3
65
88 (65 )
92 (71c)
c
(
13) (a) Kondo, T.; Mitsudo, T. Chem. ReV. 2000, 100, 3205. (b) Itoh,
52
T.; Mase, T. Org. Lett. 2004, 6, 4587. (c) Li, G. Y.; Zheng, G.; Noonan, A.
F. J. Org. Chem. 2001, 66, 8677. (d) Zheng, N.; McWilliams, J. C.; Fleitz,
F. J.; Armstrong, J. D., III; Volante, R. P. J. Org. Chem. 1998, 63, 9606.
92 (78c)
c
c
8
- (37 )
92 (68 )
(
e) Mispelacere-Canivet, C.; Spindle, J.-F.; Perrio, S.; Beslin, P. Tetrahedron
a
Unless otherwise specified, the reaction conditions are 0.2 mmol of
2
3
2
005, 61, 5253. (f) Schopfer, U.; Schlapbach, A. Tetrahedron 2000, 57,
069. (g) Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron
002, 58, 2041. (h) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513.
aryl halides, 0.22 mmol of thiols, 3 mol % of Ni catalyst, and 0.24 mmol
t
of potassium tert-butoxide (KO Bu) in 1 mL of N,N-dimethylformamide
DMF), 100 °C, 16 h. b GC yields. c Reaction run using 1.5 mol % of Ni
(
(
14) For Cu catalysts: (a) Kumar, S.; Engman, L. J. Org. Chem. 2006,
catalyst.
7
1, 5400. (b) Zheng, Y.; Du, X.; Bao, W. Tetrahedron Lett. 2006, 47, 1217.
(
1
5
c) Deng, W.; Zou, Y.; Wang, Y.-F.; Liu, L.; Guo, Q.-X. Synlett 2004,
254. (d) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
400. (e) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517. (f) Bates,
The catalytic activity was optimized at a NHC/Ni ratio of 2
C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002, 4, 2803.
15) For Ni catalysts: (a) Cristau, H. J.; Chabaud, B.; Chene, A.; Christol,
H. Synthesis 1981, 1892. (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.
16) For Co catalysts: Wong, Y.-C.; Jayanth, T. T.; Cheng, C.-H. Org.
Lett. 2006, 8, 5613.
17) (a) Liu, L.; Montgomery, J. J. Am. Chem. Soc. 2006, 128, 5348.
b) Ho, C.-Y.; Jamison, T. F. Angew. Chem., Int. Ed. 2007, 46, 782. (c)
Schaub, T.; Backes, M.; Radius, U. J. Am. Chem. Soc. 2006, 128, 15964.
18) Marion, N.; Diez-Gonzalez, S.; de Fremont, P.; Noble, A. R.; Nolan,
S. P. Organometallics 2006, 25, 4462.
21,22
(Table 1).
(
(
(19) Dorta, R.; Stevens, E. D.; Hoff, C. D.; Nolan, S. P. J. Am. Chem.
Soc. 2003, 125, 10490.
(20) Mann, G.; Baranano, D.; Hartwig, J. F.; Rheingold, A. L.; Guzei,
I. A. J. Am. Chem. Soc. 1998, 120, 9205.
(
(
(21) Representative procedure for catalyst synthesis: (3)2-Ni(0). An
amount of 82.5 mg of Ni(COD)2 (0.3 mmol) was added in a glovebox to
(
t
a mixture of 195 mg of 3 (0.6 mmol) and 68 mg of KO Bu (0.6 mmol) in
(
10 mL of DMF. The mixture was stirred for 1 h at room temperature, and
used as the catalyst stock solution for catalytic reactions.
3496
Org. Lett., Vol. 9, No. 18, 2007

6
-9 were ∼10 to 20% higher than that of (3)
2
-Ni. No
-Ni(0) Catalysta
2
byproduct was observed over bidentate catalyst systems in
Table 2. C-S Coupling Reactions over (3)
contrast to ∼3 to 5% symmetric byproduct obtained over
(
2
3) -Ni. Although the bidentate catalysts did not show
significant increase in activity, they demonstrated greater
stability compared to the monodentate catalysts. When more
ligands were introduced in the reaction system, for instance,
3
(3) -Ni or (8 + 3)-Ni, the catalytic activities decreased
substantially. This indicated that steric hindrance from over-
crowding or saturated coordination sphere of nickel center
resulted in lower activities. Further modification of the steric
and electronic properties of NHC ligand to balance the
catalyst stability and activity would be critical toward
developing superior catalytic systems.
2
Catalyst (3) -Ni was used for screening different substrates.
It showed excellent activities for deactivated aryl iodides.
Quantitative yields were achieved by using 1-1.5 mol % of
Ni catalyst in DMF at 80 °C for thiophenol (Table 2, entries
1
2
-2). For electron-rich aryl bromides, (3) -Ni also demon-
strated high activities. Reactions of thiophenol with weaker
bases (e.g., carbonate or phosphate) gave low conversions
t
t
and undesired byproducts. When KO Bu (or NaO Bu) was
used as the base, good to excellent yields were achieved for
various substrates with 3-4 mol % of Ni catalyst (Table 2,
entries 3-12). Good yield was also attained with alkyl thiol
(Table 2, entry 13).
The mechanism of Pd-PR
has been well studied.
assumed to be undergoing the same oxidative addition and
3
catalysts in coupling reactions
Here, Ni-NHC catalysts are
2
0,23
1c
reductive elimination cycle (Scheme 1). Sterically hindered
Scheme 1
a
Unless otherwise specified, the reaction conditions are 1 mmol of aryl
t
halides, 1.05 mmol of thiols, 1.1 mmol of KO Bu in 5 mL of DMF, 16 h.
Isolated yields.
b
Furthermore, bridged bidentate NHC ligands 6-9 were
prepared. Theoretically, the bidentate ligands would form
more stable Ni complexes with a longer catalytic lifetime
and prevent the formation of anionic or briding thiolate
complexes (which might undergo slow reductive elimination
as demonstrated in Pd-PR
3
systems).1 Table 1 shows the
2,17
catalytic results of the model reaction over catalysts with
bidentate ligands derived from 6-9. It was found that with
3
mol % of nickel catalysts, the activities of catalysts with
bidentate ligands were similar or slightly higher than that of
3) -Ni (NHC/Ni ) 2). However, when 1.5 mol % of nickel
catalysts was used, the activities of catalysts derived from
(
2
(
22) Representative experimental procedure for C-S coupling reaction
(
Table 2, entry 4). All reactions were performed in inert atmosphere. (3)2-
t
ligands are good in the reductive elimination step but would
slow down the oxidative addition process. On the other hand,
Ni solution (1 mL, 0.03 mmol of Ni), KO Bu (125 mg, 1.1 mmol),
thiophenol (1.05 mmol), and 4-bromotoluene (1 mmol) were mixed with 3
mL of DMF in a reaction vial. The vial was capped, and the reaction mixture
was stirred at 110 °C for 16 h. Yields were measured by gas liquid
chromatography (GLC) and isolation of pure product. Products were
confirmed by gas chromatography-mass spectrometry (GC-MS) and
nuclear magnetic resonance (NMR).
(23) (a) Komiya, S.; Hirano, M. In Fundamentals of Molecular Catalysis;
Kurosawa, H., Yamamoto, A., Eds.; Elsevier: Amsterdam, The Netherlands,
2003. (b) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852.
Org. Lett., Vol. 9, No. 18, 2007
3497

substitution and metal-catalyzed reductive elimination path-
ways to certain substrates remains unclear. A number of
publications have reported that metal complexes catalyzed
Table 3. C-S Coupling of Electron-Poor Aryl Halidesa
1
3b,e,f,16
13g
coupling of electron-poor aryl halides
with thiols.
However, we have found that control reactions between these
aryl halides with thiols also gave good to quantitative yields
of C-S coupling products under similar reaction conditions
(
Table 3). Under our reaction conditions, the rate of
2
nucleophilic substitution pathway on most electron-poor sp
carbon was competitive with or higher than that of metal-
catalyzed reductive elimination pathway. As shown in Table
3
4
, reactions between 1-chloro(bromo)-4-nitrobenzene or
-chloro(bromo)benzonitrile with thiols gave quantitative
thioether in 1 h under relatively mild conditions (entries 1-3
and 8-9). This was obviously different from the literature
13b
report. Reactions between 4-chloro(bromo)acetophenone,
2,6-dibromopyridine, and 3,5-bis(trifluoromethyl)bromoben-
zene with thiophenol also gave quantitative yields in 8-16
h with a strong base. 4-Chloro(bromo)benzotrifluoride with
thiophenol showed competitive reaction rates by two different
reaction pathways. The reaction between 4-chlorobenzotri-
fluoride and benzylthiol with base was much faster (Table
3, entry 5). Without metal catalysts, no desired products were
observed for reactions between electron-rich chloro(bromo)-
arenes with thiols (Table 3, entry 14).
In conclusion, the first NHC-based transition-metal cata-
lysts have been developed for C-S coupling reactions. Ni-
NHC catalysts showed good to excellent activities toward
various aryl halides in C-S coupling reactions. The new
catalysts were inexpensive, easy to synthesize, and environ-
mentally friendly. They could be excellent candidates to
3
replace Pd-PR for this reaction. It was also found that the
electronic and steric characteristics of NHC ligand greatly
affected the catalytic activities. Further fine-tuning of NHC
ligand to improve the catalyst performance and full charac-
terization of the new system are in progress.
a
Unless otherwise specified, the reaction conditions are 1 mmol of aryl
t
b
halides, 1.05 mmol of thiols, 1.1 mmol of KO Bu in 5 mL of DMF. Isolated
yields. No catalyst was used in entries 2-6, 8-14.
c
Acknowledgment. This work was supported by the
Institute of Bioengineering and Nanotechnology (Biomedical
Research Council, Agency for Science, Technology and
Research, Singapore).
strong electron-donating ligands may help the oxidative
addition of aryl halides but are not good in reductive
elimination. Thus, tuning the steric hindrance and electron-
donating properties of ligands is important for catalyst
development.
Although it is known that activated aryl chlorides, such
as p-nitrile chlorobenzene, can follow the nucleophilic
substitution mechanism to form a C-S coupling product and
do not need a catalyst, the competition between nucleophilic
Supporting Information Available: Experimental details
and characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL071248X
3498
Org. Lett., Vol. 9, No. 18, 2007