Efficient Negishi coupling reactions of aryl chlorides catalyzed by binuclear and mononuclear nickel-N-heterocyclic carbene complexes

Article abstract of DOI:10.1021/jo8018686

(Chemical Equation Presented) We describe the first nickel-N-heterocyclic carbene catalyzed Negishi cross-coupling reaction of a variety of unactivated aryl chlorides, heterocyclic chlorides, aryl dichlorides, and vinyl chloride. The mononuclear and binuclear nickel-NHC complexes supported by heteroarene-functionalized NHC ligands are found to be highly efficient for the coupling of unactivated aryl chlorides and organozinc reagents, leading to biaryls and terphenyls in good to excellent yields under mild conditions. For all aryl chlorides, the binuclear nickel catalysts show activities higher than those of mononuclear nickel complexes because of possible bimetallic cooperative effect.

Full text of DOI:10.1021/jo8018686

Efficient Negishi Coupling Reactions of Aryl Chlorides Catalyzed by
Binuclear and Mononuclear Nickel-N-Heterocyclic Carbene
Complexes
Zhenxing Xi,† Yongbo Zhou,† and Wanzhi Chen*,†,‡
Department of Chemistry, Zhejiang UniVersity, Xixi Campus, Hangzhou 310028, P. R. China, and School
of Chemistry and Chemical Engineering, Liaocheng UniVersity, Liaocheng 252059, P. R. China
chenwzz@zju.edu.cn
ReceiVed August 21, 2008
We describe the first nickel-N-heterocyclic carbene catalyzed Negishi cross-coupling reaction of a variety
of unactivated aryl chlorides, heterocyclic chlorides, aryl dichlorides, and vinyl chloride. The mononuclear
and binuclear nickel-NHC complexes supported by heteroarene-functionalized NHC ligands are found
to be highly efficient for the coupling of unactivated aryl chlorides and organozinc reagents, leading to
biaryls and terphenyls in good to excellent yields under mild conditions. For all aryl chlorides, the binuclear
nickel catalysts show activities higher than those of mononuclear nickel complexes because of possible
bimetallic cooperative effect.
Introduction
to mild reaction conditions and good functional group tolerance.3
Compared with the partners, organotin, organomagnesium, and
organoboron reagents, which are investigated widely, organozinc
reagents have been studied to a lesser extent. Though a few
successful examples of Negishi coupling reactions of aryl
bromides and iodides have been reported in the recent decade,4
aryl chlorides are more attractive because they are more
economic and easily accessible organic electrophiles. However,
only a few catalytic systems show good activities for unactivated
Transition-metal-catalyzed cross-coupling reactions between
Csp2 centers have been extensively used for preparing pharma-
ceuticals and agrochemical intermediates.1 In this context, there
has been great development in palladium-catalyzed coupling
reactions of a series of organometallic reagents (M ) B, Sn,
Si, Mg) for the construction of carbon-carbon bonds.2 Metal-
catalyzed cross-coupling of organozinc compounds with organic
electrophiles, known as the Negishi reaction, has become one
of the extremely powerful tools for C-C bond formation due
(3) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980,
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Zeng, X.; Qian, M.; Hu, Q.; Negishi, E. Angew. Chem., Int. Ed. 2004, 43, 2259.
(d) Qian, M.; Huang, Z.; Negishi, E. Org. Lett. 2004, 6, 1531.
† Zhejiang University.
‡ Liaocheng University.
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de Vries, J. G. AdV. Synth. Catal. 2004, 346, 1812. (c) Herbert, J. M. Tetrahedron
Lett. 2004, 45, 817. (d) Kondolff, I.; Doucet, H.; Santelli, M. Organometallics
2006, 25, 5219. (e) Huang, Z.; Qian, M.; Babinski, D. J.; Negishi, E.-I.
Organometallics 2005, 24, 475. (f) Krascsenicsova, K.; Walla, P.; Kasak, P.;
Uray, G.; Kappe, C. O.; Putala, M. Chem. Commun. 2004, 2606. (g) Corley,
E. G.; Conrad, K.; Murry, J. A.; Savarin, C.; Holko, J.; Boice, G. J. Org. Chem.
2004, 69, 5120. (h) Marquais, S.; Arlt, M. Tetrahedron Lett. 1996, 37, 5491. (i)
Okano, M.; Amano, M.; Takagi, K. Tetrahedron Lett. 1998, 39, 3001. (j) Hoye,
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10.1021/jo8018686 CCC: $40.75
Published on Web 10/08/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8497–8501 8497

Xi et al.
CHART 1. Schematic Illustration of Nickel Catalysts 1a-d and 2a-c
aryl chlorides due to low reactivity of the C-Cl bond.5 In this
line, palladium-catalyzed Negishi coupling of unactivated aryl
chlorides has recently been found to be successful under mild
conditions.6 A few nickel complexes also show good activities
for unactivated aryl chlorides.7 However, most of these nickel
and palladium catalysts require environmentally unfriendly
phosphine or phosphite ligands.6,7
Although N-heterocyclic carbenes (NHCs) have found wide
applications in a number of organic transformations as an
alternative to phosphines because of their excellent σ-donor
properties, ease of synthesis, and variable steric bulk,8,9
metal-NHC complex catalyzed Negishi cross-coupling reaction
has not been well studied. Organ et al. reported the first
Pd2(dba)3/1,3-di(diisopropylphenyl)imidazolium catalyzed Negishi
cross-coupling reaction utilizing NHC ligands.10 Nickel catalysts
based on NHC ligands for Negishi cross-coupling reaction have
not been known so far. Nickel is generally believed to be less
efficient for coupling reactions than the corresponding palladium
catalyst. The employment of hemilable heteroarene-function-
alized NHC ligands would be a possible way to enhance the
catalytic activities of nickel complexes since the dissociation
of heteroarene allows the creation of unsaturated coordination
site and the coordination of NHCs promotes the oxidative
addition of substrates in the catalytic cycle.8c,e We have recently
reported the synthesis and structural characterization of a few
nickel complexes supported by multidentate NHC ligands, and
their catalytic activities for Suzuki-Miyaura and Kumada-Corriu
couplings have been briefly studied.11 As a continuation, herein
we describe the first Negishi cross-coupling reaction of unac-
tivated aryl chlorides based on mononuclear and binuclear
nickel-NHC complexes under mild conditions. The bimetallic
catalysts exhibit strong cooperative catalytic activities for the
coupling reaction.
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(b) Miller, J. A.; Farrel, R. P. Tetrahedron Lett. 1998, 39, 6441. (c) Walla, P.;
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Kofink, C.; Manolikakes, G.; Knochel, P. Tetrahedron 2006, 62, 7521. (f)
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B. R. Chem. Asian J. 2006, 1, 417. (g) Wang, L.; Wang, Z. X. Org. Lett. 2007,
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2008, 26, 3046.
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2000, 100, 39. (b) Jafarpour, L.; Nolan, S. P. J. Organomet. Chem. 2001, 617-
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A. C.; Grasa, G. A.; Viciu, M. S.; Lee, H. M.; Yang, C.; Nolan, S. P. J.
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in Transition Metal Catalysis. In Topics in Organometallic Chemistry; Springer:
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M. G. Angew. Chem., Int. Ed. 2007, 46, 2768.
(9) (a) Lee, D.-H.; Kim, J.-H.; Jun, B.-H.; Kang, H.; Park, J.; Lee, Y.-S.
Org. Lett. 2008, 10, 1609. (b) Weck, M.; Jones, C. W. Inorg. Chem. 2007, 46,
1865. (c) Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Org. Lett.
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Org. Chem. 2002, 67, 3029.
Results and Discussion
To examine the catalytic efficiencies of the mononuclear
nickel-NHC complexes 1a-d and three binuclear nickel-NHC
complexes, 2a-c, we chose the coupling reaction of chloroben-
zene and p-tolylzinc chloride as model reaction to optimize the
reaction conditions and evaluate the catalytic activities of these
nickel complexes. The structures of the seven nickel complexes
are shown in Chart 1. The results are listed in Table 1 and
illustrate the impact of a variety of reaction parameters on the
Negishi coupling process. The results show that the desired
biaryl was obtained in a yield of 80% when 3 mol % of
mononuclear nickel complex 1a was used at 80 °C in mixed
THF/NMP within 5 h (Table 1, entry 1). When the catalyst
loading was reduced to 2 mol %, the yield was not significantly
changed (entry 2). However, further decrease of the catalyst
loading to 1 or 0.5 mol % lowered the yields of the coupling
product to 65% and 34%, respectively (entries 3 and 4). These
data illustrate that the employment of 2 mol % of nickel catalyst
is sufficient for the coupling of chlorobenzene and p-tolylzinc
chloride. We have tried to prolong the reaction time, but the
yield was not improved (entry 5). The effect of temperature
(10) (a) Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Org.
Lett. 2005, 7, 3805. (b) Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Organ,
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26, 6636. (b) Xi, Z.; Liu, B.; Chen, W. J. Org. Chem. 2008, 73, 3954. (c) Zhou,
Y.; Xi, Z.; Chen, W.; Wang, D. Organometallics, submitted for publication.
8498 J. Org. Chem. Vol. 73, No. 21, 2008

Nickel-NHC Catalyzed Negishi coupling
TABLE 1. Reactions of PhCl with p-TolylZnCl Catalyzed by
1a-d, 2a-ca
reaction rate and efficiency (entries 13 and 19). The coupling
reactions in air using either 1a or 2a did not afford the desired
products but homocoupling products of arylzinc reagents, and
aryl chlorides were not consumed. Obviously, in the Negishi
coupling the binuclear nickel complexes show activities higher
than those of the mononuclear complexes since the former
require lower catalyst loadings and shorter reaction times.
To examine the difference between the mononuclear and
binuclear nickel complexes in the Negishi coupling reactions,
we utilized 1a and 2a as catalysts for the study of the reactions
between a variety of aryl chlorides and organozinc reagents
under the optimized condition. The results are summarized in
Table 2. As can be seen, both 1a and 2a were efficient for two
heteroaryl chlorides. For example, 2-chloropyridine and 2-chlo-
ropyrimidine were easily coupled with p-tolylzinc chloride, and
the products were produced in excellent yields when 1 mol %
of 1a was used (Table 2, entries 1 and 3). For the same
heteroaryl chlorides, the corresponding products were afforded
in nearly quantitative yields at 0.1 mol % loading of 2a (entries
2 and 4). Both 1a and 2a showed good tolerance toward a few
functional groups such as ketone, ester, and nitrile. Aryl
chlorides bearing a cyanide function such as 4-chlorobenzonitrile
and 3-chlorobenzonitrile reacted smoothly with p-tolylzinc
chloride affording the desired products in more than 80% yields,
whereas 2-chlorobenzonitrile gave 2-tolylbenzonitrile in lower
yield because of steric hindrance when 2 mol % of 1a was
employed (entries 5, 7, and 9). The same reactions catalyzed
by 0.5 mol % of 2a under the same temperature led to the
corresponding products in much higher yields even within
shorter reaction time (entries 6, 8, and 10). It is worth noting
that 2-tolylbenzonitrile derived from the coupling between
2-chlorobenzonitrile and p-tolylzinc chloride is a key intermedi-
ate for a few antihypertensive drugs.12 Previous reports indicated
that aryl chlorides containing a nitrile group are usually less
active in nickel-catalyzed Negishi couplings due to the coor-
dination of the nitrile group with the catalytically active metal
center.7e,g 2-Tolylbenzonitrile can be obtained in nearly 90%
yield even in the presence of 0.5 mol % loading of 2a, providing
a new protocol for the preparation of the important intermediate.
The couplings of p-PhC(O)C6H4Cl and p-EtO2CC6H4Cl were
also successful to give the products in 95% and 93% yields,
respectively (entries 18 and 20). Unfortunately, both 1a and 2a
catalyzed Negishi reactions were found incompatible with NO2
and CHO groups; in such cases only trace amount of the desired
products could be detected by GC chromatography. The nickel
catalysts are also applied to the coupling reactions of aryl
chlorides bearing electron-donating groups. The coupling reac-
tions of 4-chloroanisole and 2-chlorotoluene with p-tolylzinc
chloride catalyzed by 2 mol % of 1a afforded the corresponding
products in 63% and 61% yields, respectively (entries 11 and
13). By replacing 1a with 2a, much higher yields of 2,4′-
dimethylbiphenyl and 4-tolylanisole were obtained (entries 12
and 14). Experimental results show that we can apply the same
protocol to the Negishi reaction of vinyl chlorides. The styrene
derivative was produced in 85% and 96% yields when 1 mol
% of 1a and 0.1 mol % of 2a were employed (entries 15 and
16).
entry catalyst catalyst amount (mol %) T (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
2a
2a
2a
2a
2a
2a
2a
2b
2c
3
2
1
0.5
2
2
2
2
2
2
2
2
1
0.5
0.2
0.1
0.5
0.5
0.5
0.5
0.5
80
80
80
80
80
90
100
70
80
80
80
80
80
80
80
80
80
80
100
80
80
5
5
5
5
10
5
5
5
5
5
5
5
2
2
2
2
1
2
2
2
2
80
79
65
34
79
80
81
52
38b
71
65
72
97
94
69
34
79
40b
95
92
75
9
10
11
12
13
14
15
16
17
18
19
20
21
a Reaction conditons: PhCl 1.0 mmol, p-tolylZnCl 1.2 mmol, THF/
NMP (1:1) 3 mL. b In THF.
has also been investigated. The reaction at 80 °C proceeded
smoothly and elevation of temperature to 100 °C showed no
obvious improvement of the yields (entries 6-8). Similar to
other known Negishi reactions,6b,7d,e,g the mixed THF/NMP
solvent is more suitable than pure THF due to low solubility of
organozinc reagent in THF (entry 9). Under the optimized
conditions stated above, the catalytic activities of 1b-d for the
coupling of chlorobenzene and p-tolylzinc chloride were tested.
We found that 1a is more efficient than 1b-d (entries 10-12).
In these reactions, no side products such as homocoupling
products were observed and the starting aryl chlorides were not
consumed completely. The higher catalytic activity of 1a is
probably ascribed to the ease of dissociation of the coordinated
pyridine groups of 1a because of the internal strain due to the
coplanarity of the four rings of bis(pyridylimidazolylidenyl)-
methane and the central nickel ion. For the other three nickel
complexes the four pyridine and imidazolylidene rings are not
coplanar due to flexibility of the ligands.
Further studies of the coupling reaction using binuclear nickel
catalyst system were carried out under the optimized conditions.
The results listed in Table 1 show that the coupling of chlo-
robenzene gave the coupling product in much higher yields by
using only 0.5 mol % of the binuclear nickel complexes 2a,b
than 2 mol % of 1a-d. The catalytic activity of 2c is relatively
poorer than that of 2a and 2b. This is probably because the
two nickel ions of 2c are tightly bonded by two 3,5-bis(N-
methylimidazolylidenylmethyl)pyrazolate, which are dissociated
with difficulty to generate coordinatively unsaturated active
species. In contrast, nickel complexes 2a and 2b can easily
dissociate pyridine groups and lose or break down the hydroxide
bridge. The high efficiency of 2a is illustrated by the moderate
yield (69%) for unactivated chlorobenzene at a catalyst loading
of 0.2 mol % (entry 15). Increasing the catalyst loading to 0.5
mol %, the coupling product can be obtained in nearly
quantitative yield (entry 14). Further increase of the reaction
temperature and the catalyst loading has little influence on the
As part of our study, the coupling reactions of steric hindered
arylzinc reagent were also investigated. Reactions between
(12) (a) Goubet, D.; Meric, P.; Dormoy, J. R.; Moreau, P. J. Org. Chem.
1999, 64, 4516. (b) Kageyama, H.; Miyazaki, T.; Kimura, Y. Synlett. 1994, 371.
(c) Miller, J. A.; Farrell, R. P. Tetrahedron Lett. 1998, 39, 6441. (d) Walla, P.;
Kappe, C. O. Chem. Commun. 2004, 564.
J. Org. Chem. Vol. 73, No. 21, 2008 8499

Xi et al.
TABLE 2. Cross-Coupling of Aryl Chlorides with Arylzinc Chlorides Catalyzed by 1a and 2aa
a Reaction conditions: aryl chloride 1.0 mmol, arylzinc reagent 1.5 mmol, THF/NMP (1:1) 3 mL, 80 °C. b 56% 2-chlorobenzonitrile was recovered.
o-tolylzinc chloride and aryl chloride containing functional
groups such as CN, PhC(O), EtO2C, OMe, and heterocyclic
chloride were examined comparatively by using 1a and 2a
(entries 21-34). The difference between 1a and 2a is that the
influence of the steric hindrance of organozinc reagent for
catalyst 1a is more prominent than for 2a. For example, in the
case of 2a o-tolylzinc chloride reacted with 4-chlorobenzonitrile,
3-chlorobenzonitrile, and 4-chloroanisole leading to the corre-
sponding products 4e (85%), 4m (87%), and 4p (71%) (entries
22, 24, and 30). In contrast, the yields of the coupling products
lowered to ca. 60% when 2 mol % of 1a was employed (entries
21, 23, and 29). Similarly, electron-poor aryl chlorides such
as p-PhC(O)C6H4Cl, p-EtO2CC6H4Cl, and 2-chloropyrimidine
coupled with o-tolylzinc chloride catalyzed by 2a affording the
products in good to excellent yields (81-97%) (entries 28, 32,
and 34), whereas the same products were obtained in moderate
yields with 1a (entries 27, 31, and 33). Especially, the difference
between 1a and 2a is more apparent in the reaction of
2-chlorobenzonitrile and o-tolylzinc chloride. Complex 1a is
nearly ineffective (entry 25), whereas complex 2a could give
the product in a yield of 79% (entry 26). Finally, we have also
studied the couplings between phenylzinc chloride with a few
aryl chlorides. The data revealed that the reactivity of phenylzinc
chloride was similar to that of p-tolylzinc chloride for both 1a
and 2a (entries 35-46).
With our optimized reaction conditions, we can also
synthesize terphenyl derivatives via one-pot double coupling
of aryl dihalides (Table 3). For example, we can generate
8500 J. Org. Chem. Vol. 73, No. 21, 2008

Nickel-NHC Catalyzed Negishi coupling
TABLE 3. Cross-Coupling of Dichlorobenzene with Arylzinc
Chlorides Catalyzed by 1a and 2aa
bis(pyridylimidazolylidenylmethyl)pyrazolate ion and display
a short distance (around 3.2 Å),11c which may allow the two
nickel ions to get access to aryl chloride simultaneously, and
thereafter bimetallic activation of inert C-Cl bond could be
achieved.
In conclusion, we have described the first successful
Negishi cross-coupling catalyzed by mononuclear and bi-
nuclear nickel complexes supported by N-heterocyclic car-
benes under mild conditions. Both mononuclear and binuclear
nickel-NHC complexes are effective for the coupling
reactions of unactivated aryl chlorides, heterocyclic chlorides,
and vinyl chloride with organozinc reagents leading to a wide
range of biphenyls and terphenyls. The catalytic data show
that binuclear nickel-NHC complexes are more active than
mononuclear nickel-NHC complexes probably due to pos-
sible bimetallic cooperativity. All the Ni(II) complexes are
air stable and can be easily prepared. We believe that these
binuclear nickel-NHC catalytic systems could provide a
complement to the protocols using expensive palladium and
environmentally unfriendly phosphine or phosphite ligands
in a number of organic transformations. Efforts are currently
underway to clarify the origin of cooperative activity as well
as the nature of active species for the catalytic coupling
reaction.
Experimental Section
General Procedure for Negishi Reactions. A Schlenk tube was
charged with nickel complexes 1a or 2a (0.01-2% mmol),
anhydrous THF (1.5 mL), NMP (1.5 mL), and aryl chloride (1.0
mmol). To the solution was added a solution of arylzinc reagent
(1.5 mL, 1.0 M in THF) at room temperature with stirring. After it
was stirred at 80 °C for 2-12 h, the reaction was ceased by addition
of water and several drops of HCl. Then the mixture was extracted
with ethyl acetate (3 × 5 mL). The combined organic layer was
dried by MgSO4. The filtrate was concentrated by rotary evapora-
tion, and the crude product was purified by column chromatography
on sillca gel to afford the desired product.
a Reaction conditions: dichlorobenzene 1.0 mmol, arylzinc reagent 3.0
mmol, THF/NMP (1:1) 3 mL, 80 °C.
1,3- and 1,4-ditolylbenzene in 76-86% yields from 1,3-
dichlorobenzene and 1,4-dichlorobenzene with p-tolylzinc
chloride (entries 3-6) using either 1a or 2a. Similarly, we
can also obtain 1,3-terphenyl and 1,4-terphenyl in 75-82%
yields (entries 9-12). Furthermore, we can produce 2,6-diaryl
pyridine in excellent yield from 2,6-dichloropyridine and
C6H5ZnCl or p-MeC6H4ZnCl (entries 2 and 8). Especially,
2,6-ditolylpyridine could be achieved in nearly quantitative
yield by using 0.5 mol % of 2a (entry 2). Obviously, the
coupling of 1,3-dichlorobenzene and 1,4-dichlorobenzene is
more difficult than that of heterocyclic dichlorides because
of the electronic deficient nature of 2,6-dichloropyridine.
Again, we found that complex 2a also showed much better
activities for the double couplings than 1a under the same
conditions.
2-p-Tolylpyrimidine (4a). 1H NMR (400 MHz, CDCl3, TMS):
δ 8.78 (d, J ) 4.8 Hz, 2H), 8.34 (d, J ) 8.0 Hz, 2H), 7.31 (d, J )
8.0 Hz, 2H), 7.15(d, J ) 4.8 Hz, 1H), 2.42 (s, 3H) ppm. MS (EI,
m/z): 170 [M+].
Acknowledgment. We gratefully acknowledge the financial
support of the NSF of China (Grant 20572096), Zhejiang
Provincial Natural Science Foundation (R405066), and Qian-
jiang Project (2007R10006).
Supporting Information Available: Experimental details and
spectroscopic data of compounds 4a-x, 6a-f. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO8018686
Many efforts have been made in the design of cooperative
metal catalysts because such catalysts are believed to exhibit
an enhancement of catalytic activity in organic transformation
and may serve as functional models for natural metalloen-
zymes.13 The bimetallic nickel complex 2a shows higher activity
than 1a with respect to their catalytic efficiency taking account
of the much lower loading of 2a and shorter reaction time. Such
advantage is tentatively ascribed to the bimetallic cooperative
effect. The two nickel centers are held together by a 3,5-
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