Room-temperature nickel-catalysed cross-couplings of aryl chlorides with arylzincs

Article abstract of DOI:10.1039/c0cc03064c

P,N,O-chelate nickel complexes efficiently catalyse the cross-coupling reaction of aryl chlorides with arylzinc reagents in a 11 THF-NMP mixture. The reactions proceed at room temperature with low catalyst loading.

Full text of DOI:10.1039/c0cc03064c

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COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Room-temperature nickel-catalysed cross-couplings of aryl chlorides with
arylzincsw
Ning Liu, Li Wang and Zhong-Xia Wang*
Received 5th August 2010, Accepted 9th November 2010
DOI: 10.1039/c0cc03064c
P,N,O-chelate nickel complexes efficiently catalyse the cross-
coupling reaction of aryl chlorides with arylzinc reagents in a
1 : 1 THF–NMP mixture. The reactions proceed at room
temperature with low catalyst loading.
Biaryl structures are found in many natural products, pharma-
ceuticals, agrochemicals, liquid crystals, and advanced
materials.1 Transition-metal-catalysed cross-coupling reactions
between aryl halides and arylmetallic reagents are powerful
tools for the synthesis of biaryl compounds.1,2 Among the
coupling reactions, the Negishi reaction is one of the most
popular approaches to biaryls.1 Organozinc reagents show
much better functional group compatibility compared with
Grignard reagents in the Kumada reaction and higher
reactivity than organoboron reagents in the Suzuki reaction,
organotin reagents in the Stille reaction and organosilicon
reagents in the Hiyama reaction.2 The high reactivity of
Fig. 1 P,N,O- and P,N,S-chelate nickel complexes.
room temperature using a mixture of THF and NMP (1 : 1) as
solvent. Other solvents such as THF, toluene, THF–toluene
(1 : 1), THF–DMA (1 : 1) and THF–NMP (5 : 1) were not
very effective, leading to a trace to moderate yield of the cross-
coupling product (Table 1). Under the same conditions as
above using THF–NMP (1 : 1) as solvent, we found that the
P,N,O-chelate complexes (I and III) displayed a higher cata-
lytic activity than the P,N,S-chelate complexes (II and IV), and
Ib showed almost the same catalytic activity as Ia.
organozinc reagents makes the coupling reaction proceed
under milder reaction conditions. Quite a few coupling reac-
tions of aryl iodides and bromides with arylzinc reagents can
be carried out at room temperature or below in the presence of
nickel or palladium catalysts.2,3 However, a Negishi reaction
of aryl chlorides often requires an elevated temperature due to
the low reactivity of the C–Cl bond.4 Only a few reports of
room temperature Negishi coupling of aryl chlorides have
been published, predominantly using activated aryl chlorides.3e,5
Very recently, Organ and co-workers reported a Pd-catalysed
reaction of 2,4,6-Me3C6H2ZnCl with 2-chloro-1,3-dimethyl-
benzene at 23 1C, giving a cross-coupling product in 90%
isolated yield.5e On the other hand, the use of aryl chlorides,
room temperature reaction conditions and less expensive
Ni-based catalysts would economically benefit a number of
industrial processes. Herein we report a class of highly efficient
nickel catalysts (Ia–IV, Fig. 1) which lead to Negishi cross-
coupling of aryl chlorides at room temperature.
We next tested the reaction using different aryl chlorides and
arylzinc reagents in the presence of Ia or III (Table 2). The
reactions were carried out in a 1 : 1 mixture of THF and NMP
using 1.5 equiv. of ArZnCl prepared in situ from ArLi and
anhydrous ZnCl2. Almost all reactions can be run at room
Table 1 Evaluation of catalytic activity of complexes Ia–IV in the
Negishi reactiona
Synthetic details of complexes Ia–IV are in the ESI.w
Complex Ia was obtained previously as a trace impurity.6
Now we can prepare it in gram scale for catalytic study. In
preliminary studies of the catalytic property, we investigated
the reaction of p-ClC6H4OMe with PhZnCl and found that the
reaction proceeded efficiently in the presence of 0.2 mol% Ia at
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
Ia
Ia
Ia
Ia
Ia
Ib
II
THF
31
THF–toluene (1 : 1)
THF–DMA (1 : 1)
THF–NMP (5 : 1)
THF–NMP (1 : 1)
THF–NMP (1 : 1)
THF–NMP (1 : 1)
THF–NMP (1 : 1)
THF–NMP (1 : 1)
Trace
78
60
98
97
67
92
62
CAS Key Laboratory of Soft Matter Chemistry and Department of
Chemistry, University of Science and Technology of China, Hefei,
Anhui 230026, People’s Republic of China.
E-mail: zxwang@ustc.edu.cn; Fax: +86 5513601592;
Tel: +86 5513603043
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization details. CCDC 787973. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0cc03064c
III
IV
a
The reactions were carried out at room temperature for 24 h in the
presence of 0.2 mol% catalyst, 0.5 mmol p-ClC6H4OMe and
b
0.75 mmol PhZnCl were employed. Isolated product yields.
c
1598 Chem. Commun., 2011, 47, 1598–1600
This journal is The Royal Society of Chemistry 2011

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temperature. However, at elevated temperatures the reactions
proceeded faster and required less catalyst loading (entries 9
and 10, Table 2). For sterically hindered deactivated aryl
chlorides such as o-ClC6H4OMe an elevated reaction tempera-
ture is necessary to drive the reaction to completion (entries 12
and 13, Table 2). While for the sterically hindered chloride
substrate with an electron-withdrawing group such as
o-ClC6H4C(O)Ph, the reactions can be completed at room
temperature in excellent yields at a catalyst loading of 2 mol%
(entries 11 and 19, Table 2). For the reactions of
p-MeC6H4ZnCl with other aryl chlorides except p-ClC6H4CN,
catalyst loading could be as low as 0.05 mol% to 0.2 mol%.
Among those substrates, unactivated and activated aryl
chlorides exhibited a higher reactivity and deactivated aryl
of other activated aryl chlorides such as p-ClC6H4COOEt,
p-ClC6H4C(O)NEt2 and p-ClC6H4CF3. For example, reaction
between p-ClC6H4CN and p-MeC6H4ZnCl requires 2 mol%
Ia and gave a cross-coupling product in 87% yield. The same
reaction required 1 mol% III and gave 99% yield of the
product. This phenomenon has been observed by us and other
groups previously and was ascribed to the coordination of the
CN group with the nickel centre.3e,4g It was also noticed that in
those reactions involving p-ClC6H4CN complex III seems to
be a more active catalyst than complex Ia. The electronic and
steric properties of the nucleophiles also affect the reactions
remarkably. p-Me2NC6H4ZnCl was more reactive than
p-MeC6H4ZnCl due to the electron-donating effect of the
NMe2 group. Reaction of the former with p-ClC6H4OMe
required only 0.1 mol% Ia, affording a cross-coupling product
in 96% yield (entry 22, Table 2). o-MeC6H4ZnCl was less
reactive than p-MeC6H4ZnCl in the coupling reaction. Its
chlorides showed
a little lower reactivity. p-ClC6H4CN
displayed different reactivity from other activated aryl
chlorides. It required much higher catalyst loading than those
Table 2 Cross-coupling of arylzinc chlorides with aryl chlorides catalysed by Ia and IIIa
Entry
Ar
Ar1Cl
Catalyst (mol%)
Time/h
Yieldf (%)
1
2
3
4
5
6
7
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-Me2NC6H4
p-Me2NC6H4
o-MeC6H4
o-MeC6H4
o-MeC6H4
o-MeC6H4
o-MeC6H4
o-MeC6H4
o-MeC6H4
o-MeC6H4
2-Furyl
PhCl
Ia (0.05)
Ia (0.1)
Ia (2)
24
24
24
24
24
12
12
24
6
99
98
87
95
99
99
99
96
98
99
97
74
98
93
94
99
98
91
98
99
99
96
97
99
96
82
99
98
86
76
94
99
79
99
99
69
75
65
67
30
p-PhC(O)C6H4Cl
p-NCC6H4Cl
p-CF3C6H4Cl
Ia (0.05)
Ia (0.1)
Ia (0.05)
Ia (0.05)
Ia (0.15)
Ia (0.03)
Ia (0.02)
Ia (2)
Ia (2.5)
Ia (2.5)
Ia (2)
III (0.05)
III (1)
III (0.1)
III (0.2)
III (2)
III (0.1)
Ia (0.05)
Ia (0.1)
Ia (0.5)
Ia (0.15)
Ia (0.1)
Ia (1)
2-ClC5H4N
p-Et2NC(O)C6H4Cl
p-EtOC(O)C6H4Cl
p-MeOC6H4Cl
p-EtOC(O)C6H4Cl
p-MeOC6H4Cl
o-PhC(O)C6H4Cl
o-MeOC6H4Cl
o-MeOC6H4Cl
5-Cl-2-MeOC6H3COOMe
p-Et2NC(O)C6H4Cl
p-NCC6H4Cl
8
9b
10b
11
12
13c
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36d
37d
38b,e
39b,e
40e
12
24
24
12
24
24
24
24
24
24
24
12
12
24
24
24
24
24
24
24
24
24
24
24
24
24
12
12
12
12
12
PhCl
p-MeOC6H4Cl
o-PhC(O)C6H4Cl
p-EtOC(O)C6H4Cl
PhCl
p-MeOC6H4Cl
p-PhC(O)C6H4Cl
p-EtOC(O)C6H4Cl
p-Et2NC(O)C6H4Cl
p-MeOC6H4Cl
p-Et2NC(O)C6H4Cl
p-EtOC(O)C6H4Cl
p-NCC6H4Cl
p-MeOC6H4Cl
p-CF3C6H4Cl
p-EtOC(O)C6H4Cl
p-NCC6H4Cl
p-NCC6H4Cl
III (0.15)
III (0.2)
III (3)
III (1)
Ia (1.5)
Ia (0.75)
Ia (2.5)
III (2)
III (1)
Ia (5)
III (5)
Ia (5)
III (5)
Ia (2)
2-Furyl
2-Furyl
2-Furyl
2-Furyl
p-EtO2CC6H4
p-EtO2CC6H4
p-EtO2CC6H4
p-EtO2CC6H4
p-MeC6H4
p-EtOC(O)C6H4Cl
p-NCC6H4Cl
p-PhC(O)C6H4Cl
p-NCC6H4Cl
p-PhC(O)C6H4Cl
p-EtOC(O)C6H4Cl
a
b
The reactions were carried out on a 0.5 mmol scale and run at 25 1C unless otherwise specified, 1.5 equiv. of ArZnCl were used. The reaction
c
d
e
was run at 70 1C. The reaction was run at 100 1C. p-EtO2CC6H4ZnBr was employed. p-RC6H4ZnI (R = COOEt or Me) was employed.
Isolated product yields.
f
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 1598–1600 1599

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reaction with various chloride substrates required 0.1–3 mol%
of Ia or III (entries 23–30, Table 2). This is ascribed to its steric
hindrance. 2-Furylzinc chloride behaved a little unusually. It is
less reactive than both p-MeC6H4ZnCl and o-MeC6H4ZnCl as
we observed previously although it seems to be an electron-
rich nucleophile.4g It can only react with activated aryl
chlorides at room temperature with a relatively high catalyst
loading. This is probably because the coordination of the
oxygen atom of the furyl ring to a metal ion (for example
Zn2+) reduces the nucleophilic activity of the 2-furyl anion.
The reaction of less nucleophilic p-EtO2CC6H4ZnBr with
either p-NCC6H4Cl or p-PhC(O)C6H4Cl at room temperature
catalysed by Ia and III, respectively, gave a relatively low
product yield (entries 36 and 37, Table 2), while with
p-MeC6H4Cl afforded trace cross-coupling product. If
p-EtO2CC6H4ZnI was employed as a nucleophile, the reaction
with p-NCC6H4Cl or p-PhC(O)C6H4Cl required an elevated
reaction temperature (entries 38 and 39, Table 2), and at room
temperature resulted in no product formation. Reaction of
p-MeC6H4ZnI with p-EtO2CC6H4Cl catalysed by 2 mol% Ia
gave a coupling product in 30% yield. This may be due to the
iodide-counterion of the zinc reagent leading to a different
reaction mechanism compared to chlorides and bromides. In
addition, the catalysts are incompatible with NO2 and CHO
groups. No cross-coupling product was obtained from the reac-
tion of p-ClC6H4NO2 with arylzinc chlorides catalysed by either
Ia or III. A similar catalytic reaction between p-ClC6H4CHO and
p-MeC6H4ZnCl gave a complicated mixture.
respectively (entries 4 and 5, Table 3). It seems that the
reaction of 1,2-dichlorobenzene was affected little by the steric
hindrance of the ortho-substituent. 1,3,5-Trichlorobenzene
also reacted smoothly with 4.5 equiv. of p-MeC6H4ZnCl at
room temperature in the presence of 1 mol% Ia, giving 1,3,5-
tri(p-tolyl)benzene in 81% yield (eqn (1)).
ð1Þ
In summary, we have developed new nickel catalysts for the
Negishi reaction of aryl chlorides. The nickel complexes are
highly active and able to catalyse cross-coupling of
unactivated and deactivated aryl chlorides efficiently with
arylzinc reagents at room temperature. The reaction showed
good functional group tolerance and required low catalyst
loading.
This work was supported by National Basic Research
Program of China (2009CB825300), the National Natural
Science Foundation of China (20772119) and Research Fund
for the Doctoral Program of Higher Education of China
(20070358031).
Notes and references
1 (a) I. Cepanec, Synthesis of Biaryls, Elsevier, Amsterdam, 2004;
(b) V. B. Phapale and D. J. Cardenas, Chem. Soc. Rev., 2009, 38,
1598.
2 (a) Metal-Catalyzed Cross-Coupling Reactions, ed. F. Diederich and
P. J. Stang, VCH, Weinheim, 1998; (b) Handbook of Organo-
palladium Chemistry for Organic Synthesis, ed. E. Negishi, Wiley,
New York, 2002.
Reactions of multichlorobenzenes with arylzinc chlorides
at room temperature catalysed by complex Ia were also
studied. Treatment of 1,4-dichlorobenzene with 3 equiv. of
p-MeC6H4ZnCl or p-Me2NC6H4ZnCl in the presence of
0.2 mol% Ia at room temperature afforded 1,4-bis(p-tolyl)-
benzene and 1,4-bis(p-dimethylaminophenyl)benzene, respec-
tively, in 91% yields (entries 1 and 2, Table 3). A similar
reaction using o-MeC6H4ZnCl required 1 mol% of Ia and
gave a coupling product in 87% yield (entry 3, Table 3).
3 (a) E. Negishi, A. O. King and N. Okukado, J. Org. Chem., 1977, 42,
1821; (b) E. R. Larson and R. A. Raphael, J. Chem. Soc., Perkin
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S. Greenberg, A. B. P. Lever, C. C. Leznoff and R. L. Cerny, Can. J.
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and P. Knochel, Tetrahedron, 2006, 62, 7521; (f) G. Manolikakes,
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Reaction of 1,2-dichlorobenzene with
3
equiv. of
p-MeC6H4ZnCl or p-Me2NC6H4ZnCl in the presence of
0.75 mol% Ia at room temperature generated the corre-
sponding cross-coupling products in 88% and 86% yields,
Table 3 Reaction of arylzinc reagents with dichlorobenzene catalysed
by Iaa
Aryl
polychloride
Amount
of cat. (mol%)
Yieldb
(%)
Entry
Ar
1
2
3
4
5
p-MeC6H4
1,4-Cl2C6H4
1,4-Cl2C6H4
1,4-Cl2C6H4
1,2-Cl2C6H4
1,2-Cl2C6H4
0.2
0.2
1
0.75
0.75
91
91
87
88
86
p-Me2NC6H4
o-MeC6H4
p-MeC6H4
5 (a) J. A. Miller and R. P. Farrell, Tetrahedron Lett., 1998, 39, 6441;
(b) B. H. Lipshutz, P. A. Blomgren and S. K. Kim, Tetrahedron
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Chem. Soc., 2004, 126, 13028; (d) C. E. Tucker and J. G. de Vries,
Top. Catal., 2002, 19, 111; (e) S. Calimsiz, M. Sayah, D. Mallik and
M. G. Organ, Angew. Chem., Int.Ed., 2010, 49, 2014.
p-Me2NC6H4
a
The reactions were carried out on a 0.5 mmol scale according to the
conditions indicated by the above equation, 3 equiv. of ArZnCl were
b
employed. Isolated product yields.
6 K. Sun, L. Wang and Z.-X. Wang, Organometallics, 2008, 27, 5649.
c
1600 Chem. Commun., 2011, 47, 1598–1600
This journal is The Royal Society of Chemistry 2011