Nickel-catalyzed cross-coupling of diarylborinic acids with aryl chlorides

Article abstract of DOI:10.1021/cs4009946

A highly efficient nickel/triarylphosphine catalyst system, Ni[P(4-MeOPh)₃]₂Cl₂/2P(4-MeOPh)₃, has been developed for cross-coupling of diarylborinic acids with a wide range of aryl chlorides. A variety of unsymmetrical biaryl and heterobiaryl compounds with various functional groups and steric hindrance could be obtained in good to excellent yields using 0.5-2 mol % catalyst loadings in the presence of K ₃PO₄·3H₂O in toluene. The high atom economy of diarylborinic acids and cost-effectiveness of the nickel/phosphine catalyst system make the cross-coupling truly practical in the production of biaryl fine chemicals. Usefulness of the nickel/phosphine catalyzed cross-coupling of diarylborinic acids with aryl chlorides has been demonstrated in the development of a scalable and economical process for synthesis of 4′-methyl-2-cyanobiphenyl, Sartan biphenyl.

Full text of DOI:10.1021/cs4009946

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Article
Nickel Catalyzed Cross-coupling of Diarylborinic Acids with Aryl Chlorides
Xiaofeng Chen, Haihua Ke, and Gang Zou
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 18 Dec 2013
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Nickel Catalyzed Cross-coupling of Diarylborinic Acids with Aryl
Chlorides
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Xiaofeng Chen, Haihua Ke and Gang Zou*
Department of Fine Chemicals
East China University of Science & Technology
130 Meilong Rd, Shanghai, China
Email: gangzou@ecust.edu.cn
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ABSTRACT
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A highly efficient nickel/triarylphosphine catalyst system, Ni[P(4ꢀMeOPh)3]2Cl2/2P(4ꢀMeOPh)3, has
been developed for crossꢀcoupling of diarylborinic acids with a wide range of aryl chlorides. A
variety of unsymmetrical biaryl and heterobiaryl compounds with various functional groups and
steric hindrance could be obtained in good to excellent yields by using 0.5ꢀ2 mol% catalyst loadings
in the presence of K3PO4ꢁ3H2O in toluene. The high atom economy of diarylborinic acids and
costꢀeffectiveness of the nickel/phosphine catalyst system make the crossꢀcoupling truly practical in
production of biaryl fine chemicals. Usefulness of the nickel/phosphine catalyzed crossꢀcoupling of
diarylborinic acids with aryl chlorides has been demonstrated in development of a scalable and
economical process for synthesis of 4’ꢀmethylꢀ2ꢀcyanobiphenyl, Sartan biphenyl.
KEYWORDS Nickel, Phosphine, Cross coupling, Diarylborinic acid, Aryl chloride
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INTRODUCTION
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The SuzukiꢀMiyaura crossꢀcoupling is more attractive than the other transition metal catalyzed
crossꢀcoupling reactions in modern organic synthesis because of the friendly properties of
organoboronic acids, e.g. nonꢀtoxicity, air/moistureꢀstability and tolerance of a variety of functional
groups.1 In the evolution of this synthetic methodology, introduction of nickelꢀbased catalysts by
Percec et al in 19952 has proven to be another milestone as important as the conquest of aryl
chlorides3 and making use of organotrifluoroborates.4 The replacement of palladium catalysts with
nickel ones in SuzukiꢀMiyaura crossꢀcoupling not only promises a great potential for its applications
in industry but also remarkably extends its scope with respect to electrophile counterparts.5 For
example, aryl chlorides, the most practical aryl halides, have represented a big challenge in
palladium catalyzed SuzukiꢀMiyaura crossꢀcoupling unless using a few privileged phosphines3aꢀe or
Nꢀheterocyclic carbene ligands.3fꢀj However, aryl chlorides, including the electronꢀrich thus
deactivated ones, could be crossꢀcoupled by using common nickel catalysts, such as NiCl2(PPh3)2
under appropriate conditions. The SuzukiꢀMiyaura crossꢀcoupling of a variety of aryl CꢀO based
electrophiles, e.g. sulfonates,2, 5d, 6 esters,5d, 6d, 7 sulfamates,5d, 6hꢀj, 8 carbamates,5d, 8, 9 phosphates,10
ethers,5d, 11 and even phenolates,12 has been effected in the last decade by using nickelꢀbased catalysts
while palladium catalysts have been rarely applied to these sorts of substrates.13 Recently, a
longꢀstanding problem, coupling of alkyl electrophiles with organoborons, has been more elegantly
solved by Fu group et al. by taking advantage of nickelꢀbased catalysts.14
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In sharp contrast to the greatly extended scope of electrophiles, arylboronic acids and derivatives
are still the overwhelming aryl nucleophile counterparts in SuzukiꢀMiyaura crossꢀcoupling, including
the nickelꢀcatalyzed one. Although highꢀorder arylborons, e.g. diarylborinic acids, triarylboranes and
tetraarylborates, have higher atomꢀeconomy as arylation reagents than arylboronic acids, they have
been rarely applied in crossꢀcoupling,15 especially SuzukiꢀMiyaura crossꢀcoupling with aryl
chlorides. In fact, highly active aryl halides (I and Br) or/and nontraditional reaction conditions had
to be used in the scatteredly reported SuzukiꢀMiyaura crossꢀcoupling of highꢀorder arylborons.16 We
have recently reported an efficient crossꢀcoupling of diarylborinic acids with aryl halides by using a
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palladium catalyst system coꢀsupported by sterically demanding Nꢀheterocyclic carbene (NHC) and
phosphite P(OR)3.17 Diarylborinic acids (Ar2B(OH)) not only have comparable properties to
arylboronic acids but also possess higher atom economy and could be more economically prepared
from arylhalides, boronates and magnesium under nonꢀcryogenic conditions if no hampered by
sensitive functional groups.18 However, high cost of the palladium/NHC/phosphite catalyst still
remains an obstacle in application of the crossꢀcoupling of diarylborinic acids in large scale
production. Compared with palladium(II) species, the divalent nickel (II) ones are not only much
cheaper but also more compatible with the high reducing ability of highꢀorder arylborons.19
Therefore, nickelꢀbased catalysts should be more suitable for a highly efficient and practical
crossꢀcoupling of diarylborinic acids with aryl chlorides.
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RESULTS AND DISCUSSION
Establishment of Catalyst System. For the convenience of stoichiometry and monitoring,
crossꢀcoupling of dehydrationꢀresisting bis(p-tolyl)borinic acid 1a with representative deactivated
aryl chloride, 4ꢀ(benzyloxy)phenyl chloride 2a, was chosen as the model reaction to screen reaction
conditions (Table 1). It was reported that simple NiCl2 without any supporting ligand could catalyze
the SuzukiꢀMiyaura coupling of arylboronic acids to some extent.20 However, no reaction was
detected using 3 mol% NiCl2 as catalyst for the model reaction. A nickel/NHC/phosphite system,
NiCl2/IPr/P(OPh)3 (IPr=N,N’ꢀbis(2,6ꢀdiisopropylphenyl)imidazolꢀ2ꢀylidene) also failed although the
corresponding palladium system, PdCl2/IPr/P(OPh)3, had worked well in crossꢀcoupling of
diarylborinic acids with aryl halides.17 However, when 3 mol% Ni(Py)2Cl2 or Ni(PPh3)2Cl2 was used
as catalyst the crossꢀcoupling product 3aa was obtained in 30% and 62% yields, respectively, with a
boron (1a) /chloride (2a) molar ratio of 0.65:1 (1.3 equiv. p-tolyl group relative to CArꢀCl) in the
presence of 2.6 equiv. K3PO4⋅3H2O in toluene (Table 1, entries 3 and 4). The 3aa yields further
increased to 83% and 90%, respectively, when two more equivalent PPh3 with respect to nickel was
used along with Ni(Py)2Cl2 and Ni(PPh3)2Cl2 although addition of two more equivalent pyridine (Py)
did not improve the catalytic performance of Ni(Py)2Cl2 (Table 1, entries 5ꢀ7).
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Table 1. Condition Screening for Nickel Catalyzed Crossꢀcoupling of Diarylborinic Acids with Aryl
Chlorides a
"Ni(II)"/L
Tol
OBn
+
Cl
OBn
(Tol)2B(OH)
7
3aa
1a
8
2a
9
Entry NiCl2(L)2 (mol%)
Extra L (mol%)
/
Base
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O t-BuOH 80
Sol.
T(oC) Yield(%)b
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1
NiCl2 (3)
110
/
2
NiCl2 (3)
NHC/P(OPh)3(3/3)
/
trace
30
3
NiCl2(Py)2 (3)
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
110
4
NiCl2(PPh3)2 (3)
NiCl2(Py)2 (3)
/
110
110
110
110
62
5
Py (6)
35
6
NiCl2(Py)2 (3)
PPh3 (6)
83
7
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
NiCl2(PCy3)2 (3)
NiCl2(dppm) (3)
NiCl2(dppe) (3)
PPh3 (6)
90
8
PPh3 (6)
K3PO4ꢁ3H2O dioxane 100
63
9
PPh3 (6)
K3PO4ꢁ3H2O DME
K3PO4ꢁ3H2O THF
80
70
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PPh3 (6)
77
PPh3 (6)
K3PO4ꢁ3H2O CH3CN 70
19
PPh3 (6)
K3PO4ꢁ3H2O DMF
110
26
PPh3 (6)
K3PO4ꢁ3H2O iꢀPrOH 80
trace
trace
trace
15
PPh3 (6)
K2CO3
Cs2CO3
KOH
Tol.
Tol.
Tol.
Tol.
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
PPh3 (6)
PPh3 (6)
PPh3 (6)
NaOH
46
PPh3 (6)
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
82 c
trace
6
PCy3 (6)
dppm (3)
dppe (3)
27
NiCl2(dppp) (3)
dppp (3)
33
NiCl2(dppb) (3)
dppb (3)
86
NiCl2(dppf) (3)
dppf (3)
66
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (2)
NiCl2(PPh3)2 (2)
NiCl2(PPh3)2 (2)
NiCl2(PPh3)2 (2)
NiCl2[(4ꢀMeOPh)3P]2 (2)
NiCl2[(4ꢀMeOPh)3P]2 (2)
NiCl2[(4ꢀMeOPh)3P]2 (1)
NiCl2[(4ꢀMeOPh)3P]2 (2)
NiCl2[(4ꢀMeOPh)3P]2 (2)
NiCl2[(4ꢀMeOPh)3P]2 (2)
(C6F5)3P (6)
(4ꢀMeOPh)3P (6)
(4ꢀMeOPh)3P (3)
(4ꢀMeOPh)3P (4)
(4ꢀMeOPh)3P (2)
(2ꢀMeOPh)3P (4)
56
98
85
93
77
62
(mꢀtrimethoxylPh)3P (4) K3PO4ꢁ3H2O Tol.
67
/
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
K3PO4ꢁ3H2O Tol.
79
(4ꢀMeOPh)3P (4)
(4ꢀMeOPh)3P (2)
(4ꢀMeOPh)3P (2)
Ph3P(4)
97
66
88
92
69 d
(4ꢀMeOPh)3P (4)
b
aReaction conditions: 1a (0.65 mmol), 2a (1.0 mmol), base (2.60 mmol), solvent (4 mL), N2, 10 h. Isolated
yields. c0.55 mmol of 1a was used. dRun in the presence of 100 mg mercury.
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Screening of several common solvents (dioxane, DME, THF, CH3CN, iꢀPrOH and DMF) and
bases (Cs2CO3, K2CO3, NaOH and KOH) provided no better results than those with the combination
of toluene and K3PO4⋅3H2O. A slight excess of bis(p-tolyl)borinic acid 1a (1.3 equiv. p-tolyl)
appeared to be necessary since the 3aa yield decreased from 90% to 82% with the molar ratios of 1a
to 2a decreased from 0.65 to 0.55 (1.1 equiv. p-tolyl) (Table 1, entries 7 and 18). Surprisingly, no
reaction was detected using NiCl2(PCy3)2/2PCy3 as catalyst under otherwise identical conditions
since tricyclohexylphosphine (PCy3) has been often reported to be a good supporting ligand in
SuzukiꢀMiyaura coupling of arylboronic acids. It was reported that some nickel complexes supported
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22
by bidentate phosphine ligands, such as Ni(dppe)Cl2,21 Ni(dppf)Cl2 or Ni(dppp)Cl2,23 displayed
high catalytic activities in the related crossꢀcoupling of arylboronic acids with aryl chlorides.
Therefore, we investigated the performance of the most common bidentate phosphines, e.g.
1,1ꢀbis(diphenylphosphino)methane
(dppm),
1,2ꢀbis(diphenylphosphino)ethane
(dppe),
1,3ꢀbis(diphenylphosphino)propane (dppp), 1,4ꢀbis(diphenylphosphino)butane (dppb) and 1,1'ꢀ
bis(diphenylphosphino)ferrocene (dppf), in the nickel/phosphine catalyst system. Generally, the
bidentate phosphines with a large bite angle,24 dppb (86%) and dppf (66%), gave the crossꢀcoupling
product 3aa in higher yields than those with a small one, dppm (6%), dppe (27%) and dppp (33%)
(Table 1, entries 20ꢀ24). However, the highest yield (86%, with Ni(dppb)Cl2/dppb) was just
comparable to that (90%) with Ni(PPh3)2Cl2/2PPh3 (Table 1, entries 7 and 23).
According to the mostly accepted mechanism for Niꢀcatalyzed crossꢀcoupling processes, only
low valent nickel (Ni(0) or Ni(I)) species are truly catalytically active.5 Divalent nickel catalyst
precursors have to be reduced at first in the catalytic cycle. In fact, strong reducing agents, such as
DIBALꢀH, BuLi3k, 3l or Zn powder5b, 25 etc. had to be used to generate catalytically active species
from nickel(II) precursors in early reported SuzukiꢀMiyaura coupling of arylboronic acids using
Ni(II)ꢀbased catalysts. It has been found later that the Ni(II)ꢀbased catalyst systems with extra free
phosphine ligands could performed well without additional reductants.5b, 5f. 26 Therefore, to elucidate
the role of extra phosphine ligands in the nickel/phophineꢀcatalyzed crossꢀcoupling of diarylborinic
acids with aryl halides, a couple of phosphine ligands with various electronic and steric properties
were investigated as extra ligands to catalyst precursor Ni(PPh3)2Cl2 in the model reaction.
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Electronꢀrich P(4ꢀMeOPh)3 performed better than PPh3 with the yield of 3aa increasing from 90% to
98% while no effect was observed for the extremely electronꢀpoor P(C6F5)3. The yield of 3aa
significantly decreased to 85% with lowering the ratio of P(4ꢀMeOPh)3 to Ni(PPh3)2Cl2 to 1:1
(mole/mole) at 3 mol% loading, which was even lower than that (93%) obtained with 2 mol%
Ni(PPh3)2Cl2 loading along with 2 equiv. (4 mol%) P(4ꢀMeOPh)3, confirming the importance of the
extra phosphine ligand. However, when the electron richer but sterically demanding
tris(2,4,6ꢀtrimethoxyphenyl)phosphine, [m-(MeO)3Ph]3P, was used as extra ligand the 3aa yield
(67%) was just comparable to that (62%) with Ni(PPh3)2Cl2 alone. A similar result was also obtained
with P(2ꢀMeOPh)3 as extra phosphine. That is to say the positive effect of extra phosphines on the
catalytic activity of Ni(PPh3)2Cl2 disappeared completely with sterically demanding P(2ꢀMeOPh)3
and [m-(MeO)3Ph]3P although they have compatible or even stronger reducing abilities than PPh3.
The divalent nickel catalyst precursor may be reduced by diarylborinic acids to initiate the catalysis,
which is consistent with the high reducing ability and requirement of an excess amount of
diarylborinic acids.
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Since P(4ꢀMeOPh)3, as extra phosphine ligand, could improve the catalytic performance of
Ni(PPh3)2Cl2, we anticipated the nickel precursor supported by P(4ꢀMeOPh)3, Ni[P(4ꢀMeOPh)3]2Cl2,
should be more efficient than Ni(PPh3)2Cl2. In fact, the model reaction catalyzed by 2 mol%
Ni[P(4ꢀMeOPh)3]2Cl2 alone could give 3aa in a significantly higher yield (79%) than that with 3
mol% Ni(PPh3)2Cl2. (62%) under otherwise identical conditions (Table 1, entries 4 and 32). The 3aa
yields further increased to 88% and 97% when 2 mol% Ni[P(4ꢀMeOPh)3]2Cl2 was used along with
1.0 equiv. (2 mol%) and 2.0 equiv. (4 mol%) extra P(4ꢀMeOPh)3, respectively, while the reaction
could not complete with 1 mol% catalyst loading (Table 1, entries 32ꢀ35). Based on these results, the
optimal catalyst system for the model reaction was set as 2 mol% NiCl2[P(4ꢀMeOPh)3]2 / 4 mol%
P(4ꢀMeOPh)3 with 2.6 equiv. K3PO4⋅3H2O in toluene. When the reaction was run in the presence of
mercury (mercury poisoning test) a modest yield (69%) of 3aa could still be obtained, supporting a
homogeneous catalyst system (Table 1, entry 37).
Scope and Limitation. Scope of the nickel catalyzed crossꢀcoupling of aryl chlorides with
diarylborinic acids was explored by using the established catalyst system (Table 2).
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Table 2. Scope of the Crossꢀcoupling of Aryl Chlorides with Diarylborinic Acidsa
NiCl2[(4-MeOPh)3P]2
(4-MeOPh)3P
Ar(Het)
R
R
(Het)Ar-Cl
+
B
R
K3PO4 3H2O
Toluene, 110oC
OH
9
1a-1h
2a-2v
3ab-3he
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Entry
1
R1 (1)
(Het)ArCl (2)
Cat. (mol%)
T (h) Yield (%)b
4ꢀMe (1a)
4ꢀMe (1a)
4ꢀMe (1a)
4ꢀMe (1a)
4ꢀMe (1a)
4ꢀMe (1a)
4ꢀMe (1a)
4ꢀMe (1a)
4ꢀMe (1a)
4ꢀMe (1a)
4ꢀMe (1a)
4ꢀMe (1a)
4ꢀMe (1a)
4ꢀMe (1a)
4ꢀMe (1a)
4ꢀMe (1a)
4ꢀMe (1a)
4ꢀMe (1a)
H (1b)
4ꢀMeC6H4Cl (2b)
2ꢀMeC6H4Cl (2c)
4ꢀMeOC6H4Cl (2d)
2ꢀMeOC6H4Cl (2e)
4ꢀMe2NC6H4Cl (2f)
4ꢀH2NC6H4Cl (2g)
2ꢀH2NC6H4Cl (2h)
4ꢀCNC6H4Cl (2i)
3ꢀCNC6H4Cl (2j)
2ꢀCNC6H4Cl (2k)
2ꢀCNC6H4Cl (2k)
4ꢀAcC6H4Cl (2l)
2
6
97 (3ab)
91 (3ac)
93 (3ad)
89 (3ae)
91 (3af)
2
2
8
3
2
10
10
10
10
10
5
4
2
5
2
6
2
78 (3ag)
73 (3ah)
94 (3ai)
7
2
8
1
9
1
5
98 (3aj)
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11
12
13
14
15
16
17
18
19c
20
21
22
23
24
25
26
27
28
1
5
89 (3ak)
98 (3ak)
98 (3al)
1.5
0.5
1
5
6
2ꢀAcC6H4Cl (2m)
4ꢀ(CO2Me)C6H4Cl (2n)
4ꢀCHOC6H4Cl (2o)
4ꢀNO2C6H4Cl (2p)
3ꢀClC5H4N (2q)
10
8
63 (3am)
95 (3an)
87 (3ao)
trace
0.5
0.5
0.5
0.5
2
8
10
8
93 (3aq)
74 (3ar)
95 (3ba)
97 (3ca)
89 (3da)
91 (3ea)
94 (3ee)
2ꢀClꢀ3ꢀ(CO2Me)C5H3N (2r)
4ꢀBnOC6H4Cl (2a)
10
10
10
10
10
10
10
10
10
10
10
2
4ꢀMeO (1c) 4ꢀBnOC6H4Cl (2a)
2
4ꢀF (1d)
2ꢀMe (1e)
2ꢀMe (1e)
2ꢀEt (1f)
2ꢀEt (1f)
4ꢀBnOC6H4Cl (2a)
4ꢀBnOC6H4Cl (2a)
2ꢀMeOC6H4Cl (2e)
4ꢀBnOC6H4Cl (2a)
2ꢀMeOC6H4Cl (2e)
2
2
2
2
78 (3fa)
2
73 (3fe)
2ꢀMeO (1g) 4ꢀBnOC6H4Cl (2a)
2
92 (3ga)
93 (3ha)
64 (3he)
3H2O (2.60 mmol), Tol. (4
2ꢀiPrO (1h)
2ꢀiPrO (1h)
4ꢀBnOC6H4Cl (2a)
2
2ꢀMeOC6H4Cl (2e)
2
aReaction conditions: diarylborinic acid (0.65 mmol), aryl chloride (1.0 mmol), K3PO4
mL), N2, 110 oC. bIsolated yields. c0.33 mmol of diphenyllborinic anhydride was used.
·
Similar to 2a, 4ꢀchlorotoluene (2b), 4ꢀchloroanisole (2d) and N,Nꢀdimethylꢀ4ꢀchloroaniline (2f)
reacted with bis(p-tolyl)borinic acid (1a) smoothly to give the corresponding products 3ab (97%),
3ad (93%) and 3af (91%) in excellent yields using 2 mol% catalyst loading (Table 2, entries 1, 3 and
5). Aryl chlorides bearing a small orthoꢀsubstituent like methyl (2c) or methoxyl (2e) still gave
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crossꢀcoupling products 3ac (91%) or 3ae (89%) in good yields (Table 2, entries 2 and 4). A free
amino group (NH2) on aryl chlorides appeared to be tolerable although the yields decreased
significantly for both 4ꢀchloroaniline (2g, 78%) and its orthoꢀisomer (2h, 73%) (Table 2, entries 6
and 7). Electronꢀdeficient aryl chlorides with an electronꢀwithdrawing group, e.g. CN, CH3CO, CHO
and CO2Me, displayed higher reactivity in reaction with 1a than the above electronꢀneutral and ꢀrich
ones. Excellent yields of the desired crossꢀcoupling products could be obtained for these activated
substrates even with lower catalyst loadings (0.5ꢀ1.5 mol%) and in shorter reaction time (5ꢀ8 h)
except for 2ꢀchloroacetophone, for which the crossꢀcoupling product 3am was obtained in a modest
yield (63%) due to dechlorination and steric hindrance as well (Table 2, entries 8ꢀ15).26, 27 A nitro
group (NO2) proved deleterious to the nickel/phosphine catalyst system since no reaction was
observed for 4ꢀchloronitrobenzene (2p). 3ꢀChloropyridine reacted smoothly with 0.5 mol% catalyst
loading to give crossꢀcoupling product (3aq) in 93% yield while methylꢀ2ꢀchloronicotinate required
2 mol% catalyst loading to achieve a modest yield (3ar) (Table 2, entries 17 and 18).
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Structural effects of diarylborinic acids on the nickel/phosphine catalyzed crossꢀcoupling
reaction were also investigated. Electronꢀdonating (MeO, 1c), neutral (H, 1b), and withdrawing (F,
1d) groups on the aromatic ring of diarylborinic acids appeared to have negligible influence on the
reaction, providing the corresponding products in excellent yields (Table 2, entries 19ꢀ21). However,
an obvious steric effect was observed (Table 2, entries 22ꢀ25). For example, the reactions of
bis(2ꢀethylphenyl)borinic acid (1f) with 4ꢀ(benzyloxy)phenyl chloride (2a) and 2ꢀchloroanisole (2e)
gave 3fa (78%) and 3fe (73%) in significantly lower yields than those of 1a. Surprisingly, the
corresponding reaction of bis(2ꢀmethoxyphenyl)borinic acid (1g) with 2a proceeded more efficiently
to afford 3ga in 92% yield. Even an orthoꢀisopropoxy group appeared not to hamper the
crossꢀcoupling. The reaction of bis(2ꢀisopropoxyphenyl)borinic acid (1h) with 2a afforded 3ha in
93% yield and a modest yield (64%) of 3he could still be obtained for the reaction of (1h) and
2ꢀchloroanisole (2e) (Table 2, entries 26ꢀ28). The exact reason is not clear for the smaller steric effect
of orthoꢀalkoxy groups than alkyl ones in the diarylborinic acids on the nickel/phosphine catalyzed
crossꢀcoupling reaction. One possibility lies in an intramolecular coordination between the oxygen
and boron atoms,28 which could facilitate the transmetallation between diarylborinic acids and
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intermediate nickel species in the catalytic cycle.
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Considering the significant steric effects observed in the reactions of 2ꢀchloroacetophone (2m)
and methylꢀ2ꢀchloronicotinate (2r), it had appeared that there could be a possibility in monoarylation
of orthoꢀpolychloroarenes since the second arylation should experience a much larger steric
hindrance than the first one. Therefore, the coupling of bis(p-tolyl)borinic acid (1a) with
2,3ꢀdichlorobenzonitrile (2s) was investigated (Scheme 1). However, a mixture consisting of
substrate 2s, diarylation product 4as and a small amount of monoarylation (inseparable 3as and
isomer 3’as) was obtained with 0.65:1 molar ratio of 1a/2s. When the 1a/2s molar ratio was
increased to 1.3:1 diarylation product 4as was isolated in 72% yield along with monoarylation
isomers 3as and 3’as (together in 20% yield).
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(Tol)2B(OH) 1a
CN
Tol
CN
1.5 mol% NiCl2[(4-MeOPh)3P]2
3 mol% (4-MeOPh)3P
Cl
CN
+
Cl
Tol
K3PO4 3H2O
Tol., 10 h, 110oC
Cl
2s, 2t
Tol
3as - 4at
CN
CN
Tol
CN
Cl
Tol
Tol
+
Cl
Tol
4as
3as + 3'as
1a/2s =0.65 (mol/mol): 13%
1a/2s =1.30 (mol/mol): 20%
47%
72%
CN
Tol
CN
+
CN
Tol
Tol
Tol
Cl
Cl
3at + 3'at
1a/2t =1.30 (mol/mol): 0
4at
97%
Scheme 1. Selectivity in Arylation of Dichloroarenes
The relative ease in overcoming the sequentially increasing steric hindrance in the double
arylation of orthoꢀdihaloarenes could be attributed to a preference of intramolecular sequential
oxidative addition of the CꢀX bond of dihaloarenes in transition metal catalyzed crossꢀcoupling,
which was firstly observed by Hu et al.29 Not surprisingly, an excellent yield (97%) of the
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doubleꢀarylation product 4at was obtained in the crossꢀcoupling of 1a and 2,4ꢀdichlorobenzonitrile
(2t) because of the absence of the sequentially increasing steric hindrance.
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In general, the aryl CArꢀO based electrophiles, except for triflates, are more inert than CArꢀCl in
palladiumꢀcatalyzed crossꢀcouplings. However, nickelꢀbased catalysts have proven efficient in
SuzukiꢀMiyaura coupling of arylboronic acids with a variety of phenol derivatives. Aryl tosylates are
the most commonly used phenol derivative in crossꢀcoupling because of their ready availability, low
cost, high stability and good crystallization property. Therefore, it is interesting to explore the
intramolecular chemical selectivity between CArꢀCl and CArꢀOTs. The crossꢀcoupling of
bis(p-tolyl)borinic acid (1a) with 2ꢀchlorophenol tosylate (2u) was investigated (Scheme 2).
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1a
1.0-1.3 equiv. (Tol)2B(OH)
Tol
OTs
Cl(OTs)
5 mol% NiCl2[(4-MeOPh)3P]2
10 mol% (4-MeOPh)3P
+
K3PO4 3H2O
Toluene, 10 h, 110 oC
Cl
Tol
Tol
3au, 5av
2u, 2v
Cl
Tol
OTs
Tol
Tol
Tol
2u:
3au
3'au
0
0
5au
(1.3 equiv.)
(1.0 equiv.)
74%
75%
21%
6%
OTs
Tol
Cl
Tol
Tol
Tol
2v:
3'av
0
3av
74%
5av
(1.0 equiv)
7%
Scheme 2. Chemical Selectivity in the Cross-coupling of Chlorophenol Tosylates
Surprisingly, only the CArꢀCl crossꢀcoupling product 3au, one of the two possible monoarylation
products, was isolated along with a small amount of diarylation product (5au). Use of 1.0 equiv. (0.5
molar ratio to CArꢀCl) bis(p-tolyl)borinic acid (1a) increased the selectivity of monoꢀ to diꢀarylation
to 75:6 from 74:21. A similar result was obtained for 4ꢀchlorophenol tosylate (2v). Similar to the
diarylation of dihaloarenes (vide supra), the bias reactivity of CArꢀOTs in the intermediate
monoarylation products (3au and 3av) to that in the initial chlorophenol tosylates (2u and 2v) could
be attributed to the preferable oxidation addition of intramolecular CArꢀOTs over the intermolecular
one to the regenerated active nickel species in the catalytic cycle.
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Application Exploration. Application of the nickel/phosphine catalyzed crossꢀcoupling of
diarylborinic acids with aryl chlorides in production of fine chemicals was demonstrated in synthesis
of 4’ꢀmethylꢀ2ꢀcyanobiphenyl (Sartan biphenyl), a key intermediate for synthesis of a family of
angiotensin II receptor antagonists, Sartans, for treatment of hypertension30. Sartan biphenyl has
been commercially produced by nickelꢀcatalyzed Kumada coupling of 2ꢀchlorobenzonitrile with
p-tolylmagnesium chloride instead of SuzukiꢀMiyaura crossꢀcoupling due to the high cost of p-tolyl
boronic acid. We have recently developed a scalable process for Sartan biphenyl via crossꢀcoupling
of di(p-tolyl)borinic acid with 2ꢀchlorobenzonitrile catalyzed by 0.2 mol% Pd(OAc)2/NHC/P(OPh)3.
However, the expensive palladium catalyst system still hampered the process in practical
applications. Therefore, to develop a more costꢀeffective and practical process for production of
Sartan biphenyl, we conducted the nickel/phosphine catalyzed crossꢀcoupling of di(pꢀtolyl)borinic
acid (1a) with 2ꢀchlorobenzonitrile (2k) in dozen gram scale. Under the above optimized conditions,
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Sartan
biphenyl
could
be
isolated
in
95ꢀ97%
yields
using
1.5
mol%
Ni[P(4ꢀMeOPh)3]2Cl2/2P(4ꢀMeOPh)3 catalyst loading in experiments in 0.2 mole scale (Scheme 3).
Cl
NiCl2(PAr3)2
NC
PAr3
B OH
+
CN
K3PO43H2O
Tol, 110oC
2k (0.20 mole)
1a (0.13 mole)
3ak
1) 1.5 mol% Ni[(4-MeOPh)3P]2Cl2/2(4-MeOPh)3P: 95-97%
2) Ni(PPh3)2Cl2/2PPh3 : 3ak (Yield)
1.5 mol%, (81%); 3.0 mol%, (92%); 5.0 mol% (95%)
Scheme 3. Synthesis of Sartan Biphenyl in Dozen Gram Scales.
The cost of nickelꢀbased catalyst was only about 10% of that using 0.2 mol%
Pd(OAc)2/NHC/P(OPh)3.31 Attempt to further decrease the catalyst cost, the synthesis was also
carried out by using the triphenylphosphine based catalyst, Ni(PPh3)2Cl2/2PPh3, which has also
showed a good activity in the model reaction during catalyst screening (Table 1, entry 7). However,
owing to the lower catalytic activity, higher catalyst loadings (3ꢀ5 mol% nickel) had to be used to
obtain satisfactory yields (92ꢀ95%) under similar conditions.
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CONCLUSION
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In summary, a highly efficient and practical nickel/triarylphosphine catalyst system,
Ni[P(4ꢀMeOPh)3]2Cl2/2P(4ꢀMeOPh)3, has been developed for crossꢀcoupling of diarylborinic acids
with a wide range of aryl chlorides in the presence of K3PO4ꢁ3H2O in toluene. Electronꢀrich and
sterically undemanding tri(4ꢀmethoxylphenyl)phosphine, P(4ꢀMeOPh)3, proven to be the most
efficient supporting ligand in the nickel/phosphine catalyst system for both activated and deactivated
aryl chlorides while tricyclohexylphosphine showed a poor performance. At least 4 equivalent
triarylphosphine relative to nickel was found to be necessary to coordinatively stabilize the
catalytically active Ni(0) or Ni(I) species as supporting ligand. As low as 0.5 mol% catalyst loading
(based on nickel) appeared to be enough for the crossꢀcoupling of activated aryl chlorides without
steric hindrance to provide products in good to excellent yields. The aryl chlorides deactivated by
either electronꢀdonating groups or steric hindrance could also be coupled efficiently by simply
increasing the catalyst loading to 1ꢀ2 mol% under otherwise identical conditions. Modest steric
hindrance in diarylborinic acids, especially that from a coordinative orthoꢀsubstituent, could be
overcome successfully. The high atom economy of diarylborinic acids and costꢀeffectiveness of
nickel/phosphine catalyst system make the crossꢀcoupling truly practical in production of biaryl fine
chemicals. As an application demonstration of the nickelꢀcatalyzed crossꢀcoupling of diarylborinic
acids with aryl chlorides, a scalable and economical process has been developed from
bis(tolyl)borinic acid and 2ꢀchlorobenzonitrile for synthesis of Sartan biphenyl, a key intermediate of
a family of angiotensin II receptor antagonists.
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AUTHOR INFORMATION
Corresponding Author
gangzou@ecust.edu.cn
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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We are grateful for financial support provided by the National Science Foundation of China (No.
20972049).
Supporting Information Available. Detailed experimental procedures, characterization data and 1H
and 13C NMR spectra of all new and known compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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(27) One reviewer suggest that a C=OꢀꢀNi interaction in the oxidation addition product, which might
stabilize this intermediate, also could lead to the low yield of 3am.
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OꢀꢀꢀHꢀOB may be an alternative explanation.
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(31) In SigmaꢀAldrich catalog, Pd(OAc)2 in (¥37000 / 100 g) is about 50 times more expensive than
anhydrous NiCl2 (¥1800 / 250 g). In fact, according to the current market price for nickel ($6ꢀ7 /
lb) and palladium metal (about $700 / oz), palladium is about 1500 times more expensive than
nickel.
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TOC Graphic
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Ar(Het)
R
0.5-2 mo%Ni[P(4-MeOPh)3]2Cl2
1-4 mol%P(4-MeOPh)3
B(OH)
(Het)Ar-Cl
1
2
R
+
2
K3PO4 3H2O, Toluene
110 oC, up to 98%
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