Triphenylphosphine as a ligand for room-temperature Ni(0)-catalyzed cross-coupling reactions of aryl chlorides with arylboronic acids

Article abstract of DOI:10.1021/jo052369i

Room-temperature Ni(0)-catalyzed cross-coupling reactions of deactivated aryl chlorides with arylboronic acids with inexpensive triphenylphosphine (PPh₃) as a supporting ligand have been accomplished in good to excellent yields. Air-stable Ni(PPh₃)₂Cl₂ has also been established as catalyst precursor, and highly active nickel catalysts were obtained when the reduction of Ni(PPh₃)₂Cl ₂ with n-BuLi was carried out in the presence of an aryl chloride.

Full text of DOI:10.1021/jo052369i

demonstrated as a privileged group of ligands for reported
catalyst systems. The bulkiness and electron-richness of these
monodentate ligands are believed to be essential for the observed
fast oxidative addition and reductive elimination rates. Less
bulky and less electron-rich monophosphines such as PPh3 have
thus been considered as inappropriate ligands for room-
temperature Suzuki-Miyaura cross-couplings of deactivated aryl
chlorides. In fact, their application as efficient ligands for room-
temperature Pd(0)- or Ni(0)-catalyzed Suzuki-Miyaura cross-
couplings of deactivated aryl chlorides has not been established,
although they have been employed as ligands for Ni(0)-catalyzed
Suzuki cross-coupling reactions at elevated temperature.1,9-11
In our laboratory, we are interested in developing highly active,
cost-effective Pd(0) and Ni(0) catalysts for cross-coupling
reactions involving challenging substrates including deac-
tivated aryl chlorides and aryl/alkenyl tosylates.7,12 On the
basis of previously reported results, we know that (a) nickel is
smaller and more nucleophilic than palladium, which suggests
that the ligand bulkiness and electron-richness requirement for
nickel might not be as stringent as that for palladium, and (b)
Ni(PPh3)3 undergoes oxidative addition with deactivated aryl
chlorides at room temperature.13 Thus, we reasoned that less
bulky and less electron-rich monophosphines such as PPh3 might
be suitable ligands for room-temperature Ni(0)-catalyzed Suzuki
cross-couplings of deactivated aryl chlorides. Here, we estab-
lished such a possibility.
Ni(PPh3)2Cl2-catalyzed cross-couplings of deactivated aryl
chlorides with arylboronic acids at elevated temperature
(80-100 °C) have been previously reported.1,10,11 Based on the
fact that Ni(PPh3)2Cl2- and Ni(acac)2/PPh3-catalyzed cross-
coupling reactions of aryl chlorides with Grignard reagents,
which are believed to have the same oxidative addition step as
that of the Suzuki cross-coupling, occurred at room tempera-
ture,14 we believed that the elevated temperature requirement
for Ni(PPh3)2Cl2-catalyzed cross-couplings of deactivated aryl
chlorides with arylboronic acids might mainly serve the purposes
of generating the catalytically active Ni(0) species in situ.
Because the catalytically active Ni(0) species could be readily
accessible from either commercially available Ni(0) complexes
such as Ni(COD)2 or reduction of Ni(II) complexes at room
temperature, we reasoned that the difficulty to employ PPh3 as
an efficient room-temperature ligand might lie in how to realize
the transmetalation/reductive eliminations at room temperature.
Our experience in this field suggested that it would be possible
Triphenylphosphine as a Ligand for
Room-Temperature Ni(0)-Catalyzed
Cross-Coupling Reactions of Aryl Chlorides with
Arylboronic Acids
Zhen-Yu Tang and Qiao-Sheng Hu*
Department of Chemistry, College of Staten Island and the
Graduate Center of the City UniVersity of New York,
Staten Island, New York 10314
qiaohu@mail.csi.cuny.edu
ReceiVed NoVember 16, 2005
Room-temperature Ni(0)-catalyzed cross-coupling reactions
of deactivated aryl chlorides with arylboronic acids with
inexpensive triphenylphosphine (PPh3) as a supporting ligand
have been accomplished in good to excellent yields. Air-
stable Ni(PPh3)2Cl2 has also been established as catalyst
precursor, and highly active nickel catalysts were obtained
when the reduction of Ni(PPh3)2Cl2 with n-BuLi was carried
out in the presence of an aryl chloride.
Room-temperature Pd(0)-catalyzed Suzuki-Miyaura cross-
coupling reactions involving deactivated aryl chlorides as
coupling partners represent a remarkable advance in organo-
metallic chemistry in recent years.1-8 Sterically hindered,
electron-rich monodentate ligands such as t-Bu3P1 and dialkyl-
arylphosphines2,3 and N-heterocyclic carbenes4,5 have been
(1) For a recent review: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
2002, 41, 4176-4211.
(2) Recent examples: (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685-4696. (b) Walker, S.
D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2004, 43, 1871-1876.
(3) For other recent examples: (a) Zapf, A.; Jackstell, R.; Rataboul, F.;
Riermeier, T.; Monsees, A.; Fuhrmann, C.; Shaikh, N.; Dingerdissen, U.;
Beller, M. Chem. Commun. 2004, 38-39. (b) Kataoka, N.; Shelby, Q.;
Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553-5566.
(4) Recent reviews: (a) Herrmann. W. A. Angew. Chem., Int. Ed. 2002,
41, 1290-130. (b) Hillier, A. C.; Grasa, G. A.; Viciu, M. S.; Lee, H. M.;
Yang, C.; Nolan, S. P. J. Organomet. Chem. 2002, 653, 69-82.
(5) For recent examples: (a) Singh, R.; Viciu, M. S.; Kramareva, N.;
Navarro, O.; Nolan, S. P. Org. Lett. 2005, 7, 1829-1832. (b) Song, C.;
Ma, Y.; Chai, Q.; Ma, C.; Jiang W.; Andrus, M. B. Tetrahedron 2005, 61,
7438-7446. (b) Navarro, O,; Oonishi, Y.; Kelly, R. A.; Stevens, E. D.;
Briel, O.; Nolan, S. P. J. Organomet. Chem. 2004, 689, 3722-3727. (c)
Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. J. Am. Chem.
Soc. 2004, 126, 15195-15201. (d) Navarro, O.; Kelly, R. A.; Nolan, S. P.
J. Am. Chem. Soc. 2003, 125, 16194-16195. (e) Altenhoff, G.; Goddard,
R.; Lehmann, C. W.; Glorius, F. Angew. Chem., Int. Ed. 2003, 42, 3690-
3693.
(9) Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047-1062.
(10) (a) Inada, K.; Miyaura, N. Tetrahedron 2000, 56, 8657-8660. (b)
Saito, S.; Oh-tani, S.; Miyaura, N. J. Org. Chem. 1997, 62, 8024-8030.
(c) Indolese, A. F. Tetrahedron Lett. 1997, 38, 3513-3516. (d) Saito, S.;
Sakai, M.; Miyaura, N. Tetrahedron Lett. 1996, 37, 2993-2996.
(11) (a) For a review on nickel-on-charcoal with PPh3 as ligand: Lipsutz,
B. H. AdV. Synth. Catal. 2001, 343, 313-326. (b) For an example of Ni-
(0)/bisphosphine-catalyzed Suzuki cross-couplings of aryl chlorides at
elevated temperature: Percec, V.; Golding, G. M.; Smidrkal, J.; Weichold,
O. J. Org. Chem. 2004, 69, 3447-3452.
(12) (a) Tang, Z.-Y.; Hu, Q.-S. J. Am. Chem. Soc. 2004, 126, 3058-
3059. (b) Tang, Z.-Y.; Hu, Q.-S. AdV. Synth. Catal. 2004, 346, 1635-
1637.
(13) Hidai, M.; Kashiwagi, T.; Ikeuchi, T.; Uchida, Y. J. Organomet.
Chem. 1971, 30, 279-282.
(14) For examples: (a) House, H. O.; Hrabie, J. A.; VanDerveer, D. J.
Org. Chem. 1986, 51, 921-929. (b) Pridgen, L. N. J. Org. Chem. 1982,
47, 4319-4323. (c) Tiecco, M.; Testaferri, L.; Tingoli, M.; Wenkert, D. C.
Tetrahedron Lett. 1982, 23, 4629-4632.
(6) Mukerjee, A.; Sarkar, A. Tetrahedron Lett. 2005, 46, 15-18.
(7) Hu, Q.-S.; Lu, Y.; Tang, Z.-Y.; Yu, H.-B. J. Am. Chem. Soc. 2003,
125, 2856-2857
(8) Roca, F. X.; Richards, C. J. Chem. Commun. 2003, 3002-3003.
10.1021/jo052369i CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/02/2006
J. Org. Chem. 2006, 71, 2167-2169
2167

TABLE 1. Solvent and Base Optimizationa
purposes, a catalyst derived from more electron-rich PCy3, i.e.,
Ni(COD)2/PCy3, has also been studied, and the data are also
listed in Table 3. Our study showed that although the over-
all efficiency of Ni(COD)2/PPh3 is comparable to that of the
Ni(COD)2/PCy3 system, our NMR study suggested that these
two catalyst systems behave differently toward the oxidative
addition with 4-chloroanisole. We found that Ni(COD)2/4PCy3
smoothly underwent oxidative addition with 4-chloroanisole to
yield the oxidative addition product, which reacted with
phenylboronic acid to give the coupling product in 100%
conversion. This oxidative addition product was observed as
the intermediate when mixing Ni(COD)2, PCy3, PhB(OH)2, and
K3PO4 in THF to give the coupling product, suggesting that
the oxidative addition step should not be the slow step. In
contrast, although Ni(PPh3)3 was reported to undergo oxidative
addition with 4-chloroanisole at room temperature,13 we were
unable to obtain the oxidative addition product in a pure form.
1H NMR showed that the oxidative addition was slow and the
oxidative addition product started to decompose before the
reaction completed. However, Ni(COD)2/PPh3 catalyst did
catalyze the cross-coupling reaction of p-chloroanisole with
phenylboronic acid (Table 3). These observations suggest that
the oxidative addition step in Ni(COD)2/PPh3 catalyst system
might be the rate-determining one.
conv
conv
(%)
entry solvent
base
(%)
entry solvent
base
KF
CsF
Na2CO3
KOH
1
2
3
4
5
6
dioxane K3PO4
toluene K3PO4
CH2Cl2 K3PO4
27
41
0
82
78
83
7
8
9
10
11
12
THF
THF
THF
THF
THF
THF
54
42
12
54
36
64
DMF
DMA
THF
K3PO4
K3PO4
K3PO4
Cs2CO3
K2CO3
a Reaction conditions: tolyl chloride (1.0 equiv), phenylboronic acid (1.5
equiv), base (3 equiv), solvent (2 mL), room temperature.
if the right combination of solvent and base was employed.7,12
We thus screened different solvents and bases for Ni(COD)2/
PPh3-catalyzed cross-coupling of p-tolyl chloride with phenyl-
boronic acid, and the results are shown in Table 1. We found
that moderate conversions were observed for dioxane and
toluene, which are excellent solvents when Ni(PPh3)2Cl2 was
the catalyst at elevated temperature.10 THF and DMF were found
to be the best solvents (Table 1, entries 4 and 6). Among the
bases screened, K3PO4 gave the best results (Table 1, entry 6).
We further established that the catalyst derived from a 1:2 ratio
of Ni(COD)2 and PPh3 gave the best results (Table 2, entries
2-5). We have also tested Ni(PPh3)4 as catalyst, and our results
showed that its efficiency was comparable to that of Ni(COD)2/
PPh3 system (Table 2, entry 6).
Our success in using PPh3 as ligand prompted us to investigate
other commercially available phosphines for this transformation,
and our results are also listed in Table 2. We found that bidentate
phosphines including 1,1′-bis(diphenylphosphino)ferrocene
(DPPF), which has been demonstrated as an active ligand at
elevated temperature for this transformation,10b,c were poor
ligands (Table 2, entries 7 and 8). Among the monophosphines
tested, only tricyclohexylphosphine showed a similar efficiency
to PPh3. Other monophosphines, bulkier and/or more electron-
rich than PPh3, only gave low to moderate conversions. These
results suggested that both the size and electron-richness of the
monophoshine play important roles in generating highly active
room-temperature Ni(0) catalyst systems.
Since Ni(COD)2 is more expensive and air-sensitive than
Ni(PPh3)2Cl2, we also sought to use Ni(PPh3)2Cl2 as cata-
lyst precursor for the reaction. We found that although
Ni(PPh3)2Cl2 and Ni(PPh3)2Cl2/Zn15 were ineffective cata-
lysts, the catalyst generated from Ni(PPh3)2Cl2/n-BuLi10b,d was
as efficient as that of Ni(COD)2/PPh3 (Table 3, entries 2 and
4). Interestingly, we observed that the catalytic property of
the nickel species generated from the reduction of Ni(PPh3)2-
Cl2 with n-BuLi was highly dependent on how it was pro-
duced: the reduction of Ni(PPh3)2Cl2 with n-BuLi in the pres-
ence of aryl chloride generated highly active catalyst, while
catalytically inactive species were obtained when the reduction
of Ni(PPh3)2Cl2 with n-BuLi was carried out in the absence of
aryl chloride. Such phenomena suggested that the newly gen-
erated low-valent nickel species could not be stabilized by mono-
dentated PPh3 alone and could aggregate if no trapping reagents
aryl chlorides, which could undergo oxidative addition with the
new generated nickel speciesswas present. These observations
were consistent with reported results of cross-coupling reac-
tions carried out at elevated temperature that catalysts gen-
erated from in situ reduction of Ni(DPPF)Cl2 with n-BuLi or
Grignard reagents were more efficient catalysts than that from
Ni(PPh3)2Cl2 because bidentate DPPF might stabilize the in situ
generated nickel catalysts better than monodentate PPh3.10,16
Under our established reaction conditions (Ni(COD)2/PPh3
as catalyst, THF as solvent and K3PO4 as base), electron-rich,
as well as electron-deficient, aryl chlorides with one or none
substituent at the ortho position coupled efficiently with
arylboronic acids and our results are shown in Table 3. However,
very sterically hindered 1-chloro-2,6-dimethylbenzene was found
to be inert substrate (Table 3, entry 12). For comparison
TABLE 2. Room-Temperature Nickel(0)-Catalyzed Cross-Couplings of p-Tolyl Chloride with Phenylboronic Acida
entry
catalyst
Ni(COD)2
Ni(COD)2 + PPh3
Ni(COD)2 + 2 PPh3
Ni(COD)2 + 3 PPh3
Ni(COD)2 + 4 PPh3
(PPh3)4Ni
conv (%)
entry
catalyst
conv (%)
1
2
3
4
5
6
7
0
44
83
78
70
77
9-13
8
9
10
11
12
13
Ni(COD)2 + 2 DPPEb
3
Ni(COD)2 + 1-4 Cy3P
Ni(COD)2 1-4 n-Bu3P
Ni(COD)2 + 1-4 i-Bu3P
Ni(COD)2 + 1-4 t-Bu3P
Ni(COD)2 + 1-2 o-Tolyl3P
74-88
35-50
24-40
0
21-43
Ni(COD)2 + 1-2 DPPF
a Reaction conditions: aryl chlorides (1.0 equiv), phenylboronic acid (1.5 equiv), K3PO4(3 equiv), THF (2 mL), room temperature. b DPPE:
1,2-bis(diphenylphosphino)ethane.
2168 J. Org. Chem., Vol. 71, No. 5, 2006

TABLE 3. Room-Temperature Nickel(0)-Catalyzed
situ generated nickel catalyst is highly dependent on how it was
generated, with highly active nickel catalyst obtained when the
reduction of Ni(PPh3)2Cl2 with n-BuLi was carried out in the
presence of an aryl chloride.
Cross-Couplings of Aryl Chlorides with Arylboronic Acidsa
Experimental Section
General Procedure for the Suzuki Couplings of Aryl Chlo-
rides with Arylboronic Acids. Method A. In a glovebox with N2
atmosphere, to a mixture of arylboronic acid (0.75 mmol), potassium
phosphate (1.5 mmol), aryl chloride (0.5 mmol), and 2 mL of THF
(in a vial) were added bis(1,5-cyclooctadiene)nickel(0) (5.5 mg,
0.02 mmol) and triphenylphosphine (11 mg, 0.04 mmol). The
mixture was allowed to stir for 30 h. After being quenched with
water, the reaction mixture was extracted with ethyl acetate. The
organic phase was washed with brine, and the solvent was
evaporated under vacuum. Flash chromatography on the silica gel
(hexane/acetate ) 100:0 to 85:15) yielded the cross-coupling
products.
Method B. In a glovebox with N2 atmosphere, to a mixture of
bis(triphenylphosphine) nickel(II) chloride (13 mg, 0.02 mmol), aryl
chloride (0.5 mmol), and 2 mL of THF (in a vial) was added
n-butyllithium (20 µL, 2.5 M in hexane). After the mixture was
stirred for 10 min (the solution turned deep red), phenylboronic
acid (0.75 mmol) and potassium phosphate (1.5 mmol) were added.
The mixture was allowed to stir for 30 h. After being quenched
with water, the reaction mixture was extracted with ethyl acetate.
The organic phase was washed with brine, and the solvent was
evaporated under vacuum. Flash chromatography on the silica gel
(hexane/acetate ) 100:0 to 85:15) yielded the cross-coupling
products.
Acknowledgment. We gratefully thank the NIH (GM69704)
for financial support. Partial support from the PSC-CUNY
Research Award programs, NYSTAR-Cart program for “Center
for Engineered Polymeric Materials”, and GRTI (The Graduate
Research and Technology Initiative) grants are also gratefully
acknowledged. We also thank the Frontier Scientific for its
generous gifts of arylboronic acids.
a Reaction conditions: aryl chlorides (1.0 equiv), arylboronic acids (1.5
equiv), Ni(COD)2PPh3 (4 mol %/8 mol %) or Ni(COD)2/PHy3 (4 mol %/16
mol %), K3PO4 (3 equiv), THF (2 mL), room temperature. b Isolated yields
(average of tow runs). c 4 mol % of Ni(PPh3)2Cl2/n-BuLi was used as
catalyst.
In summary, we have demonstrated that widely available,
inexpensive PPh3 as well as PCy3 can be used as efficient ligands
for room temperature Ni(0)-catalyzed cross-coupling reactions
of deactivated aryl chlorides with arylboronic acids, a process
that previously required the use of expensive, bulky, electron-
rich monophosphines and N-heterocyclic carbenes. We have also
established that air-stable Ni(PPh3)2Cl2 can be used as catalyst
precursor and observed that the catalytic properties of the in
Supporting Information Available: General experimental
procedure for Ni(0)-catalyzed cross-coupling of aryl chlorides with
arylboronic acids and characterization of the cross-coupling products
and intermediate. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO052369I
(16) For examples of nickel catalysts generated from in situ reduction
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A.; Kumada, M. Bull. Chem. Soc. Jpn. 1976, 49, 1958-1969.
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A. S.; Liebeskind, L. S.; Braitsch, D. M. Tetrahedron Lett. 1975, 3375-
3378. (b) Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H. J. Org. Chem. 1995,
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