Synthesis of Biaryls via a Nickel(0)-Catalyzed Cross-Coupling Reaction of Chloroarenes with Arylboronic Acids

Article abstract of DOI:10.1021/jo9707848

The cross-coupling reaction of arylboronic acid with chloroarenes to give biaryls was carried out in high yields at 70-80°C in the presence of a nickel(0) catalyst and K₃PO₄ (3 equiv) in dioxane or benzene. The nickel(0) catalyst in situ prepared from NiCl₂·L (L = dppf, 2PPh₃) (3-10 mol %) and 4 equiv of BuLi at room temperature was recognized to be most effective. The reaction can be applicable to a wide range of chloroarenes having an electron-withdrawing or an electron-donating group such as 4-NC, 4-CHO, 2- or 4-CO₂Me, 4-COMe, 4-NHAc, 4-Me, 4-OMe, 4-NH₂, and 4-NMe₂. The Hammett's plot of the substituent effect of chloroarenes revealed that the reaction involves a rate-determining oxidative addition of chloroarenes to the nickel(0) complex.

Full text of DOI:10.1021/jo9707848

8024
J . Org. Chem. 1997, 62, 8024-8030
Syn th esis of Bia r yls via a Nick el(0)-Ca ta lyzed Cr oss-Cou p lin g
Rea ction of Ch lor oa r en es w ith Ar ylbor on ic Acid s
Syun Saito, Saori Oh-tani, and Norio Miyaura*
Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University,
Sapporo 060, J apan
Received May 2, 1997X
The cross-coupling reaction of arylboronic acid with chloroarenes to give biaryls was carried out in
high yields at 70-80 °C in the presence of a nickel(0) catalyst and K3PO4 (3 equiv) in dioxane or
benzene. The nickel(0) catalyst in situ prepared from NiCl2‚L (L ) dppf, 2PPh3) (3-10 mol %) and
4 equiv of BuLi at room temperature was recognized to be most effective. The reaction can be
applicable to a wide range of chloroarenes having an electron-withdrawing or an electron-donating
group such as 4-NC, 4-CHO, 2- or 4-CO2Me, 4-COMe, 4-NHAc, 4-Me, 4-OMe, 4-NH2, and 4-NMe2.
The Hammett’s plot of the substituent effect of chloroarenes revealed that the reaction involves a
rate-determining oxidative addition of chloroarenes to the nickel(0) complex.
The palladium-catalyzed cross-coupling reaction of
the nickel-catalyzed cross-coupling reaction with Grig-
nard reagents developed by Kumada and Tamao.9 The
recent report by Percec also demonstrated the efficiency
of a nickel catalyst for the cross-coupling reaction of less
reactive arenesulfonates with arylboronic acids.10 Herein,
we wish to report the use of the nickel catalyst for the
cross-coupling between arylboronic acids and chloroare-
nes (eq 1).11,12
arylboronic acids with aryl halides or triflates gives
biaryls.1 High yields have been achieved with many
substrates having various functional groups on either
coupling partner, when using aryl bromides, iodides,2 or
triflates3 as an electrophile. Chloroarenes are an eco-
nomical and easily available substrate, but they have
been rarely used for the palladium-catalyzed cross-
coupling reaction of arylboronic acids because the oxida-
tive addition of chloroarenes to palladium(0) is too slow
to develop the catalytic cycle. Thus, the palladium
catalysts have been limitedly used for activated chloro-
arenes such as chloropyridines,4 (chloroarene)chromium
tricarbonyl,5 and chloroarenes having an electron-
withdrawing group.6 The superiority of trialkylphos-
i
phines as the ligand for palladium catalysts, e.g., Pr3P,
i
Cy2PCH2CH2PCy2, and Pr2PCH2CH2CH2PiPr2 (dippp),
was demonstrated by Milstein and Hiyama on the
carbonylation and the formylation of chloroarenes,7 and
the cross-coupling reaction with organosilanes.8 How-
ever, chloroarenes have been an efficient substrate for
The nickel(0) complexes, in situ prepared from NiCl2‚-
(dppf) (dppf abbreviate 1,1′-bis(diphenylphosphino)fer-
rocene) or NiCl2‚2PPh3 and n-BuLi (4 equiv), was recog-
nized to be an efficient catalyst, thus allowing the
selective coupling with both chloroarenes having an
electron-withdrawing and an electron-donating group.
X Abstract published in Advance ACS Abstracts, October 15, 1997.
(1) For reviews: (a) Snieckus, V. Chem. Rev. 1990, 90, 879-939.
(b) Martin, A. R.; Yang, Y. Acta. Chem. Scand. 1993, 47, 221-230. (c)
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483. (d) Miyaura,
N. Fine Chemical 1997, 26(6), 5-15 and 26(7), 13-26.
(2) (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981,
11, 513-516. (b) Watanabe, T.; Miyaura, N. Suzuki, A. Synlett 1992,
207-210 and ref 1.
(3) (a) Huth, A.; Beetz, I.; Schumann, I. Tetrahedron 1989, 45, 6679-
6696. (b) Fu, J .-M.; Snieckus, V. Tetrahedron Lett. 1990, 31, 1665-
1668. (c) Shieh, W.-C.; Carlson, J . A. J . Org. Chem. 1992, 57, 379-
411. (d) Oh-e, T.; Miyaura, N.; Suzuki, A. J . Org. Chem. 1993, 58,
2201-2268.
(4) Mitchell, M. B.; Wallbank, P. J . Tetrahedron Lett. 1991, 32,
2273-2276. Ali, N. M.; McKillop, A.; Mitchell, M. B.; Rebelo, R. A.;
Wallbank, P. J . Tetrahedron 1992, 48, 8117-8126. Alcock, N. W.;
Brown, J . M.; Hulmes, D. I. Tetrahedron: Asymmetry 1993, 4, 743.
J anietz, D.; Bauer, M. Synthesis 1993, 33-34. Achab, S.; Guyot, M.;
Potier, P. Tetrahedron Lett. 1993, 34, 2127-2130.
(5) Uemura, M.; Nishimura, H.; Kamikawa, K.; Nakayama, K.;
Hayashi, Y.; Tetrahedron Lett. 1994, 35, 1905-1908. Kamiyama, K.;
Watanabe, T.; Uemura, M. J . Org. Chem. 1996, 61, 1375.
(6) (a) Poetsch, E.; Meyer, V.; Komper, H. M.; Krause, J . Ger. Pat.
DE4340490A1, 1992. (b) Poetsch, E.; Meyer, V. Presented at the 7th
IUPAC Symposium on Organometallic Chemistry Directed towards
Organic Synthesis, Kobe, J apan, 1993; S-20. (c) Shen, W. Tetrahedron
Lett. 1997, 38, 5575.
Rea ction Con d ition s
The effects of catalysts and their ligands were studied
at 80 °C in the presence of K3PO4 (3 equiv) and a 3 mol
% of nickel(II) chloride phosphine complex using the
reaction between phenylboronic acid (1.1 equiv) and
3-chlorotoluene (Table 1).
(9) (a) Tamao, K.; Sumitani, K.; Kumada, M. J . Am. Chem. Soc.
1972, 94, 4374-4376. (b) Tamao, K.; Sumitani, K.; Kiso, Y.; Zemba-
yashi, M.; Fujioka, A.; Kodama, S.; Nakajima, I.; Minato, A.; Kumada,
M. Bull. Chem. Soc. J pn. 1976, 49, 1958-1969. For reviews, see: (c)
Tamao, K. Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Pattenden, G., Eds.; Pergamon: New York, 1991; Vol. 3, p 435. (d)
Farina, V. Comprehensive Organometallic Chemistry II; Abel, E. W.,
Stone, F. G. A., Wilkinson, G., Hegedus, L. S., Eds.; Pergamon: New
York, 1995; Vol. 12, p 161.
(10) Percec, V.; Bae, J .-Y.; Hill, D. H. J . Org. Chem. 1995, 60, 1060-
1065.
(7) (a) Ben-David, Y.; Portnoy, M.; Milstein, D. J . Am. Chem. Soc.
1989, 111, 8742-8744. (b) Ben-David, Y.; Portnoy, M.; Milstein, D.
J . Chem. Soc., Chem. Commun. 1989, 1816-1817.
(8) Gouda, K.; Hagiwara, E.; Hatanaka, Y.; Hiyama, T. J . Org.
Chem. 1996, 61, 7232-7233.
(11) Preliminary results were reported in Saito, S.; Sakai, M.;
Miyaura, N. Tetrahedron Lett. 1996, 37, 2993-2996.
(12) It was recently reported that the similar reaction can be carried
out at 95 °C without the reduction the nickel(II) chloride complex:
Indolese, A. F. Tetrahedron Lett. 1997, 38, 3513.
S0022-3263(97)00784-6 CCC: $14.00 © 1997 American Chemical Society

Nickel(0)-Catalyzed Synthesis of Biaryls
J . Org. Chem., Vol. 62, No. 23, 1997 8025
Ta ble 1. Effects of Ca ta lysts a n d Liga n d s on th e
Cr oss-Cou p lin g Rea ction of P h en ylbor on ic Acid s w ith
3-Ch lor otolu en ea
Ta ble 2. Rea ction Con d ition s for th e Ni(d p p f)-Ca ta lyzed
Cou p lin g Rea ction of P h en ylbor on ic Acid s w ith
3-Ch lor otolu en ea
ligand
(equiv)
reducing
agent
entry
solvent
base
temp/°C time/h yield/%b
entry
catalyst
time/h yield/%b
1
2
3
4
5
6
7
8
9
dioxane/H2O K3PO4‚nH2O
80
80
80
80
80
80
80
100
67
80
80
8
8
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppe)c
NiCl2(dppp)d
NiCl2(dppb)e
NiCl2(PPh3)2
none
Zn
8
8
59 (2)
73 (2)
90 (3)
89 (2)
41 (2)
92 (3)
93 (4)
89 (2)
89 (5)
54 (8)
61 (6)
33 (8)
33 (8)
84 (5)
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMF
THF
DME
benzene
K3PO4‚nH2O
K3PO4‚nH2O
Na2CO3
Cs2CO3
CH3CO2Na
CsF
K3PO4‚nH2O
K3PO4‚nH2O
K3PO4‚nH2O
K3PO4‚nH2O
89 (2)
89 (4)
11 (5)
trace
3 (1)
13 (1)
2 (2)
55 (6)
67 (9)
69 (5)
24
16
16
16
16
16
24
24
24
DIBAH
BuLi
BuLi
BuLi
BuLi
8
8
8
dppf (1)
dppf (1)
PPh3 (2)
AsPPh3 (2) BuLi
SbPPh3 (2) BuLi
24
16
24
24
16
16
16
16
16
10
11
BuLi
BuLi
BuLi
BuLi
a
All reactions were carried out in 6 mL of solvent using
phenylboronic acid (1.1 mmol), 3-chlorotoluene (1.0 mmol), base
(3 mmol), and NiCl2(dppf) (0.03 mmol). The NiCl2(dppf) was in
situ reduced to the Ni(0) complex with BuLi (0.12 mmol) prior to
NiCl2(PPh3)2 PPh3 (2)
BuLi
a
b
All reactions were carried out in dioxane (6 mL) at 80 °C using
phenylboronic acid (1.1 mmol), 3-chlorotoluene (1.0 mmol),
K3PO4‚nH2O (3 mmol), catalyst (0.03 mmol), and an additional
ligand shown in the table. The nickel catalyst was in situ reduced
to the Ni(0) complex with BuLi (0.12 mmol) or DIBAH (0.12 mmol),
use for the next coupling reaction. GC yields based on 3-chloro-
toluene and the yields of biphenyl were shown in the parentheses.
phosphate suspended in dioxane was recognized to be the
most effective to complete the reaction within 8 h (entries
2 and 3). The yields increased as the basicity increased
(entries 2-6), but lower yields resulted in strong bases
such as sodium hydroxide. Cesium fluoride is a mild
base, accelerating the palladium-catalyzed cross-coupling
reaction of organoboronic acids,13 but it was, unfortu-
nately, not effective for the nickel-catalyzed reaction
(entry 7). Higher yields can be obtained in less polar
solvents such as dioxane, DME, and benzene (entries
8-11).
b
prior to use the coupling reaction. GC yields based on 3-chloro-
toluene and the yields of biphenyl were shown in the parentheses.
c Dppe is 1,2-bis(diphenylphosphino)ethane. Dppp is 1,3-bis-
d
(diphenylphosphino)propane. e Dppb is 1,4-bis(diphenylphosphi-
no)butane.
The highly active nickel(0) catalysts were in situ
obtained by treating the nickel chloride complexes with
4 equiv of n-BuLi at room temperature (entry 4).12 The
reduction with DIBAH similarly gave good results (entry
3), but low yields resulted in the reaction with the nickel
chloride complexes themselves or their reduction with
zinc dust (entries 1 and 2). The catalytic activity strongly
depended on the phosphine ligands decreasing in the
order of dppf > dppp > dppe > dppb ∼ PPh3 (entries 4
and 10-13). The nickel(0) complexes are highly reactive,
but they are a very labile species slowly decomposing on
prolonged reaction times. Thus, the use of higher
concentration of the catalyst was apparently advanta-
geous to achieve high yields; however, a 3 mol % catalyst
similarly gave high yields of cross-coupled products when
an additional phosphine ligand was added to NiCl2(dppf)
or NiCl2(PPh3)2. Although the addition of 1 equiv of dppf
to NiCl2(dppf) slowed the reaction rate (entry 5), a 92%
yield was easily obtained after 24 h at 80 °C (entry 6).
The addition of 2 equiv of triphenylphosphine, -arsine,
and -antimony also gave good results (entries 7-9). A
combination of 2 equiv of PPh3 and NiCl2(PPh3) 2 allowed
the use of an economical and readily available nickel
catalyst based on triphenylphoshine (entry 14).
Scop e a n d Lim ita tion
The results of the nickel(0)-catalyzed cross-coupling
reaction of arylboronic acid with representative chloro-
arenes are summarized in Table 3.
The NiCl2(dppf)-catalyzed reaction with chloroarenes
having an electron-withdrawing group, such as 4-CN,
4-CHO, 2- or 4-CO2Me, and 4-COCH3, gave excellent
yields of biaryls, often exceeding 90% (entries 1-6).
However, the reaction completely failed for 4-chloroni-
trobenzene (entry 7). The catalyst may lose its activity
by the formation of a stable (nitroso)nickel(II) species
because the reaction of nitrobenzene with Ni(PPh3)4 gives
nitrosobenzene and triphenylphosphine oxide.14 For the
substrates having an electron-donating group, a 3 mol
% of catalyst is not sufficient to complete the reaction.
Although the addition of 1 equiv dppf to NiCl2(dppf)
improved the yields, the best results can be more
conveniently achieved by using a 10 mol % of the catalyst
(entries 10 and 11).
Heteroatoms which coordinate to transition metals
often retard the cross-coupling reactions of organome-
tallics.15 7-Chloroindole and 2-chlorothiophene smoothly
coupled with phenylboronic acid (entries 12 and 17), but
2-chloroquinoline was strongly resistant to the reaction
(entries 13 and 14). A combination of NiCl2(PPh3)2 (3 mol
%) and 2 equiv of PPh3 exceptionally gave a high yield of
2-phenylquinoline (entry 15).
The reaction was accompanied with some biphenyl
arising from the homocoupling of phenylboronic acid. The
yield of biphenyl was less than 5% in most cases, but it
improved when the cross-coupling resulted in low yields
(entries 10, 11, and 13). However, the homocoupling of
3-chlorotoluene was not observed.
The NiCl2(dppf)-catalyzed reaction between phenylbo-
ronic acid and 3-chlorotoluene was carried out at 80 °C
using various bases and solvents (Table 2).
Various functionalized arylboronic acids can be used
for the cross-coupling reaction. However, arylboronic
The palladium-catalyzed cross-coupling reaction of
arylboronic acid with bromo- or iodoarenes can be best
conducted in the presence of an aqueous base such as
sodium carbonate or potassium phosphate.1 However,
aqueous bases should be avoided because the arylnickel-
(II) species involved in the catalytic cycle seem to be
rather sensitive to water (entry 1). Finally, potassium
(13) (a) Ichikawa, J .; Moriya, T.; Sonoda, T.; Kobayashi, H. Chem.
Lett. 1991, 961-965. (b) Wright, S. W.; Hageman, D. L.; McClure, L.
D. J . Org. Chem. 1994, 59, 6095-6097.
(14) Serman, R. S.; Kochi, J . K. Inorg. Chem. 1980, 19, 248-254.
(15) Yang, Y. Synth. Commun. 1989, 19, 1001-1004.

8026 J . Org. Chem., Vol. 62, No. 23, 1997
Saito et al.
Ta ble 3. Syn th esis of Bia r yls via th e Nick el(0)-Ca ta lyzed Cr oss-Cou p lin g of Ar ylbor on ic Acid s w ith Ch lor oa r en esa

Nickel(0)-Catalyzed Synthesis of Biaryls
J . Org. Chem., Vol. 62, No. 23, 1997 8027
Ta ble 3 (Con tin u ed )
acids having electron-withdrawing groups often resulted
in low yields due to the C-B bond cleavage with the
base.2c,16 For example, the cross-coupling of 4-acetylphe-
nylboronic acid with 3-methoxychlorobenzene gave only
36% of biary accompanied with a large amount of
acetophenone, even in the presence of 10 mol % of NiCl2-
(dppf) (entry 19). For such arylboronic acids, 1,2-
dimethoxyethane (DME) was a better solvent than
dioxane because the hydrolytic protodeborylation is
rather slow in DME (entry 20).
The nickel-catalyzed cross-coupling reaction is more
sensitive to the steric hindrance of both arylboronic acids
and chloroarenes than the palladium-catalyzed reaction.
Presumably, this is partly due to the shorter bond lengths
of Ni-C and Ni-Cl than that of the palladium complexes.
However, ortho-monosubstituted arylboronic acids, such
as o-tolylboronic acid, readily coupled with various chlo-
roarenes having ortho-monosubstituents or heteroatoms
(entries 21-31). The use of an additional phosphine
ligand apparently gave better results in most cases. It
is interesting that benzene was advantageous over diox-
ane for chloroarenes sensitive to bases, whereas the
inorganic base is insoluble in such solvent (entries 27-
31). It was more difficult to achieve high yields in the
reaction of mesitylboronic acid due to its large steric
hindrance in the transmetalation step. Although the
presence of an electron-withdrawing group allowed a very
smooth coupling (entry 32), the reactions were extremely
slow for electron rich chloroarenes. A combination of
NiCl2(dppf) and Ph3Sb17 in benzene was found to be
effective in the reaction with 3-methylchlorobenzene
(entry 35), but all attempts at the arylation of ortho-
substituted chloroarenes were unsuccessful (for example
36). Thus, it can be rather difficult to achieve high yields
in the synthesis of ortho trisubstituted biaryls by the
nickel-catalyzed reaction.
Mech a n ism
The nickel-catalyzed cross-coupling reaction of Grig-
nard reagents with organic halides was extensively
studied by Kumada and Tamao.9 The unique mecha-
nism18 proceeding through the oxidative addition, trans-
metalation, and reductive elimination has been a guide
to the theoretical fundamentals and the synthetic ap-
plications to other cross-coupling reactions of orga-
nozinc,19 -stannanes,20 -boron,1 and -silicones21 with the
palladium catalysts (Figure 1).
The nickel(II) chloride phosphine complexes are readily
reduced to the nickel(0) species by treatment with BuLi22
or other various organometallics via a transmetalation
(16) Kuvilla, H. G.; Nahabedian, K. V. J . Am. Chem. Soc. 1961, 83,
2159, 2164 and 2167. Kuvila, H. G.; Reuwer, J . F.; Mangravite, J . A.
J . Am. Chem. Soc. 1964, 86, 2666.
(17) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585-
9595.

8028 J . Org. Chem., Vol. 62, No. 23, 1997
Saito et al.
F igu r e 2. Effect of substituents on arylboronic acids.
F igu r e 1. Catalytic cycle.
and reductive elimination or â-hydride elimination se-
quence. The electron-rich nickel(0) complexes thus ob-
tained are highly reactive, undergoing the oxidative
addition to various chloroarenes. The addition of sub-
stituted chloroarenes to Ni(PPh3)4 reported by Casser23
exhibited a unique Hammett’s correlation suggesting two
different mechanisms in the regions of electron-donating
groups and -withdrawing groups (the dotted lines in
Figure 3). The reactivity linearly increased by electron-
withdrawing groups with σ > 0.23 (F ) 8.6), but it was
quite insensitive to the electron-donating substituents
with σ < 0.23 (F ) 0.59). The results are in sharp
contrast to the substitution effect in the oxidative addi-
tion of chloroarenes to the palladium(0) complex which
revealed a linear correlation to σ- in a range of -0.26 to
1.126 (F ) 5.2).24 Thus, chloroarenes having electron-
donating groups, even 4-amino- (σ, -0.66) and 4-(dim-
ethylamino)chlorobenzene (σ, -0.83), exhibit a quite
similar reactivity to chlorobenzene itself in the reaction
with the nickel(0) complexes, whereas the palladium-
catalyzed reaction is greatly retarded by such substitu-
ents. The yields of biaryls in the palladium- and nickel-
catalyzed cross-coupling reactions of phenylboronic acid
with substituted chloroarenes are shown in Table 4.
F igu r e 3. Effects of substituents on chloroarenes (Table 6).
The solid lines (O) show the effect on the present reaction, and
the dotted lines (0) indicate the correlation in the oxidative
addition of ArCl to Ni(PPh3)4 reported by Casser.
The palladium-catalyzed reaction was limitedly used
for the substituents with σ > 0.45, whereas all substit-
uents in a range of -0.83 to 0.66 well accommodated the
nickel-catalyzed reaction.
The effects of substituents on arylboronic acids and
chloroarenes are shown in Figures 2 and 3.
The nucleophilicity of aryl groups on the boron atom
may affect the rates of either transmetalation or reduc-
tive elimination,25 but the two steps did not determine
the total reaction rate because the relative reactivity was
quite insensitive to the substituents on arylboronic acids
(Figure 2). Thus, K3PO4 suspended in dioxane has
sufficient basicity to assist the transmetalation step, the
mechanism of which is, however, not yet obvious at
(18) The nickel-catalyzed reaction; (a) Morrell, D. G.; Kochi, J . K.
J . Am. Chem. Soc. 1975, 97, 7262-7270. The palladium-catalyzed
reaction: (b) Ozawa, F.; Kurihara, K.; Fujimori, M.; Hidaka, T.;
Toyoshima, T.; Yamamoto, A. Organometallics 1989, 8, 180-188. For
general reviews: (c) Kochi, J . K. Organometallic Mechanisms and
Catalysis; Academic: New York, 1978. (d) Hartley, F. R.; Patai, S.
The Chemistry of Metal-Carbon Bond; Wiley: New York, 1985; Vol.
3. (e) Hegedus, L. S. Organometallics in Organic Synthesis; Schlosser,
M., Ed.; Wiley: New York, 1994; p 383.
(19) Negishi, E. Acc. Chem. Res. 1982, 15, 340-348.
(20) Stille, B. J . Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
(21) (a) Hagiwara, E.; Gouda, K.; Hatanaka, Y.; Hiyama, T. Tetra-
hedron Lett. 1997, 38, 439-442. (b) Hatanaka, Y.; Fukushima, S.;
Hiyama, T. Chem. Lett. 1989, 1711-1714. For a review: (c) Hatanaka,
Y.; Hiyama, T. Synlett 1991, 845-853.
(22) The treatment of the nickel(II) chloride complexes with n-BuLi
(3 equiv) gives the corresponding nickel(0) complexes with evolution
of 1-butene, butane, and octane.18a
(23) Foa´, M.; Cassar, L. J . Chem. Soc., Dalton Trans. 1975, 2572-
2576.
(24) Portnoy, M.; Milstein, D. Organometallics 1993, 12, 1665-1673.
(25) Moriya, T.; Miyaura, N.; Suzuki, A. Synlett 1994, 149-151.

Nickel(0)-Catalyzed Synthesis of Biaryls
J . Org. Chem., Vol. 62, No. 23, 1997 8029
Ta ble 4. P a lla d iu m - ver su s Nick el-Ca ta lyzed
Cr oss-Cou p lin g of P h en ylbor on ic Acid w ith
Ch lor oa r en es
of organometallics with the aryl groups on the phosphine
ligands.31 The formation of the dimer of electrophiles was
reported in the oxidative addition of organic halides to
nickel(0) complexes via an electron-transfer mechanism.32
Although there are many probable processes to give the
byproducts, arylboronic acids undergo a clean cross-
coupling reaction by the nickel catalyst. The observed
byproducts were the dimers of arylboronic acids in less
than 2%. The mechanism is not obvious at present;
however, the process may not involve the oxidative
addition of the C-B bond to the nickel(0) complex29
because the reaction between phenylboronic acid and the
Ni(0)dppf did not produce biphenyl at 80 °C for 16 h in
the presence of K3PO4 (3 equiv). The coupling with
electron-rich chloroarenes was often contaminated with
very small amounts of arene resulting from the displace-
ment of chlorine with the hydrogen atom, but the
formation of the chloroarene dimers were less than 1%.32
yield/%
b
entry
substituent
σa
Pd(PPh3)4
NiCl2(dppf)c
1
2
3
4
5
6
4-CtN
0.66
0.50
0.45
0.12
-0.07
-0.83
80
64
40
<1
<1
0
74
96
87
72
89
85d
4-COCH3
4-CO2CH3
3-OCH3
3-CH3
4-NMe2
a
b
Hammett constant. A mixture of PhB(OH)2 (1.1 mmol), ArCl
(1 mmol), Na2CO3 (1.5 mmol), and Pd(PPh3)4 (0.03 mmol) in
aqueous DME was heated at 80 °C for 16 h. c A mixture of
PhB(OH)2 (1.1 mmol), ArCl (1 mmol), K3PO4‚nH2O (3 mmol), and
NiCl2(dppf) (0.03 mmol) in dioxane was heated at 80 °C for 16 h.
d
A 10 mol % of NiCl2(dppf) was used.
present. The rate-determining role of the oxidative
addition step in the reaction of chloroarenes with aryl-
boronic acids was suggested by the plot of the relative
reactivity of substituted chloroarenes to the σ constants.
A small change in the rate constants (F ) 0.74) in a range
of -0.27 to 0.06 and a high electronic effect (F ) 5.26) in
0.37 to 0.66 were characteristic of the correlation ob-
served in the oxidative addition of chloroarenes to Ni-
Exp er im en ta l Section
All experiments were carried out under an argon atmo-
sphere. THF, DME, dioxane, and benzene were distilled from
benzophenone ketyl.
Rea gen ts. The reaction of NiCl2‚6H2O with a commercially
available phosphine ligand in benzene at 50 °C gave the nickel
chloride complexes with dppf (1,1′-bis(diphenylphosphino)-
ferrocene), dppe (Ph2PCH2CH2PPh2), dppp (Ph2PCH2CH2-
CH2PPh2), dppb (Ph2PCH2CH2CH2CH2PPh2), and triphe-
nylphosphine.33 Chloroarenes purchased from Aldrich were
distilled or recrystalized before use. Phenylboronic acid was
obtained from Strem Chemical, and other arylboronic acids
were prepared by the reported procedures.34 K3PO4‚nH2O from
Nakarai Chem. Co. was used directly.
Ca u tion . The alkaline hydrogen peroxide oxidation of
organoboron compounds is a convenient way to remove the
residual organoboron species remaining in the reaction mixture.
However, the addition of hydrogen peroxide to the mixtures
containing nickel catalyst should be absolutely avoided because
the nickel forms an explosive nickel peroxide.
Effect of Ca ta lyst a n d Liga n d (Ta ble 1). The flask was
charged with NiCl2‚L (L ) dppf, dppe, dppp, dppb, and 2 PPh3)
(0.03 mmol) and then flushed with argon. The catalyst was
dissolved in dioxane (6 mL) and treated with n-BuLi in hexane
(0.12 mmol) at room temperature for 10 min to give a solution
of the nickel(0) complex. Phenylboronic acid (1.1 mmol), K3-
PO4‚nH2O (3 mmol), 3-chlorotoluene (1.0 mmol), and an
additional ligand shown in Table 1 (0.03 mmol of dppf or 0.06
mmol of other monodentate ligands) were added to the flask.
The reaction mixture was stirred at 80 °C during the period
shown in Table 1. The reduction with zinc powder was in situ
23
(PPh3)4 (Figure 3).
The catalytic processes exhibited a strong dependence
on the ligands utilized for the catalyst. The ligands may
affect all three steps involved in the catalytic cycle, but
the catalysts which accelerate the rate-determining step
will be desirable. It was reported that alkylphosphines
are superior to triarylphosphines on the oxidative addi-
tion of chloroarenes to the palladium(0) complexes,7,8 and
the nucleophilicity of the metal center increases upon the
decrease of the P-M-P angle in the bis(phosphine)-
palladium(0) or -platinum(0) complex.26 However, alkyl-
phosphines such as NiCl2(PiPr3)2 and NiCl2(tricyclo-
hexylphosphine)2 were less effective than triarylphos-
phines. The nickel catalysts based on dppf apparently
gave better results than the dppe or dppp complexes
(Table 1), that can be reverse to the order of nucleophi-
licity of the metal center.26 Thus, the effect of ligands
can be attributable to their ability to stabilize the labile
nickel(0) species during the cross-coupling reaction.
Indeed, the use of 10 mol % of the catalyst or an
additional ligand to 3 mol % of NiCl2‚L2 always gave
higher yields than NiCl2(dppf) itself, and they were
essential for sterically hindered or electron-rich chloro-
arenes (Table 3).
(29) The oxidative addition of the C-B bond to the palladium(0)
complexes has been reported; however, this process has still remained
obscure: (a) Moreno-Man˜as, M.; Pe´rez, M.; Pleixats, R. J . Org. Chem.
1996, 61, 2346-2349. (b) Cho, C. S.; Motofusa, S.; Ohe, K.; Uemura,
S. J . Org. Chem. 1995, 60, 883-888.
(30) The mixture of arylboronic acids, Pd(OAc)2, and Na2CO3 in
aqueous ethanol catalytically gives symmetrical biaryls and phenols
on exposure to air.35 The reaction may involve the oxidation of the
palladium(0) complexes to the Pd(II)(OH)OOH.36
(31) Kong, K. C.; Cheng, C.-H. J . Am. Chem. Soc. 1991, 113, 6313-
6315. Morita, D. K.; Stille, J . K.; Norton, J . R. Ibid. 1995, 117, 8576-
8581.
(32) (a) Tsou, T. T.; Kochi, J . K. J . Am. Chem. Soc. 1979, 101, 6319-
6332. (b) Elson, L. H.; Morrell, D. G.; Kochi, J . K. J . Organomet. Chem.
1975, 84, C7-10.
(33) Booth, G.; Chatt, J . J . Chem. Soc. 1965, 3238-3241.
(34) Nesmeyanov, A. N.; Sokolik, R. A. Methods of Elemento-Organic
Chemistry; North-Holland: Amsterdam, 1967; Vol. 1. Mikhailov, B.
M.; Bubnov, Yu. N. Organoboron Compounds in Organic Synthesis;
Harwood Academic Pub.: Amsterdam, 1983.
(35) Smith, K. A.; Campi, E. M.; J ackson, W. R.; Marcuccio, S.;
Naeslund, C. G. M.; Deacon, G. B. Synlett 1997, 131-132.
(36) Sheldon, R. A.; Kochi, J . K. Metal-Catalyzed Oxidation of
Organic Compounds; Academic Press: New York, 1981; Chapter 4.
The cross-coupling reaction catalyzed by palladium or
nickel complexes often affords unexpected byproducts
including the homocoupling products of electrophiles and
organometallics. The reaction of Grignard reagents has
suffered from the homocoupling resulting from the
metal-halogen exchange.9,27 The metathesis of RMX to
R2M and MX2 (M ) Ni, Pd) produced both dimers of
electrophiles and organometallics.28 The oxidative ad-
dition of the metal-carbon bonds to the low-valent
transition-metals29 or their oxidation with oxygen or
other oxidizing sources30 has been another route leading
to the dimer of organometallics. Exchange of metal- and
phosphine-bound aryls produced the coupling products
(26) Otsuka, S. J . Organomet. Chem. 1980, 200, 191-205.
(27) Bumagin, N. A.; Ponomarev, A. B.; Beletskaya, I. P. J . Org.
Chem. USSR 1987, 23, 1215-1222.
(28) Ozawa, F.; Hidaka, T.; Yamamoto, T.; Yamamoto, A. J . Orga-
nomet. Chem. 1987, 330, 253-263.

8030 J . Org. Chem., Vol. 62, No. 23, 1997
Saito et al.
Ta ble 5. Rela tive Rea ctivity of Su bstitu ted Ar ylbor on ic
Acid s to 3-Meth oxych lor oben zen e
carried out by directly heating the all mixture at 80 °C. The
yields of biphenyl and 3-methylbiphenyl were analyzed by GC.
Effects of Ba se a n d Solven ts (Ta ble 2). The flask was
charged with NiCl2(dppf) (0.03 mmol) and solvent (6 mL). The
catalyst was reduced with n-BuLi in hexane (0.12 mmol) at
room temperature for 10 min. Phenylboronic acid (1.1 mmol),
a base (3 mmol), and 3-chlorotoluene (1.0 mmol) were added
to the flask. The reaction mixture was then stirred at the
temperature and during the period shown in Table 2.
Rep r esen ta tive P r oced u r e (Ta ble 3). The following
procedure for the cross-coupling of 2-methylphenylboronic acid
with 4-amino-2,4-dimethoxychlorobenzene is representative
(entry 24). A 50 mL-flask was charged with NiCl2(dppf) (0.021
g, 0.03 mmol) and dppf (0.018 g, 0.03 mmol) and flushed with
argon. The catalyst was dissolved in dioxane (6 mL) and then
reduced with n-BuLi (1.6 M, 0.075 mL, 0.12 mmol) at room
temperature for 10 min to give a solution of nickel(0) complex.
2-Methylphenylboronic acid (0.15 g, 1.1 mmol), K3PO4‚nH2O
(0.636 g, 3 mmol), and 4-amino-2,4-dimethoxychlorobenzene
(0.188 g, 1 mmol) were added through the neck of the flask
keeping a slow stream of argon. The mixture was stirred at
80 °C for 16 h. The product was extracted with ether, washed
with brine, and dried over MgSO4. Chromatography over silica
gel with hexane/ethyl acetate ) 2/1 gave 0.220 g (91%) of the
corresponding biaryl: 1H NMR δ 2.15 (s, 3 H), 3.54 (broad s,
2 H), 3.67 (s, 3 H), 3.91 (s, 3 H), 6.54 (s, 1 H), 6.55 (s, 1 H),
7.15-7.25 (m, 4 H),; MS, m/e 115 (15), 168 (13), 196 (29), 197
(34), 213 (10), 228 (52), 243 (M+, 100), 244 (18); exact mass
calcd for C15H16O2N 243.1259, found 243.1231.
XC6H4B(OH)2 YC6H4B(OH)2
X )
Y )
yield/%a yield/%b rel rate (Y/X)
H
4-CH3
H
H
4-CH3CO
4-F
4-CH3
4-CH3O
13.6
15.1
19.5
20.9
17.6
19.8
20.8
28.3
1.29
1.31
1.07
1.36
a
b
Yields of 3-CH3OC6H4C6H4X. Yields of 3-CH3OC6H4C6H4Y.
Ta ble 6. Rela tive Rea ctivity of Su bstitu ted
Ch lor oa r en es to 3-Meth oxyp h en ylbor on ic Acid
XC6H4Cl
X )
YC6H4Cl
Y )
yield/%a
yield/%b
rel rate (Y/X)
3-CO2CH3
H
H
4-F
4-F
H
4-CN
1.6
4.2
51.1
76.6
69.4
30.2
29.2
18.4
18.5
31.9
18.2
3.27
0.742
1.25
4-COCH3
3-CO2CH3
4-CH3
4-OCH3
4-CH3
21.1
40.7
23.3
37.2
38.8
0.495
0.495
H
4-OCH3
a
b
Yields of 3-CH3OC6H4C6H4X. Yields of 3-CH3OC6H4C6H4Y.
(0.03 mmol), and Na2CO3 (3 mmol) and flushed with argon.
DME (3 mL), water (0.5 mL), and a chloroarene (1 mmol) were
added, and the mixture was then stirred for 16 h at 80 °C.
For the nickel-catalyzed reactions, see the entries 1-11 in
Table 3.
The following biaryls were synthesized by the above general
procedure.
Effect of Su bstitu en ts on Ar ylbor on ic Acid (F igu r e 2).
The cross-coupling reaction in dioxane did not give a good
correlation due to the hydrolytic protodeboration of arylboronic
acids. Thus, all the reactions were carried out in DME. NiCl2-
(dppf) (0.045 mmol) in DME (6 mL) was treated with n-BuLi
in hexane (0.108 mmol) at room temperature for 10 min. Two
arylboronic acids (1.65 mmol of XC6H4B(OH)2 and 1.65 mmol
of YC6H4B(OH)2), K3PO4 (45 mmol), and 3-methoxychloroben-
zene (1.5 mmol) were successively added to the above catalyst
solution. The mixture was stirred for 3 h at 80 °C. The
relative reactivity was estimated from the yields of two biaryls.
The same reaction was repeated three times, and their
averages are shown in Table 5.
Effect of Su bstitu en ts on Ch lor oa r en es (F igu r e 3). To
a solution of NiCl2(dppf) (0.045 mmol) in dioxane (6 mL) was
added n-BuLi in hexane (0.18 mmol) at room temperature.
3-Methoxyphenylboronic acid (1.65 mmol), K3PO4 (4.5 mmol),
and two chloroarenes (1.5 mmol of XC6H4Cl and 1.5 mmol of
YC6H4Cl) were added, and the mixture was then stirred for 3
h at 80 °C. The same reaction was repeated three to four
times, and their yields were averaged to give the relative
reactivity (Table 6).
2-P h en ylqu in olin e: 1H NMR δ 7.44-7.60 (m, 4 H), 7.70-
7.75 (m, 1 H), 7.82 (d, 1 H, J ) 8.1 Hz), 7.87 (d, 1 H, J ) 8.8
Hz), 8.15-8.25 (m, 4 H); MS, m/e 76 (9), 102 (24), 128 (6), 151
(4), 176 (7), 204 (81), 205 (M+, 100); exact mass calcd for
C15H11N 205.0892, found 205.0899.
1
7-P h en ylin d ole: IR 3375 cm-1; H NMR δ 6.72 (m, 1 H),
7.18-7.50 (m, 6 H), 7.71 (m, 2 H), 8.18 (broad s, 1 H); MS, m/e
117 (10), 139 (4), 154 (32), 165 (38), 193 (M+, 100); exact mass
calcd for C14H11N 193.0892, found 193.0882.
2-Met h yl-6-(2-m et h ylp h en yl)b en zoxa zole: 1H NMR δ
2.26 (s, 3 H), 2.66 (s, 3 H), 7.22-7.29 (m, 5 H), 7.49 (d, 1 H, J
) 8.3 Hz), 7.59 (d, 1 H, J ) 1.7 Hz); MS, m/e 152 (32), 153
(43), 154 (29), 167 (32), 181 (42), 222 (25), 223 (M+, 100); exact
mass calcd for C15H13ON 223.0997, found 223.0979.
3-(2-Meth ylp h en yl)-4-m eth yl-7-m eth oxycou m a r in : 1H
NMR δ 2.16 (s, 3 H), 2.17 (s, 3 H), 3.89 (s, 3 H), 6.80-6.50 (m,
2 H), 7.11 (d, 1 H, J ) 7.1 Hz), 7.15-7.25 (m, 3 H), 7.57 (d, 1
H, J ) 8.7 Hz); MS, m/e 165 (27), 178 (6), 194 (5), 221 (5), 237
(24), 252 (5), 263 (38), 265 (100), 280 (M+, 62); exact mass calcd
for C18H16O3N 280.1100, found 280.1120.
2-(2-Met h ylp h en yl)-4,6-d im et h oxy-1,3,5-t r ia zin e: 1H
NMR δ 2.70 (s, 3 H), 4.10 (s, 6 H), 7.20-7.40 (m, 3 H), 8.10 (d,
1 H, J ) 8.1 Hz); MS, m/e 116 (85), 159 (31), 173 (4), 216 (100),
231 (M+, 16); exact mass calcd for C12H13O2N3 231.1008, found
231.1027.
P a lla d iu m - ver su s Nick el-Ca ta lyzed Cr oss-Cou p lin g
(Ta ble 4). The palladium-catalyzed cross-coupling reactions
were carried out by the following general procedure. The flask
was charged with phenylboronic acid (1.1 mmol), Pd(PPh3)4
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra of biaryls (23 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O9707848