Efficient synthesis of biaryls through the kumada reaction catalyzed by carbene adducts of cyclopalladated ferrocenylimine

Article abstract of DOI:10.1002/ejoc.200901495

A series of carbene adducts of cyclopalladated ferrocenylimine were prepared, and evaluated in the cross-coupling reaction of aryl halides with Grignard reagents (the Kumada reaction). Complex d exhibited high catalytic activity for the coupling of aryl chlorides with sterically hindered Grignard reagents and the reaction tolerated various functional groups. A wide range of biaryls were efficiently obtained in good to excellent yields in the presence of 0.5 mol-% catalyst under mild reaction conditions.

Full text of DOI:10.1002/ejoc.200901495

FULL PAPER
DOI: 10.1002/ejoc.200901495
Efficient Synthesis of Biaryls through the Kumada Reaction Catalyzed by
Carbene Adducts of Cyclopalladated Ferrocenylimine
Gerui Ren,[a] Xiuling Cui,[a] and Yangjie Wu*[b]
Keywords: Biaryls / Carbene ligands / Palladium / Ferrocene / Cross-coupling
A series of carbene adducts of cyclopalladated ferrocenyl-
imine were prepared and evaluated in the cross-coupling re-
action of aryl halides with Grignard reagents (the Kumada
reaction). Complex d exhibited high catalytic activity for the
coupling of aryl chlorides with sterically hindered Grignard
reagents and the reaction tolerated various functional
groups. A wide range of biaryls were efficiently obtained in
good to excellent yields in the presence of 0.5 mol-% catalyst
under mild reaction conditions.
Introduction
(2 mol-%). For these reasons, use of the Kumada coupling
protocol remains an attractive and potentially highly ef-
ficient alternative route to unsymmetrical biaryls.
Unsymmetrical biaryls are important building blocks for
the synthesis of functional materials,[1] natural products,[2]
and pharmaceuticals.[3] The Kumada reaction[4] is one of
the most powerful and versatile methods with which to as-
semble such fragments. However, only modest progress in
the development of this reaction has been made in recent
years[5] compared to other cross-coupling reactions, such as
the Suzuki,[6] Still,[7] and Negishi reactions,[8] due to the in-
herently inferior functional group tolerance. On the other
hand, the Kumada reaction could offer a more direct ap-
proach to the synthesis of biaryls because aryl boronic acids
(Suzuki coupling), stannanes (Stille coupling), and zinc
compounds (Negishi coupling) are usually prepared from
either Grignard or organolithium precursors.[9] Direct use
of Grignard reagents in coupling reactions could efficiently
shorten the synthetic procedure and reduce the cost. How-
ever, there are some challenges that still exist for this reac-
tion, such as limitations in the use of the less expensive and
more available aryl chlorides as substrates, inferior toler-
ance of functional groups, less efficient synthesis of steri-
cally hindered biaryls and requirement for high loading of
catalyst (1–5 mol-%). Nolan’s group[5b] reported the cou-
pling of aryl chlorides with aryl Grignard reagents at ele-
vated reaction temperature (80 °C) in the presence of 1 mol-
% N-heterocyclic carbene-Pd complex. However, this proto-
col was less tolerant of functional groups. Organ et al.[5r]
described a successful application of the Kumada reaction
using PEPPSI as catalyst with a higher catalyst loading
Over the past decade, part of our research effort has fo-
cused on the synthesis and application of cyclopalladated
ferrocenylimines.[10] We found that they were highly versa-
tile in coupling reactions, such as the Suzuki and the Heck
reactions. Moreover, carbene adducts (Scheme 1) exhibited
high activity with sterically hindered aryl chlorides as sub-
strates in the Suzuki coupling.[10d] This has prompted us to
explore the potential applications of such palladacycles in
the Kumada reaction. Herein, we disclose our results on the
application of carbene adducts of cyclopalladated ferrocen-
ylimine as efficient catalysts for the coupling of a wide
range of aryl halides with Grignard reagents, especially or-
tho-substituted Grignard reagents, with low catalyst loading
(0.5 mol-%) under mild reaction conditions.
Scheme 1. Cyclopalladated ferrocenylimine and its adducts.
[a] Department of Chemistry, Zhengzhou University,
Zhengzhou 450052, P. R. China
[b] Henan Key Laboratory of Chemical Biology and Organic
Chemistry, Key Laboratory of Applied Chemistry of Henan
Universities, Department of Chemistry, Zhengzhou University,
Zhengzhou 450052, P. R. China
Results and Discussion
Palladacycles a–f were prepared according to the pre-
Fax: +86-371-67979408
E-mail: wyj@zzu.edu.cn
viously reported procedures.[10,11] At the outset of our stud-
2372
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2372–2378

Efficient Synthesis of Unsymmetrical Biaryls
ies, the coupling of 4-chlorotoluene with phenylmagnesium
bromide was chosen as a model reaction to evaluate the
catalytic activity of complexes a–f. As shown in Table 1,
complexes c and d showed higher catalytic activity; in the
presence of 1.0 mol-% catalyst loading, these complexes
provided the desired products in 90 and 94% yields, respec-
tively (Entries 3 vs. 4). However, when catalyst loading was
reduced to 0.5 mol-%, use of complex c only gave 80%
yield, whereas complex d remained highly efficient (Entries
4 vs. 7).
Figure 1. The Kumada reaction catalyzed by complexes c and d at
room temperature. Reaction conditions: 4-Chlorotoluene
(1.0 mmol), PhMgBr (3.0 equiv.) in THF (2.0 mL), cat. (0.5 mol-
%), LiCl (2.0 equiv.), THF (2.0 mL), 24 h; yields based on 4-chloro-
toluene and assessed by GC.
Table 1. Screening of catalysts for the Kumada coupling.
Entry[a]
Cat.
Cat. [mol-%]
Yield [%][b]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.5
trace amounts
trace amounts
90
94
78
25
94
80
d
c
[a] Reaction conditions: 4-chlorotoluene (1.0 mmol), PhMgBr
(3.0 equiv.) in THF (2.0 mL), LiCl (2 equiv.), THF (2.0 mL), 24 h.
[b] Yields based on 4-chlorotoluene and assessed by GC.
To further compare the catalytic activity of complexes c
and d, first, the coupling of 4-chlorotoluene with phenyl-
magnesium bromide was performed at room temperature
(Figure 1); this coupling was affected by the depressed tem-
perature in two cases, however, the yield decreased dramati-
cally when complex c was used as catalyst. Secondly, when
the coupling of sterically hindered substrates 2-chloroani-
sole with (2-methylphenyl)magnesium bromide was as-
sessed, complex d was found to be significantly superior to
Figure 2. The Kumada reaction of 2-chloroanisole with (2-meth-
ylphenyl)magnesium bromide catalyzed by complexes c and d. Re-
action conditions: 2-Chloroanisole (1.0 mmol), (2-methylphenyl)
magnesium bromide (3.0 equiv.) in THF (2.0 mL), cat. (0.5 mol-%),
LiCl (2.0 equiv.), THF (2.0 mL), 24 h; yields based on 2-chloroani-
sole and assessed by GC.
complex c (Figure 2). A catalyst loading of 0.5 mol-% com- shortening the reaction time from 24 to 12 h did not affect
plex d was therefore established for the following studies. the yields (Entries 5 vs. 10), and 96% yield was obtained
We believe that the enhancement of “steric-bulk” in relation using 4-bromotoluene and phenylmagnesium bromide as
to the topography of the metal center is critical to the suc- substrates at room temperature (Entry 11).
cess of the palladacycle-catalyzed Kumada reactions, al-
though the exact reason for the superiority of complex d is timized conditions. The major disadvantage of the Kumada
not clear. reaction is the low tolerance of functional groups. There-
The range of substrates was then extended under the op-
We then investigated the influence of solvents, additives, fore, our preliminary study was focused on aryl bromides
and reaction temperature on the Kumada reaction. The re- with either functional groups or heteroatoms as substrates
action of 4-chlorotoluene with phenylmagnesium bromide at room temperature (Table 3). The reaction of 2-bromo-
was again chosen as a model reaction. As shown in Table 2, benzonitrile with p-tolylMgBr afforded the desired o-(p-
the cross-coupling product was obtained in 73% yield when tolyl)benzonitrile in 80% yield (Entry 1), which is a key
tetrahydrofuran (THF) was used as solvent (Entry 1). The intermediate in the synthesis of antihypertensive drugs.[12]
use of mixed solvents, such as THF/toluene, THF/dioxane, Gratifyingly, the Boc protecting group was also tolerated to
THF/N,N-dimethylformamide (DMF), only gave the prod- give the product 2, which is also an important drug inter-
uct in 52, 60, and 31% yields, respectively (Entries 2–4); the mediate (Entry 2).[13] Unactivated vinyl bromides were also
homocoupling product of the Grignard reagent was ob- applied to the Kumada coupling to provide the desired
served in all cases. The yields of cross-coupling product in- products. 1-(2-Bromovinyl)benzene and 2-bromo-1,1-di-
creased significantly in the presence of two equivalents of phenylethene substrates gave the corresponding products in
LiCl (Entries 1 vs. 5) and decreased when the reaction was 95 and 90% yields, respectively (Entries 4 and 5). So far,
carried out at room temperature (Entries 5 vs. 7). Moreover, coupling reactions of vinyl halides with Grignard reagents
Eur. J. Org. Chem. 2010, 2372–2378
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2373

G. Ren, X. Cui, Y. Wu
FULL PAPER
Table 2. Coupling reaction of 4-chlorotoluene with phenylmagnesium bromide.
Entry[a]
Solvent
Additive
T [°C]
Time [h]
Yield [%][b]
1
THF
–
60
60
60
60
60
r.t.
r.t.
60
60
60
r.t.
24
24
24
24
24
24
24
4
73
52
60
31
94
20
50
69
30
93
96
2
THF/toluene (1:1)
–
3
THF/dioxane (1:1)
–
–
4
THF/DMF (1:1)
THF
5
LiCl (2 equiv.)
–
6
THF
7
THF
LiCl (2 equiv.)
LiCl (2 equiv.)
LiCl (3 equiv.)
LiCl (2 equiv.)
LiCl (2 equiv.)
8
THF
9
THF
4
10
THF
12
12
11[c]
THF
[a] Reaction conditions: 4-chlorotoluene (1.0 mmol), PhMgBr (3.0 equiv.) in THF (2.0 mL), cat. d (0.5 mol-%), solvent (2.0 mL). [b] Yields
are based on aryl halides, and assessed by GC. [c] Reaction conditions: 4-bromotoluene (1.0 mmol), PhMgBr (3.0 equiv.) in THF (2.0 mL),
cat. d (0.5 mol-%), solvent (2.0 mL).
have rarely been reported.[5p,5u] Furthermore, the coupling
Table 4. Coupling of aryl chlorides with arylmagnesium halides.
of aryl Grignard reagents proceed smoothly with benzo-
thiophene, thiophene, and aldehyde-derived halides (Entries
3, 6, and 7).
Table 3. Coupling of aryl bromides with arylmagnesium halides at
room temperature.
[a] Reaction conditions: aryl bromide (1.0 mmol), ArMgBr
(3.0 equiv.) in THF (2.0 mL), cat. d (0.5 mol-%), LiCl (2.0 equiv.),
THF (2.0 mL), r.t., 12 h. [b] Isolated yields based on aryl bromides
after two runs.
[a] Reaction conditions: Aryl chloride (1.0 mmol), ArMgBr
We then investigated the Kumada coupling of aryl chlo-
(3.0 equiv.) in THF (2.0 mL), cat. d (0.5 mol-%), LiCl (2.0 equiv.),
THF (2.0 mL), 60 °C, 12 h. [b] Isolated yields based on aryl chor-
rides (Table 4). In all cases, aryl chlorides with both elec-
tron-withdrawing (such as CN and CF3) and electron-do- ides after two runs.
2374
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2372–2378

Efficient Synthesis of Unsymmetrical Biaryls
nating (such as CH3 and CH3O) groups gave excellent in 95% yield (Entry 2). (2,6-Dimethylphenyl)magnesium
yields (89–97%, Entries 1–7 and 9–13). Chloronaphthalene bromide coupled with chlorobenzene, 4-chlorotoluene, 2-
coupled with both phenylmagnesium bromide and (4-meth- chlorotoluene, 3-chloroanisole, 4-chloroanisole, and chloro-
oxyphenyl)magnesium bromide to afford the desired prod- naphthalene, to provide the desired products in 83–94%
ucts in 98 and 94% yields, respectively (Entries 8 and 14). yields (Entries 3–8). Biaryls 26 and 27 were obtained in 88
Moreover, increased steric bulk in the aryl chloride did not and 91% yields from the coupling of (2-methylnaphthyl)-
significantly affect the yields; for example, 2-chloro-m- magnesium bromide with chlorobenzene and 4-chloro-
xylene gave excellent yields (Entries 5 and 12). These results anisole, respectively (Entries 9 and 10). Moreover, tri-ortho-
prompted us to investigate the synthesis of more sterically substituted biaryls 23, 25, and 28 were obtained in good
hindered C–C biaryl compounds catalyzed by complex d.
yields from 2-chlorotoluene and chloronaphthalene upon
As shown in Table 5, this reaction system is capable of reaction with ortho-substituted Grignard reagents (Entries
efficiently synthesizing di- and tri-ortho-substituted biaryls, 5, 8, and 11).
even when electron-rich chlorides that are generally reluc-
tant to undergo oxidative addition under mild conditions,
were used as substrates. Coupling of 2-chloroanisole with
2-tolylmagnesium bromide gave the corresponding biaryl 21
Conclusions
In summary, we have found that complex d, which bears
a strongly electron-donating and sterically hindered carbene
moiety, is highly efficient for the cross-coupling of aryl ha-
lides with Grignard reagents in the presence of 0.5 mol-%
catalyst and two equivalents of LiCl under mild reaction
conditions. This reaction system tolerates various func-
tional groups, and could be efficiently applied to the synthe-
sis of di- and tri-ortho-substituted biaryls.
Table 5. Coupling of sterically hindered substrates.
Experimental Section
General: Melting points were measured with a XT-5 microscopic
apparatus. GC analyses were performed with an Agilent 4890D gas
chromatograph. 1H NMR and 13C NMR spectra were recorded
with a Bruker DPX 400 instrument using CDCl3 as the solvent and
TMS as the internal standard. Elemental analyses were conducted
with a Carlo Erba 1160 elemental analyzer. All chemicals were rea-
gent grade and used without further purification.
General Procedure for the Kumada Coupling Reaction: Aryl halide
(1.0 mmol), ArMgBr (3.0 mmol) in THF (2.0 mL), complex d
(0.5 mol-%), LiCl (2.0 mmol), and anhydrous THF (2.0 mL) were
added to an oven-dried flask under an N2 atmosphere. The reaction
was stirred at either r.t. or 60 °C. The reaction mixture was cooled
to r.t., quenched with HCl (1.0 ), and extracted three times with
dichloromethane. The combined organic phase was washed with
brine, dried with MgSO4, filtered, and concentrated under reduced
pressure. After purification by flash chromatography (petroleum
ether/ethyl acetate) the yields were assessed based on the amount
1
of aryl halide. The products were characterized by H NMR and
13C NMR analyses and the data were consistent with those re-
ported in the literature. The identities of the new compounds were
further confirmed by elemental analysis.
o-(p-Tolyl)benzonitrile (1):[14] White solid; m.p. 47–49 °C (ref.[14] 49–
51 °C). 1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 7.7 Hz, 1
H), 7.76–7.60 (m, 1 H), 7.50–7.39 (m, 4 H), 7.30–7.25 (m, 2 H),
2.41 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.4, 138.6,
135.2, 133.6, 132.7, 129.9, 129.4, 128.59, 128.55, 127.2, 118.8,
111.1, 21.2 ppm.
tert-Butyl 4-(4Ј-Methylbiphenyl-4-yl)piperazine-1-carboxylate (2):
White solid; m.p. 189–191 °C. 1H NMR (400 MHz, CDCl3): δ =
7.50 (d, J = 8.6 Hz, 2 H), 7.45 (d, J = 8.1 Hz, 2 H), 7.21 (d, J =
7.9 Hz, 2 H), 6.97 (d, J = 8.7 Hz, 2 H), 3.60–3.58 (m, 4 H), 3.18–
3.15 (m, 4 H), 2.37 (s, 3 H), 1.48 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 154.7, 150.2, 137.8, 136.2, 132.9, 129.4,
[a] Reaction conditions: Aryl chloride (1.0 mmol), ArMgBr
(3.0 equiv.) in THF (2.0 mL), cat. d (0.5 mol-%), LiCl (2.0 equiv.),
THF (2.0 mL), 60 °C, 24 h. [b] Isolated yields based on aryl chlo-
ride after two runs. [c] Reaction time: 12 h.
Eur. J. Org. Chem. 2010, 2372–2378
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2375

G. Ren, X. Cui, Y. Wu
FULL PAPER
127.6, 126.4, 116.7, 79.9, 49.3, 28.4, 21.0 ppm. C22H28N2O2: calcd.
C 74.97, H 8.01, N 7.95; found C 74.93, H 8.09, N 7.90.
7.58 (m, 2 H), 7.50–7.40 (m, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 145.7, 139.2, 132.6, 129.1, 128.6, 127.7, 127.2, 118.9,
110.9 ppm.
3-(4-Methylphenyl)benzothiophene (3): White solid; m.p. 120–
1
3-(Trifluoromethyl)biphenyl (14):[20] Colorless liquid. 1H NMR
(400 MHz, CDCl3): δ = 7.82 (s, 1 H), 7.72 (d, J = 7.6 Hz, 1 H),
7.59–7.55 (m, 3 H), 7.50 (t, J = 7.7 Hz, 1 H), 7.46–7.42 (m, 2 H),
7.38–7.35 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 142.0,
139.8, 131.0 (q, J = 32 Hz), 130.4, 129.3, 129.0, 128.8, 128.0, 127.2,
124.2 (q, J = 275.2 Hz), 122.9, 120.2 ppm.
121 °C. H NMR (400 MHz, CDCl3): δ = 8.01 (s, 1 H), 7.92 (d, J
= 8.4 Hz, 1 H), 7.59–7.55 (m, 3 H), 7.47 (d, J = 5.4 Hz, 1 H), 7.38
(d, J = 5.4 Hz, 1 H), 7.28 (d, J = 7.9 Hz, 2 H), 2.41 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 140.2, 138.5, 138.4, 137.6, 136.9,
129.5, 127.2, 126.9, 124.0, 123.8, 122.6, 121.7, 21.1 ppm. C15H12S:
calcd. C 80.31, H 5.39, S 14.29; found C 79.96, H 5.35, S 14.37.
(Z)-1-(4-Methylphenyl)-2-phenylethene (4):[15] Colorless oil. 1H
NMR (400 MHz, CDCl3): δ = 7.26–7.24 (m, 2 H), 7.21–7.15 (m, 3
H), 7.13 (d, J = 8.1 Hz, 2 H), 7.00 (d, J = 7.9 Hz, 2 H), 6.53 (s, 2
H), 2.28 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.4,
136.8, 134.2, 130.1, 129.5, 128.9, 128.84, 128.83, 128.80, 128.7,
128.14, 128.13, 126.9, 21.2 ppm.
2-(4-Methylphenyl)-1,1-diphenylethene (5):[16] Colorless oil. 1H
NMR (400 MHz, CDCl3): δ = 7.31–7.19 (m, 10 H), 6.93–6.91 (m,
5 H), 2.24 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 143.6,
141.7, 140.6, 136.6, 134.5, 130.4, 129.5, 128.79, 128.76, 128.7,
128.22, 128.18, 128.15, 127.6, 127.39, 127.36, 21.2 ppm.
1-Phenylnaphthalene (15):[19] Colorless liquid. 1H NMR (400 MHz,
CDCl3): δ = 7.87–7.83 (m, 2 H), 7.81–7.78 (m, 1 H), 7.48–7.44 (m,
6 H), 7.43–7.14 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
140.8, 140.3, 133.8, 131.7, 130.1 128.3, 127.7, 127.3, 127.0, 126.1,
125.8, 125.4 ppm.
4-Methoxy-4Ј-methylbiphenyl (16):[5n] Colorless solid; m.p. 117–
1
118 °C (ref.[5n] 107.9–108.1 °C). H NMR (400 MHz, CDCl3): δ =
7.51 (d, J = 8.7 Hz, 2 H), 7.45 (d, J = 8.0 Hz, 2 H), 7.23 (md, J =
8.0 Hz, 2 H), 6.96 (d, J = 8.7 Hz, 2 H), 3.84 (s, 3 H), 2.38 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 158.9, 138.0, 136.3, 133.7,
129.4, 127.9, 126.6, 114.1, 55.3, 21.0 ppm.
1
2-(1-Naphthyl)thiophene (6):[17] Colorless oil. H NMR (400 MHz,
4-Methoxy-2Ј-methylbiphenyl (17):[5n] Light-yellow liquid. 1H
NMR (400 MHz, CDCl3): δ = 7.25–7.19 (m, 6 H), 6.94 (d, J =
8.8 Hz, 2 H), 3.83 (s, 3 H), 2.27 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 158.5, 141.6, 135.5, 134.4, 130.3, 130.2, 129.9, 127.0,
125.8, 113.5, 55.3, 20.6 ppm.
CDCl3): δ = 8.23–8.21 (m, 1 H), 7.89–7.83 (m, 2 H), 7.56 (d, J =
6.9 Hz, 1 H), 7.51–7.46 (m, 3 H), 7.42–7.40 (m, 1 H), 7.245–7.236
(m, 1 H), 7.18–7.16 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 141.7, 133.8, 132.4, 131.8, 128.4, 128.3, 128.2, 127.4, 127.2,
126.4, 126.0, 125.7, 125.6, 125.2 ppm.
4Ј-Methoxy-2,6-dimethylbiphenyl (18):[21] White solid; m.p. 49–
50 °C (ref.[21] 52–53 °C). 1H NMR (400 MHz, CDCl3): δ = 7.14–
7.04 (m, 5 H), 6.96 (d, J = 8.5 Hz, 2 H), 3.85 (s, 3 H), 2.04 (s, 6 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 158.2, 141.5, 136.5, 133.3,
130.0, 127.2, 126.9, 113.8, 55.2, 20.9 ppm.
2-[4Ј-Methyl(1,1Ј-biphenyl)-2-yl]-1,3-dioxolane (7):[18] Colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.72–7.70 (m, 1 H), 7.40–7.38
(m, 2 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.28–7.21 (m, 3 H), 5.68 (s, 1
H), 4.18–4.15 (m, 2 H), 3.95–3.91 (m, 2 H), 2.40 (s, 3 H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 142.1, 137.0, 136.9, 134.5, 130.0,
129.5, 129.0, 128.7, 127.4, 126.5, 101.2, 65.4, 21.2 ppm.
4Ј-Methoxy-3-(trifluoromethyl)biphenyl (19):[5n] Colorless liquid. 1H
NMR (400 MHz, CDCl3): δ = 7.78 (s, 1 H), 7.70–7.68 (m, 1 H),
7.54–7.47 (m, 4 H), 7.00–6.96 (m, 2 H), 3.84 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 159.7, 141.6, 132.2, 131.1 (d, J =
31.8 Hz), 129.9, 129.2, 128.9, 128.2 (q, J = 272.2 Hz), 123.4 (q, J
= 3.8 Hz), 123.3 (q, J = 3.8 Hz), 114.4, 55.3 ppm.
4-Methylbiphenyl (8):[5q] White solid; m.p. 44–45 °C (ref.[5q] 43–
45 °C). 1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 7.4 Hz, 2
H), 7.49 (d, J = 8.0 Hz, 2 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.31 (t, J
= 7.3 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 2 H), 2.39 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 141.1, 138.3, 137.0, 129.4, 128.7,
127.0, 21.1 ppm.
2-Methylbiphenyl (9):[19] Colorless liquid. 1H NMR (400 MHz,
CDCl3): δ = 7.40–7.36 (m, 2 H), 7.32–7.29 (m, 3 H), 7.25–7.21 (m,
4 H), 2.25 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 142.0,
135.4, 130.4, 129.9, 129.3, 128.8, 128.1, 127.3, 126.8, 125.8, 20.5
ppm.
1-(4-Methoxyphenyl)naphthalene (20):[24] Solid; m.p. 115–117 °C
(ref.[24] 116–117 °C). 1H NMR (400 MHz, CDCl3): δ = 7.93–7.88
(m, 2 H), 7.83 (d, J = 8.2 Hz, 1 H), 7.52–7.45 (m, 2 H), 7.44–7.39
(m, 4 H), 7.04–7.01 (m, 2 H), 3.14 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 158.9, 139.9, 133.8, 133.1, 131.8, 131.1,
128.2, 127.3, 126.9, 126.1, 125.9, 125.7, 125.4, 113.7, 55.3 ppm.
2-Methoxy-2Ј-methylbiphenyl (21):[5t] Colorless liquid. 1H NMR
(400 MHz, CDCl3): δ = 7.33–6.94 (m, 8 H), 3.74 (s, 3 H), 2.14 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.6, 138.7, 136.8,
131.0, 130.9, 130.0, 129.6, 128.6, 127.3, 125.4, 120.5, 110.7, 55.4,
19.9 ppm.
1
2-Methoxybiphenyl (10):[5q] Colorless liquid. H NMR (400 MHz,
CDCl3): δ = 7.52 (d, J = 7.7 Hz, 2 H), 7.41–7.38 (m, 2 H), 7.32–
7.29 (m, 3 H), 7.04–6.96 (m, 2 H), 3.78 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 156.4, 138.5, 130.8, 130.7, 129.5, 128.6,
127.9, 126.9, 120.8, 111.2, 55.5 ppm.
2,6,4Ј-Trimethylbiphenyl (22):[22] Colorless liquid. 1H NMR
(400 MHz, CDCl3): δ = 7.21 (d, J = 7.8 Hz, 2 H), 7.14–7.12 (m, 1
H), 7.09–7.08 (m, 2 H), 7.02 (d, J = 8.0 Hz, 2 H), 2.39 (s, 3 H),
2.03 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 141.9, 138.1,
136.3, 136.2, 136.1, 129.2, 129.0, 127.3, 126.9, 21.3, 20.9 ppm.
4-Methoxybiphenyl (11):[5q] White solid; m.p. 84–86 °C (ref.[5q] 85–
87 °C). 1H NMR (400 MHz, CDCl3): δ = 7.56–7.52 (m, 4 H), 7.43–
7.39 (m, 2 H), 7.30–7.25 (m, 1 H), 6.99–6.97 (m, 2 H), 3.85 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.1, 140.8, 133.8,
128.7, 128.1, 126.7, 126.6, 114.2, 55.3 ppm.
2,6,2Ј-Trimethylbiphenyl (23):[5t] Colorless liquid. 1H NMR
(400 MHz, CDCl3): δ = 7.26–7.02 (m, 7 H), 1.96 (s, 3 H), 1.94 (s,
6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 141.1, 140.5, 135.8,
135.6, 129.9, 129.8, 129.3, 128.8, 127.2, 127.0, 126.9, 126.0, 125.5,
20.3, 19.4 ppm.
2,6-Dimethylbiphenyl (12):[5b] Colorless liquid. 1H NMR
(400 MHz, CDCl3): δ = 7.41–7.38 (m, 2 H), 7.32–7.29 (m, 1 H),
7.16–7.08 (m, 5 H), 2.02 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 141.9, 141.2, 136.1, 129.1, 128.5, 127.3, 127.1, 126.7,
20.9 ppm.
4-Cyanobiphenyl (13):[5n] White solid; m.p. 84–86 °C (ref.[5n] 85–
87 °C). 1H NMR (400 MHz, CDCl3): δ = 7.74–7.67 (m, 4 H), 7.60–
3Ј-Methoxy-2,6-dimethylbiphenyl (24):[22] Colorless liquid. 1H
NMR (400 MHz, CDCl3): δ = 7.31–7.27 (m, 1 H), 7.13–7.09 (m, 1
2376
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2372–2378

Efficient Synthesis of Unsymmetrical Biaryls
Frisch, F. Rataboul, A. Zapf, M. Beller, J. Organomet. Chem.
2003, 687, 403–409; h) M. Nakamura, K. Matsuo, S. Ito, B.
Nakamura, J. Am. Chem. Soc. 2004, 126, 3686–3687; i) T. Na-
gano, T. Hayashi, Org. Lett. 2004, 6, 1297–1299; j) L. M. Yang,
L. F. Huang, T. Y. Luh, Org. Lett. 2004, 6, 1461–1463; k) A. C.
Frisch, A. Zapf, O. Briel, B. Kayser, N. Shaikh, M. Beller, J.
Mol. Catal. A 2004, 214, 231–239; l) M. E. Limmert, A. H.
Roy, J. F. Hartwig, J. Org. Chem. 2005, 70, 9364–9370; m) T. J.
Korn, M. A. Schade, M. N. Cheemala, S. Wirth, S. A. Guev-
ara, G. Cahiez, P. Knochel, Synthesis 2006, 3547–3574; n) L.
Ackermann, A. Althammer, Org. Lett. 2006, 8, 3457–3460; o)
N. Roques, L. Saint-Jalmes, Tetrahedron Lett. 2006, 47, 3375–
3378; p) L. Ackermann, C. J. Gschrei, A. Althammer, M. Rie-
derer, Chem. Commun. 2006, 1419; q) F. Y. Tsai, B. N. Lin,
M. J. Chen, C. Y. Mou, S. T. Liub, Tetrahedron 2007, 63, 4304–
4309; r) G. M. Organ, M. Abdel-Hadi, S. Avola, N. Hadei, J.
Nasielski, J. C. O’Brien, C. Valente, Chem. Eur. J. 2007, 13,
150–157; s) R. Martin, S. L. Buchwald, J. Am. Chem. Soc.
2007, 129, 3844–3845; t) C. Wolf, H.-H. Xu, J. Org. Chem.
2008, 73, 162–167; u) Z.-X. Xi, B. Liu, W.-Z. Chen, J. Org.
Chem. 2008, 73, 3954–3957; v) C. E. Hartmann, S. P. Nolan,
S. J. C. Cazin, Organometallics 2009, 28, 2915–2919.
For Suzuki cross-couplings, see: a) N. Miyaura, A. Suzuki, Tet-
rahedron Lett. 1979, 20, 3437–3440; b) N. Miyaura, A. Suzuki,
Chem. Rev. 1995, 95, 2457–2483; c) A. Suzuki, J. Organomet.
Chem. 2002, 653, 83–90; d) J. Yin, M. P. Rainka, X.-X. Zhang,
S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 1162–1163; e)
J. F. Jensen, M. Johannsen, Org. Lett. 2003, 5, 3025–3028; f)
O. Navarro, R. A. Kelly, S. P. Nolan, J. Am. Chem. Soc. 2003,
125, 16194–16195; g) G. Altenhoff, R. Goddard, C. Lehmann,
F. Glorius, J. Am. Chem. Soc. 2004, 126, 15195–15201; h) R.
Singh, M. S. Viciu, N. Kramareva, O. Navarro, S. P. Nolan,
Org. Lett. 2005, 7, 1829–1832; i) N. Marion, O. Navarro, J.
Mei, E. D. Stevens, N. M. Scott, S. P. Nolan, J. Am. Chem. Soc.
2006, 128, 4101–4111.
H), 7.05 (d, J = 7.2 Hz, 2 H), 6.85–6.82 (m, 1 H), 6.70–6.65 (m, 2
H), 3.76 (s, 3 H), 2.00 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 159.6, 142.5, 141.7, 136.0, 129.4, 127.2, 127.0, 121.4, 114.5,
112.1, 55.2, 20.7 ppm.
1-(2,6-Dimethylphenyl)naphthalene (25):[23] White solid; m.p. 70–
71 °C (ref.[23] 71–72 °C). 1H NMR (400 MHz, CDCl3): δ = 7.90–
7.84 (m, 2 H), 7.55–7.51 (m, 1 H), 7.48–7.44 (m, 1 H), 7.33 (d, J
= 3.6 Hz, 2 H), 7.27–7.22 (m, 2 H), 7.17 (d, J = 7.5 Hz, 2 H), 1.90
(s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 139.6, 138.8,
137.0, 133.8, 131.8, 128.3, 127.33, 127.27, 127.2, 126.4, 126.0,
125.8, 125.7, 125.4, 20.4 ppm.
2-Methyl-1-phenylnaphthalene (26):[25] Colorless liquid. 1H NMR
(400 MHz, CDCl3): δ = 7.83 (d, J = 7.6 Hz, 1 H), 7.77 (d, J =
8.4 Hz, 1 H), 7.49–7.26 (m, 9 H), 2.23 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 139.8, 138.2, 133.1, 133.0, 131.9, 130.1,
128.6, 128.4, 128.3, 128.2, 127.7, 127.2, 127.0, 126.1, 125.8, 124.7
ppm.
1-(4-Methoxyphenyl)-2-methylnaphthalene (27):[26] White solid; m.p.
1
95–97 °C (lit.[26] 96–98 °C). H NMR (400 MHz, CDCl3): δ = 7.81
[6]
(d, J = 8.0 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.45–7.19 (m, 4 H),
7.17 (d, J = 1.9 Hz, 1 H), 7.02 (d, J = 8.6 Hz, 1 H), 3.88 (s, 3 H),
2.24 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.6, 137.8,
133.5, 133.3, 132.0, 131.9, 131.2, 128.6, 127.7, 127.1, 126.2, 125.7,
124.7, 113.8, 55.3, 20.9 ppm.
2-Methyl-1,1Ј-binaphthyl (28):[27] Colorless solid; m.p. 131–134 °C
(lit.[27] 132–134 °C). 1H NMR (400 MHz, CDCl3): δ = 7.92–7.82
(m, 5 H), 7.56–7.15 (m, 8 H), 2.08 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 137.6, 134.4, 133.8, 128.7, 128.4, 127.9,
127.8, 127.7, 127.6, 126.3, 126.2, 126.08, 126.06, 125.98, 125.95,
128.9, 125.7, 125.4, 124.9, 20.6 ppm.
[7]
For Stille cross-couplings, see: a) M. Kosugi, S. Sasazama, Y.
Shimizu, T. Migita, Chem. Lett. 1977, 301–302; b) D. Milstein,
J. K. Stille, J. Am. Chem. Soc. 1978, 100, 3636–3638; c) J. K.
Stille, Angew. Chem. 1986, 98, 504–519; d) C. Wolf, X. Mei, J.
Am. Chem. Soc. 2003, 125, 10651–10658; e) G. E. Tumambac,
C. Wolf, J. Org. Chem. 2004, 69, 2048–2055; f) W. Su, S. Ur-
gaonkar, P. A. McLaughlin, J. G. Verkade, J. Am. Chem. Soc.
2004, 126, 16433–16439; g) G. E. Tumambac, C. Wolf, J. Org.
Chem. 2005, 70, 2930–2938; h) X. Mei, R. M. Martin, C. Wolf,
J. Org. Chem. 2006, 71, 2854–2861.
Acknowledgments
We are grateful to the National Science Foundation of China
(NSFC) (20772114) and the National Science Foundation (NSF)
of Henan (082300423201) for the financial support of this research.
[1] a) L. Pu, Chem. Rev. 1998, 98, 2405–2494; b) X. Mei, C. Wolf,
Chem. Commun. 2004, 2078–2079; c) G. E. Tumambac, X. Mei,
C. Wolf, Eur. J. Org. Chem. 2004, 3850–3856; d) X. Mei, C.
Wolf, J. Am. Chem. Soc. 2004, 126, 14736–14737; e) G. E. Tum-
ambac, C. Wolf, Org. Lett. 2005, 7, 4045–4048; f) C. Wolf, S.
Liu, B. C. Reinhardt, Chem. Commun. 2006, 4242–4444; g) X.
Mei, C. Wolf, Tetrahedron: Asymmetry 2006, 47, 7901–7904; h)
X. Mei, C. Wolf, J. Am. Chem. Soc. 2006, 128, 13326–13327.
[2] O. Baudoin, F. Gueritte, Stud. Nat. Prod. Chem. 2003, 29, 355–
417.
[3] a) A. V. R. Rao, M. K. Gurjar, K. L. Reddy, A. S. Rao, Chem.
Rev. 1995, 95, 2135–2167; b) K. C. Nicolaou, C. N. C. Boddy,
S. Bräse, N. Winssinger, Angew. Chem. Int. Ed. 1999, 38, 2096–
2152; c) G. Bringmann, A. J. P. Mortimer, P. A. Keller, M. J.
Gresser, J. Garner, M. Breuning, Angew. Chem. Int. Ed. 2005,
44, 5384–5427.
[8]
For Negishi cross-couplings, see: a) A. O. King, N. Okukado,
E. Negishi, J. Chem. Soc., Chem. Commun. 1977, 683–684; b)
E. Negishi, A. O. King, N. Okukado, J. Org. Chem. 1977, 42,
1821–1823; c) E. Negishi, Acc. Chem. Res. 1982, 15, 340–348;
d) J. E. Milne, S. L. Buchwald, J. Am. Chem. Soc. 2004, 126,
13028–13032; e) M. Genov, B. Fuentes, P. Espinet, B. Pelaz,
Tetrahedron: Asymmetry 2006, 17, 2593–2595; f) M. Genov, A.
Almorin, P. Espinet, Tetrahedron: Asymmetry 2007, 18, 625–
627.
a) E. Negishi, Handbook of Organopalladium Chemistry for Or-
ganic Synthesis, Wiley, New York, 2002; b) A. de Meijere, F.
Diederich, Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.,
Wiley-VCH, Weinheim, Germany, 2004; c) G.-H. Fang, Z.-J.
Yan, J. Yang, M.-Z. Deng, Synthesis 2006, 1148–1154.
a) C. Xu, J.-F. Gong, S.-F. Yue, Y. Zhu, Y.-J. Wu, Dalton Trans.
2006, 4730–4739; b) J.-Y. Li, A.-J. Yu, Y.-J. Wu, Y. Zhu, C.-X.
Du, H.-W. Yang, Polyhedron 2007, 26, 2629–2637; c) J. Ma, X.-
L. Cui, B. Zhang, M.-P. Song, Y.-J. Wu, Tetrahedron 2007, 63,
5529–5538; d) M.-J. Cui, J.-Y. Li, A.-J. Yu, J.-L. Zhang, Y.-J.
Wu, J. Mol. Catal. A 2008, 290, 67–71.
a) S.-Q. Huo, Y.-J. Wu, C.-X. Du, Y. Zhu, H.-Z. Yuan, X.-A.
Mao, J. Organomet. Chem. 1994, 483, 139–146; b) I. P. Belets-
kaya, A. V. Cheprakov, J. Organomet. Chem. 2004, 689, 4045–
4082; c) J.-F. Gong, G.-Y. Liu, Y. Zhu, C.-X. Du, M.-P. Song,
Y.-J. Wu, Chem. J. Chin. Univ. 2006, 27, 1266–1271.
[9]
[10]
[4] K. Tamao, K. Sumitani, M. Kumada, J. Am. Chem. Soc. 1972,
94, 4374–4376.
[5] a) T. Kamikawa, T. Hayashi, J. Org. Chem. 1998, 63, 8922–
8925; b) J. K. Huang, S. P. Nolan, J. Am. Chem. Soc. 1999, 121,
9889–9890; c) V. Bonnet, F. Mongin, F. Trecourt, G. Queguiner,
P. Knochel, Tetrahedron Lett. 2001, 42, 5717–5719; d) J. Terao,
H. Watanabe, A. Ikumi, H. Kuniyasu, N. Kambe, J. Am. Chem.
Soc. 2002, 124, 4222–4223; e) A. C. Frisch, N. Shaikh, A. Zapf,
M. Beller, Angew. Chem. 2002, 114, 4218–4221; f) T. J. Korn,
G. Cahiez, P. Knochel, Synlett 2003, 1892–1894; g) A. C.
[11]
Eur. J. Org. Chem. 2010, 2372–2378
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2377

G. Ren, X. Cui, Y. Wu
FULL PAPER
[12] a) H. Kageyama, T. Miyazaki, Y. Kimura, Synlett 1994, 371– [19] Z.-X. Xi, B. Liu, W.-Z. Chen, J. Org. Chem. 2008, 73, 3954–
372; b) J. A. Miller, R. P. Farrell, Tetrahedron Lett. 1998, 39, 3957.
6441–6444; c) P. Walla, C. O. Kappe, Chem. Commun. 2004, [20] M. A. D. Heiden, H. Plenio, Chem. Eur. J. 2004, 10, 1789–1797.
564–565.
[21] D. Stefano, Synthesis 2006, 1117–1123.
[22] R. Singh, M. S. Viciu, N. Kramareva, O. Navarro, S. P. Nolan,
Org. Lett. 2005, 7, 1829–1832.
[23] C. J. O’Brien, E. A. B. Kantchev, C. Valente, N. Hadei, G. A.
Chass, A. Lough, A. C. Hopkinson, M. G. Organ, Chem. Eur.
J. 2006, 12, 4743–4748.
[24] L. Q. Wang, W. J. Lu, Org. Lett. 2009, 11, 1079–1082.
[25] A. C. Glass, B. B. Morris, L. N. Zakharov, S.-Y. Liu, Org. Lett.
2008, 10, 4855–4857.
[26] A. N. Cammidge, V. H. M. Goddard, H. Gopee, N. L. Har-
rison, D. L. Hughes, C. J. Schubert, B. M. Sutton, G. L. Watts,
A. J. Whitehead, Org. Lett. 2006, 8, 4071–4074.
[27] R. P. J. Bronger, P. J. Guiry, Tetrahedron: Asymmetry 2007, 18,
1094–1102.
[13] a) L. C. Meurer, R. L. Tolman, E. W. Chapin, R. Saperstein,
P. P. Vicario, M. M. Zrada, M. MacCoss, J. Med. Chem. 1992,
35, 3845–3857; b) C. Tahtaoui, I. Parrot, P. Klotz, F. Guillier,
J. L. Galzi, M. Hibert, B. Ilien, J. Med. Chem. 2004, 47, 4300–
4315; c) H.-L. Zheng, M. W. Lev, B. A. Orit, E. Silvina, Z. I.
Cabantchik, W. Abraham, B. H. Y. Moussa, F. Mati, Bioorg.
Med. Chem. 2005, 13, 773–783.
[14] M. Lombardo, M. Chiarucci, C. Trombini, Green Chem. 2009,
11, 574–579.
[15] H. Zhao, Y. Wang, J.-C. Sha, S.-R. Sheng, M.-Z. Cai, Tetrahe-
dron 2008, 64, 7517–7523.
[16] E. F. Corsico, R. A. Rossi, J. Org. Chem. 2004, 69, 6427–6432.
[17] S. E. Denmark, J. D. Baird, Org. Lett. 2006, 8, 793–795.
[18] N. Kokuni, T. Yamane, T. Nakamura, M. Watanabe, Jpn. Ko-
kai Tokkyo Koho 1996, JP 08231454, 19960910.
Received: December 23, 2009
Published Online: March 11, 2010
2378
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2372–2378