Cp2Ni-KOt-Bu-BEt3 (or PPh3) catalyst system for direct C - H arylation of benzene, naphthalene, and pyridine

Article abstract of DOI:10.1021/ol900778m

Ni-catalyzed direct C - H arylation of benzene and naphthalene using aryl halides was investigated. For the first time, the arylation was successfully catalyzed by Cp₂Ni (5 mol %) in the presence of KOt-Bu and BEt ₃. This Ni catalyst system was also applied to direct C - H arylation of pyridine, an electron-deficient heteroarene; PPh₃ was used instead of BEt₃ in this case.

Full text of DOI:10.1021/ol900778m

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2679-2682
Cp2Ni-KOt-Bu-BEt3 (or PPh3) Catalyst
System for Direct C-H Arylation of
Benzene, Naphthalene, and Pyridine
Osamu Kobayashi, Daisuke Uraguchi,† and Tetsu Yamakawa*
Sagami Chemical Research Center, 2743-1 Hayakawa, Ayase,
Kanagawa 252-1193, Japan
t_yamakawa@sagami.or.jp
Received April 10, 2009
ABSTRACT
Ni-catalyzed direct C-H arylation of benzene and naphthalene using aryl halides was investigated. For the first time, the arylation was successfully
catalyzed by Cp2Ni (5 mol %) in the presence of KOt-Bu and BEt3. This Ni catalyst system was also applied to direct C-H arylation of pyridine,
an electron-deficient heteroarene; PPh3 was used instead of BEt3 in this case.
Metal-catalyzed intermolecular coupling of arenes is one of
the useful methods in organic synthesis of biaryls.1 Recently,
catalytic direct C-H arylation of arenes using aryl halides,
tosylates, or triflates for biaryl synthesis has attracted
considerable attention as this process is environmentally
benign. So far, many examples of direct C-H arylation of
arenes having various functional groups have been reported.
The arylation occurs selectively at the ortho-position of an
N- or O-containing functional group by Ru,2 Pd,3 or Rh4
catalysts. The highly acidic C-H bonds of highly fluorinated
benzenes are arylated by aryl halides with Cu5 or Pd6
catalyst. Rh-catalyzed arylation of anisole using p-nitroiodo-
benzene provides a mixture of 2′-methoxy-4-nitrobiphenyl
and 4′-methoxy-4-nitorobiphenyl; the ratio of this ortho- and
para-isomer is consistent with the orientation of electrophilic
metalation.7
In contrast, metal-catalyzed direct C-H arylation of
unfunctionalized simple aromatic hydrocarbons using aryl
halides has been reported in only a few studies: Pd-catalyzed
arylation of benzene,8,9 naphthalene,8 and azulene10 and Ir-
¨
(2) (a) Ozdemir, I.; Demir, S.; Cetinkaya, B.; Gourlaouen, C.; Maseras,
F.; Bruneau, C.; Dixneuf, P. H. J. Am. Chem. Soc. 2008, 130, 1156–1157.
(b) Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008, 10, 2299–
2302. (c) Ackermann, L.; Althammer, A.; Born, R. Angew. Chem., Int. Ed.
2006, 45, 2619–2622. (d) Ackermann, L. Org. Lett. 2005, 7, 3123–3125.
(e) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue, Y. Org.
Lett. 2001, 3, 2579–2581
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(3) (a) Ackermann, L.; Althammer, A.; Fenner, S. Angew. Chem., Int.
Ed. 2009, 48, 201–204. (b) Shabashov, D.; Daugulis, O. J. Org. Chem.
2007, 72, 7720–7725. (c) Chiong, H. A.; Pham, Q.-N.; Daugulis, O. J. Am.
Chem. Soc. 2007, 129, 9879–9884. (d) Lazareva, A.; Daugulis, O. Org.
Lett. 2006, 8, 5211–5213. (e) Kalyani, D.; Deprez, N. R.; Desai, L. V.;
Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330–7331. (f) Kawamura,
Y.; Satoh, T.; Miura, M.; Nomura, M. Chem. Lett. 1999, 961–962. (g) Satoh,
T.; Inoh, J.; Kawamura, Y.; Kawamura, Y.; Miura, M.; Nomura, M. Bull.
Chem. Soc. Jpn. 1998, 71, 2239–2246. (h) Satoh, T.; Kawamura, Y.; Miura,
† Present address: Nagoya University, Graduate School of Engineering,
Department of Applied Chemistry, Furo-cho, Chikusa, Nagoya, Aichi
464-8603, Japan.
(1) Recent book and reviews: (a) Modern Aryation Methods; Ackermann,
L., Ed.; VCH: Weinheim, 2009. (b) Lewis, J. C.; Bergman, R. G.; Ellman,
J. A. Acc. Chem. Res. 2008, 41, 1013–1025. (c) Li, B.-J.; Yang, S.-D.; Shi,
Z.-J. Synlett 2008, 949–957. (d) Chinchilla, R.; Na´jera, C. Chem. ReV. 2007,
107, 874–922. (e) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007,
107, 174–238. (f) Yin, L.; Liebscher, J. Chem. ReV. 2007, 107, 133–173.
(g) Ackermann, L. Synlett 2007, 507–526. (h) Campeau, L.-C.; Stuart, D. R.;
Fagnou, K. Aldrichimica Acta 2007, 40, 35–41. (i) Daugulis, O.; Zaitsev,
V. G.; Shabashov, D.; Pham, Q.-N.; Lazareva, A. Synlett 2006, 3382–3388.
(j) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006, 4, 4041–4047.
M.; Nomura, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1740–1742
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10.1021/ol900778m CCC: $40.75
Published on Web 05/19/2009
 2009 American Chemical Society

catalyzed arylation of benzene.11 It should be noted that Pd
and Ir are the only metals used as catalysts.
Table 2. Coupling of Benzene and Various Aryl or Pyridyl
The first C-H activation of an arene by Ni was reported
in 1963: the ortho metalation of diazobenzene by Cp2Ni.12
Thereafter, Ni-catalyzed reactions including C-H activation
of some aryl compounds other than the synthesis of biaryls
have been reported.13 Very recently, Ni-catalyzed direct
arylation of the C-H bond in heteroarenes using aryl halides
or triflates was explored for the first time;14 these reactions
are noteworthy from an economical viewpoint as well.
In this study, we investigated direct C-H arylation of
unfunctionalized simple aromatic hydrocarbons such as
benzene and naphthalene using aryl halides with Ni com-
pounds as a catalyst and found that a combination of Cp2Ni,
KOt-Bu, and BEt3 is an effective catalyst system for the
arylation. Moreover, when PPh3 was used instead of BEt3,
this Ni catalyst system was also effective in direct C-H
arylation of pyridine using aryl halides.15
Halidesa
First we examined arylation of benzene using 4-bromoanisole
(Table 1). When Cp2Ni (0.025 mmol) and 4-bromoanisole (0.5
Table 1. Coupling of Benzene and 4-Bromoanisole with Ni
Compoundsa
entry
Ni compound
additive I
additive II
yield (%)b
1
Cp2Ni
Cp2Ni
-
-
-
0
76
0
0
0
trace
7
0
0
trace
0
0
2
KOt-Bu
KOt-Bu
KOt-Bu
BEt3
BEt3
-
3
4
Cp2Ni
Cp2Ni
Cp2Ni
Cp2Ni
Cp2Ni
Cp2Ni
Cp2Ni
Cp2Ni
Cp2Ni
Cp2Ni
Cp2Ni
Cp2Ni
Cp2Ni
Cp2Ni
Cp2Ni
Cp2Ni
Cp2Ni
Ni(acac)2
NiF2
5
BEt3
BEt3
BEt3
BEt3
BEt3
BEt3
BEt3
BEt3
BBu3
BH3·THF
9-BBN
AIBN
AlMe3
AlEt3
ZnEt2
PPh3
BEt3
BEt3
BEt3
BEt3
BEt3
BEt3
-
6
KOMe
7
KOEt
8
K2CO3
9
K3PO4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25d
26e
KOAc
LiOt-Bu
NaOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
46
14
54
0
a Benzene 5.0 mL (56 mmol), X-Ar 0.5 mmol. b Isolated yield.
3
15
12
2-3c
37
47
25
45
50
32
(entry 2). Since the use of the two additives in the absence of
Cp2Ni did not yield any desired product (entry 3), it can be
concluded that Cp2Ni is indispensable for the arylation. We
believe this is the first example of a Ni-catalyzed direct C-H
arylation of an unfunctionalized simple aromatic hydrocarbon.
When either KOt-Bu or BEt3 was absent, the arylation did not
take place (entries 4 and 5): this strongly suggests that Cp2Ni,
KOt-Bu, and BEt3 are all essential for the arylation. The use of
other potassium salts (entries 6-10) or tert-butoxides (entries
11 and 12) as additiVe I and radical initiators or reductants other
than BEt3 as additiVe II (entries 13-20) either afforded a small
amount of the desired product or did not yield the desired
product at all. Although other Ni compounds including a Ni(0)
complex, Ni(cod)2, gave 4-methoxybiphenyl in the presence of
KOt-Bu or BEt3, the yield of the desired product obtained by
NiBr2
Ni(cod)2
Cp2Ni
Cp2Ni
a Benzene 5.0 mL (56 mmol), 4-bromoanisole 0.5 mmol. b GC yield.
c 100-150 °C. d Benzene 3.0 mL (34 mmol). e Benzene 1.0 mL (11 mmol).
mmol) were dissolved in benzene (5.0 mL, 56 mmol) and the
resulting solution was heated at 80 °C for 12 h, 4-methoxybi-
phenyl was not obtained (entry 1). The addition of 1.5 mmol
of KOt-Bu (additiVe I) and 0.025 mmol of BEt3 (additiVe II)
was found to provide the desired product in moderate yield
2680
Org. Lett., Vol. 11, No. 12, 2009

Table 3. Coupling of Naphthalene and Various Aryl Halidesa
Table 4. Coupling of Pyridine and Various Aryl Halidesa
a Pyridine 2.5 mL (31 mmol), X-Ar 0.5 mmol. b The sum of the isolated
yields of 2-, 3-, and 4-isomers. c Calculated from the isolated yields of 2-,
3-, and 4-isomers.
and 2-isomer ratios were obtained. Nu´n˜ez and co-workers
reported that the reaction with naphthalene and the pyridyl
radical formed from 2-bromopyridine by AIBN and tris(t-
rimethylsilyl)silane produced a mixture of the 1-isomer and
2-isomer with the ratio of 3.0.16 The 1- and 2-isomer ratios
of 3.0-4.8 were observed in electrophilic Pd-catalyzed direct
C-H arylation of naphthalene using various aryl iodides.8
Finally, we applied this Ni catalyst system to direct C-H
arylation of pyridine with various aryl bromides. On compar-
ing this reaction to the arylation of benzene and naphthalene,
the reaction condition for moderate yield in this reaction is
slightly different: (1) the higher reaction temperature (100
°C) was required, (2) 1.0 equiv of KOt-Bu was sufficient,
and (3) as additiVe II, PPh3 was superior to BEt3.17 Table 4
shows the results of the arylation of pyridine. The product
was a mixture of 2-, 3-, and 4-arylpyridines, and the ratio of
these isomers ranged from approximately 2:2:1 to 4:4:1. The
formation of 3- and 4-arylpyridine indicates that the arylation
of pyridine does not proceed through ortho metalation,18
which should provide only 2-arylpyridine selectively. More-
over, the ratios of 2-, 3-, and 4-arylpyridine in Table 4 differ
a Naphthalene 1.60 g (12.5 mmol), X-Ar 1.0 mmol. b Heating at 80
°C results in a homogeneous solution (see Supporting Information). c The
sum of the isolated yields of 1- and 2-isomers. d Calculated from the isolated
yields of 1- and 2-isomers.
the use of Cp2Ni was the highest among those of all catalysts
(entries 21-24). The use of a smaller amount of benzene than
5 mL afforded lower yields (entries 25 and 26).
Table 2 lists the yields of products by arylation of benzene
using various aryl halides with a Cp2Ni-KOt-Bu-BEt3 catalyst
system. 4-Methoxybiphenyl and 4-methylbiphenyl were
obtained moderately from the corresponding 4-iodoanisole
or 4-bromoanisole and 4-iodotoluene or 4-bromotoluene
(entries 1, 2, 4, and 5), while the reaction using 4-chloro-
toluene or 4-chloroanisole afforded the desired products in
rather low yield (entries 3 and 6). This trend in the yield of
the desired products is consistent with reactivity of aryl
halides in coupling via oxidative addition of aryl halides,
Ar-I, Ar-Br > Ar-Cl. The yield obtained with 2-bromo-
toluene was lower than those with 3- and 4-bromotoluene,
presumably due to steric hindrance. This Ni catalyst system
could also be used for arylation using bromopyridines, giving
moderate yields (entries 12 and 13).
(9) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496–
16497.
(10) Dyker, G.; Borowski, S.; Heiermann, J.; Ko¨rning, J.; Opwis, K.;
Henkel, G.; Ko¨ckerling, M. J. Organomet. Chem. 2000, 606, 108–111.
(11) Fujita, K.; Nonogawa, M.; Yamaguchi, R. Chem. Commun. 2004,
1926–1927.
(12) Kleiman, J. P.; Dubeck, M. J. Am. Chem. Soc. 1963, 85, 1544–
1545.
Naphthalene was also arylated by a Cp2Ni-KOt-Bu-BEt3
catalyst system, and the product was obtained in moderate
yield (Table 3). The product was a mixture of 1-arylnaph-
thalene and 2-arylnaphthalen, and the ratio of the 1- and
2-isomer ranged from 2.3 to 3.8. In the previously reported
C-H arylation of naphthalene using aryl halides, similar 1-
(13) (a) Nakao, Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama, T. J. Am.
Chem. Soc. 2008, 130, 16170–16171. (b) Kanyiva, K. S.; Nakao, Y.;
Hiyama, T. Angew. Chem., Int. Ed. 2007, 46, 8872–8874. (c) Keen, A. L.;
Johnson, S. A. J. Am. Chem. Soc. 2006, 128, 1806–1807.
(14) (a) Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009,
11, 1737–1740. (b) Canivet, J.; Yamaguchi, J.; Ban, I.; Itami, K. Org. Lett.
2009, 11, 1733–1736.
(15) Li, M.; Hua, R. Tetrahedron Lett. 2009, 50, 1478–1481.
Org. Lett., Vol. 11, No. 12, 2009
2681

from those previously observed in the arylation of pyridine
with an aryl radical formed from an aryl halide by Au
catalyst15 or by microwave irradiation.19 We now consider
that the mechanism seems so complex and cannot be
presumed from the isomer ratios in Table 3 and Table 4 in
this way. A detailed investigation of the mechanism is
currently in progress.
In summary, we demonstrated the Ni-catalyzed direct
C-H arylation of unfunctionalized aromatic hydrocarbons
using aryl halides. To the best of our knowledge, this is the
first time this reaction has been successfully carried out. The
catalyst system consists of Cp2Ni, KOt-Bu, and BEt3, and
all the components have been found to be indispensable for
the arylation. We were able to apply this Ni catalyst system
to the direct C-H arylation of pyridine; PPh3 was more
favorable than BEt3. Because the catalyst is inexpensive, the
process presented in this paper is more economical than the
processes in the previous report.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL900778M
(18) (a) Cotton, F. A.; Poli, R. Organometallics 1987, 6, 1743–1751.
(b) Beringhelli, T.; Carlucci, L.; D’Alfonso, G.; Ciani, G.; Proserpio, D. M.
J. Organomet. Chem. 1995, 504, 15–26.
(16) Nu´n˜ez, A.; Sa´nchez, A.; Burgos, C.; Alvarez-Builla, J. Tetrahedron
2004, 60, 6217–6224.
(17) The use of BEt3 (5.0 mol % of an aryl halide) instead of PPh3
afforded 62% yield under the same conditions of Table 4.
(19) Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett. 2008,
10, 4673–4676.
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Org. Lett., Vol. 11, No. 12, 2009