Received: October 8, 2015 | Accepted: October 10, 2015 | Web Released: October 20, 2015
CL-150936
Nickel-catalyzed Cross-coupling of Anisole Derivatives with Trimethylaluminum
through the Cleavage of Carbon-Oxygen Bonds
Toshifumi Morioka,1 Akihiro Nishizawa,1 Keisuke Nakamura,1 Mamoru Tobisu,*1,2,3 and Naoto Chatani*1
1Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871
2Center for Atomic and Molecular Technologies, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871
3ESICB, Kyoto University, Katsura, Kyoto 615-8510
(E-mail: tobisu@chem.eng.osaka-u.ac.jp, chatani@chem.eng.osaka-u.ac.jp)
Table 1. Optimization of reaction conditionsa
Nickel-catalyzed cross-coupling of methoxyarenes with
trimethylaluminum is described. The use of 1,3-dicyclohexyl-
imidazol-2-ylidene as a ligand and NaOtBu as a base promotes
the methylation of anisole derivatives via the cleavage of
normally unreactive aryl carbon-oxygen bonds.
[Ni(cod)2]
ICy·HCl
AlMe3
5 mol%
5 mol%
1 equiv
OMe
Me
NaOtBu
2 equiv
Ph
toluene
Ph
80 °C, 18 h
1
2
standard conditions
GC yields/%
Methoxyarene is a common structural motif found in natural
and unnatural organic molecules. It is therefore important to
develop catalytic methods that can elaborate anisole derivatives.
Although the synthetic methods for the conversion of anisole
derivatives are dominated by the functionalization of aromatic
C-H bonds, catalytic substitution of a methoxy group in anisole
derivatives has recently attracted much attention as a new tool
for organic synthesis.1,2 Despite the advances made in the last
decade, the diversity of the nucleophile used for methoxy
substitution still remains limited because of the inertness of
C(aryl)-O bonds in anisole derivatives compared with those in
aryl sulfonates and carboxylates. To date, the nucleophiles
that can be used for the substitution of methoxyarenes include
Grignard,3-5 organolithium,6 organoboron,7 organozinc,8 hy-
dride,9 amine,10 and boron11 reagents. It has been reported that
the scope of aryl ether substrates strongly depends on the nature
of the nucleophile, probably because it influences the mecha-
nism of the key C-O bond cleavage process, as indicated by
several theoretical studies.9d,12 Therefore, systematic exploration
of the various nucleophiles used in nickel-catalyzed cross-
coupling of aryl ethers is of fundamental importance to
understand the nickel-mediated activation of inert C-O bonds.
We report herein the first cross-coupling of anisole derivatives
with an organoaluminum reagent: methylation using trimethyl-
aluminum (AlMe3).13
Entry
Variation from standard conditions
2
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14b
none
97
0
without [Ni(cod)2], ICy¢HCl
without ICy¢HCl
PCy3 instead of ICy¢HCl
0
3
5
39
14
6
10
8
85
56
60
43
15
50
68
65
66
32
0
IPr¢HCl instead of ICy¢HCl
IMes¢HCl instead of ICy¢HCl
ItBu¢HCl instead of ICy¢HCl
[Ni(acac)2] instead of [Ni(cod)2]
Ni(OAc)2 instead of [Ni(cod)2]
DABCO¢2AlMe3 instead of AlMe3
AlMe3 0.33equiv instead of 1.0 equiv
Al(OEt)Me2 instead of AlMe3
NaOtBu (10 mol %) instead of 2 equiv
ICy¢HBF4 instead of ICy¢HCl
23
48
93
0
88
0
>99 (99)
N
N
R
R
Me3Al
N
N AlMe3
ICy (R = cyclohexyl)
(R = 2,6-iPr2C6H3)
IPr
DABCO·2AlMe3
(R = 2,4,6-Me C H )
IMes
3
6 2
ItBu (R = tBu)
aReaction conditions: 1 (0.25 mmol), AlMe3 (0.25 mmol), [Ni(cod)2]
(0.013 mmol), ligand (0.013 mmol), NaOtBu (0.50 mmol) in toluene
(1.0 mL) for 6 h at 80 °C. The reaction was performed for 6 h instead
b
of 18 h, and the yield in parentheses is the isolated yield.
We first examined the nickel-catalyzed methylation of 4-
methoxybiphenyl (1) with AlMe3 (Table 1). After screening
various conditions, it was found that the reaction of 1
(0.25 mmol) with AlMe3 (0.25 mmol, 1.8 M solution in toluene)
in the presence of [Ni(cod)2] (5 mol %) and ICy¢HCl (5 mol %,
ICy: 1,3-dicyclohexylimidazol-2-ylidene) in toluene at 80 °C for
18 h gave 4-methylbiphenyl (2) in 97% yield according to GC
analysis (Entry 1). The methylation did not proceed in the
absence of a nickel catalyst, which excludes a pathway via the
SNAr mechanism (Entry 2).14 Replacing the ICy ligand with
PCy32 (Entry 4) or other NHCs (Entries 5-7) led to a substantial
decrease in the yield of 2, highlighting the prominent ability of
ICy to activate C-OMe bonds.4b,5,7c Methylation occurred much
less efficiently when [Ni(acac)2] or Ni(OAc)2 was used as the
catalyst precursor instead of [Ni(cod)2] (Entries 8 and 9).
product under these conditions. Although the yield of 2
decreased to 48% when 0.33 equiv of AlMe3 was used
(Entry 11), the use of Al(OEt)Me2 (1.66 M in toluene solution)
in place of AlMe3 afforded 2 in 93% yield (Entry 12). The
amount of base added is critical, as evidenced by the fact that no
methylated product 2 was formed when the amount of NaOtBu
was decreased to 10 mol % (Entry 12).
Having optimized the reaction conditions, we explored the
scope of this nickel-catalyzed cross-coupling of aryl methyl
ethers with AlMe3 (Table 2). The effect of the alkoxy group on
the methylation reaction was then examined. Primary alkoxy
groups, including EtO and the longer nC8H17O groups, were
efficiently methylated under these conditions, as exemplified by
the reactions of 3b and 3c. Notably, the bulkier iPrO group also
underwent this methylation efficiently (3d), whereas the PhO
15
Air-stable DABCO¢2AlMe3 (Entry 10) and AlEt3 (data not
shown) did not provide the corresponding cross-coupling
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