Angewandte
Chemie
DOI: 10.1002/anie.201402922
Aryl Ether Cross-Coupling
ꢀ
Metal-Catalyzed Dealkoxylative Caryl Csp3 Cross-Coupling—
Replacement of Aromatic Methoxy Groups of Aryl Ethers by
Employing a Functionalized Nucleophile**
Matthias Leiendecker, Chien-Chi Hsiao, Lin Guo, Nurtalya Alandini, and Magnus Rueping*
ꢀ
Abstract: The direct replacement of aromatic methoxy groups
with activated carbon nucleophiles would give rise to novel
synthetic pathways for targeted and diversity-oriented synthe-
ses. We demonstrate here that this transformation can be
achieved in a one-step reaction involving a bifunctional
ments given the high stability of the CAr O bond, the
availability of diverse natural anisoles, and the ecological
and economic advantages over aromatic halides as cross-
coupling electrophiles.[12] However, methoxy-group-replacing
ꢀ
CAr Csp3 bond-forming reactions are so far limited to meth-
ꢀ
organolithium nucleophile in combination with a CAr OMe
ylations.
bond-cleaving nickel catalyst. The resulting products are
stable, a-CH active, and suitable for various further modifi-
cations.
The ability to substitute the methoxy group with an
activated carbon atom (Scheme 1) would open a pathway to
novel and simple synthetic strategies. One could, for example,
T
he ability to activate aromatic systems while being inert
towards common cross-coupling catalysts is a key feature of
methoxy groups.[1] Synthetic applications include the optimi-
zation of activity and regioselectivity in electrophilic aromatic
substitutions such as Friedel–Crafts-type reactions,[2] ortho-
metalation,[3] and transition-metal-catalyzed cross-coupling
reactions.[4]
Scheme 1. Concept of the methoxy-group-replacing aryl functionaliza-
tion.
During our attempts to synthesize gephyrotoxin, we
realized that the option to replace an aromatic methoxy
group with a functional carbon moiety in the 5-methoxy-
tetrahydroquinoline framework could lead to a tremendous
shortcut in one of the rationalized synthetic pathways.[5] Since
a method as such did not exist, but would be a powerful and
ꢀ
design syntheses where the methoxy group first acts as
a directing and/or an activating group and is subsequently
replaced by a functional moiety. This concept could be
beneficial for targeted as well as diversity-oriented syntheses
and could ideally be applied to a wide range of substrates.
With the aim of transforming this concept into a synthetic
method we searched for potential catalysts and nucleophiles.
The latter could consist of a bifunctional CH2 moiety, for
example organometallic species, necessary for the replace-
ment of the methoxy group, and a direct or indirect a-C-
activating group. Thus, we decided to target ArCH2SiMe3
products since they are stable and offer various options for
subsequent transformations (Scheme 2) and are at the same
time inert towards common cross-coupling catalysts.[13–20]
With these considerations in mind we began to evaluate
MCH2SiMe3 nucleophiles in the presence of readily available
nickel catalysts. Grignard reagents of the XMgCH2SiMe3 type
showed reduced reactivity because of the trimethylsilane
(TMS) functionality. Organolithium reagents had so far not
been successfully applied in methoxy-group-replacing cou-
pling reactions because of their high reactivity and fast
decomposition under the coupling conditions.[21] However,
LiCH2SiMe3 proved to be a good nucleophile under the
reaction conditions.
generally useful synthetic tool, we decided to study CAr
bond-cleavage reactions. Wenkert et al. reported in 1979
nickel-catalyzed reaction of anisoles with aromatic
O
a
Grignard reagents that afforded biaryls.[6] The initially limited
scope was expanded in 2004 by Dankwardt, who found
a significant improvement in the reactivity with PCy3 ligands
(Cy = cyclohexyl).[7] Furthermore, Shi and co-workers
reported a one-step methylation procedure through the use
of methylmagnesium bromide.[8] However, a general alkyla-
tion method is not known due to the dominating b-H
elimination side reaction.[9,10]
More recently, the reductive cleavage of aromatic
methoxy groups with hydride donors in the presence of a Ni
catalyst gained attention.[11] These are important advance-
[*] Dipl.-Chem. M. Leiendecker, M. Sc. C.-C. Hsiao, M. Sc. L. Guo,
N. Alandini, Prof. Dr. M. Rueping
Institut fꢀr Organische Chemie, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
To our delight the reaction of LiCH2SiMe3 with 2-
methoxynaphthalene in the presence of [NiCl2(PCy3)2] in
toluene at 808C yielded 93% of the corresponding product 3a
(Table 1, entry 1). The yield could even be increased to 99%
when the catalytic complex was formed in situ from [Ni(cod)2]
(cod = 1,5-cyclooctadiene) and PCy3 (Table 1, entry 2). Fur-
thermore, the same result could be achieved with only
E-mail: magnus.rueping@rwth-aachen.de
[**] M.L. was supported by a Kekulꢁ fellowship (Fonds der Chemischen
Industrie) and the Studienstiftung des Deutschen Volkes, C.-C.H.
was supported by a DAAD fellowship, L.G. was supported by the
China Scholarship Council.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!