Nickel-Catalyzed Formal Homocoupling of Methoxyarenes for the Synthesis of Symmetrical Biaryls via C-O Bond Cleavage

Article abstract of DOI:10.1021/acs.orglett.5b03151

A new method has been developed for the nickel-catalyzed homocoupling of methoxyarenes via C-O bond cleavage using a diboron reagent. The use of 1,3-dicyclohexylimidazol-2-ylidene as a ligand was found to be critical to the success of the reaction. This new method allows the synthesis of a wide range of biaryl compounds.

Full text of DOI:10.1021/acs.orglett.5b03151

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Formal Homocoupling of Methoxyarenes for the
Synthesis of Symmetrical Biaryls via C−O Bond Cleavage
Keisuke Nakamura,† Mamoru Tobisu,*,†,‡ and Naoto Chatani*,†
†Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
‡Center for Atomic and Molecular Technologies, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: A new method has been developed for the nickel-catalyzed
homocoupling of methoxyarenes via C−O bond cleavage using a diboron reagent.
The use of 1,3-dicyclohexylimidazol-2-ylidene as a ligand was found to be critical to
the success of the reaction. This new method allows the synthesis of a wide range of
biaryl compounds.
iven the numerous applications of biaryl substructures
across a broad range of fields, including pharmaceuticals
Our ongoing interest in the catalytic transformation of aryl
ethers7b,8 led us to investigate the borylation of 1 using the
diboron reagent 2. When Ni(cod)2 was used as a catalyst in
conjunction with 1,3-dicyclohexylimidazol-2-ylidene (ICy),9 the
expected borylated product 3 was obtained in 58% yield.
Interestingly, however, we also obtained the homocoupling
product 1-di in 36% yield (Scheme 2). Although we were
G
and organic materials, the development of catalytic methods for
their efficient synthesis has turned into an intense area of
research.1 Despite the outstanding progress made in metal-
catalyzed cross-coupling technologies in the past few decades,
the homocoupling reactions of aryl halides and their equivalents
continue to serve as powerful methods for the synthesis of
symmetrical biaryl compounds.2 Since Ullmann reported the
first homocoupling of aryl halides using stoichiometric copper
salts,3 a variety of advanced procedures have been developed
for this transformation, which have culminated in the
widespread use of homocoupling methods, as exemplified by
the syntheses of natural products4 and conjugated polymers.5 In
terms of the scope of the aryl electrophiles used in the catalytic
homocoupling reactions reported to date, aryl halides and
sulfonates have been used extensively (Scheme 1, top). Herein
Scheme 2. Ni-Catalyzed Reaction of 1 with 2
Scheme 1. Catalytic Homocoupling of Aryl Electrophiles
Leading to Biaryls
unable to obtain 3 selectively using the Ni(cod)2/ICy system,
we developed a keen interest in the optimization of this
reaction for the selective formation of 1-di. We were especially
interested in the novelty of this transformation as a means of
satisfying the growing demands for new homocoupling
methodologies from the synthetic chemistry community.4,5 It
is noteworthy that Martin and co-workers recently reported the
successful development of a nickel-catalyzed C−O borylation of
aryl ethers using a Ni(cod)2/PCy3 system.10 Interestingly, no
homocoupling product was formed under the Ni(cod)2/PCy3
conditions, highlighting the profound effect of the ligand on the
product selectivity of this process.
we report the first catalytic homocoupling of aryl ethers via the
nickel-catalyzed activation of strong C(aryl)−O bonds (Scheme
1, bottom).6,7 In addition to the ready availability and low
toxicity of aryl ether substrates, the use of an inert methoxy
group as a handle for homocoupling would allow for the rapid
extension of the π system through sequential cross-/
homocoupling processes.
After a series of screening experiments, we found that
decreasing the amount of 2 to 0.80 equiv relative to the aryl
Received: October 31, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03151
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ether substrate led to the selective formation of the
homocoupling product.11 For example, aryl ether 1 formed 1-
di in 90% NMR yield (78% isolated yield) under these nickel-
catalyzed conditions, and neither 3 nor 1 was observed by GC
analysis of the crude reaction mixture (Scheme 3). The reaction
could be conducted on a 10 mmol scale with 5 mol % catalyst
without a noticeable loss of the yield of 1-di. A series of 2,2′-
binaphthalene derivatives, including those bearing alkyl (4-di),
amide (5-di), and amine (6-di) groups, were successfully
synthesized under these conditions. This catalytic homocou-
pling was found to be sensitive to the steric environment of the
aryl ether substrate, since an increase in the steric hindrance of
the substrate leads to a 2-fold increase in the steric hindrance
developed in the transition state for the C−C bond-forming
event (e.g., 7-di). Nevertheless, this method allowed the
synthesis of the sterically demanding 1,1′-binaphthalene
system, as in 8-di. The extent of the π conjugation in the
substrate had a significant impact on its reactivity toward this
homocoupling reaction. For example, anisole afforded the
homocoupling product 9-di in 33% yield under these
conditions, along with PhB(nep) (16%) and 9 (41%). These
results indicate that the C−O bond activation of anisole is less
efficient than that of naphthalene derivatives, which is
consistent with the reactivity trend observed in the nickel-
catalyzed cross-coupling reactions of aryl ethers with relatively
less nucleophilic reagents.7b Methoxybiphenyls were deter-
mined to be suitable substrates for this nickel-catalyzed
homocoupling process, providing quaterphenyls 10-di and
11-di. Further π-extended methoxyarenes such as phenan-
threne 12 and pyrene 13 were also homocoupled under these
conditions, allowing facile access to much larger aromatic
molecules. This homocoupling method also worked well for
heteroarenes, as exemplified by the formation of 14-di.
Importantly, 2-naphthylmethyl methyl ether (15) also afforded
a dimerized product via the activation of its C(sp3)−O
bond.9a,10 This method was also found to be suitable for the
homocoupling of biologically active methoxyarenes. For
example, the dimeric derivative of naproxen (16) was
successfully synthesized using our homocoupling protocol.
Of all the additives evaluated in the current study, only the
diboron reagent 2 produced a homocoupling product.11 The
yield of the homocoupling product reached its highest level
when 0.80 equiv of 2 relative to the methoxyarene substrate
was added to the reaction, with the use of excess 2 leading to
the formation of the C−O borylated product (Scheme 2).
Taken together, all of these observations suggested that the
homocoupling product is formed through two sequential
nickel-catalyzed C−O activation reactions, including borylation
of the methoxyarene with 210 followed by cross-coupling of the
borylated arene with the starting methoxyarene (Scheme 4a).9a
The catalytic homocoupling of aryl halides via a similar pathway
has been reported previously.12 This mechanistic hypothesis led
us to question why the use of PCy3 as a ligand instead of ICy
failed to provide any of the desired homocoupling product even
a
Scheme 3. Ni/ICy-Catalyzed Homocoupling of Aryl Ethers
Scheme 4. Possible Pathway and Ligand Effect
a
Reaction conditions: aryl ether (0.50 mmol), 2 (0.40 mmol),
Ni(cod)2 (0.050 mmol), ICy·HCl (0.10 mmol), and NaOtBu (0.10
mmol) in toluene (1.5 mL) at 120 °C for 12 h. Isolated yield on a 10
mmol scale using 5.0 mol % catalyst. Yield determined by GC because
of the volatility of the product. PhB(nep) (16%) and anisole (41%)
were also observed. 2 (0.50 mmol) was used. At 140 °C.
b
c
d
e
f
B
DOI: 10.1021/acs.orglett.5b03151
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Organic Letters
Letter
though PCy3 and ICy are capable of promoting the borylation10
and Suzuki−Miyaura-type cross-coupling reactions of methox-
ynaphthalenes.9a,13 To develop a deeper understanding of the
differences between these two ligands, we investigated the
cross-coupling of 1 with phenylboronic ester (Scheme 4b).
When PCy3 was used as the ligand in the absence of an extra
base, we found that none of the arylated product was formed,
which was consistent with the results of our previous study.13 In
contrast, the use of ICy as the ligand for this reaction led to the
cross-coupling product in good yield, even in the absence of a
stoichiometric base.14,15 These results therefore provide a clear
explanation for the unique activity of ICy toward the nickel-
catalyzed homocoupling of methoxyarenes. It is noteworthy
that the superior activity of ICy toward the activation of
C(aryl)−OMe bonds allowed the successful reaction of the less
reactive non-naphthalene substrates 9, 10, and 11, which did
not react with the Ni/PCy3 system.9a
transformation of inert C−O bonds are currently underway in
our laboratories.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03151.
Detailed experimental procedures and characterization of
products (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: tobisu@chem.eng.osaka-u.ac.jp.
*E-mail: chatani@chem.eng.osaka-u.ac.jp.
The robust nature of the methoxy group under the
conditions commonly used for organic synthesis allows this
homocoupling to be conducted at the later stage of synthesis.
For example, the rapid assembly of highly π-extended
molecules was achieved by implementing sequential cross-/
homocoupling processes with halogenated methoxyarenes
(Scheme 5).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research from MEXT, Japan and ACT-C from JST, Japan. We
also thank the Instrumental Analysis Center, Faculty of
Engineering, Osaka University, for their assistance with HRMS.
Scheme 5. Rapid Expansion of π Systems via Sequential
Cross-/Homocoupling Reactions of Halogenated Aryl
Ethers
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