1,3-dicyclohexylimidazol-2-ylidene as a superior ligand for the nickel-catalyzed cross-couplings of aryl and benzyl methyl ethers with organoboron reagents

Article abstract of DOI:10.1021/ol502583h

A new catalytic system has been developed involving the use of Ni(cod)₂ in conjunction with 1,3-dicyclohexylimidazol-2-ylidene for the cross-coupling of aryl and benzyl methyl ethers with organoboron reagents. This method not only allows for the use of readily available methyl ethers as halide surrogates but also provides a functional group tolerant method for the late-stage derivatization of complex molecules.

Full text of DOI:10.1021/ol502583h

Letter
pubs.acs.org/OrgLett
1,3-Dicyclohexylimidazol-2-ylidene as a Superior Ligand for the
Nickel-Catalyzed Cross-Couplings of Aryl and Benzyl Methyl Ethers
with Organoboron Reagents
Mamoru Tobisu,*,‡ Ayaka Yasutome,† Hirotaka Kinuta,† Keisuke Nakamura,† 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 catalytic system has been developed involving the
use of Ni(cod)2 in conjunction with 1,3-dicyclohexylimidazol-2-ylidene for
the cross-coupling of aryl and benzyl methyl ethers with organoboron
reagents. This method not only allows for the use of readily available
methyl ethers as halide surrogates but also provides a functional group
tolerant method for the late-stage derivatization of complex molecules.
Table 1. Ni-Catalyzed Cross-Coupling of 1 with 2a: The
Effect of the Ligand
he replacement of organic halides with alcoholic
Tderivatives as electrophiles for use in cross-coupling
reactions allows for the utilization of a naturally abundant
feedstock.1 Traditionally, this process has been accomplished
by converting hydroxyl groups into better leaving groups, such
as triflates. Recent efforts, however, have focused instead on the
use of relatively inert yet readily available alcohol derivatives,
including carboxylates and carbamates, which provide several
advantages over activated sulfonates in terms of their general
stability, cost, and atom efficiency.2 In this context, methyl
ethers represent particularly good candidates as prospective
electrophiles.3 The C−OMe bonds of methyl ethers, however,
are very electron-rich, which renders their activation by
oxidative addition challenging, and this factor has limited
their widespread application in cross-coupling reactions.4−11
Particularly nascent is their cross-coupling with organoboron
reagents; applicable substrates have been limited to aryl ethers
containing a fused aromatic ring (e.g., naphthalenes)10a or an
ortho-directing group11 as well as alkenyl ethers.10b Herein, we
report the use of 1,3-dicyclohexylimidazol-2-ylidene (ICy) as a
ligand to enable the nickel-catalyzed12 Suzuki−Miyaura cross-
coupling of methyl ethers with a substantially broadened scope,
including an unprecedented C(sp3)-OMe/organoboron cou-
pling.13
a
Benzyl methyl ether 1 was selected as our initial test
substrate, because there have been no reports pertaining to the
successful cross-coupling of alkyl ethers with organoboron
reagents, even with compounds possessing this class of
activated (i.e., benzylic) C(sp3)−OMe bond.14,15 The Ni-
(cod)2/PCy3 system is recognized as the state-of-the-art catalyst
for C(sp2)−OMe/organoboron cross-coupling.10a Unfortu-
nately, however, its application to the cross-coupling of 1
with 2a proved to be a total failure, with none of the desired
product 3a being detected (Table 1, entry 1). We subsequently
examined a series of N-heterocyclic carbene (NHC) ligands
a
Reaction conditions: 1 (0.30 mmol), 2a (0.45 mmol), Ni(cod)2
(0.030 mmol), ligand (0.060 mmol), NaOtBu (0.075 mmol), and CsF
b
(0.60 mmol) in toluene (1.0 mL) at 120 °C for 12 h. NaOtBu was
c
not added. Isolated yield.
with the expectation that their pronounced electron-donating
abilities16 would facilitate the difficult oxidative addition of the
Received: September 1, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502583h | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
C(sp3)−OMe bond of 1. Although the NHC ligands bearing
aryl groups on their nitrogen atoms (i.e., L1, L2, L11, L12) all
failed to promote the cross-coupling reaction, those bearing
alkyl groups afforded promising results. Ligand L4, for example,
under the optimized conditions to give the corresponding
coupling products 4a−h in an efficient manner. Esters, amides,
and carbamates18 proved to be compatible (i.e., 4e, 4g, and 4h),
which highlights the synthetic advantage of our reaction over
Kumada-type reactions.4e,f,l Sterically hindered aromatics (i.e.,
4d and 4i) and heteroaromatics (i.e., 4j and 4k) were also
successfully incorporated at the benzylic position. Moreover, an
alkenylboron reagent was also found to be applicable to form
the corresponding cross-coupling product 4l, which could be
converted to an alkylated compound via the hydrogenation of
the alkene moiety. With respect to the scope of the benzyl
ethers, the methoxy group at the electron-rich benzylic center
could also be substituted to form compounds such as 5a under
these nickel-catalyzed conditions. A lower yield was observed
with simple benzyl ether 7, presumably due to a lesser tendency
to form the key π-benzylnickel intermediate.19 Sterically
congested methyl ethers, such as 8a and 9a, as well as
electron-rich and -deficient heteroaromatics, such as 10a and
11a, all underwent the cross-coupling in the presence of the
Ni/L7 catalytic system.
i
bearing Pr groups on its nitrogen atoms, provided the desired
product 3a in 29% yield (entry 5), although L3 and L5 bearing
n- and tert-butyl groups, respectively, provided much poorer
results (entries 4 and 6). Further screening of the secondary
alkyl-substituted NHC ligands revealed that cyclohexyl
derivatives L7 and L8 effectively promoted the cross-coupling
of 1 to form 3a (entries 8 and 9).17 It is noteworthy that subtle
structural changes in L7, including the ring size (entries 7 and
10), backbone saturation (entry 15), and substitution (entries
16 and 17), resulted in a marked decrease in activity. The
narrow window of opportunity for the development of suitable
ligands in this case highlights the difficulties associated with
designing suitable catalysts for the cross-coupling of unactivated
methyl ethers with relatively unreactive organoboron nucleo-
philes.
Having identified L7 as an optimal ligand, we proceeded to
explore the scope of this nickel-catalyzed cross-coupling
reaction of benzyl methyl ethers with organoboron reagents
(Scheme 1). Regarding the organoboron component, several
substituted phenylboronic acid derivatives reacted smoothly
It should also be noted that the current protocol was
amenable to gram-scale synthesis (eq 1). Although we routinely
Scheme 1. Ni/L7-Catalyzed Cross-Coupling of Benzyl
a
Methyl Ethers with Organoboron Reagents
used 10 mol % catalyst in our exploratory studies, the catalyst
loading in this reaction could be reduced to 2 mol % without
any discernible decrease in the yield.
One of the key limitations of the Ni(cod)2/L7 system,
however, was that it could not be applied to secondary benzylic
ethers, in that the introduction of a methyl group at the
benzylic position completely inhibited the reaction. A notable
exception to this observation was provided by the diarylmethyl
methyl ether 12, which afforded the triaryl methane derivative
12a in 51% yield, along with a reduced product (28%).20 These
results suggested that the oxidative addition of a secondary
C(sp3)−OMe bond in 12 to a nickel center must have
proceeded smoothly and that the subsequent transmetalation
with 2a was slow, which would provide an opportunity to form
the reduced product.
Pleasingly, the Ni(cod)2/L7 system was also found to
catalyze the cross-coupling of an array of aryl methyl ethers
with organoboron reagents (Table 2). In sharp contrast to the
Ni(0)/PCy3 system,10a anisole derivatives containing no fused
aromatic ring (e.g., 13, 14, 16, 17, 18, 20, and 24) successfully
underwent the cross-coupling with 2a when L7 was used as the
ligand. This reaction also exhibited a high level of tolerance
toward substrates bearing a bulky ortho substituent, such as 17,
as well as substrates bearing an acidic NH group, such as 18.
Although electron-rich anisoles (e.g., 15) performed poorly as
substrates for this reaction, electron-rich naphthalene deriva-
tives, such as 19, behaved as viable substrates when PCy3 was
replaced with L7. Selective diarylation of 1,2-dimethoxyarene
a
Reaction conditions: benzyl methyl ether (0.30 mmol), boronate 2a−
l (0.45 mmol), Ni(cod)2 (0.030 mmol), L7 (0.060 mmol), NaOtBu
(0.075 mmol), and CsF (0.60 mmol) in toluene (1.0 mL) at 120 °C
b
for 12 h. Isolated yield is shown. Ni(cod)2 (0.060 mmol), L7 (0.12
mmol), and NaOtBu (0.14 mmol) were used. The corresponding
c
Ar′-B(pin) was used. d Isolated as a 4.3:1 mixture of 4h and isomeric 2-
(cyclohexylidenemethyl) naphthalene.
B
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Letter
Table 2. Ni/L7-Catalyzed Cross-Coupling of Aryl Methyl
Ethers
Scheme 2. Sequential Cross-Coupling of Aryl Pivalates and
Methyl Ether with Organoboron Reagents
a
facilitate a Suzuki−Miyaura-type cross-coupling reaction of a
range of aryl methyl ethers that have not previously been
successful (i.e., those containing no fused aromatic rings and
heteroaryl methyl ethers). Further studies directed toward the
application of L7 to the cross-coupling reactions of methyl
ethers with various nucleophiles, as well as the activation of
other strong σ-bonds, are currently underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and details pertaining to the
characterization of the products. This material is available free
of charge via the Internet at http://pubs.acs.org.
a
AUTHOR INFORMATION
Corresponding Authors
Reaction conditions: aryl methyl ether (0.30 mmol), 2a (0.45 mmol),
■
Ni(cod)2 (0.030 mmol), L7 (0.060 mmol), NaOtBu (0.075 mmol),
and CsF (0.60 mmol) in toluene (1.0 mL) at 120 °C for 12 h. Isolated
yield is shown. PCy3 (0.012 mmol) was used. CsF (1.4 mmol) at
*E-mail: tobisu@chem.eng.osaka-u.ac.jp.
*E-mail: chatani@chem.eng.osaka-u.ac.jp.
Notes
b
c
d
e
160 °C for 24 h. 2a (0.60 mmol) and CsF (0.80 mmol). Ni(cod)2
(0.060 mmol), L7 (0.12 mmol), and NaOtBu (0.15 mmol) for 36 h.
f
g
2a (1.5 mmol) and CsF (1.6 mmol) in toluene (2.0 mL). The
The authors declare no competing financial interest.
reaction afforded a mixture of 21, 2-(4-tolyl)naphthalene, and
h
diarylated product. 2a (0.90 mmol), Ni(cod)2 (0.060 mmol), L7
ACKNOWLEDGMENTS
(0.12 mmol), NaOtBu (0.14 mmol), and CsF (1.1 mmol) in toluene
(2.0 mL).
■
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Molecular Activation Directed
toward Straightforward Synthesis” from MEXT, Japan and
ACT-C from JST, Japan. H.K. expresses his special thanks for a
JSPS Research Fellowship for Young Scientists. We also thank
the Instrumental Analysis Center, Faculty of Engineering,
Osaka University, for their assistance with HRMS.
21 was also possible, which could serve as a useful method for
the extension of the π-system. Another notable benefit of using
L7 instead of PCy3 was the ability to couple heteroaryl ethers.
The catalyst poisoning, which was attributed to the presence of
an sp2-nitrogen atom in the examples involving 22, 23, and 24,
was overcome by the use of L7, which allowed for the
formation of arylated quinoline and pyridine derivatives. Highly
deactivated electron-rich heteroaromatics, such as 25, also
reacted smoothly under these newly developed conditions. This
arylation protocol could potentially be used to modify natural
products containing a methoxyarene moiety, such as 26.
Interestingly, L7 was a less effective ligand than PCy3 for
promoting the reaction of 2-naphthyl pivalates and naphthalen-
2-yl diethylcarbamate with 2a (8% and 67% yield, respectively).
This specific reactivity of L7 in the nickel-catalyzed Suzuki−
Miyaura-type cross-couplings of different phenolic electrophiles
allows for orthogonal cross-couplings of aryl pivalates21 and
methyl ethers (Scheme 2).
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C
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