Selective C-O Bond Reduction and Borylation of Aryl Ethers Catalyzed by a Rhodium-Aluminum Heterobimetallic Complex

Article abstract of DOI:10.1021/jacs.1c03038

We report the catalytic reduction of a C-O bond and the borylation by a rhodium complex bearing an X-Type PAlP pincer ligand. We have revealed the reaction mechanism based on the characterization of the reaction intermediate and deuterium-labeling experiments. Notably, this novel catalytic system shows steric-hindrance-dependent chemoselectivity that is distinct from conventional Ni-based catalysts and suggests a new strategy for selective C-O bond activation by heterobimetallic catalysis.

Full text of DOI:10.1021/jacs.1c03038

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Selective C−O Bond Reduction and Borylation of Aryl Ethers
Catalyzed by a Rhodium−Aluminum Heterobimetallic Complex
Rin Seki, Naofumi Hara, Teruhiko Saito, and Yoshiaki Nakao*
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ABSTRACT: We report the catalytic reduction of a C−O bond and the borylation by a rhodium complex bearing an X-type PAlP
pincer ligand. We have revealed the reaction mechanism based on the characterization of the reaction intermediate and deuterium-
labeling experiments. Notably, this novel catalytic system shows steric-hindrance-dependent chemoselectivity that is distinct from
conventional Ni-based catalysts and suggests a new strategy for selective C−O bond activation by heterobimetallic catalysis.
a
henol and aryl ether moieties are ubiquitous structural
motifs in natural resources such as lignin and other related
Scheme 1. Previous Studies and This Work
P
biomass (Figure 1),1−3 and their functionalization via C(sp2)−
Figure 1. Natural products that contain multiple C−O bonds.
O bond activation would render them attractive chemical
feedstocks.2,3 In this context, transformations of a variety of
C(sp2)−O bonds have been developed.4−14 Among these, the
functionalization of intrinsically less reactive C(sp2)−OMe
bonds in aryl methyl ethers, which are widely encountered in a
variety of products such as lignin, is particularly attractive. In
addition, controlling the chemoselectivity during the scission
of the C−O bond is crucial to enable accessing various
aromatic products starting from compounds that contain
multiple C−O bonds.
Since the pioneering work by Wenkert,15 a variety of
transformations of C(sp2)−OMe bonds such as deoxygenative
hydrogenations,16−23 borylations,24−26 Suzuki−Miyaura-type
cross-couplings,27−31 and Kumada−Tamao−Corriu-type cross-
couplings32−39 have been uncovered, and most of these are
promoted by Ni catalysts (Scheme 1a).40−56 However, on
account of the poor reactivity of thermodynamically stable
C(sp2)−OMe bonds, reactions with less nucleophilic reagents
such as H2, hydrosilanes, or diboranes usually suffer from a
limited substrate scope; for example, monocyclic anisole
derivatives, especially electron-rich ones, react
poorly.16−22,24−26 Overcoming this limitation normally re-
quires harsh reaction conditions and/or more nucleophilic
a
B(nep) = 5,5-dimethyl-1,3,2-dioxaborolane; B(pin) = 4,4,5,5-
tetramethyl-1,3,2-dioxaborolane.
evaluated via the hydrogenolysis of lignin models.17,55,56
However, examples that exhibit selectivity distinct from this
method remain elusive. In this regard, the development of a
differential strategy for the chemoselective cleavage of C−OMe
bonds is highly desired.
Received: March 22, 2021
Published: April 22, 2021
23
i
agents such as Pr2NBH2. Besides, the chemoselective
activation of C−OMe bonds has remained challenging. One
pioneering study was reported by Hartwig, wherein the relative
reactivities of C−O bonds in aryl and benzyl ethers were
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To tackle the aforementioned challenges associated with the
functionalization of C−O bonds, we envisioned using Rh
complexes bearing an X-type aluminyl ligand, which have
recently been developed in our group.57−59 Experimental and
theoretical studies on the previously reported Ar−F bond
magnesiation suggested that the activation of Ar−F bonds by
these Rh−Al complexes proceeds probably in a cooperative
manner via the coordination of the Lewis-basic F atom to the
Lewis-acidic Al center.60 We considered the possibility that the
Lewis-basic O atom of a C(sp2)−OMe bond could also
coordinate to the Al center, thus enabling the cleavage of
unreactive C(sp2)−OMe bonds. Moreover, site-selectivity of
the C(sp2)−OMe functionalization by the Rh−Al catalysis
may be controlled on the basis of the reaction rates depending
on the relative coordination ability of the O atom tuned by
steric hindrance in addition to electronic features to ultimately
realize a chemoselectivity that is distinct from that of
conventional Ni-based methods (Scheme 1b).
optimization of the reaction conditions (for details, see the SI),
we found that the reaction proceeded smoothly at 80−120 °C
to give biphenyl (3a) in good yield when hydrosilane 2a was
used. We then investigated the substrate scope. 3-Methox-
ybiphenyl (1b) also afforded biphenyl in good yield, whereas
2-methoxybiphenyl (1c) afforded the product only in low
yield, even at 150 °C. These results imply that a bulky
substituent in the vicinity of a C(sp2)−O bond could hamper
access to the Rh−Al catalyst, resulting in low reaction
efficiency. 4-Butoxybiphenyl (1d) also engaged in the
reduction to afford the corresponding product in 87% yield.
Electron-deficient 4-(2-pyridyl)-anisole (1e) was also appli-
cable to the reduction. It should be noted here that the
reductive cleavage of electron-rich monocyclic anisole
derivatives 1f and 1g, which are less reactive under Ni-
catalyzed conditions,16−23 proceeded well to afford the
corresponding products in good yield. One could imagine
that the higher Lewis-basicity of the methoxy group could
enhance the reactivity because of its plausible coordination to
the Al center at the C−O activation step (vide infra), but this
would be unlikely, according to a competition experiment
favoring the reaction of 1e over that of 1g (for details, see the
SI). Various functional groups such as boryl, silyl, amino, and
TBS-protected hydroxy groups in 1h−1k were compatible
with these reaction conditions. The reduction could also be
applied to C(sp2)−OMe bonds of naphthalene and pyridine
substrates 1l and 1m, which afforded the corresponding
products in good yield. Alkenyl methyl ether 1n furnished
cyclooctene in 67% yield, notably without the hydrosilylation
of the olefin moiety.
Herein, we report the catalytic reduction and borylation of
C−O bonds of various anisole derivatives catalyzed by a Rh
complex with an X-type PAlP pincer ligand. We demonstrate
that the Rh−Al catalyst exclusively activates sterically less
crowded C−O bonds, leading to the unprecedented chemo-
selectivity during the functionalization of the C(sp2)−OMe
bond.
We first examined the reduction of 4-methoxybiphenyl (1a)
with hydrosilanes using 4 as a catalyst (Scheme 2). After the
Scheme 2. C−O Bond Reduction of Anisole Derivatives
To further expand the utility of this heterobimetallic catalyst
for the functionalization of C(sp2)−O bonds, we examined the
borylation of anisole derivatives with B2pin2 (4,4,4′,4′,5,5,5′,5′-
octamethyl-2,2′-bi-1,3,2-dioxaborolane) as a coupling partner
to obtain borylated arenes, which can be converted into a
variety of valuable substituted arenes (Scheme 3). Under
Scheme 3. Borylation of the C−O Bonds of Anisole
Derivatives
a
Reaction with 7.5 mol % of 4 and 1.0 mmol of 5.
slightly modified reaction conditions involving 3,3-dimethyl-
but-1-ene as a scavenger of HB(pin), which was derived from
an unidentified side reaction, through hydroboration, the
borylation of 4-methoxybiphenyl generated borylation product
6a in 95% yield. Electron-deficient pyridyl substrate was also
applicable to the reaction. Moreover, electron-rich 4-
morpholinoanisole, which acts as a poor substrate in previously
reported C−O borylation reactions,24−26 gave 6c in 74% yield.
It should be noted here that the borylation of 2-(2,4-
dimethoxyphenyl)pyridine overrides the 2-pyridyl directing
group to produce only C4-borylated product 6d in a
a
GC yield determined using C12H26 as the internal standard.
b
Reaction conducted at 150 °C.
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chemoselective manner.61,62 The chemoselectivity associated
with the present Rh−Al catalysis is further discussed below in
more detail.
Scheme 5. Identification and Reactivity of 8
A plausible catalytic cycle of the reduction of the C−O
bond, based on our previous theoretical calculations on the
magnesiation of C−F bonds, is shown in Scheme 4.60 Anisole
Scheme 4. Plausible Reaction Mechanism
coordinates to the Rh atom in an η2-fashion before the OMe
moiety interacts with the Al center. The activation of the C−O
bond by the Rh and Al atoms occurs cooperatively to afford
AlIII(μ-OMe)RhIPh intermediate 8. The reaction of 8 with
hydrosilane then affords arenes and MeO−SiMe(OSiMe3)2 to
complete the catalytic cycle.
To gain further insight into the reaction mechanism, we
attempted to identify any potential reaction intermediates. For
that purpose, we examined the reaction of Z-type PAlP−Rh
complex 9, which serves as a synthetic precursor of 4,57 with
anisole in the presence of KC8 (Scheme 5a). The reaction
furnished complex 8, which was characterized by NMR
spectroscopy and X-ray diffraction analysis. 8 was also
observed when 4 was reacted with anisole in the presence of
HSiMe(OSiMe3)2. The crystal structure of 8 shows that AlIII
bears the OMe moiety, which coordinates to RhI (Al−O
1.7452(17) Å; Rh−O 2.3501(17) Å), and the RhI center also
bears the Ph group. This activation of the C−O bond below
room temperature stands in sharp contrast to the conditions
required by Ni complexes.50−56 Under the applied catalytic
reaction conditions, 8 serves as a catalyst for the C−O bond
reduction of 1a to give 3a in 90% yield, which is comparable to
that obtained using 4 as a catalyst. Benzene derived from 8 and
hydrosilane was also detected (Scheme 5b). We further
confirmed the formation of benzene-d1 from 8 upon treatment
with 2b-d1 in THF at rt (Scheme 5c), while a possible reaction
intermediate observed by 31P NMR spectroscopy could not be
characterized due to its instability. In addition, the 31P NMR
spectrum of the reaction mixture supported the presence of 8
under the catalytic reaction conditions, while other many
species were also detected (for details, see SI). It is thus
feasible to conclude that 8 is an intermediate of this reaction.
To reveal the source of hydride incorporated into the arene
products, we carried out deuterium-labeling experiments.
Related mechanistic studies on the Ni-catalyzed reduction of
C−O bonds proposed two possible hydride sources, i.e., a
hydride generated from the OMe moiety via β-hydride
elimination, or a hydride generated directly from the
hydrosilane.23,50 As shown in Scheme 6a, deuterium
Scheme 6. Deuterium-Labeling Experiments
incorporation was not observed at any position of 3a thus
obtained when 1a-d3 was used. In contrast, the reaction of 1g
with DSiMePh2 furnished deuterated arene 3g-d1, albeit that
the incorporation of deuterium was low (48% D) (Scheme
6b).63 The low deuterium ratio can probably be ascribed to
intramolecular deuterium scrambling of DSiMePh2 and to
intermolecular deuterium scrambling with benzene.64 On the
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Scheme 7. Chemoselectivity Study
a
b
Reaction with 1o (0.50 mmol), H−SiMe(OSiMe3)2 (0.60 mmol), and 4 (5.0 mol %) in toluene (0.25−2.5 mL) for 2 h at 120 °C. Isolated yield.
Reaction with 1o−r (0.15 mmol), H−SiEt3 (3.8 mmol), Ni(cod)2 (20 mol %), SIPr·HCl (40 mol %), and NaOtBu (0.41 mmol) in toluene (0.30
c
d
e
mL) for 3 h at 140 °C. 1H NMR yield determined using mesitylene or 1,3,5-trimethoxybenzene as the internal standard. GC yield determined
using C12H26 as the internal standard.
basis of these experimental results, it seems feasible to
conclude that the hydride most likely stems from the
hydrosilanes, while β-hydride elimination to deliver a hydride
from the MeO group can be ruled out in this system.
2-pyridyl group in the vicinity of the C(2)−O bond and the
PiPr2 groups in the ligand can be expected to hamper the 2-
MeO coordination toward the Al center and thus favor the
activation of the C(4)−O bond (Scheme 7a).66 A similar steric
effect was also observed for a methyl group at the o-position in
1p to afford 3pa in 96% yield; conversely, under Ni-catalyzed
conditions, lower selectivity and reactivity were observed (eq
2). The reduction of benzyl biphenyl ether (1q) by 4
exclusively proceeded at the Ar−O bond to give biphenyl in
91% yield, whereas under Ni-catalyzed conditions, the Bn−O
bond was preferentially activated to generate 4-phenylphenol
in excellent yield (eq 3).17,20,23 The distinct site-selectivity to
activate the Ar−O bond by a Rh−Al complex can be
rationalized in terms of steric hindrance with the ligand Me
group, which is smaller for the Ar−O activation than for the
Bn−O activation at the bimetallic centers (Scheme 7b). In a
similar manner, 4 readily differentiates the OMe and OBu
groups in 1r to afford 3ra through the exclusive activation of
the C−OMe bond, while the Ni system affords an almost 1:1
mixture of 3ra and 3rb (eq 4). The rather low yield of 3ra was
ascribed to the low solubility of 1r in toluene, and while the
yield of 3ra could be improved by extending the reaction time,
a higher amount of 3rc was also obtained. These results clearly
The experimentally supported mechanism, especially the
cooperative activation of the C−O bond, prompted us to
demonstrate a site-selective C−O bond activation controlled
by steric effects. We expected that our Rh−Al catalyst could
differentiate alkoxy groups on the basis of steric hindrance as
the key step of our reaction could accompany the coordination
of the O atom in the substrate to the Al center prior to the
activation of the C−O bond. On the basis of this working
hypothesis, we investigated the reactivity of substrates that bear
multiple C−O bonds (Scheme 7). For a comparison of the
site-selectivity, the Ni-catalyzed conditions were also examined
as control experiments (for details, see the SI).16,17 When using
2-(2,4-dimethoxyphenyl)pyridine (1o), in which the 2-pyridyl
group may act as a typical directing group,65 Rh−Al complex 4
overrides the 2-pyridyl direction and preferentially reduces the
less hindered C(4)−OMe bond, as was expected from the
borylation (Scheme 3); conversely, under Ni-catalyzed
conditions, the reduction occurred preferentially on the
C(2)−OMe bond (eq 1). The steric repulsion between the
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Substituted Carbonic Ether Moiety as Potential Antitumor Agents.
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demonstrate that the cooperative activation of the C−O bond
by the heterobimetallic Rh−Al system via the plausible
coordination of oxygen atoms in the substrates affords a
selectivity that is fundamentally different from that of
conventional Ni catalysis systems.
In conclusion, we have developed a method for the
cooperative reduction and borylation of C(sp2)−O bonds
using a Rh complex that bears an X-type aluminyl ligand.
Notably, our system exhibits a steric-hindrance-dependent site-
selectivity that is different from that of hitherto reported Ni-
based catalyst systems with substrates that bear multiple C−O
bonds.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03038.
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Detailed experimental procedures as well as spectro-
scopic and analytical data (PDF)
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Accession Codes
CCDC 2064804 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Yoshiaki Nakao − Department of Material Chemistry,
Graduate School of Engineering, Kyoto University, Kyoto
615-8510, Japan; orcid.org/0000-0003-4864-3761;
Email: nakao.yoshiaki.8n@kyoto-u.ac.jp
Authors
(14) Ohgi, A.; Nakao, Y. Selective Hydrogenolysis of Arenols with
Hydrosilanes by Nickel Catalysis. Chem. Lett. 2016, 45, 45−47.
(15) Wenkert, E.; Michelotti, E. L.; Swindell, C. S. Nickel-Induced
Conversion of Carbon−Oxygen into Carbon−Carbon Bonds. One-
Step Transformations of Enol Ethers into Olefins and Aryl Ethers into
Biaryls. J. Am. Chem. Soc. 1979, 101, 2246−2247.
Rin Seki − Department of Material Chemistry, Graduate
School of Engineering, Kyoto University, Kyoto 615-8510,
Japan
Naofumi Hara − Department of Material Chemistry,
Graduate School of Engineering, Kyoto University, Kyoto
615-8510, Japan
Teruhiko Saito − Department of Material Chemistry,
Graduate School of Engineering, Kyoto University, Kyoto
615-8510, Japan
́
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Inert C−O Bonds: A New Strategy for Using Aryl Ethers as Easily
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Angew. Chem., Int. Ed. 2013, 52, 12674−12678.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c03038
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(20) Tobisu, M.; Morioka, T.; Ohtsuki, A.; Chatani, N. Nickel-
Catalyzed Reductive Cleavage of Aryl Alkyl Ethers to Arenes in
Absence of External Reductant. Chem. Sci. 2015, 6, 3410−3414.
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Catalyzed by Nickel. Chem. Commun. 2018, 54, 1521−1524.
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This work was supported by the JST CREST program
(JPMJCR14L3) via the project “Establishment of Molecular
Technology towards the Creation of New Functions” and by
JSPS KAKENHI grant JP20H00376. N.H. is grateful for a
Research Fellowship of the Japan Society for the Promotion of
Science (JSPS) for Young Scientists.
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Journal of the American Chemical Society
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Communication
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reduction to afford 3oc.
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