Lewis Acid Assisted Nickel-Catalyzed Cross-Coupling of Aryl Methyl Ethers by C-O Bond-Cleaving Alkylation: Prevention of Undesired β-Hydride Elimination

Article abstract of DOI:10.1002/anie.201510497

In the presence of trialkylaluminum reagents, diverse aryl methyl ethers can be transformed into valuable products by C-O bond-cleaving alkylation, for the first time without the limiting β-hydride elimination. This new nickel-catalyzed dealkoxylative alkylation method enables powerful orthogonal synthetic strategies for the transformation of a variety of naturally occurring and easily accessible anisole derivatives. The directing and/or activating properties of aromatic methoxy groups are utilized first, before they are replaced by alkyl chains in a subsequent coupling process.

Full text of DOI:10.1002/anie.201510497

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Communications
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International Edition: DOI: 10.1002/anie.201510497
German Edition: DOI: 10.1002/ange.201510497
C(sp2)–C(sp3) Coupling
Lewis Acid Assisted Nickel-Catalyzed Cross-Coupling of Aryl Methyl
À
Ethers by C O Bond-Cleaving Alkylation: Prevention of Undesired
b-Hydride Elimination
Xiangqian Liu, Chien-Chi Hsiao, Indrek Kalvet, Matthias Leiendecker, Lin Guo,
Franziska Schoenebeck,* and Magnus Rueping*
Dedicated to Professor Dieter Enders on the occasion of his 70th birthday
Abstract: In the presence of trialkylaluminum reagents, diverse
aryl methyl ethers can be transformed into valuable products
strategies where the methoxy group could first serve as
a directing and/or activating group before it is replaced by
a new functional group. Whereas nickel-catalyzed cross-
couplings[7] of anisole derivatives were already pioneered in
the late 1970s by Wenkert et al.,[8] aryl ether cross-couplings
are limited to arylation,[9] methylation,[10] alkynylation,[11]
amination,[12] ipso borylation,[13] and reduction where the
methoxy group is exchanged with a hydrogen atom.[14]
Furthermore, we recently reported a functionalization strat-
egy that enables the transformation of anisole derivatives into
À
by C O bond-cleaving alkylation, for the first time without the
limiting b-hydride elimination. This new nickel-catalyzed
dealkoxylative alkylation method enables powerful orthogonal
synthetic strategies for the transformation of a variety of
naturally occurring and easily accessible anisole derivatives.
The directing and/or activating properties of aromatic methoxy
groups are utilized first, before they are replaced by alkyl
chains in a subsequent coupling process.
À
diverse products by C O bond cleavage in a two-step
T
ransition-metal-catalyzed carbon–carbon and carbon–het-
process.[15]
eroatom cross-coupling reactions play an important role in
modern organic chemistry and are widely used in the
synthesis of organic materials, natural products, and thera-
peutics.[1] Typically, organic halides or activated phenol
derivatives such as triflates are used as the electrophiles and
can be coupled with a variety of organic or organometallic
nucleophiles, both on the laboratory and industrial scale.[1d–h]
Owing to their natural availability, lower toxicity, and reduced
cost, unactivated phenol derivatives have emerged in the last
few years to further complement organic halides as cross-
coupling partners.[2] In particular, the use of simple, stable,
inexpensive, and in many cases naturally available anisole
derivatives is not only economically attractive but also an
environmentally friendly alternative to existing methods.
Aromatic methoxy groups activate aromatic systems for
However, the introduction of alkyl groups as nucleophiles
by nickel catalysis may suffer from competing b-hydride
elimination (Scheme 1a). Thus far, this has limited the scope
to transformations where this side reaction is either not
possible or highly unfavorable. These examples include
methylation[10,16,17] and the replacement of methoxy groups
with an adamantyl or a cyclopropyl group[17b] (Scheme 1b).
The unwanted b-hydride elimination, the high activation
barrier of the oxidative-addition step,[18] and the poor leaving-
group properties of methoxy groups render the use of aryl
Friedel–Crafts reactions,[3] ortho metalations,[4] and electro-
philic aromatic substitutions.[3a,5] Furthermore, the C(sp )
2
À
OMe bond is often considered to be inert towards harsh
reaction conditions and most cross-coupling catalysts.[6] In
combination with new cross-coupling reactions targeting the
2
À
C(sp ) OMe bond, these properties could enable synthetic
[*] M. Sc. X. Liu, Dr. C.-C. Hsiao, M. Sc. I. Kalvet, Dr. M. Leiendecker,
M. Sc. L. Guo, Prof. Dr. F. Schoenebeck, Prof. Dr. M. Rueping
Institute of Organic Chemistry
RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: magnus.rueping@rwth-aachen.de
Prof. Dr. M. Rueping
King Abdullah University of Science and Technology (KAUST)
KAUST Catalysis Center (KCC)
Thuwal, 23955-6900 (Saudi Arabia)
À
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201510497.
Scheme 1. Catalytic C C bond formation after activation of unreactive
À
C O bonds.
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Table 1: Substrate scope of the aryl ether alkylation.
methyl ethers as electrophiles in cross-coupling reactions
highly challenging. Reaction conditions, which can facilitate
the energetically demanding cleavage, promote simultane-
ously the competing b-hydride elimination, so that the direct
introduction of a long-chain alkyl group was previously not
possible. We were thus very interested in developing the first
dealkoxylative alkylation reaction (Scheme 1c). The use of
easily accessible anisole derivatives allows orthogonal syn-
thetic strategies that initially use the directing and/or activat-
ing properties of aromatic methoxy groups, before they are
replaced by an alkyl chain bearing b-hydrogen atoms.
Our studies began with examining the activation of the
À
C O bond. We envisioned that Lewis acids might be able to
2
À
lower the activation energy of C(sp ) OMe bond cleavage
through polarization/activation.[19] Aluminum reagents, for
example, benefit from their strong Lewis acidity and high
oxophilicity,[20,21] and the transmetalation step could be
energetically favored by the formation of stable dialkylalu-
À
minum methoxide. Although no dealkoxylative C C bond
formation was observed in the nickel-catalyzed hydrogenol-
ysis of aryl methyl ethers[14b] in the presence of AlMe3, the
development of a first dealkoxylative alkylation appeared
feasible based on our earlier experiences.
With these considerations in mind, we chose to study the
reaction between 2-methoxynaphthalene and triethylalumi-
Reaction conditions: 1a’ (0.25 mmol), 2 (0.5 mmol), [Ni(cod)2]
(0.0125 mmol), dcype (0.0125 mmol), iPr2O/toluene (1:1, 1.5 mL),
sealed reaction tube, 1008C, 72 h. [a] 12 h. [b] 1208C, 72 h. [c] R3Al was
prepared in situ from AlCl3 and the corresponding lithium reagent.
[d] R3Al was prepared in situ from AlCl3 and the corresponding Grignard
reagent. [e] A mixture of 2-isopropyl- and 2-propylnaphthalene was
formed. dcype=1,2-bis(dicyclohexylphosphino)ethane.
À
num to investigate C O bond cleavage in the presence of
various nickel catalysts in iPr2O. Whereas the combination of
À
[Ni(cod)2] and PCy3 has previously proven to be key for C O
bond activation, no product was formed in our reaction (see
the Supporting Information, Table S1, entry 1). Moreover,
other monodentate ligands were not successful either. On the
other hand, the bidentate dcype ligand[22] led to full con-
version into the desired product under the applied conditions.
Further studies resulted in the optimized reaction conditions,
which entailed the use of a solvent mixture of iPr2O/toluene
(1:1) at 1008C (Table S1). In situ generated triethylalumi-
num[21] gave rise to a slightly lower yield (Table S1, entry 22).
Control experiments further showed that no conversion was
achieved without the addition of a nickel catalyst (Table S1).
Moreover, other nucleophiles, including Li, Mg, or Zn
organometallic reagents, did not provide comparable reac-
excellent yields of the corresponding products at slightly
elevated temperatures (4d–g). Furthermore, substrates with
a bulky trimethylsilyl (TMS) moiety are also suitable for the
reaction (4h, 4j) even when this group is in direct vicinity to
the OMe group. ortho-Arylated anisole was also converted in
good yield (4g) as well as substrates with a conjugated double
bond (4i, 4k), including naturally available anethole. The
amino-substituted aryl methyl ether 1l and a series of
heterocyclic pyrrole, pyrazole, pyridine, or quinoline sub-
strates (1m–p) were also suitable for the alkylation reaction.
Different indole derivatives were directly coupled in the C4 as
well as in the C5 position (4p–s). Anisole 1t (Ar= 4-F-1,1’-
biphenyl) was bis-alkylated in good yield to product 4t.
Anisole derivatives with cyano, ester, and amide groups,
however, are not compatible with the reaction conditions.
To demonstrate the different synthetic applications of the
developed method, we synthesized three products that would
not be as readily accessible without this method (Scheme 2).
Owing to the broad variety of natural and pharmacologically
or agrochemically relevant anisole derivatives, the developed
dealkoxylative alkylation method might be used for the late-
stage modification of various compounds. As an example, we
submitted dimethoxy-b-estradiol (5) to our nickel-catalyzed
reaction conditions and isolated the corresponding alkylation
product 6 in 70% yield (Scheme 2a). Furthermore, we were
able to show that the two methoxy groups in 1,7-dimethoxy-
naphthalene (7) can be functionalized selectively.
À
tivities. Both C O bond activation by Lewis acidic trialkyl-
aluminum and the dcype ligand appear to be critical for the
desired alkylation process.
With the optimized reaction conditions in hand, the scope
of the alkylation was investigated. A series of short- and long-
chain trialkylaluminum nucleophiles with phenyl, alkenyl,
and ether moieties as well as a cyclopentyl derivative were
employed in this reaction after being prepared in situ from
easily accessible lithium and Grignard reagents (Table 1). The
corresponding products 3a–k were obtained in good yields.
The reaction with the iPr reagent led to a 1:1.15 mixture of 2-
isopropyl- and 2-propylnaphthalene in 65% yield (see the
Supporting Information).
Subsequently, a large variety of aryl methyl ethers were
subjected to the nickel-catalyzed reaction and coupled with
different aluminum reagents (Table 2). 1,4-Dimethoxynaph-
thalene, for example, gave rise to the doubly functionalized
product 4b in good yield. Biphenyl substrates also led to
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Table 2: Substrate scope of the aryl ether alkylation.
Scheme 2. The developed alkylation method enables the facile syn-
thesis of products that are otherwise difficult to access.
methyl iodide furnished 1-methyl-2-methoxynaphthalene
(11), which was then selectively brominated in the C5 posi-
tion.
Then, the C5 position was arylated in a Pd-catalyzed
Suzuki–Miyaura reaction; subsequently, our nickel-catalyzed
reaction led to methoxy cleavage and alkylation. This reaction
sequence is an example of an orthogonal synthetic strategy,
which further enhances the possibilities for the synthesis of
diverse novel alkyl-functionalized products.
Reaction conditions: 1a (0.25 mmol), 2 (0.5 mmol), [Ni(cod)2]
(0.0125 mmol), dcype (0.0125 mmol), iPr2O/toluene (1:1, 1.5 mL),
sealed reaction tube, 1008C, 12 h. [a] With 1.0 mmol of AlEt3. [b] R3Al was
generated in situ from the Grignard reagents and AlCl3. [c] 1208C, 72 h.
[d] 1408C, 72 h. [e] [Ni(cod)2] (0.025 mmol), dcype (0.025 mmol).
[f] Starting from 1t (Ar=4-F-1,1’-biphenyl); AlEt3 (0.75 mmol). 1208C,
72 h.
To confirm the significant coordination between the aryl
methyl ethers and trialkylaluminum, we studied our reaction
system by 27Al and 1H NMR spectroscopy (Figures S1–S6). A
significant shift of the 27Al resonance of AlEt3 from 158 to
181 ppm was observed in the presence of 2-methoxynaph-
1
thalene. At the same time, the H methoxy resonance was
With bulky triisobutylaluminum, alkylation first took
place selectively at the C7 position. Subsequently, the
C1 position could be functionalized with LiCH2SiMe3 for
further transformations (Scheme 2b). The developed method
also enabled us to approach an orthogonal synthetic strategy
that would first temporarily make use of the directing and/or
activating characteristics of the methoxy group and then
enable its further functionalization (Scheme 2c). Therefore,
2-methoxynaphthalene was first selectively brominated in the
C1 position. Subsequent lithiation followed by reaction with
shifted from 3.40 to 3.49 ppm. Furthermore, the 1H signals of
AlEt3 were shifted in the presence of 2-methoxynaphthalene
(CH2: from 0.29 to 0.16 ppm, CH3; from 1.09 to 1.30 ppm).
Furthermore, we conducted computational studies using
the CPCM (Et2O) M06L/def2-TZVP// wB97X-D/6-31G(d)
(SDD for Ni) method to gain greater insight.[23] Our
calculations (summarized in Figure 1) revealed that oxidative
À
addition to the aryl ether C O bond strongly benefits from
the coordination of the Lewis acid (DG°OA = 18.6 kcal
molÀ1).[24] In contrast, a prohibitively high activation free
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To support our calculated reaction profile experimentally,
we analyzed the reaction of a [NiII(X)(Ar)] complex with
AlEt3.[28] Successful transmetalation should result in a [NiII-
À
(Et)(Ar)] complex, which eventually forms Ar Et. Our
À
studies indeed led to quantitative formation of Ar Et,
underlining the presence of a competent NiII intermediate
(see the Supporting Information).
In conclusion, the newly developed Lewis acid assisted
nickel-catalyzed cross-coupling reaction constitutes the first
broadly applicable method for the alkylation of anisole
À
derivatives under C OMe bond cleavage. This was achieved
as a result of the effective interplay of various factors: the
Lewis acidic trialkylaluminums facilitate the oxidative addi-
À
tion by activating the C OMe bond, the formation of stable
dialkylaluminum methoxide favors an efficient transmetala-
tion step, and the nickel catalyst with a bidentate dcype ligand
undergoes the catalytic cycle for the tested substrates
efficiently, suppressing the competing b-hydride elimination
and affording the desired products with high yields. Naturally
occurring and synthetically easily accessible structurally
diverse anisole derivatives can thus be efficiently transformed
into a variety of alkyl-substituted molecules. Building on our
newly developed Lewis acid assisted cross-coupling reaction,
we further demonstrated diversity-oriented, anisole-based
strategies for the synthesis of a variety of novel products. The
À
development of further C O bond-cleaving cross-coupling
reactions is an ongoing effort in our laboratories.
Acknowledgments
X.L. and L.G. were supported by the China Scholarship
Council, C.-C.H. was supported by a DAAD fellowship, and
M.L. was supported by a KekulØ fellowship (Fonds der
Chemischen Industrie) and the Studienstiftung des deutschen
Volkes. We gratefully acknowledge the computing time
granted on the RWTH Bull Cluster in Aachen (JARA0091).
Figure 1. a) Proposed catalytic cycle for the [(dcype)Ni(cod)] catalyzed
alkylation of 2-methoxynaphthalene with AlEt3. b) Calculated reaction
pathway (Gibbs energy in kcalmolÀ1) at the CPCM (Et2O) M06L/def2-
TZVP//wB97X-D/6-31G(d) (SDD for Ni) level of theory.
À
À
Keywords: C O bond activation · C C cross-coupling ·
cross-coupling · nickel · trialkylaluminum
energy barrier of 40.0 kcalmolÀ1 was calculated in the absence
of the Lewis acid. Furthermore, our calculations suggest that
the coordination of AlEt3 to the OMe group strongly favors
the formation of NiII complex IV. Thereafter, transmetalation
from the NiII intermediate was calculated to be relatively
facile, with a barrier of DG°TM ꢀ 19 kcalmolÀ1,[25] which is
then followed by an irreversible reductive elimination from
VI (DG°RE = 27.4 kcalmolÀ1). The competing b-hydride elim-
ination was predicted to have an activation barrier that is
How to cite: Angew. Chem. Int. Ed. 2016, 55, 6093–6098
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Angew. Chem. Int. Ed. 2016, 55, 6093 –6098
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 6097

Angewandte
Communications
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(DDG° = 0.6 kcalmolÀ1) in 1) the “LLHT mechanism” with
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À
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À
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calculations indicate that this pathway is not favored (DG°
=
ate
33.9 kcalmolÀ1).
[25] Owing to a flat potential energy surface, the transition state for
the transmetalation was estimated by scanning of the Ni–Et
distance in Intermediate IV.
[26] Our calculations show that the b-hydride elimination step can
proceed via two different but energetically close transition states
Received: November 12, 2015
Revised: January 4, 2016
Published online: April 8, 2016
6098 www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 6093 –6098