Nickel-Catalyzed Alkoxy–Alkyl Interconversion with Alkylborane Reagents through C?O Bond Activation of Aryl and Enol Ethers

Article abstract of DOI:10.1002/anie.201607646

A nickel-catalyzed alkylation of polycyclic aromatic methyl ethers as well as methyl enol ethers with B-alkyl 9-BBN and trialkylborane reagents that involves the cleavage of stable C(sp²)?OMe bonds is described. The transformation has a wide substrate scope and good chemoselectivity profile while proceeding under mild reaction conditions; it provides a versatile way to form C(sp²)?C(sp³) bonds that does not suffer from β-hydride elimination. Furthermore, a selective and sequential alkylation process by cleavage of inert C?O bonds is presented to demonstrate the advantage of this method.

Full text of DOI:10.1002/anie.201607646

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201607646
German Edition: DOI: 10.1002/ange.201607646
Alkylation
Nickel-Catalyzed Alkoxy–Alkyl Interconversion with Alkylborane
À
Reagents through C O Bond Activation of Aryl and Enol Ethers
Lin Guo+, Xiangqian Liu+, Christoph Baumann, and Magnus Rueping*
Abstract: A nickel-catalyzed alkylation of polycyclic aromatic
methyl ethers as well as methyl enol ethers with B-alkyl 9-BBN
and trialkylborane reagents that involves the cleavage of stable
num reagents.[10] However, these methods have serious
restrictions in terms of the alkyl group that can be introduced.
In general, none of these approaches features a high tolerance
to functional groups, and good yields were obtained only for
methylation, where no competing b-hydride elimination can
take place. The high reactivity of the organometallic nucle-
ophiles enables the use of substrates bearing less reactive
functional groups whereas it is not compatible with deriva-
tives containing carbonyl (esters/ketones), silyl, or amino
groups.
Therefore, the disclosure of new methods within this field
is still a highly desirable goal. With these considerations in
mind, we began to search for a more general catalytic system
and nucleophiles that can be used for the efficient alkylation
of aromatic ethers. Owing to their environmentally friendly
nature, operational simplicity, and superior functional group
tolerance, alkylboranes are widely used in the synthesis of
natural products and bioactive molecules.[11,12] Hence, the use
2
À
C(sp ) OMe bonds is described. The transformation has
a wide substrate scope and good chemoselectivity profile
while proceeding under mild reaction conditions; it provides
a versatile way to form C(sp ) C(sp ) bonds that does not
2
3
À
suffer from b-hydride elimination. Furthermore, a selective
À
and sequential alkylation process by cleavage of inert C O
bonds is presented to demonstrate the advantage of this
method.
À
I
n recent years, CAr O electrophiles have emerged as
powerful alternatives to the commonly used aryl halide
coupling partners mainly owing to the environmentally
benign nature, natural abundance, and ready availability of
phenols and derivatives thereof.[1] Compared with aryl
tosylates, esters, carbamates, and sulfonates, aryl ethers, and
in particular aryl methyl ethers, are the simplest derivatives in
the phenol series. Nevertheless, they have only been scarcely
used as substrates in metal-catalyzed cross-coupling reactions.
The key challenges are associated with the high activation
of alkylboranes as coupling partners in cross-coupling reac-
2
À
tions with C(sp ) O electrophiles, in particular methoxy-
naphthalene derivatives, seemed advantageous. In addition,
the limitations associated with undesired side reactions,
including the often observed b-hydride elimination, might
be overcome. Furthermore, alkylboranes can act as Lewis
acids, and coordination to the alkoxy group should have
a positive effect on the oxidative addition of the naphthyl
À
energy required for C OMe bond scission and the low
propensity of methoxy residues to act as leaving groups.[1i]
Since Wenkert and co-workers reported the first Ni-catalyzed
alkylation reaction of aryl methyl ethers with aromatic
Grignard reagents,[2] the scope of metal-catalyzed cross-
couplings of aryl ethers has been expanded considerably,
and now includes a wide range of nucleophilic coupling
partners. Whereas various nucleophiles were successfully
applied for the arylation,[3] amination,[4] borylation,[5] alkyny-
lation,[6] and reductive deoxygenation[7] of methoxyarenes, an
efficient and general method for replacing the alkoxy with an
alkyl group is still missing.
À
ether C O bond (Scheme 1).
Shi, Chatani, and our group have independently devel-
oped methods for the metal-catalyzed alkylation of alkoxyar-
enes with alkylmagnesium,[8] alkyllithium,[9] and alkylalumi-
Scheme 1. Considerations for the alkylation of naphthyl ethers by
À
C OMe bond activation.
[*] M. Sc. L. Guo,[+] Dr. X. Liu,[+] C. Baumann, Prof. Dr. M. Rueping
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
Herein, we describe the development of a new method for
the direct nickel-catalyzed alkylation[13] of naphthyl ethers
and related polyaromatic systems with alkylboranes, which
exhibits high reactivity and wide substrate scope. In addition,
the transformation is applicable to a range of methyl enol
ethers, providing access to alkylated vinylarenes.
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)
We began our investigations by examining the reactivity
of 2-methoxynaphthalene (1a) with B-alkyl 9-BBN 2a in the
presence of Ni(COD)2 (10 mol%) and IPr·HCl (20 mol%) in
diisopropyl ether (Table 1). As expected, the nature of the
E-mail: magnus.rueping@Kaust.edu.sa
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201607646.
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Table 1: Optimization of the nickel-catalyzed alkylation of 2-methoxy-
Table 2: Substrate scope for polycyclic aromatic methyl ethers.[a,b]
naphthalene.[a]
Entry
Base
Ligand (x mol%)
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
Cs2CO3
K3PO4
Na2CO3
CsCl
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
IPr·HCl (20)
IPr·HCl (20)
IPr·HCl (20)
IPr·HCl (20)
IPr·HCl (20)
PPh3 (20)
dcype (10)
PCy3 (20)
PCy3 (20)
PCy3 (20)
PCy3 (20)
PCy3 (40)
PCy3 (40)
PCy3 (40)
PCy3 (40)
–
12
12
12
12
12
12
12
12
36
60
84
60
60
60
60
60
2
0
trace
5
18
0
0
28
53
61
9
10
11
12
13[c]
14[e]
15[f]
16
56
91
95 (93)[d]
31
0
0
[a] Reaction conditions: 1 (0.20 mmol), 2a (0.32 mmol, 1.6 equiv),
Ni(COD)2 (10 mol%), PCy3 (40 mol%), CsF (1.5 equiv) in Pr2O (0.2m)
at 1108C for 60 h. [b] Yields of isolated products are given. [c] Ni(COD)2
(20 mol%), PCy3 (80 mol%).
[a] Reaction conditions: 1a (0.20 mmol), 2a (0.32 mmol, 1.6 equiv),
Ni(COD)2 (10 mol%), ligand (x mol%), base (1.5 equiv), Pr2O (0.2m),
i
i
1308C. [b] Yields determined by NMR analysis using 1,3,5-(OMe)3C6H3
as the internal standard. [c] 1108C. [d] Yield of isolated product.
[e] 1008C. [f] Without Ni(cod)2. 9-BBN=9-borabicyclo[3.3.1]nonane,
COD=cyclooctadiene, dcype=1,2-bis(dicyclohexylphosphino)ethane,
IPr·HCl=1,3-bis(2,6-diisopropylphenyl)imidazolium chloride,
PMP=para-methoxyphenyl.
Notably, the chemoselectivity profile of this method was
nicely illustrated by the fact that functional groups such as
silyl, ester, and amine groups (1e–g) were tolerated under the
present conditions. It was further demonstrated that nitrogen-
base played a critical role for the success of the reaction.[14] As
shown in entries 1–5, the alkylated product 3a was obtained in
18% yield when cesium fluoride was employed as the base
whereas the use of other bases could not improve the yield
further. Furthermore, the ligand plays a crucial role in the
containing heterocycles, including quinoline (1h), pyrrole
2
À
(1i), and morpholine (1j), did not interfere with the C(sp )
C(sp3) bond formation, giving the desired products in good
yields. Phenyl methyl ethers were also tested under the
optimized conditions; however, only traces of the alkylated
products were formed probably owing to their higher
À
C O bond-cleaving reaction. Therefore, the replacement of
À
IPr·HCl by PCy3 under otherwise identical reaction condi-
tions significantly improved the yield (entry 8), whereas the
use of other phosphine and N-heterocyclic carbene ligands
was unsatisfactory (entries 6 and 7).[15] Pleasingly, extending
the reaction time led to better results (entries 9–11). Interest-
ingly, the ratio of Ni(cod)2 and PCy3 ligand had a dramatic
effect on the reactivity, and 3a was obtained in 91% yield
when the ratio was changed from 1:2 to 1:4 (entry 10 vs.
12).[3b,16] Furthermore, a slight decrease in temperature
enabled the isolation of 3a in 93% yield (entry 13). The
yield of the reaction decreased dramatically when the
reaction was performed at 1008C (entry 14). Furthermore,
control experiments revealed that the reaction did not
occur in the absence of nickel catalyst or ligand (entries 15
and 16).
aromaticity and slightly lower propensity to undergo C O
bond cleavage.[17]
We subsequently turned our attention to the preparative
scope of our reaction with respect to various B-alkyl 9-BBN
nucleophiles 2a–o in combination with 2-methoxynaphtha-
lene (1a) as the coupling partner. As shown in Table 3, two
B-alkyl 9-BBN derivatives bearing short and long phenyl-
substituted alkyl chains underwent this reaction in excellent
yields (4a, 4b). The use of methyl-substituted alkylboranes
smoothly provided the corresponding cross-coupling products
(4c, 4d), whereas the use of a benzodioxole-substituted
alkylborane gave 4e in 88% yield. Aliphatic substituents (4 f–
i) are also perfectly suitable for the alkylation, which further
enhances the utility and applicability of this method. With
2-methyl-substituted B-alkyl 9-BBN 2j as the coupling
partner, the yield was only moderate, probably owing to
steric hindrance. Furthermore, the chemoselectivity profile of
this method was illustrated by the fact that substrates with
olefin (2k), dioxolane (2l), boronic ester (2m), silyl (2n), and
ester groups (2o) all afforded the corresponding products in
good to high yields.
Encouraged by our initial results, we next focused on the
preparative scope and generality of our nickel-catalyzed
alkylation reaction. As shown in Table 2, a range of polycyclic
aromatic methyl ethers 1a–j with different substitution
patterns could be easily converted into the desired products
3a–j by employing B-alkyl 9-BBN 2a as the coupling partner.
2
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Table 3: Substrate scope for B-alkyl 9-BBN derivatives.[a,b]
Table 4: Substrate scope for enol ethers.[a,b]
[a] Reaction conditions: 5 (0.25 mmol), 2a (0.5 mmol), Ni(COD)2
i
(5 mol%), PCy3 (10 mol%), Cs2CO3 (2.0 equiv) in Pr2O (1.5 mL) at
1008C for 18 h. [b] Yields of isolated products are given. [c] 48 h. [d] 5
(0.25 mmol), 2a (0.5 mmol), Ni(COD)2, (10 mol%), PCy3 (20 mol%),
i
Cs2CO3 (2.0 equiv) in Pr2O (1.5 mL) at 708C for 18 h.
high efficiency. Different aromatic and aliphatic groups were
compatible with our coupling reaction, and the corresponding
products 7a–h were obtained in high yields. The Suzuki–
Miyaura alkylation was also suitable for sensitive functional
groups that are usually not compatible with organometallic
reagents, such as ester, amide, acetal, and boronic ester
moieties, providing products 7i–m in very high yields.
We then decided to examine the reactivity of other
alkylboron species. Although B-alkyl 9-BBNs are the most
efficient and commonly used Suzuki-type alkylating reagents,
the use of commercially available alkylating reagents such as
trialkylboranes could simplify the transformation. Gratify-
ingly, we observed that polycyclic aromatic methyl ethers
bearing various functional groups could be cross-coupled with
triethylborane 8 in good yields (Table 6).
Overall, we believe that the results shown in Tables 2–6
nicely illustrate the good reactivity and applicability of our
method for using B-alkyl 9-BBN and trialkylborane reagents
as coupling partners. This approach is attractive owing to its
substrate scope and chemoselectivity profile as aryl methyl
ethers and methyl enol ethers bearing various functional
groups can be used in an alkylative cross-coupling for the first
time.
[a] Reaction conditions: 1a (0.20 mmol), 2 (0.32 mmol, 1.6 equiv),
Ni(COD)2 (10 mol%), PCy3 (40 mol%), CsF (1.5 equiv) in Pr2O (0.2m)
at 1108C for 60 h. [b] Yields of isolated products are given. [c] Ni(COD)2
(20 mol%), PCy3 (80 mol%).
i
Subsequently, our attention was drawn to enol ethers[16a]
as potential substrates for the alkylation process. With (E)-2-
(2-methoxyvinyl)naphthalene (5a) and B-alkyl 9-BBN 2a as
the coupling partner, we searched for suitable reaction
conditions (see the Supporting Information, Table S9). With
the optimized reaction conditions in hand, the scope with
respect to enol ethers was investigated (Table 4). Not only
extended aromatic substrates, but also simple aryl alkenes
were suitable for this transformation (6a–f). It should be
noted that when a 1:1 E/Z mixture of a substrate was exposed
to the reaction conditions, the desired product was isolated
with high stereoselectivity (E/Z > 10:1) as isomerization takes
place under the reaction conditions.[16a] Furthermore, the
alkylation protocol could be extended to alkenyl silyl ethers
with slightly modified coupling conditions (6g–i).
To demonstrate the usefulness of our method, a selective
À
and sequential C O bond activation process was attempted
(Scheme 2). For this purpose, the pivalate group in compound
10 was first alkylated in a cross-coupling reaction developed
in our group[18] that involves the use of an N-heterocyclic
carbene ligand and cesium carbonate and left the methoxy
Next, we examined the preparative scope and generality
of our cross-coupling reaction with various B-alkyl 9-BBN
derivatives. As shown in Table 5, a broad range of B-alkyl
9-BBN reagents bearing different substituents reacted with
À
group intact. Subsequently, the stable C OMe bond could be
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Table 5: Substrate scope for B-alkyl 9-BBNs.[a]
À
Scheme 2. Sequential alkylation of two different inert C O bonds.
2
3
À
a practical and versatile way to form various C(sp ) C(sp )
bonds that does not suffer from b-hydride elimination. This
enables the synthesis of various products in high yields.
Diverse synthetically readily accessible and naturally occur-
ring methoxy arenes were efficiently transformed into
a variety of alkyl-substituted molecules. As such, this process
will be of interest for the replacement of methoxy groups, for
example, after their use as directing groups in Friedel–Crafts
À
reactions, ortho lithiations, or metal-catalyzed C H function-
[a] Reaction conditions: 5a (0.25 mmol), 2 (0.5 mmol), Ni(COD)2
(5 mol%), PCy3 (10 mol%), Cs2CO3 (2.0 equiv) in Pr2O (1.5 mL) at
1008C for 18 h.
i
alizations. In retrosynthesis planning, methoxy groups can
thus be considered as directing groups and, at the same time,
as placeholders for alkyl groups. Furthermore, this method is
applicable to a range of methyl enol ethers, providing access
to valuable alkyl vinylarenes.
Table 6: Substrate scope for the reaction of aromatic methyl ethers with
triethylborane as the coupling partner.[a,b]
Acknowledgements
L.G. and X.L. were supported by the China Scholarship
Council.
Keywords: alkylation · alkylboron reagents ·
À
aromatic methyl ethers · C O activation · nickel catalysis
À
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iPr2O (0.2m) at 1108C for 60 h. [b] Yields of isolated products are given.
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À
methyl ethers for C O bond cleavage are crucial for efficient
À
sequential C O bond activation and the functionalization of
À
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À
involves the cleavage of highly inert C OMe bonds. This
reaction shows broad functional group tolerance, providing
4
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À
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[17] For the reaction of phenyl derivatives, see Table S8 in the
Supporting Information.
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Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457 – 2483; b) A.
Received: August 6, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Alkylation
L. Guo, X. Liu, C. Baumann,
M. Rueping*
&&&& — &&&&
Nickel-Catalyzed Alkoxy–Alkyl
Interconversion with Alkylborane
2
À
À
Reagents through C O Bond Activation
No side reactions: A nickel-catalyzed
Suzuki-type alkylation of aryl methyl
ethers and methyl enol ethers with B-alkyl
9-BBN and trialkylborane reagents has
been developed, which involves the
cleavage of highly inert C(sp ) OMe
bonds. This transformation provides
of Aryl and Enol Ethers
2
3
À
a versatile way to build C(sp ) C(sp )
bonds that does not suffer from b-hydride
elimination.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!