Decarbonylative Methylation of Aromatic Esters by a Nickel Catalyst

Article abstract of DOI:10.1021/acs.orglett.8b01233

A Ni-catalyzed decarbonylative methylation of aromatic esters was achieved using methylaluminums as methylating agents. Dimethylaluminum chlorides uniquely worked as the methyl source. Because of the Lewis acidity of aluminum reagents, less reactive alkyl esters could also undergo the present methylation. By controlling the Lewis acidity of aluminum reagents, a chemoselective decarbonylative cross-coupling between alkyl esters and phenyl esters was successful.

Full text of DOI:10.1021/acs.orglett.8b01233

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Decarbonylative Methylation of Aromatic Esters by a Nickel Catalyst
Toshimasa Okita, Kei Muto, and Junichiro Yamaguchi*
Department of Applied Chemistry, Waseda University, 3-4-1 Ohkubo, Shinjuku, Tokyo 169-8555, Japan
S
* Supporting Information
ABSTRACT: A Ni-catalyzed decarbonylative methylation of
aromatic esters was achieved using methylaluminums as
methylating agents. Dimethylaluminum chlorides uniquely
worked as the methyl source. Because of the Lewis acidity of
aluminum reagents, less reactive alkyl esters could also undergo
the present methylation. By controlling the Lewis acidity of aluminum reagents, a chemoselective decarbonylative cross-coupling
between alkyl esters and phenyl esters was successful.
evelopment of a novel and efficient C−C bond-forming
Dreaction is a topic of utmost importance in the field of
organic chemistry. Transition-metal-catalyzed cross-coupling
between haloarenes and organic metals has been regarded as
one of the most useful and reliable synthetic methods and has
been utilized for the synthesis of various functional organic
molecules ranging from pharmaceuticals to organic electronic
devices.1 Recently, several advanced methods using unconven-
tional aryl electrophiles such as phenols,2 anilines,3 and
thiophenols4 have emerged. The utilization of these alternatives
to haloarenes is beneficial because it opens a new synthetic
strategy and it allows chemists to exploit other inexpensive
sources of chemical feedstock.
In this context, our continuous interest has been aimed at the
development of coupling reactions using arenecarboxylate
derivatives such as aromatic esters as unconventional aryl
electrophiles (Figure 1A).5−8 Successful examples have been
the development of decarbonylative C−C couplings such as
arylation6a−d and alkynylation.6e However, a decarbonylative
coupling involving alkyl nucleophiles has remained a challenge.
Owing to the low reactivity of alkyl nucleophiles toward
transition metal catalysts and the involvement of several
undesired pathways such as β-H elimination in a catalytic
cycle,9 the utilization of alkylmetal species for the decarbon-
ylative cross-coupling of esters is still a challenging trans-
formation. In 2017, Rueping’s group reported the decarbon-
ylative coupling of aromatic esters with alkylzincs by a nickel/
dcype catalyst (dcype: 1,2-bis(dicyclohexylphosphino)ethane)
(Figure 1B).10a Later, the same group extended this chemistry
for the reaction using alkylborons.10b These are successful
examples of decarbonylative alkylation; however, only aromatic
phenyl esters are applicable substrates. Herein, we report that
the use of dimethylaluminum chlorides realizes the decarbon-
ylative methylation of aromatic esters.11 Harnessing the dual
role of aluminum chlorides as methyl nucleophiles and Lewis
acids, we also succeeded in using simple aromatic alkyl esters in
this reaction.
Figure 1. (A) Decarbonylative C−C bond formations of aromatic
esters. (B) Decarbonylative alkylation of aromatic esters.
(Scheme 1). To our surprise, among various methylaluminums,
dimethylaluminum chloride (2a) gave the best result, giving the
corresponding methylated product in 64% yield. Other
aluminum reagents such as trimethylaluminum and methyl-
aluminum dichloride were found to be less effective for this
transformation.
Encouraged by this initial discovery, we subjected another
aromatic ester 1B to react with 2a in the presence of Ni/dcypt
(Table 1, entry 1).14 However, the reaction yield was not
satisfactory (32%); thus, we set out to investigate more general
conditions. Ethylene-bridged diphosphines furnished 3Ba,
albeit in poor yields (Table 1, entries 2 and 3). Gratifyingly,
We began this investigation to find applicable methylalumi-
nums12 with phenyl 1-naphthoate (1A) under our in-house
catalyst, Ni(OAc)2/dcypt,13 as the initial reaction conditions
Received: April 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01233
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Investigation of Applicable Methylaluminums
Scheme 2. Substrate Scope Using Phenyl Esters 1
a
Table 1. Screening of Reaction Conditions
b
entry
Ni
ligand
dcypt
3Ba, GC yield (%)
1
2
3
4
5
6
7
8
9
10
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(OAc)2
Pd(acac)2
none
32
13
29
53
9
dcype
dppe
dppp
c
PCy3·HBF4
ICy·HBF4
none
dppp
dppp
dppp
c
2
trace
52
33
0
a
Conditions: 1B (0.20 mmol), 2a (hexane solution, 1.5 equiv), Ni salt
(5 mol %), ligand (10−20 mol %), 1,4-dioxane (0.50 mL), 150 °C, 16
b
h. GC yield was determined by using n-decane as an internal
c
standard. Ligand (20 mol %) and NaOt-Bu (20 mol %) were used.
a
Conditions: (A) Ni(acac)2 (10 mol %), dppp (20 mol %), 1 (0.40
mmol), 2 (hexane solution, 1.5 equiv), 1,4-dioxane (1.0 mL), 170 °C,
16 h. (B) Ni(acac)2 (5 mol %), dcypt (10 mol %), 1 (0.40 mmol), 2
it was found that an inexpensive and simple diphosphine, dppp,
gave a better yield (Table 1, entry 4). The use of electron-rich
monodentate ligands such as PCy3 as well as an NHC ligand
decreased the reaction yield (Table 1, entries 5 and 6). A
methylated arene product was not obtained when the ligand
was omitted (Table 1, entry 7). This reaction allowed the use of
Ni(OAc)2 to produce 3Ba in almost the same yield as the
Ni(acac)2 conditions. It is noteworthy that palladium is also an
effective metal, although the reaction efficiency was inferior to
nickel (Table 1, entry 9). This reaction did not proceed in the
absence of transition metals (Table 1, entry 10). Throughout
this screening process, we did not detect any nondecarbony-
lative products, such as methyl ketones.
Using the optimized conditions, the substrate scope of this
reaction was investigated (Scheme 2). The reaction yields of
several compounds were determined by GC or NMR analysis
due to the high volatility of the products. π-Extended aromatic
systems such as naphthalenes as well as anthracenes showed
good reactivity to generate the corresponding methylated
arenes. Benzoate derivatives could also undergo the present
methylation. This catalytic system was not influenced by steric
hindrance (e.g., 1G), giving the corresponding ortho-substituted
methyl arene. Benzoates bearing electron-donating substituents
were also methylated. Highly polar substituents such as
b
(hexane solution, 1.5 equiv), 1,4-dioxane (1.0 mL), 170 °C, 16 h. GC
yield. Ni(OAc)2 (10 mol %) and LiCl (1.5 equiv) were used. NMR
yield. 0.20 mmol scale. dppp (10 mol %) and LiCl (1.5 equiv) were
used.
c
d
e
f
sulfonamide (1I) were compatible under the catalytic
conditions.
This methylation protocol was also applicable to hetero-
aromatic esters. The methylation of aromatic esters containing
five-membered heteroaromatics, such as benzothiophene (1L),
indole (1M), and thiazole (1N), was successful. Electron-
deficient azines (1O) could be methylated. Regarding the
applicable other alkyl nucleophiles, diethylaluminum chloride
(2b) was also reactive, although 2b potentially undergoes β-H
elimination as an undesired pathway.
Based on the hypothesis that the Lewis acidity of
methylaluminums would enhance the electrophilicity of the
ester moiety, we modified the ester starting material from
phenyl esters to alkyl esters (Scheme 3).7h,15 Delightfully,
slightly modified reaction conditions using a Ni(OTs)2/dcypt
catalyst worked well for the alkylation of aromatic methyl esters
(4A), delivering the corresponding methylated arenes.
B
DOI: 10.1021/acs.orglett.8b01233
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
In summary, we have developed a decarbonylative
methylation of aromatic esters by a nickel catalyst.
Dimethylaluminum chlorides work not only as alkylating
agents but also as Lewis acids in this reaction, realizing the
methylation of otherwise unreactive aromatic alkyl esters.
Further studies of the Lewis acid effect for other decarbon-
ylative transformations are ongoing in our group.
Scheme 3. Substrate Scope of Aromatic Methyl Esters 4
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01233.
Detailed experimental procedures, spectral data for all
1
compounds, and H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: junyamaguchi@waseda.jp.
ORCID
a
Conditions: Ni(OTs)2 (5 mol %), dcypt (10 mol %), 4 (0.40 mmol),
2a (hexane solution, 1.5 equiv), 1,4-dioxane (1.0 mL), 170 °C, 16 h.
Kei Muto: 0000-0001-8301-4384
Junichiro Yamaguchi: 0000-0002-3896-5882
Notes
b
c
GC yield. 1H NMR yield.
Similarly, ethyl (5A) and n-Bu ester (6A) showed good
reactivity; however, sterically bulky esters such as isopropyl
(7A) resulted in a poor yield. With this result, we further
investigated the scope of aromatic methyl esters. Generally, we
found that most aromatic alkyl esters showed similar reactivity
to the corresponding phenyl esters to afford methyl arenes 3.
Naphthoates (4A, 4C, 4P, and 4Q) and benzoates (4B and
4G) could be methylated in good yields. Sterically hindered 4G
also underwent a reaction to give 3Ga. Heteroaromatic esters
(4L and 4M) could be methylated. Although recent computa-
tional work done by Uchiyama and Wang documented that an
electron-rich nickel catalyst can accelerate the ether C−O bond
scission with the support of a Lewis acid,16 the methoxy group
was completely tolerated under these reaction conditions.
Next, we wanted to investigate whether this reaction is
applicable to the chemoselective functionalization of alkyl
versus phenyl esters using methyl phenyl naphthalene-
dicarboxylate 8 (Scheme 4A). It is envisaged that the
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant Number
JP18H04272, JP16H04148 (to J.Y.), JP17K14453, and
JP18H04661 (to K.M.). The Materials Characterization Central
Laboratory in Waseda University is acknowledged for HRMS
measurement.
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DOI: 10.1021/acs.orglett.8b01233
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DOI: 10.1021/acs.orglett.8b01233
Org. Lett. XXXX, XXX, XXX−XXX