Aerobic oxidative homocoupling reaction of anilides using heterogeneous metal catalysts

Article abstract of DOI:10.1016/j.tetlet.2017.01.075

We have developed a heterogeneous catalytic oxidative homocoupling reaction of dimethoxyanilides under an oxygen atmosphere. The resulting homo-dimers are useful for the construction of heterocycles, demonstrating the potential of heterogeneous metal catalysts.

Full text of DOI:10.1016/j.tetlet.2017.01.075

Accepted Manuscript
Aerobic Oxidative Homocoupling Reaction of Anilides Using Heterogeneous
Metal Catalysts
Shigenobu Fujimoto, Kenji Matsumoto, Takayuki Iwata, Mitsuru Shindo
PII:
S0040-4039(17)30106-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.075
TETL 48578
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
21 December 2016
17 January 2017
23 January 2017
Please cite this article as: Fujimoto, S., Matsumoto, K., Iwata, T., Shindo, M., Aerobic Oxidative Homocoupling
Reaction of Anilides Using Heterogeneous Metal Catalysts, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.01.075
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Graphical Abstract
Aerobic Oxidative Homocoupling Reaction
of Anilides Using Heterogeneous Metal
Catalysts
Leave this area blank for abstract info.
Shigenobu Fujimoto, Kenji Matsumoto, Takayuki Iwata and Mitsuru Shindo

1
Tetrahedron Letters
Aerobic Oxidative Homocoupling Reaction of Anilides Using Heterogeneous Metal
Catalysts
Shigenobu Fujimoto,a Kenji Matsumoto,b Takayuki Iwatac and Mitsuru Shindoc,
aInterdisciplinary Graduate School of Engineering Sciences, Kyushu University, Kasuga, Fukuoka, Japan
bFaculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
cInstitute for Materials Chemistry and Engineering, Kyushu University, 6-1, Kasugako-en, Kasuga, Fukuoka, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We have developed a heterogeneous catalytic oxidative homocoupling reaction of
dimethoxyanilides under an oxygen atmosphere. The resulting homo-dimers are useful for the
construction of heterocycles, demonstrating the potential of heterogeneous metal catalysts.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Oxidative homocoupling
Heterogeneous metal catalyst
Anilide
Oxidative homocoupling reactions of aromatic compounds
represent
a fundamental, convenient and atom-economical
method for the construction of biaryl skeletons, which are
ubiquitously found in natural products and materials.1 Especially,
electron-rich aromatic compounds bearing alkoxy substituents
are suitable substrates for this type of transformation owing to
thier oxidative potential.2 Anilines can also be dimerized by
oxidants to give the corresponding homocoupled biarylamines.3
Recently, we demonstrated the synthetic utility of commercially
available heterogeneous metal catalysts for aerobic oxidative
coupling reactions of aromatic compounds, including the
intermolecular homo- and hetero-coupling reactions of aryl
amines4 and the intramolecular aromatic coupling reactions5
(Scheme 1 (a) and (b)). Although anilides are much more stable
and easy to handle N-functional groups than anilines, and they
can be converted into other functionalities, only few examples of
intermolecular homocoupling of aromatic compounds substituted
by an amide moiety have been reported to date (Scheme 1 (c)). 6-8
Furthermore, there have been no reports on the catalytic
dimerization of anilides so far. Herein, we present an aerobic,
heterogeneous metal-catalyzed intermolecular homocoupling
reaction of anilides (Scheme 1 (d)).
During the course of our studies on the aerobic heterogeneous
metal-catalyzed oxidation of aromatic compounds, we attempted
the intramolecular coupling reaction of benzanilide 1a, but the
homodimer of this anilide 2a was obtained in excellent yield
(Scheme 2) in place of the cyclized product 3.
Scheme 1. Homo- and hetero-coupling reactions of aryl amines and
anilid
———
 Corresponding author. Tel.: +81-092-583-7802; fax: +81-092-583-7803; e-mail: shindo@cm.kyushu-u.ac.jp

2
Tetrahedron
3
5% Pd/C
5% Pd/ CaCO3
5% Pd/ Al2O3
5% Pt/C
TFA
TFA
TFA
TFA
24
22
8
>99
>99
4
5
6
7
8
9
>99
1.5
24
17
3
>99
5% Pd/Al2O3
5% Pd/Al2O3
5% Pd/Al2O3
5% Pd/Al2O3
5% Pd/Al2O3
5% Pd/Al2O3
5% Pd/Al2O3
CH2Cl2
TFA
MsOH
TfOH
TfOH
TfOH
TfOH
TfOH
15 (85)a
CH2Cl2
CH2Cl2
THF
>99
Scheme 2. Homocoupling reaction of aryl anilide 1a.
>99
Inspired by this result, we decided to carry out a systematic
study on this oxidative dimerization of anilides. Non-substituted
and monomethoxy-substituted benzanilides 4 were subjected to
oxidative homocoupling reactions under our standard conditions
(Pd/Al2O3 or Rh/C in the presence of various acids under an
oxygen atmosphere),9 but they were completely unreactive,
probably because the oxidation potential of simple anilides was
not low enough for the oxidation to take place in the presence of
metal catalysts. Interestingly, N-methylacylanilides 5 were also
found to be inert. Therefore, 3,4-dimethoxyanilide 1a was used
as standard substrate to examine the reaction conditions.
10
11
3
>99
HFIP
3
>99
12b
13c
HFIP
3
60
HFIP
1
>99
a Recovery yield of 1a. bUnder argon. cUnder oxygen.
To confirm the generality of the method, various types of 3,4-
dimethoxyanilides bearing different N-acyl groups were
subjected to the oxidative coupling reaction under an oxygen
atmosphere (Table 2). N-Benzoyl- and naphtoyl-anilides (entries
1-7) were found to be good substrates for this transformation, and
N-acetylanilides and related aliphatic anilides (entries 8-11) were
also converted into the corresponding dimers in good yields. The
oxidative coupling of N-pivaloyl anilide (entry 9) was found to
be very sluggish. It is noteworthy that a methylcarbamate
analogue (entry 12) underwent a very fast coupling under the
same conditions to give the corresponding dimer in good yield.
Figure 1. Unreactive substrates in the oxidative coupling reaction
under standard conditions.
The reactivity of dimethoxyanilides other than 3,4-substituted
derivatives in the oxidative coupling was also examined (Figure
2). The oxidation of 2,3- and 2,4-dimethoxyanilides (2n-q)
furnished 5,5’-dimers, although 3,5-, 2,5-, and 2,6-
dimethoxyanilides were inert to this type of oxidation.
The reactivity of several commercially available
heterogeneous metal catalysts was examined under air in TFA
(Table 1, entries 1-6). Palladium catalysts, especially Pd on
Al2O3, and Pt/C were found to be suitable for this reaction under
air (entries 3-6), while Rh catalysts supported on C and Al2O3
were less active (entries 1 and 2).
From these experimental results, the following trends of
suitable substrates for this coupling reactions could be deduced:
1) two methoxy substituents were required along with one
secondary amide (N-H) substituent, 2) the coupling position
(oxidized C-H bond) was located at the para-position of a
methoxy group, 3) one of the neighboring groups to the coupling
position was not substituted.
We then optimized the reaction conditions in terms on acids
and solvents based on our previous reports4,5 (Table 1, entries 7-
13). As a result, TfOH was found to be an efficient acid in HFIP,
which was selected in view of the solubility of the substrates. The
reaction required oxygen, because the reaction was incompleted
under argon (entry 12) and completed in 1 h under oxygen (entry
13). To confirm the heterogeneous catalytic reaction, we carried
out the leaching test as follows: After completion of the coupling
of 1a under the condition of entry 11, the Pd catalyst was
removed with a membrane filter (0.45 mm). Then, 1a was added
to the filtrate under oxygen at room temperature, and the mixture
was stirred. After 15 h, 1a could be recovered without generation
of 2a. This result indicates that the active species was not
leaching metal but heterogeneous metal.
Table 1. Optimization of the homocoupling reaction using
heterogeneous metal catalysts.
Entry
Metal catalyst
5% Rh/C
Solvent
TFA
TFA
Acid
Time (h)
24
Yield (%)
23 (76)a
33 (65)a
1
2
5% Rh/Al2O3
24

3
Table 2. Substrate scope of the homocoupling reaction of 3,4-
However, the electron-donating ability of the amide group is
dimethoxyanilides.
dependent on its conformation, since the oxidation potential of
the N-Me analogue, in which the lone pair on the amide nitrogen
is not conjugated with the aromatic ring, was not sufficiently
low.11 The steric factor might be important in this coupling,
judging from the neighboring effect. Although the reaction
mechanism is unclear, it can be assumed that radical cation
intermediates could be generated.12
Entry
1
R
3,4-dimethoxyphenyl
3,4,5-trimethoxyphenyl
2-bromophenyl
3-bromophenyl
4-bromophenyl
1-naphthyl
Time (h)
Yield (%)
44
2b
2c
2d
2e
2f
1.5
3
2
69
3
23
4
80
4
>99
>99
63
Scheme 3. Homocoupling reaction of 1,2,4-trimethoxybenzene.
5
4
6
2g
2h
2i
2
To show the synthetic utility of this reaction, 2m was
hydrolyzed to afford 2,2’-diamine 8, which can be used as a
precursor of heterocycles such as carbazole13 and
benzo[c]cinnoline14 (Scheme 4). Since the direct oxidative
dimerization of 3,4-dimethoxyaniline was not successful under
various conditions, this oxidative homocoupling of anilides can
be useful for the construction of a biphenyl-2,2’-diamine
skeleton.
7
2-naphthyl
2
60
8
Me
4
87b
32a
9
t-Bu
2j
38
4
10
11
12
cyclohexyl
2k
2l
72a
benzyl
4
87b
82b
methoxy
2m
0.5
a 5% Pt/C (5 mol%) and TFA (2.0 equiv.) were used instead of Pd/Al2O3 and
TfOH. b The reaction was carried out under air instead of O2.
Scheme 4. Transformation of biaryl 2m to benzo[c]cinnoline 9.
Figure 3. Oxidation potential (V vs SCE) referred from Dinnocenzo
et al.11
In conclusion, we have developed
heterogeneous catalytic oxidative
dimethoxyanilides under mild conditions. Although this reaction
is limited to electron-rich anilides, the resulting dimers might be
useful for the construction of heterocycles, demonstrating the
potential of heterogeneous metal catalysts.
a
method for the
Figure 2. Substrate scope in the homocoupling reaction of
dimethoxyanilides other than 3,4-substituted analogues.
homocoupling of
Many examples of oxidative homocoupling of 1,2,4-
trimethoxybenzene 6 have been reported,2d,10 and we could also
obtain the corresponding dimer in good yield from 1,2,4-
trimethoxybenzene under our reaction conditions (Scheme 3).
Considering the oxidation potential, not only a methoxy group
but also an amide group can effectively reduce the oxidation
potential of benzene (Figure 3). Therefore, these types of
electron-rich anilides could be oxidized to afford the dimers.
Acknowledgments
This work was partially supported by JSPS KAKENHI Grants
(No.16H01157, No.26293004), the Science and Technology
Research Promotion Program for Agriculture, Forestry, Fisheries
and Food Industry (M.S.), the Asahi Glass Foundation (K.M.),

4
Tetrahedron
and the Cooperative Research Program of the Network Joint
Supplementary Material
Research Center for Materials and Devices.
Supplementary data associated with this article can be found
in the online version, at
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