Electrochemical Oxidative C?H Amination of Phenols: Access to Triarylamine Derivatives

Article abstract of DOI:10.1002/anie.201800240

Dehydrogenative C?H/N?H cross-coupling serves as one of the most straightforward and atom-economical approaches for C?N bond formation. In this work, an electrochemical reaction protocol has been developed for the oxidative C?H amination of unprotected ph

Full text of DOI:10.1002/anie.201800240

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Accepted Article
Title: Electrochemical oxidative C-H Amination of Phenols: Access to
Triarylamine Derivatives
Authors: Shan Tang, Siyuan Wang, Yichang Liu, Hengjiang Cong, and
Aiwen Lei
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800240
Angew. Chem. 10.1002/ange.201800240
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10.1002/anie.201800240
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Electrochemical Oxidative C-H Amination of Phenols: Access to
Triarylamine Derivatives
Shan Tang,+ Siyuan Wang,+ Yichang Liu, Hengjiang Cong, and Aiwen Lei*
Abstract: Dehydrogenative C-H/N-H cross-coupling serves as one
of the most straightforward and atom-economical approaches for C-
N bond formation. In this work, an electrochemical reaction protocol
has been developed for the oxidative C-H amination of unprotected
phenols under undivided electrolytic conditions. Neither metal
catalysts nor chemical oxidants are needed to facilitate the
dehydrogenation process. A series of triarylamine derivatives could
be obtained with good functional group tolerance. The electrolysis is
scalable and can be performed at ambient conditions.
chemists.[6] Electrochemical anodic oxidation serves as an ideal
option for replacing chemical oxidants in oxidative C-H
functionalization reactions.[7] In this field, great progress has
been made in the dehydrogenative C-C cross-couplings.[8] In
comparison, the construction of C-N bonds has achieved much
less successful results.[9] In 2013, Yoshida and co-workers
developed an oxidative aryl C-H amination of electron-rich
arenes to access anilines with the combination of the
electrochemical and chemical reactions.[10] Waldvogel applied a
similar reaction approach to achieve the electrochemical aryl C-
H amination of less activated, alkylated arenes by using boron-
doped carbon electrodes.[11] As for the direct electrooxidative C-
H/N-H cross-coupling, the group of Xu recently achieved the
intramolecular dehydrogenative C(sp2)-N bond formation for the
synthesis of benzimidazoles.[12] Until now, there is still a lack of
direct electrochemical intermolecular oxidative C(sp2)-H
amination methods. In this work, we would like to communicate
our recent progress in an intermolecular electrooxidative C-H/N-
H cross-coupling (Scheme 1b). N-aryl phenothiazines have been
reported to be highly efficient photocatalysts in polymer
Amination of aromatic compounds is of great importance in
organic synthesis since C(sp2)-N bonds widely exist in natural
products, pharmaceuticals and fundamental materials.[1]
Transition metal catalyzed amination of aryl halides or aryl
boronic acids has been developed as reliable methods for the
construction of C(sp2)-N bonds.[2] Over the past few years, great
attention has been paid to the direct aryl C-H amination since it
has successfully skipped the pre-functionalization of arene
substrates and broadened the substrate scope.[3] Among these
transformations, dehydrogenative C(sp2)-H/N-H cross-coupling
serves as one of the most straightforward and atom-economical
approaches for C(sp2)-N bond formation.[4] However, these
transformations usually require using stoichiometric amount of
chemical oxidants (Scheme 1a). From the view of atom-
economical and sustainable chemistry, developing chemical
oxidant-free reaction protocols for the oxidative C-H amination of
aromatic compounds would be much more appealing.[5]
synthesis.[13] Our method provides
a simple and atom
economical way for the synthesis of N-aryl phenothiazines from
unprotected phenols and phenothiazine derivatives with up to
93% yield.[14]
n
By utilizing Bu4NBF4 as the electrolyte and CH3CN/MeOH
as co-solvents, the cross-coupling between p-methoxyphenol
(1a) and phenothiazine (2a) could afford 3a in a 93% yield under
7 mA constant current for 100 min in an undivided cell (Table 1,
entry 1). Slightly decreased reaction yields were obtained either
by decreasing or increasing the operating current (Table 1,
entries 2 and 3). The effect of solvent was also explored. Good
reaction reactivity could still be achieved by using acetonitrile or
methanol as the only solvent (Table 1, entries 4 and 5). However,
using water instead of methanol led to a lower reaction yield
(Table 1, entry 6). As for the choices of supporting electrolyte,
LiClO4, nBu4NClO4 and nBu4NPF6 demonstrated similar reactivity
Scheme 1. Intermolecular dehydrogenative amination of aromatic compounds.
n
with Bu4NBF4 (Table 1, entry 7). Notably, a good reaction yield
could still be obtained by reducing the amount of supporting
electrolyte (Table 1, entry 8). The effect of the electrode material
was also demonstrated. Quite similar yields were obtained by
replacing the carbon rod anode with carbon cloth or platinum
plate anode (Table 1, entries 9 and 10). Platinum plate cathode
showed a similar reactivity with nickel plate cathode (Table 1,
entry 11) while graphite rod cathode was less effective than
nickel plate cathode (Table 1, entry 12). A slightly decreased
reaction yield could be obtained in open air (Table 1, entry 13)
while no reaction took place without electric current (Table 1,
entry 14). As was expected, large amount of hydrogen gas could
be detected by GC analysis under standard conditions.
As a versatile and environmentally friendly synthetic tool,
electrochemistry has aroused continuous interest of synthetic
[*]
Dr. S. Tang,[+] Mr. S. Wang,[+] Mr. Y. Liu, Dr. H. Cong, Prof. Dr. A.
Lei
College of Chemistry and Molecular Sciences, Institute for
Advanced Studies (IAS), Wuhan University, Wuhan 430072, Hubei,
P. R. China
Homepage: http://aiwenlei.whu.edu.cn/
E-mail: aiwenlei@whu.edu.cn
Prof. Dr. A. Lei
State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, P. R. China.
S. Tang and S. Wang contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
Table 1. Effects of reaction parameters.[a]
[+]
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10.1002/anie.201800240
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mL), room temperature, N2, 100 min (Q = 42 C, 2.2 F). Isolated yields were
shown. Yields shown in parentheses are of current efficiency. [b] The reaction
was conducted at controlled potential (E = 0.70 V vs Ag/AgCl) and stopped
until complete consumption of 2 (monitored by TLC). [c] 130 min. [d] The yield
was determined by 1H NMR spectroscopy with CH2Br2 as the internal standard.
Entry
Variation from the standard conditions
Yield (%)
The scope of this electrooxidative C(sp2)-H/N-H cross-
coupling was then explored. Firstly, different para-substituted
phenols were applied as substrates in this amination reaction.
1
2
none
3.5 mA instead of 7 mA, 200 min
14 mA instead of 7 mA, 50 min
without MeOH
93
83
3
86
Phenols
bearing
electron-donating
or
electron-neutral
substituents at the para position could form the desired
amination products in good to high yields (Table 2, 3a-3f).
Notably, chloro, bromo and free-hydroxyl group were well
tolerated (Table 2, 3d-3f). Phenols bearing electron-withdrawing
acetyl or ester group at the para position could only give the C-N
bond formation products in low yields (Table 2, 3g and 3h).
Strong electron-rich 3,4-dimethoxyphenol was able to generate
the amination product in 93% yield (Table 2, 3i). 2,4-
Dimethylphenol selectively furnished an ortho amination product
in 88% isolated yield with 80% current efficiency (Table 2, 3j).
When 2,6-dimethylphenol was applied as the substrate, a para
amination product could be obtained in 56% yield (Scheme 2a,
4a).
4
88
5
without MeCN
86
6
H2O instead of MeOH
83
7
LiClO4, nBu4NClO4 or nBu4NPF6 instead of nBu4NBF4
nBu4NBF4 (0.005 M)
88-90
85
8
9
carbon cloth anode
85
10
11
12
13
14
platinum plate anode
86
platinum plate cathode
graphite rod cathode
95
84
under air
88
without electric current, under air
n.r.
[a] Reaction conditions: graphite rod anode, nickel plate cathode, constant
current = 7 mA, 1a (1.2 equiv, 0.24 mmol), 2a (1.0 equiv, 0.20 mmol),
nBu4NBF4 (0.50 equiv, 0.10 mmol), MeCN/MeOH (8.0 mL/2.0 mL), room
temperature, N2, 100 min (Q = 42 C, 2.2 F). Isolated yields were shown. n.r. =
no reaction.
Table 2. Electrooxidative ortho C-H amination of phenols with phenothiazine
derivatives.[a]
Scheme 2. Electrooxidative para C-H amination of phenols with phenothiazine.
[a] The reaction was conducted at controlled potential (E = 0.70 V vs Ag/AgCl)
and stopped until complete consumption of 1 (monitored by TLC).
Interestingly, the reaction with simple phenol only afforded
the ortho amination product 3k in 17% yield while a para and
ortho double amination product 5a could be isolated in 42% yield
(Scheme 2b). By increasing the amount of phenothiazine and
prolonging the reaction time, the double amination products of
ortho-substituted phenols could be obtained in good to high
yields (Scheme 3, 5b-5g). As for other aromatic phenols, α-
naphthol gave a C-4 amination product (Scheme 2c, 3l) while β-
naphthol could selectively furnish a C-1 amination product
[a] Reaction conditions: graphite rod anode (ϕ 6 mm), nickel plate cathode (15
mm×18 mm×1.0 mm), constant current = 7.0 mA (Janode ≈ 6.5 mA/cm2), 1
(0.24 mmol), 2 (0.20 mmol), nBu4NBF4 (0.10 mmol), MeCN/MeOH (8.0 mL/2.0
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10.1002/anie.201800240
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(Table 2, 3m).[15] In addition, the scope of the amine moiety was
also studied. Phenothiazines bearing chloride, electron-donating
or electron-withdrawing substituents were all able to give the
amination products in good to high yields (Table 2, 3n-3q).
Notably, phenoxazine was also suitable in this electrooxidative
amination reaction, which furnished the C(sp2)-N bond formation
product in 85% yield (Table 2, 3r).
synthesized with only 5 mol% of supporting electrolyte in the
open air (Scheme 5).
Scheme 5. Gram scale synthesis.
Since the method has been established, attentions were
then paid to understand the reaction mechanism. Cyclic
voltammetry (CV) experiments were conducted to study the
redox potential of the substrates (Figure 1). Two obvious
oxidation peaks of phenothiazine 2a in CH3CN/CH3OH were
observed at 0.70 V and 0.91 V while two reduction peaks were
observed on the reverse scan at 0.74 V and 0.61 V (Figure 1a).
The first oxidation peak of 2a was quasi-reversible and only one
electon was transferred in the oxidation process (See
Supporting Information for detailed data analysis). The oxidation
potentials of phenols were also measured by conducting CV
experiments. Even strong electron-rich p-methoxyphenol
demonstrated higher oxidation potential than 2a (Figure 1b).
These results indicated that 2a was likely to be first oxidized
under electrolytic conditions. To confirm this assumption, the
electrolysis was performed at the first peak oxidation potential of
2a (0.70 V). The potential controlled electrolysis furnished the
desired products in slightly decreased reaction yields for the
mono C-H amination of p-methoxylphenol and 2,4-
dimethylphenol and α-naphthol (Table 2, 3a, 3j and 3l).
Meanwhile, a slightly increased reaction yield could be obtained
for the double amination reaction of 2-methylphenol by utilizing
potential controlled electrolysis instead of constant current
electrolysis (Scheme 3, 5b). Based on the above experimental
results and previous reports,[14] a plausible mechanism for the
electrooxidative C(sp2)-H/N-H cross-coupling between 1a and 2a
was proposed and described in Supporting Information, Scheme
S1. The reaction is initiated by the anodic oxidation of 2a to
generate a radical cation.
Scheme 3. Electrooxidative double C-H amination of ortho substituted phenols
with phenothiazine. [a] The reaction was conducted at controlled potential (E =
0.70 V vs Ag/AgCl) and stopped until complete consumption of 1 (monitored
by TLC).
Triphenylamines have been reported to serve as potential
optoelectronic materials.[16] In order to access triphenylamines,
efforts were taken to expand the scope of amine moiety from
phenothiazine derivatives to diarylamines. By utilizing
CH2Cl2/HFIP as co-solvents, the ortho C-H amination of p-
methoxylphenol with electron-neutral diphenylamines could
afford triphenylamines (Scheme 4a, 3s and 3t). Since the
reaction with diarylamines suffered from low efficiency, another
way to access triphenylamines was developed. By using a
reduction system of NiCl2•6H2O and NaBH4,[17] triphenylamine
3u could also be obtained from the direct reduction of N-aryl
phenothiazine 3a in 69% yield (Scheme 4b). Thus, our
electrochemical method was also able to access a series of
functionalized triphenylamines.
Scheme 4. Synthesis of triphenylamines. HFIP = Hexafluoro-2-propanol.
Figure 1. Cyclic voltammograms on a glassy carbon electrode (ϕ 3 mm) at
0.10 V•s−1 in CH3CN/CH3OH under nitrogen. a) Phenothiazine. b) Different
phenols.
The synthetic potential of this electrooxidative C-H amination
was then evaluated by performing a 50 mmol scale reaction. By
using 130 mA constant current, 13.3 g of 3a could be
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21390402, 21520102003) and the Hubei
Province Natural Science Foundation of China (2017CFA010).
The Program of Introducing Talents of Discipline to Universities
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Keywords: C-N bond formation • electrochemistry • C-H
functionalization • amination • hydrogen evolution
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COMMUNICATION
S. Tang, S. Wang, Y. Liu, H. Cong, A.
Lei*
Page No. – Page No.
Electrochemical Oxidative C-H
Amination of Phenols: Access to
Triarylamine Derivatives
An atom economical oxidative C-H amination of unprotected phenols was achieved
via an external oxidant-free electrochemical reaction protocol. Under undivided
electrolytic conditions, triarylamines derivatives were produced in high functional
group tolerance along with H2 generation.
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