Electrooxidative and Regioselective C?H Azolation of Phenol and Aniline Derivatives

Article abstract of DOI:10.1002/anie.201901762

A general and practical protocol was developed for the regioselective C?H azolation of phenol and aniline derivatives by electrooxidative cross-coupling. The reaction occurs under metal-, oxidant-, and reagent-free conditions, allowing access to a wide variety of synthetically useful heteroarene derivatives. The reaction also tolerates a broad range of functional groups and is amenable to gram-scale synthesis. Finally, a preliminary mechanistic study indicated that a radical–radical-combination pathway might be involved in the coupling reaction.

Full text of DOI:10.1002/anie.201901762

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Accepted Article
Title: Electro-oxidative and Regioselective C-H Azolation of Phenol and
Aniline Drivatives
Authors: Pengju Feng, Guojian Ma, Xiaoguang Chen, Xing Wu, Ling
Lin, Peng Liu, and Tianfeng Chen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901762
Angew. Chem. 10.1002/ange.201901762
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10.1002/anie.201901762
Angewandte Chemie International Edition
COMMUNICATION
Electro-oxidative and Regioselective C-H Azolation of Phenol and
Aniline Drivatives
Pengju Feng,*‡[a] Guojian Ma,‡[a] Xiaoguang Chen,[a] Xing Wu,[a] Ling Lin,[a] Peng Liu[b] and Tianfeng Chen*[a]
Abstract: A general and practical protocol for regioselective C-H
azolation of phenol and aniline derivatives via electro-oxidative cross
coupling has been demonstrated. The reaction runs under metal,
oxidant and reagent free condition, allowing access to a wide variety
of synthetically useful hetero-arene derivatives. The reaction also
tolerates a wide range of functional groups, and is amenable to gram
scale synthesis. Finally, preliminary mechanistic study indicated a
radical-radical combination pathway might be involved for the
coupling reaction.
the intermolecular azolation of arenes, are still rare.9 Limited
number of examples showed that imidazole derivatives as
nucleophiles could react with aromatic and benzylic compounds
intermolecularly to form mixture of C/N adducts of naphtha(1,2-a)
pyrene,10 tosyl-protected imidazolium ions11 and pyren-1-
ylazoliums.12 Given the importance of N-arylated azoles, clean
and practical protocols to derivatize structurally diverse azoles
are highly desirable. Recent literatures revealed that both
phenols and azoles could be electrochemically oxidized to form
the corresponding radical intermediates under various conditions
for versatile transformation, while combination of the two
compounds under electrochemical condition are not achived.13
Although the coupling of radicals can be useful for organic
synthesis, it is not clear such transformation would be feasible
due to high reactivities of the involved reaction intermediate and
significant side reactions.14 We report here that, under constant
cell potential, the intermolecular combination between
phenol/aniline derivatives and azoles to form N-arylated azoles
in high yields (Scheme 1, c) and preliminary mechanism insights.
Owing to their ubiquitous presence in natural products,
pharmaceuticals,
and
functional
materials,
N-arylated
heterocycle syntheses are of constant interest in organic
synthesis.1 The most known way to access these molecules is
through SNAr-type reactions between azoles and electron
deficient halogenated arenes (Scheme 1, a).2 During the last
decade, the rapid development of transition metal-catalyzed
amination reactions, such as Buchwald-Hartwig amination and
the Ullmann-type coupling reaction, provided elegant azolation
methods with constantly developing catalysts (Scheme 1, b).3
Moreover, direct C-H activation enabled the opportunity for
generation of complex molecules via a more straightforward and
economical sequence. For example, visible-light-mediated
photocatalysis provides attractive approach to generate azolated
arene via direct C-H amination of aromatic compounds under
mild conditions without the requirement of preactivation and/or
preoxidation of the substrates.4 Other methods, such as metal-
catalyzed C-H azolation and hypervalent-iodine-mediated
CH/NH cross-coupling are also useful options for the generation
of azolated scaffold.5 Undoubtedly, significant progress has
been made for the synthesis of azolated arenes, while demand
for more economical and environment friendly protocols to avoid
tedious workup procedures, expensive catalyst or excess
external oxidants still exists.
With the increasing environmental pressure, electrochemical
synthesis, using electric current in place of chemical oxidants,
has received unprecedented attention for the construction of C-X
bonds via C-H functionalization.6 In this field, the formation of
C(sp2) –N bond under metal free condition is a main focus and
several intramolecular C-N bond formation methods have been
reported.7 However, due to product over oxidation, synthetically
useful examples of intermolecular aryl C-H amination,8 especially
Scheme 1. Overview of Methodologies for the Synthesis of Azolation Arenes.
We chose 4-methoxyphenol (1a) as the model substrate to
couple with simple pyrazole.15 As outlined in table 1, the optimal
condition was set by utilizing Bu4NPF6 (0.05 M) as supporting
electrolyte, DCM/HFIP mixture as solvent, 0.60 mmol of 4-
methoxyphenol (1a), and 0.50 mmol of pyrazole (2a). The
reaction regioselectively furnished o-azolated phenol 3a in 97%
yield in an undivided cell equipped with Pt anode and cathode
under 2.5 V constant cell potential and N2 atmosphere (Table 1,
entry 1). The solvent was crucial for achieving sufficient
reactivity.15 Decreased reaction yields were observed when
using DCM or HFIP as the only solvent (entries 2-3). Other
solvent mixture, such as MeOH/HFIP, gave lower reaction
efficiency than HFIP alone. Another control experiment exhibited
slightly lower yield with Bu4NBF4 as supporting electrolyte (entry
5). Both lower and higher potentials decreased the reaction
[a]
Prof. P. Feng,‡Guojian Ma,‡Xiaoguang Chen, Xing Wu, Ling Lin,
Prof. Tianfeng Chen
Department of Chemistry, Jinan University, Guangzhou, 510632 China
E-mail: pfeng@jnu.edu.cn; tchentf@jnu.edu.cn
[b]
Prof. P. Liu
Guangdong Engineering and Technology Research Center for
Advanced Nanomaterials, School of Enviroment and Civil
Engineering, Dongguan University of Technology, Dongguan,
523808 China
[‡]
These authors contributed equally.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201901762
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COMMUNICATION
Table 1. Optimization of Reaction Conditions[a]
yields (entries 6-7). When the reaction was conducted in the air,
the yield decreased to 81% (entries 8). No desired product was
observed when the reaction was run without electricity.
Under the optimized condition with necessary adjustments,
the substrate scope and generality of this electrochemical cross-
coupling reaction were explored, and the results were tabulated
in Scheme 2. Pyrazoles with different functional groups, such as
Cl, Br, NO2, p-PhBr, successfully reacted with 4-methoxyphenol
(1a) to give desired products in good yields (3b-3e). Electron
deficient pyrazole was relatively less reactive (3d). It was
noteworthy that different protecting groups such as Bn, TBS,
and allyl could be introduced without problem for hydroquinone
to deliver corresponding coupling products (3f-3g, 3i). The alkyl
group with carboxylic acid is also compatible with the electron
chemical coupling process (3h).
Various azoles (3j-3t) with a wide range of substituents were
also tested for coupling with 4-methoxyphenol (1a). Notably,
[a] Reaction condition: Platinum plate cathode and anode (10 mm  10 mm 
0.1 mm), Constant cell potential, 1a (1.2 equiv, 0.6 mmol), 2a (1.0 equiv, 0.5
mmol), Bu4NPF6 (1.0 equiv, 0.5 mmol), DCM/HFIP (3.0 mL : 7.0 mL), rt, N2,
10h. [b]isolated yield.
1,2,4-triazole,
1,2,3-triazole,
tetrazole,
indazole
and
benzotriazole regioselectively gave single isomer of the C-N
bond formation product in moderate to good yield (3j-3n, 3m),
while 5-methoxy-indazole delivered the single amination product
(3m) whose structure was confirmed by X-ray diffraction study.
Table 2. Selected Examples of Electro-oxidative ortho C-H Azolation of Phenols[a]
[a]Reactions were run on a 0.6 mmol scale of 1 and 0.5 mmol scale of 2 in 10 mL mix-solvent under N2 at rt by using both Platinum plate cathode and anode (10
mm  10 mm  0.1 mm) until the disappearance of 2. [b]isolated yield. [c]the ratio of inseparable isomers. [d]the ratio of separable isomers.
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10.1002/anie.201901762
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COMMUNICATION
Iodoindazole also underwent smooth electrochemical process,
furnishing separable N1 and N2 isomers of 3p. The structure of
3p was further confirmed by X-ray study and NMR spectrum
reaction also exhibit high regioselectivity to deliver sterically less
hindered ortho azolated anilines.
To demonstrate the practicality and scalability of current
reaction, the coupling reaction was performed on gram scale
with 1r and 2c under standard condition. Promisingly, the
synthesis delivered 4.44 g of the desired product 3ag in 85%
yield, only marginally lower than the small scale reaction
(Scheme 2, a). And the functional groups on products offer
possibility for further manipulation. For example, the OMe group
of 3a delivered metal-catalyzed cross-coupling product 6 and
oxidation product benzoquinone 7 which is viable for moreuseful
transformations (Scheme 2, b).17
analysis.
Bromoindazole,
indazole
carboxylic
acid,
chloroindazole and 5-methyl-benzotriazole furnished mixtures of
separable isomers (3q-3r) and inseparable isomers (3o, 3t) in
high yields. Next, phenols with different functional groups were
investigated. Several substituted 4-methoxyphenol were also
proved to be good coupling partners for the electrochemical
transformation
(3u-3af).
Remarkably,
azoles
always
regioselectively attached to sterically less hindered ortho
position of phenols (3y-3af, 3ak). The substrate scope can be
successfully extended to para-substituted phenols with
a
sulfonamide or methyl sulphide substituent (3ag-3al). Finally,
high yield and good site selectivity has been achieved with 6-
methoxypyridin-3-ol (3am).
Table 3. Selected Examples Electro-oxidative ortho C-H Azolation of
Anilines.[a]
Scheme 2. Scalability Studies and Functional Group Manipulations
To gain insights into the reaction mechanism,1t was oxidized
to compound 8 which was directly injected into the standard
cross-coupling condition. It was found that 8 decomposed under
the reaction condition rather than form the desired product 3aj,
which excluded the Michael addition pathway (Scheme 3, a).18
During the study of electrochemical azolation, phenol 9 was
found to form homo-coupling compound 10 as a major side
product, which indicated that a radical intermediate of 9 may be
generated during the reaction process (Scheme 3, b).19
Additionally, both cross-coupling product 5g and the homo-
coupling product tosylbenzenesulfonohydrazide 11 possibly
formed via N radical recombination, were obtained when 4a was
the starting material (Scheme 3, c).20 Furthermore,
Cyclicvoltammetry (CV) experiments on both reactants 1a and
2a were conducted (Figure S1). The results revealed that
compound 2a shows higher oxidation potential (oxidation onset
of 2a, 1.20 V vs SCE) than that of 1a (oxidation peaks of 1a
(0.001M), around 1.0 V vs SCE). A control experiment was also
conducted under corresponding anode potentials (1.00 V and
1.20 V vs SCE) for comparison (Scheme 3, d). Under constant
anode potential of 1.00 V vs SCE, the desired product (3a) was
not detected, excluding the possibility of nucleophilic addition of
pyrozole to phenol cation radical.9,10,11,12 In addition, compound
3a could be formed in 6% yield under constant anode potential
of 1.20 V vs SCE, which indicated that oxidation of 2a was
essential to facilitate the reaction(see Supporting Information for
details).12b,16 These observations, along with previous
literatures,22 suggested that radical recombination between N
and C radicals during product formation may be involved. The
[a]Reactions were run on a 0.5 mmol scale of 2 and 0.6 mmol scale of 4 in 10
mL mix-solvent under N2 at rt by using both Platinum plate cathode and anode
(10 mm  10 mm  0.1 mm) until the disappearance of 2. [b]isolated yield.
Furthermore, the reaction was successfully conducted with
para-methoxyl aniline derivatives under the same condition.
Tosylp-methoxylaniline (4a) coupled with pyrozole to afford 5a in
91% yield. It was found the protecting group of amine was vital
to the success of azolation. Replacement of Tosyl with Ac for 4a
would cause dramatic decrease in yield (5b, 75%). No product
was observed when methyl (4-methoxyphenyl)carbamate (5c)
was used in the azolation reaction. Coupling 4a with different
azoles, such as nitropyrazole, triazole, tetrazole, chloroindazole,
benzotriazole, under standard electrochemical condition gave
desired products in good yields (5d-5k). Notably, Tosylanilines
show similar reaction activity with phenols, and the coupling
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10.1002/anie.201901762
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COMMUNICATION
detailed mechanism is presented in the supporting information
(Scheme S1).
Acknowledgements
We thank Dr. Yang Zhao, the research directorof Francool®
Technologyfor useful discussions and advice. This work was
supported by theNational Natural Science Foundation of China
(No. 21602078, 21877049), “the Fundamental Research Funds
for the Central Universities”(21617432), Innovation Projects of
Universities in Guangdong province (217KTSCX011), National
Program for Support of Top-notch Young Professionals
(W02070191) and Jinan University.
Keywords: Electro-oxidation • C-H azolation • amidation •
electrochemical synthesis • N-arylated heterocycle
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Scheme 3. Evidences for the proposed reaction mechanism.
In summary, we presented in this paper a mild and general
protocol for effective azolation of phenol and aniline derivatives
under electrochemical condition. The reaction exhibits several
useful advantages: (i) a wide range of azoles could react with
structurally diverse phenol and aniline derivatives under
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Experimental Section
Representative procedure: 4-Methoxy-2-(1H-pyrazol-1-yl)phenol (Table 2,
3a) A solution of 4-methoxyphenol (1a) (0.6 mmol), pyrazole (2a) (0.5
mmol) and Bu4NPF6 (0.025 mmol) in HFIP/DCM = 7/3 (5.0 mL, 0.100 M
of 2a) was stirred at room temperature under N2 atmosphere in a three-
necked bottle which was equipped with platinum electrodes (1.0 cm×1.0
cm×0.1 mm) as both the anode and cathode. The reaction mixture was
stirred and electrolyzed at a constant potential of 2.5 V until the
completely consumption of 2a around 20 h (detected by GC). The
reaction mixture was directly concentrated in vacuo. The residue was
purified by chromatography on silica gel, eluting with petroleum
ether/ethyl acetate = 10 : 1 (v/v), to afford compound 3a as a colourless
oil (92 mg，97 % yield).
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COMMUNICATION
PengjuFeng,*‡[a]Guojian Ma,‡[a]Xiaoguang
Chen,[a] Xing Wu,[a] Ling Lin,[a] Peng
Liu[b]and Tianfeng Chen*[a]
Page 1. – Page 5.
Electro-oxidative and Regioselective
C-H Azolation of Phenol and Aniline
Drivatives
What a move:Regioselective C-H azolation of phenol and aniline derivatives has
been achieved through electro-oxidative cross coupling. The reaction runs under
metal, oxidant and reagent free condition, allowing access to a wide variety of
synthetically useful hetero-arene derivatives. The reaction alsotolerates a wide range
of functional groups, and is amenable to gram scale synthesis.
This article is protected by copyright. All rights reserved.