Angewandte
Communications
Chemie
Redox Chemistry
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À
Electrochemical C H/N H Functionalization for the Synthesis of
Highly Functionalized (Aza)indoles
Zhong-Wei Hou, Zhong-Yi Mao, Huai-Bo Zhao, Yared Yohannes Melcamu, Xin Lu,*
Abstract: Indoles and azaindoles are among the most
important heterocycles because of their prevalence in nature
and their broad utility in pharmaceutical industry. Reported
herein is an unprecedented noble-metal- and oxidant-free
electrochemical method for the coupling of (hetero)arylamines
with tethered alkynes to synthesize highly functionalized
indoles, as well as the more challenging azaindoles.
widely employed Larock indole synthesis.[3] Nonetheless, the
reported methods frequently suffer from one or more of the
following disadvantages, such as low regioselectivity when
applied to similarly substituted alkynes (e.g., diaryl[2h] or
dialkyl alkynes[2a]), as well as the requirement for noble-metal
reagents and terminal oxidants.[4] Therefore, it is highly
desirable to develop a more efficient and sustainable
method for constructing indoles from easily available building
blocks without relying on a noble-metal catalyst or oxidant.[5]
Azaindoles are indole bioisosteres and possess a variety of
beneficial biological properties.[6] However, access to struc-
turally diverse azaindoles remains challenging. Traditional
methods including the Fischer indole synthesis often fail[7] or
are inefficient when electron-deficient pyridine-derived sub-
strates are employed.[6] In contrast, preparation of azaindoles
by annulation of alkynes with aminopyridines has been
reported only once, in which a series of 7-azaindoles were
constructed using a rhodium-based catalyst and a stoichio-
metric amount of silver oxidant.[8]
I
ndoles and azaindoles are prevalent in pharmaceutical
agents and natural products.[1] Therefore, the development
of general, efficient, and sustainable methods for the con-
struction of these structures have long been pursued by
organic chemists. In this context, the noble-metal-catalyzed
À
coupling of anilides or anilines with internal alkynes by C H/
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N H functionalization has emerged in recent years as
a modular and step-economical approach for the synthesis
of indoles (Scheme 1a).[2] This approach advantageously
eliminates the need for prefunctionalized substrates (e.g.,
ortho-haloanilines) which are commonly required in the
Organic electrosynthesis,[9] which employs electrons as
reagents, has been demonstrated to be a versatile and
environmentally friendly synthetic tool and attracted
renewed interests.[10] We[11] have recently developed an
electrochemical method for generating amidyl radicals and
demonstrated in one example that they could participate in
cascade cyclization reactions to afford indolines.[12] Inspired
by this work and that of Nevado and co-workers on cascade
radical reactions,[13] we report herein an unprecedented
electrochemical synthesis of highly functionalized indoles
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À
and azaindoles by C H/N H functionalization of (hetero)-
arylamines using tethered alkynes (Scheme 1b). The noble-
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Scheme 1. (Aza)indole synthesis by C H/N H functionalization.
Cp=cyclopentadiene.
metal reagent- and oxidant-free reaction employs inexpensive
[14]
ferrocene ([Cp2Fe])
as the redox catalyst, is compatible
with a broad range of sensitive functional groups, and
produces valuable H2 as the only theoretical byproduct.[15]
The easily available urea 1a (see Scheme 2, R1 = R3 = H,
R2 = Ph, R4 = Me) was chosen as a model substrate and
electrolyzed in a round-bottom flask under the reaction
conditions we recently developed for the electrochemical
olefin hydroamidation reaction but without addition of the
reducing reagent 1,4-cyclohexadiene.[11] Regiospecific forma-
tion of the unsymmetrical 2,3-diarylsubstituted indole 2a was
achieved in 85% yield with 5 mol% of [Cp2Fe] as the redox
catalyst. The structure of 2a was confirmed by single-crystal
X-ray diffraction studies.[16] The ferric catalyst and electricity
were indispensable for the success of the transformation (see
Table S1 in the Supporting Information). Importantly, con-
ducting the electrolysis under air exerted no significant
impact on reaction efficiency (see Table S1).
[*] Z.-W. Hou, Z.-Y. Mao, H.-B. Zhao, Y. Y. Melcamu, Prof. Dr. X. Lu,
Dr. J. Song, Prof. Dr. H.-C. Xu
Collaborative Innovation Center of Chemistry for Energy Material
State Key Laboratory of Physical Chemistry of Solid Surfaces
Key Laboratory of Chemical Biology of Fujian Province and Depart-
ment of Chemistry, Xiamen University
Xiamen 361005 (P.R. China)
E-mail: xinlu@xmu.edu.cn
Dr. J. Song
Fujian Institute of Research on Structure of Matter
Chinese Academy of Sciences, Fuzhou 350002 (P.R. China)
Supporting information and the ORCID identification number(s) for
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!