10.1002/anie.201814509
Angewandte Chemie International Edition
COMMUNICATION
Formal Aza-Wacker Cyclization by Tandem Electrochemical
Oxidation and Copper Catalysis
Xiangli Yi and Xile Hu*
proposed that electrochemical oxidation generated an amidyl
radical, which underwent intramolecular cyclization to give an
alkyl radical. The latter was oxidized by the electrode to afford
alkene moiety upon proton loss. Despite the elegant concept, this
method relied on having tertiary alkyl radical intermediates,
probably due to inefficient direct oxidation of secondary and
primary alkyl radicals at the electrode.9 Thus, the scope of the
method was limited. Additionally, this method still required an
elevated temperature (110 oC). Taking advantage of the ability of
Cu species to mediate oxidative transformation of alkyl radicals
into alkenes,10 we incorporated Cu catalysis into the
electrochemical oxidative amination process (Scheme 1c). This
approach enabled, for the first time, the transformation of
secondary and even primary alkyl radical intermediates, leading
to a broad-scope methodology for formal aza-Wacker cyclization.
The Cu catalysis also enabled the reactions at room temperature.
Abstract: In oxidative electrochemical organic synthesis, radical
intermediates are often oxidized to cations en route to final product
formation. Here we describe an approach to transform
electrochemically generated organic radical intermediates into neutral
products via reaction with a metal catalyst. This approach combines
electrochemical oxidation with Cu catalysis to effect formal aza-
Wacker cyclization of internal alkenes. The Cu catalyst is essential for
transforming secondary and primary alkyl radical intermediates into
alkenes. A wide range of 5-membered N-heterocycles including
oxazolidinone, imidazolidinone, thiazolidinone, pyrrolidinone and
isoindolinone can be prepared under mild conditions.
Electrochemical organic synthesis has witnessed
a
renaissance in the last decade.1 Compared with traditional
organic synthesis which uses chemical redox agents,
electrochemical synthesis employs electric current which is
readily available, waste-free, and potentially renewable. Moreover,
the reactivity can be tuned by changing the applied potential in
electrochemical synthesis, overcoming the limitations of redox
potentials of chemical reagents. In electrochemical oxidations of
anionic species, radicals are the most frequent intermediates,
which are usually further oxidized to give carbocations en route to
final product formation.2 Trapping radical intermediates by metal
complexes is a strategy with a significant potential to expand the
scope of electrochemical synthesis.1g,3. In elegant examples, Lin
and co-workers used Mn(III)-N3 and Mn(III)-Cl complexes to
convert alkyl radical intermediates into alkyl azides and chlorides
via radical group transfer.1g,3a,3b Nevertheless, this strategy
remains under-developed. Herein, we describe an approach to
use Cu catalysis to convert electrochemically generated alkyl
radicals into alkenes, leading to a formal aza-Wacker cyclization
of internal alkenes.
Pd-catalyzed aza-Wacker cyclization is an attractive approach
to generate nitrogen-containing five-membered heterocycles
(Scheme 1a),4 which are ubiquitous in many natural products and
synthetic bio-active compounds.5 However, Pd catalysis usually
works for acidic nitrogen nucleophiles such as sulfonamides (pKa
Scheme 1. a) Pd-catalyzed aza-Wacker cyclization. b) Electrochemical
oxidative amination by Xu et al. c) Tandem electrochemical oxidation and Cu
catalysis for formal aza-Wacker cyclization.
=
13-18 in DMSO),6a,6b while less acidic substrates like
carbamates and amides (pKa 20-26)6 are sluggish reaction
partners.4b,7 A Cu-catalyzed method was developed for a similar
transformation of carbamates and ureas, but a high reaction
temperature and a strong oxidant (Dess–Martin periodinane)
were required.8 The group of Xu developed an electrochemical
protocol of intramolecular oxidative amination of alkenes that
avoided the use of chemical oxidants (Scheme 1b).9 It was
We began by investigating the electrochemical oxidative
amination of crotyl N-phenylcarbamate 1a in the presence of a Cu
catalyst (Table 1). After initial exploration of conditions, we found
that in a divided cell with MeOH as solvent, carbon fiber as
working electrode, 0.2 M LiClO4 as electrolyte, Cu(OAc)2 (30
mol%) as catalyst, 2 eq. of NaOAc as base, and under constant
current (3 mA, j = 0.19 mA/cm2), the desired product 2a could be
obtained in a yield of 33% after passing 2.2 F electron at room
temperature (entry 1, table 1). Increasing the amount of base to 4
eq. increased the yield to 51% (entry 2, Table 1), while without
base the reaction could hardly proceed (entry 3, Table 1). The use
of NaHCO3 or LiOtBu as base led to precipitation of Cu salts and
low yields (entries 4 and 5, Table 1). The use of NaOPiv (OPiv=
X. Yi, Prof. X. Hu
Laboratory of Inorganic Synthesis and Catalysis, Institute of
Chemical Sciences and Engineering, École Polytechnique Fédérale
de Lausanne (EPFL),
Lausanne1015, Switzerland
Supporting information for this article is given via a link at the end of
the document.
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