European Journal of Organic Chemistry
10.1002/ejoc.202000377
COMMUNICATION
A Mild Method for Electrochemical Reduction of Heterocyclic N-
Oxides.
[
a]
[b]
[a]
Yasuaki Fukazawa, Aleksandr E. Rubtsov, and Andrei V. Malkov*
[
a]
Prof. A. M. Malkov, Y. Fukazawa
Department of Chemistry, School of Science, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK Department
Loughborough University
Loughborough, Leicestershire, LE11 3TU, UK
[
b]
Dr A. E. Rubtsov,
Department of Chemistry
Perm State University
Bukireva 15, Perm 614990, Russia
Supporting information for this article is given via a link at the end of the document.
Abstract: Deoxygenation of heteroaromatic N-oxides is commonly
accomplished using chemical or enzymatic methods. In this work, we
report on an expedient protocol for electrochemical reduction of
pyridine N-oxide derivatives under mild conditions. A diverse range of
mono- and bis-N-oxides were converted into the corresponding
nitrogen bases in good yields. Importantly, the method is highly
selective towards N-oxides and tolerates challenging halo and nitro
substituents in the heteroaromatic ring.
focused on developing the deoxygenation process to reveal free
bases.
For optimization of the reaction conditions, 2-phenylpyridine N-
oxide 1a was chosen as a model substrate (Table 1). The most
efficient protocol was identified as follows: the reaction was
carried out in an undivided electrochemical cell with two carbon
electrodes at a constant current of 10 mA at rt in a 1:1
4
acetonitrile/water mixture using LiBF (0.04 M) as a supporting
electrolyte. The reaction was complete in just under 4 h to furnish
the reduced pyridine 2a in an 89% isolated yield. Earlier,[10] we
In the chemistry of pyridines and related heterocyclic compounds,
N-oxides occupy an important niche. First, they represent a
separate class of compounds with distinct biological activity;[1] and
secondly, N-oxidation dramatically alters reactivity of the parent
base by activating the heteroaromatic ring towards both
nucleophilic and electrophilic reagents.[2] Depending on the
transformation, the oxygen is either removed during the process
or remain in the molecule. For the removal of oxygen without
further functionalization plethora of methods have been
developed over the years.[3] The most recent protocols include
photocatalytic reduction of N-oxides,[ catalytic hydrogenation
using water as a source of hydrogen,[5] metal-catalyzed,[6] and
metal-free[7] oxygen transfer methods. Despite the great number
of chemical and biochemical methods for deoxygenation of
aromatic N-oxides, there is still room for protocols that are
operationally simple, atom-economical, easily scalable and
applicable to a wide range of substrates. Our attention turned
3
observed that the addition of Ph PO to the electrochemical cell
seemed to suppress the reduction of N-oxide. Indeed, this has
been now confirmed by running the model reaction under the
3
standard conditions in the presence of 1.5 equiv of Ph PO. The
yield dropped to just 28% (Table 1, entry 2). The reduction also
proceeded sluggishly in dry acetonitrile (Table 1, entry 3),
however, the yield gradually improved with the addition of
triethanolamine (TEOA), which may serve as both a sacrificial
reducing agent, by providing a paired oxidation reaction on anode,
and also a proton source (Table 1, entries 4-6).[11]
4]
The influence of pH on the reaction efficiency was investigated
using buffer solutions, however no much difference was observed
between acidic (pH 4), neutral (pH 7) and basic (pH 10) media
(
Table 1, entries 7-9). Variation of the anode material was
assessed briefly. Sacrificial Zn electrode furnished the result
similar to carbon (Table 1, entry 10), whereas with Fe anode the
reaction slowed down and with Cu it hardly proceeded at all
towards electrochemical methods.
A
few examples of
(
Table 1, entries 11 and 12, respectively). An investigation into
electrochemical reduction of pyridine N-oxides at the dropping
mercury electrodes were published nearly three decades ago[8]
but they were of limited scope and practicality. While our work was
in progress, an electrochemical reduction of heteroaromatic N-
oxides was reported by Xu,[9] though in their protocol, halo-
substituted hetarenes were not tolerated. Herein, we present a
mild method for the reduction of N-oxides with a wide scope,
including challenging derivatives with halo and nitro substituents
present in the heterocyclic ring.
the role of the electrolyte revealed that quaternary ammonium
salts with an inert anion, like bisulfate, can also be used in the
reaction, however salts with a halide as a counterion, particularly
iodide, inhibited reduction (entry 14). The reaction can be scaled
up with little or no effect of the yield either by increasing the
substrate concentration from 0.022 M to 0.18 M (entry 15) or by
using a larger reaction vessel and keeping the same proportions
of the reaction components (entry 16).
Having established the optimal conditions, we next embarked on
an investigation into the reaction scope (Table 2). Alkyl and aryl
Earlier, while developing an electrochemical coupling of
deprotonated chiral pyridine N-oxide derivatives, we optimized
the reaction conditions to retain the N-oxide functionality in the
resulting bis-N-oxides by suppressing possible electrochemical
reduction of the N-O functionality.[10] In contrast, this work is
(
1b, 1c, 1n), as well as heteroaromatic substituents (1p, 1q)
around the pyridine ring are tolerated well. Fused heterocycles,
isoquinoline (1i) and quinoline (1j) derivatives, as well as aliphatic
N-oxide 1o followed the trend. On the other hand, pyridine N-
1
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