Simple electrochemical reduction of nitrones to amines

Article abstract of DOI:10.1039/C8SC04337J

The use of electricity allows the reduction of nitrones containing aromatic and heteroaromatic rings to the corresponding amines. The main advantage of this protocol relies on the fact that only electrons are needed, avoiding the use of different chemical

Full text of DOI:10.1039/C8SC04337J

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Simple electrochemical reduction of nitrones to
amines†
Cite this: DOI: 10.1039/c8sc04337j
All publication charges for this article Eduardo Rodrigo and Siegfried R. Waldvogel
*
have been paid for by the Royal Society
of Chemistry
The use of electricity allows the reduction of nitrones containing aromatic and heteroaromatic rings to the
corresponding amines. The main advantage of this protocol relies on the fact that only electrons are needed,
avoiding the use of different chemicals and harsh procedures, something that reinforces some green aspects.
The conversion tolerates different moieties and a large variety of functional groups. In addition, this
electrolysis can be performed on a simple undivided beaker-type cell with constant current conditions.
Received 29th September 2018
Accepted 8th December 2018
DOI: 10.1039/c8sc04337j
rsc.li/chemical-science
reducing agents, something that offers many advantages and
benets from both an ecological and an economic perspective,
Introduction
The role of nitrones in organic chemistry is very well stablished, providing the development of sustainable procedures.
1
fundamentally due to its synthetic versatility. This is caused
We envisioned that we could carry out the direct reduction of
principally by the electrophilicity of the double C–N bond, which nitrones to amines using electrochemistry. The cleavage of N–O
allows them to act as dipoles in 1,3-dipolar additions in order to bonds with electricity has been described and it is known for some
2
12
afford nitrogen-containing heterocycles, such as isoxazolidines.
Another reaction of interest is their reduction, which has there are some electrochemical examples of reductive processes
primarily been guided to the synthesis of hydroxylamines.
organic moieties, such as nitrile N-oxides or oximes, whereas
1
,3
13,14
with imines, although guided to the synthesis of diamines.
However, nitrones can also be reduced and transformed into the
Herein we present an electro-reduction methodology of
corresponding amines. In fact, the reduction of open nitrones to nitrones for the synthesis of secondary amines. This approach
amines needs two independent steps or at least two different allows the reduction of experimental steps to the minimum and
4
reagents for both reductions. The rst step, which allows the the avoidance of two different reagents for such a process
formation of the imine through a deoxygenation process, is (Fig. 1), being the rst time that this double reduction is per-
4,5
normally performed using a metal, even though there are also formed with one single reagent, something which has not been
6
examples using different organic reagents. However, many of described yet with any other classical chemical. In addition, the
these methods are limited by harsh procedures, side reactions or green aspects of the transformation are also important, since
lack of chemoselectivity, whereas the second one to yield the only electric current is utilized, something very signicant in

nal amine has been oen carried out through hydrogenation or terms of atom economy and from an ecological point of view.
7
the use of hydrides. Therefore, the reduction of a nitrone into
the corresponding amine using one single reagent remains
elusive. This is an important aspect, since, for instance, amines
Results and discussion
are usually synthesized in the pharmaceutical industry through The initial experiments were carried out to adjust the required
8
reductive aminations, and in some cases, anilines are more quantity of charge and to determine the reaction medium.
9
expensive than the corresponding aryl nitroderivatives.
These results are summarized in Table 1.
Recently, the eld of organic electrochemistry has experi-
10
enced a renaissance, a fact that has permitted the opening of
new paths in organic synthesis, as well as the development of
11
novel concepts in the eld. The use of electricity as “single
reagent” allows the avoidance of big amounts of oxidizers or
Institut f u¨ r Organische Chemie, Johannes-Gutenberg-Universit a¨ t Mainz, Duesbergweg
1
0–14, 55128 Mainz, Germany. E-mail: waldvogel@uni-mainz.de
†
Electronic supplementary information (ESI) available: Detailed experimental
1
13
procedures, characterization data and copies of H and C NMR spectra. See
DOI: 10.1039/c8sc04337j
Fig. 1 Classical approach vs. electrochemical approach.
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Table 1 Optimization of solvent and additive
mixture of CH
CN and EtOH gave a complex mixture with no
3
formation of the amine (Entry 4), whereas the use of CH CN
3
with another protic solvent such as water was found as optimal
(Entry 5). In an electrochemical process for a radical addition of
imines to acrylates, the use of triethylamine proved to be effi-
1
5
cient to increase the adduct yields. When using NEt
additive the yield increased up to 42% (Entry 6). Therefore,
other bases such as NaOH and Na CO were tested (Entries 7
3
as
2
3
and 8, respectively), being the last one the one who gave better
results, raising the yield up to 44%.
a
c
d
Entry
Solvent
Additive
Conv.
Yield (2a)
b
At that point, we decided to test how the current density and
the electrodes affected the outcome of the reaction (Table 2). To
our surprise, an increase of the current density up to 30 mA
cm led to an increase of the yield (compare Entries 1–3), with
larger values decreasing both the conversion and the yield
1
2
3
4
5
6
7
8
CH
DMF
EtOH
3
CN
—
—
—
—
—
NEt
NaOH
Na CO
>95%
>95%
94%
>95%
>95%
>95%
>95%
>95%
11%
10%
24%
0%
29%
42%
38%
44%
CH
CH
CH
CH
CH
3
3
3
3
3
CN/EtOH (1 : 1)
ꢀ2
CN/H
CN/H
CN/H
CN/H
2
2
2
2
O (1 : 1)
O (1 : 1)
O (1 : 1)
O (1 : 1)
3
(Entry 4). A plausible explanation for this fact is that, the higher
the current density is, the faster the reaction is, and therefore,
the intermediates and the radical species involved do not evolve
2
3
a
b
0
.15 mmol of nitrone were dissolved in 5 mL of solvent. With Q ¼ 4F,
c
only 70% was achieved; with Q ¼ 5F, 83%. 0.3 mmol of additive were into secondary or undesired products so easily. We have
d
used. Yields were determined by NMR using 1,3,5-trimethoxybenzene
recently observed in our research group in the electrochemical
as internal standard.
16
reduction of nitrile oxides, which present an analogue struc-
ture to nitrones, that iminoxyl radicals dimerized to aldazine
bis-N-oxides, evolving to aldehydes by loss of nitrogen. This
issue seems to be eliminated at higher current densities,
probably because the further reduction occurs faster when this
value is increased. In addition, both the nitrone and the inter-
mediate imine can be sensitive to hydrolysis in the reaction
media, so if the reaction time is reduced, this circumstance is
also minimized. Finally, it is also well known that when imines
are reduced through the intermediate formation of radicals
Firstly, we evaluated the quantity of charge needed for
completion of the reaction, in CH CN as solvent, with a glassy
3
carbon anode, a leaded bronze cathode (CuSn
7
Pb15) and
NBu
4
2
BF
4
as supporting electrolyte, at a current density of 15 mA
ꢀ
cm . A minimum theoretical amount of 4F was not enough,
with some remaining nitrone in the reaction crude. Increasing
the charge up to 6F yielded the amine, although the yield was
very low (Entry 1). The use of DMF did not afford any
improvement (Entry 2), while the utilization of a protic solvent
such as EtOH (Entry 3) raised the yield. An equimolecular
17
18
using metals, photocatalysis or metal-mediated electro-
14
chemistry, the diamine is obtained, a fact that could also
contribute to decrease the nal yield of the reaction.
Table 2 Optimization of electrolytic conditions
a
ꢀ2
b
Entry
Anode
Cathode
Q (F)
j (mA cm
)
Conv.
Yield
1
2
3
4
5
6
7
8
9
Glassy carbon
Glassy carbon
Glassy carbon
Glassy carbon
Glassy carbon
Glassy carbon
Glassy carbon
Glassy carbon
Graphite
Leaded bronze
Leaded bronze
Leaded bronze
Leaded bronze
Leaded bronze
Platinum
Lead
Lead
Lead
Lead
6
6
6
6
6.5
6.5
6.5
7
6.5
6.5
18
24
30
45
30
30
30
30
30
30
>95%
>95%
93%
87%
<95%
80%
50%
51%
55%
46%
56%
19%
65%c
67%
9%
95%
>95%
>95%
>95%
1
0
BDD
15%
a
c
b
0
.15 mmol of nitrone were dissolved in 5 mL of solvent. Yields were determined by NMR using 1,3,5-trimethoxybenzene as internal standard.
Isolated yield: 60%.
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ꢀ2
To get full conversion with j ¼ 30 mA cm , 6.5F of charge
were needed (Entry 5). Other metallic cathodes were tested,
being Pb the best one (Entry 7) in comparison to Pt or leaded
bronze, though another small increase of charge up to 7F was
mandatory to get full conversion (Entry 8). Although the counter
electrode doesn't always play an important role in electro-
chemical transformations, in this case the use of other carbon
based electrodes as anodes dropped the yield dramatically
(Entries 9 and 10), an issue that we observed recently in the
Scheme 2 Proposed mechanism for the nitrone reduction.
electrochemical reduction of nitro derivatives in aqueous
19
conditions. In this case, its function cannot be considered as
secondary, since water seems to provide protons for the
reduction and nal formation of the amine, while it is also
decomposed at the same time at the anode. Furthermore, the
basic pH of the reaction media favours this process, since the
oxidation potential of water is lower at higher pH values.
At this point, we started to evaluate the scope of the reaction.
The results are summarized in Scheme 1.
Firstly, we observed that the reaction went smoothly, no
matter the nature of the substituent or the substituted position
at the ring, with both EWG and EDG, as well as ortho, meta and
para positions (amines 2a–2g). Only in the case of nitrones 1b
and 1c a small increase of charge (8F) was needed to achieve the

nal amines 2b and 2c, owing to solubility reasons. Regarding
the use of halogens, only uorine was tolerated for the reaction,
affording amine 2h, although in lower yields than other
functionalities.
Different nitrones with heterocycles were also studied (1i–1l),
as well as nitrones with different substituents at the ring
directly bonded with the nitrogen atom (1m–1p). Amines 2i–2l
containing heterocycles and aryl amines 2m–2p were obtained
with moderate to good yields in all the examples.
Aliphatic nitrones were also studied, however their low
20
stability in aqueous solutions was a major issue and only
complex mixtures were observed aer isolation. In the case of
aliphatic substituents bonded to the nitrogen atom, the reac-
tion was possible, but yields were extremely low and not
21
comparable with the aryl ones.
In order to prove the usefulness of the process, nitrone 1a
was reduced into its corresponding amine 2a in a 25 mL beaker-
type cell, with a very similar yield (58%) under the same reaction
conditions. The experimental simplicity of the reaction, in
which just a two-electrode arrangement in a beaker-type cell
under constant current conditions is used, it also important to
be pointed out.
A plausible mechanism for the described transformation is
proposed in Scheme 2. Four electrons are needed for the
reduction. The rst two electrons yield the imine aer cleavage
of the N–O bond. The double bond of the imine is subsequently
reduced with two more electrons to afford the corresponding
amine aer protonation. In order to reinforce this mechanistic
proposal, we have performed two experiments. In the rst one,
we have carried out the reduction of 1a under the optimized
conditions and stopped the reaction at Q ¼ 3F, observing the
presence of a small amount of imine (ca. 7%) along with 1a and
2a in the crude. Secondly, we took commercial N-benzylide-
neaniline and applied Q ¼ 0, 1, 2 and 3F under the optimized
conditions, recording all the NMR spectra. We could see the
formation of the corresponding amine from this imine and
some byproducts which also explain the loss of yield and
Faraday efficiency (see ESI† for more details).
Conclusions
In summary, we have described an electrochemical method for
the reduction of nitrones to amines. A broad scope of aromatic
and heteroaromatic amines, containing a large variety of func-
tional groups, was accessible using this methodology. The
a
Scheme 1 Scope of the reaction. 58% yield in a 25 mL beaker type-
cell. 8F of charge were needed.
b
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utilization of electric current allows for the rst time the
avoidance of two different reagents for this reduction, some-
thing that resulted mandatory if this transformation was per-
formed. Furthermore, the simplicity of the method, consisting
on an undivided cell under constant current conditions, may
open new paths and approaches in terms of amine synthesis.
9 For example, the price of 100 g of m-toluidine (99%) in
Sigma-Aldrich (November 2018) is 28.60V, while the price
of 100 g of m-nitrotoluene (99%) in the same company is
only 15.90V. For the ortho derivatives, the price of 100 g of
o-toluidine ($99%) is 41.10V, whereas the price of 100 mL
of o-nitrotoluene ($99%) goes down to 23.30V.
10 (a) S. R. Waldvogel and B. Janza, Angew. Chem., Int. Ed., 2014,
5
3, 7122; (b) S. R. Waldvogel and S. M ¨o hle, Angew. Chem., Int.
Conflicts of interest
Ed., 2015, 54, 6398; (c) S. R. Waldvogel and M. Selt, Angew.
Chem., Int. Ed., 2016, 55, 12578; (d) M. Navarro, Curr. Opin.
Electrochem., 2017, 2, 43.
There are no conicts to declare.
11 For some recent reviews in organic electrochemistry, see: (a)
M. Yan, Y. Kawamata and P. S. Baran, Chem. Rev., 2017, 117,
Acknowledgements
The authors thank the DFG (Wa 1278/17-1) for nancial
support. Support by the Advanced Lab of Electrochemistry and
Electrosynthesis – ELYSION (Carl Zeiss Stiung) is gratefully
acknowledged. The authors highly appreciate the nancial
support by the Center for INnovative and Emerging MAterials
1
3230; (b) A. Wiebe, T. Gieshoff, S. M ¨o hle, E. Rodrigo,
M. Zirbes and S. R. Waldvogel, Angew. Chem., Int. Ed.,
018, 57, 5594; (c) S. M ¨o hle, M. Zirbes, E. Rodrigo,
T. Gieshoff, A. Wiebe and S. R. Waldvogel, Angew. Chem.,
Int. Ed., 2018, 57, 6018.
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