Kolbe Anodic Decarboxylation as a Green Way to Access 2-Pyrrolidinones

Article abstract of DOI:10.1021/acs.orglett.0c00056

Nootropic compounds are a group of pharmacologically active pyrrolidones. These molecules, which enhance cognition properties and possess a large prescription field, are particularly interesting synthetic targets for the pharmaceutical industry. In this Article, we disclose an effective and environmentally friendly pyrrolidinone synthesis using electrosynthesis. The newly developed methodology includes a Kolbe decarboxylation, followed by an intramolecular radical cyclization and a radical-radical cross-coupling.

Full text of DOI:10.1021/acs.orglett.0c00056

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Letter
Kolbe Anodic Decarboxylation as a Green Way To Access
2‑Pyrrolidinones
́
́
Mathilde Quertenmont, Iain Goodall, Kevin Lam,* Istvan Marko, and Olivier Riant*
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ABSTRACT: Nootropic compounds are a group of pharmacologically active
pyrrolidones. These molecules, which enhance cognition properties and possess a
large prescription field, are particularly interesting synthetic targets for the
pharmaceutical industry. In this Article, we disclose an effective and environmentally
friendly pyrrolidinone synthesis using electrosynthesis. The newly developed
methodology includes a Kolbe decarboxylation, followed by an intramolecular
radical cyclization and a radical−radical cross-coupling.
Scheme 1. Proposed Mechanistic Sequence: Kolbe
Decarboxylation−Radical Cyclization−Radical Capture
ootropic compounds are a group of pharmacologically
1
Nactive pyrrolidones. These molecules, which enhance
cognition properties and possess a large prescription field, are
particularly interesting synthetic targets for the pharmaceutical
industry.2 Synthetic organic electrochemistry takes its roots
from the classic works of Faraday3 and Kolbe4 on the
electrolysis of aliphatic carboxylic acids. Although numerous
transformations have been developed since then,5−9 and many
of them were successfully used in several industrial
processes,10,11 the potential of preparative organic electro-
chemistry remains underestimated, even though electrosyn-
thesis represents one of the safest and greenest method to
perform organic redox reactions. Hopefully, the new
commercially available Electrasyn 2.0 electrolysis setup will
facilitate the use of electrosynthesis in organic synthetic
laboratories.12 The Kolbe anodic decarboxylation is among the
oldest and probably the most famous oxidative electro-organic
reactions.4 This approach enables the environmentally friendly
synthesis of long-chain alkanes from short-chain carboxylic
acids, in three steps.13,14
the scope of the synthetic applications of the Kolbe
electrocyclization reaction.
̈
Schafer et al. have previously shown that the electro-
generated radical 5a can undergo radical cyclization and that
the final cyclic radical 6a could be trapped by radicals
generated by the anodic decarboxylation of a coacid present in
excess. An excess of the coacid is used in order to prevent the
homocoupling of substrate 6a. Unfortunately, the yields in
cyclic compounds 7a remains modest (see Scheme 1).15
Our group has showed formerly that the presence of an
electron-withdrawing substituent on the C−C double bound
dramatically increases the yield of the desired cyclic
compounds 7b since the electrodeficient double bond is a
better coupling partner for the nucleophilic electrogenerated
radical (see Scheme 1).16 It also stabilizes the cyclic radical.
In this Article, we will describe a new, original, and
environmentally friendly electrosynthesis of pyrrolidinones of
pharmaceutical interest (see Scheme 2). This process expands
At the outset of this investigation, compounds 8a−8d were
synthesized in a straightforward manner, according to the
sequence outlined in the Supporting Information. Potassium
salts (8a−8d) were used as the substrates of the electro-
cyclization, because of the instability of the corresponding
carboxylic acids.17 The amide group was functionalized with
various groups, such as allyl, benzyl, isopropyl, or neopentyl, to
avoid the amide function oxidation under the electrolytic
conditions.18 For instance, the allyl and benzyl protecting
Received: January 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00056
© XXXX American Chemical Society
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substitution of that position has been reported to have a
major effect on the biological activity of this class of
compounds.2 In the presence of acetic acid and propionic
acid, the electrocyclization proceeded smoothly and afforded
aliphatic pyrrolidinones 12a, 12b, 12h, and 12j in good yields
(60%−71%). Furthermore, the use of monomethyl hydrogen
succinate (13f), ethyl potassium malonate (13e), and 4-
acetylbutyric acid (13g) as coacids also enables the formation
of pyrrolidinones 12e, 12f, 12g, and 12i in good yields. 3,3,3-
Trifluoropropionic acid (13d) and fluoropropionic acid (13c)
allowed the formation of fluorinated pyrrolidinones 12c and
12d but lower yields are obtained with the latest. This result is
due to the higher acidity of the fluoroacetic acid. Besides,
comparable yields are obtained in the presence of the four
protecting groups, which enables one to produce several N-
substituted pyrrolidones (12a−12n). In the presence of a
benzyl protecting group, there is the formation of the side
product 14a, which is generated by the cross-coupling of the
radical 10 and the radical which comes from the oxidative
decarboxylation of the coacid 13b. This phenomenon might be
due to the steric hindrance of substrate 8d, which limits the
amide C−N bond rotation or absorption phenomenon of the
benzyl-substituted radicals on the electyrode surface. Finally, in
order to expand the scope of this electrocyclization reaction,
we applied the optimized conditions to substrate 8e bearing a
homoallyl function. The reaction of substrate 8e also
proceeded smoothly and provided the corresponding 6-
membered ring product 12l. However, as the 6-exo cyclization
is known to proceed at a lower speed, compared to 5-exo
cyclization, the primary radical 10 can then dimerize and we
observed the formation of the side-product dimer 14c, along
with the desired piperidinone.
Scheme 2. Electrosynthesis of Pyrrolidones
groups could easily be deprotected or further functionalized
after the oxidative reaction, opening the way to more chemical
diversity, which is especially important for drug design.19,20
With the desired precursors in hand, the electrolysis
parameters were optimized (see Table 1). Bulk electrolysis
that has been performed using previously reported conditions
led to the formation of the desired pyrrolidones in very modest
yields.3 In order to avoid homocoupling of the radical 11, the
substrate should be highly diluted in methanol (66 mM in
methanol), and the current density, which is a key parameter,
should be kept between 25 mA/cm2 and 37.5 mA/cm2. In
addition, a temperature between 10 °C and 20 °C, the use of
smooth platinum electrodes, and an excess of coacid (5 equiv)
provided the optimum results. Finally, the use of 5 equiv of
supporting electrolyte (KOH) avoided the decarboxylation of
the substrate by maintaining basic conditions.
To broaden the scope of the functionalized pyrrolidinones
cyclization, we synthesized the allylic and propargylic
substrates 8f and 8g in a straightforward manner, according
to the sequence outlined in the Supporting Information. The
electrocyclization of those substrates allowed the formation of
With the optimized conditions ready, the scope and
limitation of the methodology were investigated (see Table
2). The variation of the coacid nature allowed the synthesis of
several pyrrolidinones substituted in position 4. The
Table 1. Optimization of the Electrocyclization Reaction
entry
C (mol/L)
current density (mA/cm2)
temperature, T (°C)
electrodes
solvent
[KOH] (equiv)
yield (%)
1
2
3
4
5
6
7
8
0.033
0.066
0.132
0.066
0.066
0.066
0.066
0.066
0.066
0.066
0.066
0.066
0.066
0.066
0.066
0.066
25
25
25
12,5
25
50
25
25
25
25
25
25
25
25
25
25
10
10
10
10
10
10
0
10
40
10
10
10
10
10
10
10
platinum
platinum
platinum
platinum
platinum
platinum
platinum
platinum
platinum
platinum
platinum
platinum
platinum
platinum
platinum
platinum
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
CH3CN
MeOH
MeOH
MeOH
MeOH
5
5
5
5
5
5
5
5
5
5
5
5
68
71
26
56
71
64
29
71
37
71
49
70
71
54
66
71
9
10
11
12
13
14
15
16
5
0.05
0.33
5
B
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Table 2. Scope and Limitations of Substrates
C
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Table 3. Diastereoselective Pyrrolidinone Electrosynthesis
the position 5-substituted pyrrolidinones 12m and 12n, in 66%
and 64% yields, respectively.
AUTHOR INFORMATION
Corresponding Authors
■
Because of the importance of being able to control the
chirality while developing bioactive molecules, we investigated
the possibility to develop a diastereoselective electrocyclization
of pyrrolidinones. Our strategy to induce a stereoselectivity
during the cyclization was to incorporate a chiral center in the
structure of the precursor. With this intention, substrate 15
was synthesized from the (R)-(+)-α-methylbenzylamine. The
desired precursor available for use, the electrochemical reaction
was performed using the previously optimized conditions.
Finally, the product was analyzed by high-performance liquid
chromatography−mass spectroscopy (HPLC-MS). Those
analyses have showed a good diastereoselective ratio for this
electrochemical transformation. As a result, the use of (R)-
(+)-α-methylbenzylamine as chiral inductor has led to the
formation of the enantio-enriched pyrrolidinones 16 with a
diastereoselective ratio of 96:4 (see Table 3). One of the main
advantages of using benzylamine derivatives as chiral inductors
is that they can easily be removed after the electrochemical
process by catalytic hydrogenation,21 catalytic transfer hydro-
genation,22 and other reactions.23
Kevin Lam − Department of Pharmaceutical, Chemical and
Environmental Sciences, Faculty of Engineering and Science,
University of Greenwich, Chatham Maritime ME4 4TB, United
Kingdom; orcid.org/0000-0003-1481-9212;
Email: k.lam@greenwich.ac.uk
Olivier Riant − Institute of Condensed Matter and Nanosciences
(IMCN), Molecular Chemistry, Materials and Catalysis
́
(MOST) unit, Universite Catholique de Louvain (UCL), 1348
Louvain-la-Neuve, Belgium; orcid.org/0000-0003-4852-
6469; Email: olivier.riant@uclouvain.be
Authors
Mathilde Quertenmont − Institute of Condensed Matter and
Nanosciences (IMCN), Molecular Chemistry, Materials and
́
Catalysis (MOST) unit, Universite Catholique de Louvain
(UCL), 1348 Louvain-la-Neuve, Belgium
Iain Goodall − Department of Pharmaceutical, Chemical and
Environmental Sciences, Faculty of Engineering and Science,
University of Greenwich, Chatham Maritime ME4 4TB, United
Kingdom
§
́
́
Istvan Marko − Institute of Condensed Matter and
Nanosciences (IMCN), Molecular Chemistry, Materials and
In summary, we have developed methodology for the
efficient and environmentally friendly electrochemical syn-
thesis of functionalized pyrrolidinones. Our approach includes
a Kolbe decarboxylation, followed by a radical cyclization and,
finally, a cross-coupling step between the radical formed and a
radical engendered by the concomitant decarboxylation of a
coacid. This reaction enables the formation of two carbon−
carbon bonds in one step. The functional group tolerance of
this method proved to be quite broad. Indeed, the electrolysis
can be successfully accomplished in the presence of ester,
olefin, ketone, halogen, amide, and alkyne functions. Finally,
the methodology was successfully transposed toward the
synthesis of the stereoenriched pyrrolidinone 16 with a
diastereoselective ratio of 96:4 by using a chiral inductor
group on the precursors. The methodology represents an
attractive procedure for the synthesis of diversely function-
alized pyrrolidinones.
́
Catalysis (MOST) unit, Universite Catholique de Louvain
(UCL), 1348 Louvain-la-Neuve, Belgium
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00056
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
§Deceased (July 31, 2017).
ACKNOWLEDGMENTS
■
Financial support for this research by the Fonds pour la
Formation a la Recherche dans l’Industrie et dans l’Agriculture
(F.R.I.A.) and the Universite Catholique de Louvain are
̀
́
gratefully acknowledged.
ASSOCIATED CONTENT
■
sı
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General experimental section; details regarding the
synthesis of various compounds used/produced in this
work; table of details regarding optimization of the
electrocyclization reaction; NMR spectra (PDF)
D
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