Electrochemical deamination of alkoxyamine lactams

Article abstract of DOI:10.1016/j.tetlet.2020.152279

An anodic electrochemical deamination of 3-alkoxyamine lactams to 3-hydroxy lactams was developed. The electrochemical transformation was achieved by using reticulated vitreous carbon (RVC) and stainless-steel electrodes in aqueous ethanolic solution of NaOAc. This simple electrochemical procedure represents an ecofriendly alternative to the traditional chemical reductive deamination, which requires of a large excess of Zn (up to 40 equivalents) and acetic acid.

Full text of DOI:10.1016/j.tetlet.2020.152279

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Electrochemical deamination of alkoxyamine lactams
Julio Romero-Ibañez, Enrique Cruz-Gregorio, Silvano Cruz-Gregorio, Leticia
Quintero, Sylvain Bernès, Mario González-Perea, Fernando Sartillo-Piscil
PII:
S0040-4039(20)30746-2
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152279
TETL 152279
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
5 June 2020
14 July 2020
21 July 2020
Please cite this article as: Romero-Ibañez, J., Cruz-Gregorio, E., Cruz-Gregorio, S., Quintero, L., Bernès, S.,
González-Perea, M., Sartillo-Piscil, F., Electrochemical deamination of alkoxyamine lactams, Tetrahedron
Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152279
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Electrochemical deamination of alkoxyamine lactams
Julio Romero-Ibañez, Enrique Cruz-Gregorio, Silvano Cruz-Gregorio, Leticia Quintero, Sylvain Bernès, Mario
González-Perea,* and Fernando Sartillo-Piscil.*

1
Tetrahedron Letters
Electrochemical deamination of alkoxyamine lactams
a
a
a
a
Julio Romero-Ibañez, Enrique Cruz-Gregorio, Silvano Cruz-Gregorio, Leticia Quintero, Sylvain
b
a
a
Bernès, Mario González-Perea,  and Fernando Sartillo-Piscil. *
a
Centro de Investigación de la Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP), 14 Sur Esq. San Claudio, Col. San
Manuel, 72570, Puebla, México
b
Instituto de Física, Benemérita Universidad Autónoma de Puebla (BUAP), Av. San Claudio y 18 Sur, 72570 Puebla, México.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An anodic electrochemical deamination of 3-alkoxyamine lactams to 3-hydroxy lactams was
developed. The electrochemical transformation was achieved by using reticulated vitreous
carbon (RVC) and stainless-steel electrodes in aqueous ethanolic solution of NaOAc. This
simple electrochemical procedure represents an ecofriendly alternative to the traditional
chemical reductive deamination, which requires of a large excess of Zn (up to 40 equivalents)
and acetic acid.
Available online
Keywords:
Deamination
2
009 Elsevier Ltd. All rights reserved.
Alkoxyamine lactams
Hydroxy lactams
Anodic oxidation
Green reaction
Introduction
3
-Hydroxy lactams (A) are ubiquitous organic compounds that
are frequently found in nature or are prepared in the laboratory as
versatile intermediates for the synthesis of biologically important
1
alkaloids. Despite of their notable relevance in the field, there
2
are few synthetic methods reported to date. For instance, alpha
oxygenation of either enolized amides or lactams (e.g., B) with
TEMPO (C) to 3-alkoxyamine lactams (e. g., D) followed by Zn-
3
mediate deamination reaction (route A, Scheme 1); and the
direct dual C−H oxidation of N-heterocycles E mediated by
TEMPO/NaOCl/NaClO
D followed by the same deamination process (route B, Scheme
).
2
system to 3-alkoxyamine intermediate
4
Scheme 1. Synthesis of alkoxyamine lactams D followed by
reductive deamination to 3-hydroxy lactams A with excess of Zn in
acetic acid media.
1
Although both routes provide apparent economic and
ecological advantages over the traditional long routes of 3-
hydroxy lactams, which involve protection-deprotection and
cyclization procedures, the excessive use of Zn and acetic acid
Results and Discussion
5
Knowing that electrochemical reactions fulfill many aspects of
6
for the deamination step demerits the green spirit of both
the green chemistry, we explored the benefits that offer the
3
oxygenation reactions, especially to the dual C(sp )−H oxidation
methanol/water media along the supporting electrolyte
AcOH/NaOAc mixture in organic electrochemical reactions, and
7
mediated by TEMPO, NaOCl and NaClO
2
. Consequently, we
present here the development of an electrochemical deamination
protocol of 3-alkoxyamine lactams to 3-hydroxy lactams, from
which the former is directly prepared from simple N-heterocycles
we decided to employ this environmentally friendly reaction
conditions to remove the 2,2,6,6-tetramethylpiperidine group of
the 3-alkoxyamine lactams.
(
route B).
Accordingly, it can be anticipated two modes of chemical
transformation of putative alkoxyamine radical cation F, which
would be generated through anodic oxidation of alkoxyamine
—
——

Corresponding author. Tel.: +52-222-295-5500 ext. 7391; fax: + 52-222-245-4972; e-mail: fernando.sartillo@correo.buap.mx (F. Sartillo-
Piscil). E-mail: margonzal68@hotmail.com (M. González-Perea).

2
Tetrahedron Letters
lactam 1: mesolytic cleavage to G or nucleophile substitution to
provided good yields of 3-hydroxy lactam 2, its p-methoxy
benzylated analogue (3a) did not provide the expected 3-hydroxy
lactam 4a, instead, the starting material was degraded. Probably
this is due to the electron rich p-methoxybenzyl group, which is
H (Scheme 2). Although photocatalytic method for accessing
carbocation intermediates via the mesolytic cleavage of benzylic
alkoxyamine radical cations has been reported by Knowles,
Bissember and Coote showcased the difficulties of this
transformation in the electrochemical oxidation of TEMPO-Me;
instead, the respective radical cation TEMPO-Me can be
employed as methylating reagent of carboxylic acids via
N
nucleophilic substitution type S 2.
8
1
1
preferentially oxidized rather than the alkoxyamine group.
a
Table 1. Screening conditions for anodic deamination of 3-
.
+
alkoxyamine lactams.
9
Electrolyte
Equiv)
1
[mM]
5
Time
(h)
5.5
b
Entry
1
Anode
RVC
Yield (%)
(
NaOAc (13)
NaOAc (13)
NaOAc (20)
NaOAc (20)
NaOAc (20)
NaOAc (50)
NaOAc (50)
NaOAc (50)
NaOAc (50)
traces
n.r.
n.r.
35
c
2
RVC
GE
5
2
2
2
2
2
2
2
8.5
2
3
4
5
6
7
8
9
GE
5
Scheme 2. Putative radical cation F and electrochemical outcomes.
RVC
GE
6
30
We initiated the current investigation by studying the
electrochemical behavior of N-benzyl 3-alkoxyamine piperidone
4
52
1
. Solubility tests indicated that compound 1 was better dissolved
in ethanol rather than methanol. Therefore, ternary system
ethanol-water-sodium acetate reached high solubility at 10 mM
concentration. In a similar way to electrochemical oxidation of
GE
5
64
RVC
RVC
4
75
9
TEMPO-Me, cyclic voltammetry of alkoxyamine lactam 1
5
44
showed an oxidation peak at 1.26 V, a reduction peak at 0.57 V
and another oxidation peak (0.66 V) that only appeared after the
first cycle, suggesting that TEMPO is released.
a
E
ref: Ag/AgCl, Cathode: SS, Solvent: 80 mL EtOH:H
2
O (8:2), I: 80 mA.
b
c
Chemical yield after chromatography purification. I: 42 mA.
Table 2. Scope of the electrodeamination study of 3-
alkoxyamine lactams.
Figure 1. Cyclic voltammetry of 1 in ethanol-water (50:50) media
-
1
and 0.1 M of NaOAc; v = 100 mV s .
Galvanostatic electrolysis of 1 was conducted with a simple
1
0
direct current power supply. By employing 13 equivalents of
NaOAc at 5 mM concentration under a constant current of 80
mA, and using RVC (reticulated vitreous carbon) as anode and
SS (stainless steel) as cathode, the reaction afforded traces of 2
(entry 1, Table 1). Starting material was recovered when current
was modified to 42 mA (entry 2); the same result was observed
by using a graphite electrode (GE) (entry 3). Increasing the
reaction time from 2 to 5 h, 35% yield of deaminated product 2
was observed (entry 4). Similar result was obtained when RVC
was employed as anode (entry 5). By using GE and more
equivalents of electrolyte, the chemical yield was improved up to
6
4% (entries 6 and 7). Switching to RVC electrode and keeping
the same 50 equivalents of NaOAc, the best chemical yield was
obtained in 4 h (entry 8). Longer reaction time did not improve
the chemical yield (entry 9). Electrolysis of 3-alkoxyamine
piperidone 1 at 80 mA were carried out in a divided cell, and
product 2 was only found in the anolyte, whereas the
alkoxyamine lactam 1 remained unchanged in the catholyte,
confirming thus that the electrochemical process is an anodic
deamination.
a
b
c
Degradation of starting material. Trans/cis mixture ~ 2/1. Trans/cis mixture
d
~ 3/1. Obtained from 3-alkoxyamine-4-hydroxy-4-phenyl-2-piperidone.
However, related benzylated precursor N-(2-bromobenzyl)-3-
alkoxyamine piperidone (3b) provided moderate chemical yield
of the corresponding deaminated product (4b). N-Benzylated-4-
substituted alkoxyamine piperidones (3c-3i) provided moderate
to good chemical yield of the corresponding 3-hydroxy lactams
After to establish the standard conditions, the scope of the
anodic deamination was explored to representative 3-
alkoxyamine lactams (Table 2). Although benzyl piperidine 1

3
(4c: 66%, 4d: 68%, 4e: 63%, 4f: 70%; 4g: 42%, 4h: 59%, 4i:
Scheme 4. Mechanistic considerations for the anodic deamination.
2
6%; Table 2). It appears that, except for 4-O-allyl group (4i),
alkyl and aryl groups at C-4 position did not significantly affects
the chemical yield. Interestingly, for the case of 3-alkoxyamine-
4
-hydroxy-4-phenyl-2-piperidone (3h), the deamination occurred
via intramolecular substitution reaction by hydroxyl group
affording glycidic amine 4h in good yield.
We also explored the anodic deamination of 2-alkoxyamine-3-
morpholinone (3j), and deamination occurred with substitution
reaction by ethanol (4j). Anodic deamination of N-methyl-
dioxolane-3-alkoxyamine lactam 3k provided good yield of the
corresponding 3-hydroxy lactam 4k (65%). However, like the
case of substrate 3a, alkoxyamine lactam bearing indole moiety
(3l) only afforded degradation of the starting material. On the
other hand, 3-alkoxyamine pyrrolidinone 3m afforded moderate
chemical yield of 3-hydroxy pyrrolidinone 4m (62%).
Based on the stereochemical outcome of the anodic
deamination of cis/trans mixture of 4-substituted alkoxyamine
1
2
lactams (3c and 3d) and trans-4-substituted analogues (3g and
f) to the corresponding 3-hydroxy lactams (4c, 4d) and (4g, 4f),
3
respectively, from which, the ratio mixture and the preservation
of the relative stereochemistry is retained (Scheme 3), we
propose that the current anodic deamination occurs in a similar
way to the substitution route depicted in Scheme 2, albeit in this
case, through an nucleophilic substitution (S
F to 2, eq. 1, Scheme 4). Moreover, nucleophilic substitution
mediated by hydroxide anion, which it can be formed by
N 2
2) mediated by H O
(
1
3
2
electrochemical reduction of H O, is another pathway that
might account the deamination process. Retention of the trans
relative configuration of 4-aryl-3-alkoxyamine lactams 3g and 3f
to 4g and 4f, respectively, can be rationalized by neighboring
1
4
group participation of the 4-aryl group;
whereby the
stereochemical proof is provided by the formation of the glycidic
1
5
amide 4h from 3h, via intermediates I and J (eq 2, Scheme 4).
Additionally, the formation of 2-ethoxymorpholinone 4j from 2-
alkoxyamine morpholinone 3j can also be explained in terms of a
N
S 1 mechanism: nucleophilic attack of EtOH to oxocarbenium
ion L which is formed from radical cation K (eq. 3, Scheme 4).
Scheme 3. Stereochemical outcome in the anodic deamination of
representative 4-substituted alkoxyamine lactams.
Conclusion
In summary, we have developed a simple electrochemical
deamination process of 3-alkoxyamine lactams to their
corresponding 3-hydroxy lactams. This electrochemical reaction,
which is performed at room temperature in the presence of
environmentally friendly reagents, represents a convenient
alternative to the traditional reductive chemical deamination
reaction. Additionally, this ecofriendly reaction provides
mechanistic insights that may open up new avenues for
electrochemical functionalization of 3-alkoxyamine lactams with
different nucleophiles.
Acknowledgments
The authors thankfully acknowledge Consejo Nacional de
Ciencia y Tecnología (CONACyT). Grant Number: A1-S-21450.
Partial support was provided by BUAP-VIEP.
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4
Tetrahedron Letters
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5
Graphical Abstract
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Electrochemical deamination of alkoxyamine lactams
Julio Romero-Ibañez, Enrique Cruz-Gregorio, Silvano Cruz-Gregorio, Leticia Quintero, Sylvain Bernès, Mario
González-Perea,* and Fernando Sartillo-Piscil.*
Fonts or abstract dimensions should not be changed or altered.
Highlights:


Deamination green process of 3-
alkoxyamine lactams
Electrochemical nucleophilic substitution of
3
-hydroxy-2-piperidones to 3-alkoxyamine
lactams by water.


Anodic oxidation of alkoxyamine lactams
by using a reticulated vitreous carbon and
stainless steel as anode and cathode,
respectively.
Alkoxyamine
electrochemically activated
respective alkoxyamine radical cations.
lactams
were
their
to