Electrochemical Functional-Group-Tolerant Shono-type Oxidation of Cyclic Carbamates Enabled by Aminoxyl Mediators

Article abstract of DOI:10.1002/anie.201803539

An electrochemical method has been developed for α-oxygenations of cyclic carbamates by using a bicyclic aminoxyl as a mediator and water as the nucleophile. The mediated electrochemical process enables substrate oxygenation to proceed at a potential that is approximately 1 V lower than the redox potential of the carbamate substrate. This feature allows for functional-group compatibility that is inaccessible with conventional Shono oxidations, which proceed by direct electrochemical substrate oxidation. This reaction also represents the first α-functionalization of non-activated cyclic carbamates with oxoammonium oxidants.

Full text of DOI:10.1002/anie.201803539

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Electrochemical Functional-Group-Tolerant Shono-Type
Oxidation of Cyclic Carbamates Enabled by Aminoxyl Mediators
Authors: Fei Wang, Mohammad Rafiee, and Shannon S Stahl
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201803539
Angew. Chem. 10.1002/ange.201803539
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10.1002/anie.201803539
Angewandte Chemie International Edition
COMMUNICATION
Electrochemical Functional-Group-Tolerant Shono-Type Oxidation
of Cyclic Carbamates Enabled by Aminoxyl Mediators
Fei Wang, Mohammad Rafiee, and Shannon S. Stahl*
Abstract: An electrochemical protocol has been developed for α-
oxygenation of cyclic carbamates by using a bicyclic aminoxyl as a
mediator and water as the nucleophile. The mediated electrochemical
method enables substrate oxygenation to proceed approximately 1 V
lower than the redox potential of carbamate substrate. This feature
allows for functional-group compatibility that is inaccessilble with
conventional Shono oxidations that proceed via direct electrochemical
substrate oxidation. This chemistry also represents the first α -
functionalization of non-activated cyclic carbamates with
oxoammonium as the oxidant.
as the nucleophile, the substrate was completely consumed
without forming the desired oxygenated product. In contrast,
when the unsubstituted piperidine carbamate 1b was subjected to
identical conditions, the a-hydroxylated product was obtained in
89% yield (Scheme 2, top). The basis for these observations is
evident from cyclic voltammetry (CV) data. Substrate 1a and
anisole exhibit oxidation peaks at 1.28 and 1.38 V, respectively vs
Fc/Fc+. Analysis of 1b, however, reveals a peak potential at 1.61
V. These results show that the electron-rich aromatic ring is more
readily oxidized than the carbamate fragment in 1a, thereby
accounting for the observed decomposition under Shono
conditions.
Electrolysis is
a versatile approach to achieve redox
transformations in organic synthesis that provides a compelling
alternative to traditional reagent-based methods.[ 1 , 2 , 3 ] Shono
oxidations (Scheme 1a) [4] are among the most widely employed
electrochemical methods for the functionalization of C–H bonds
adjacent to nitrogen atoms, and they have been featured in the
Scheme 1. Alpha-functionalization of cyclic carbamates.
a) Shono oxidation: Direct electrolysis
R
R
R
[
5 ]
synthesis of natural products,
synthesis and late-stage
R’’OH
Shono oxidation
(ET-PT-ET)
+
[6]
functionalization of pharmaceuticals, and preparation of drug
N
H
N
N
OR’’
[7]
metabolites. The reactions proceed via direct electron transfer
CO2R’
CO2R’
CO2R’
High applied potential
to the electrode, and a sequence of electron-proton-electron
transfer (ET-PT-ET) steps affords an iminium species that is
trapped by a nucleophile, such as MeOH or H2O. The functional
group compatibility of this method for both substrates and
nucleophiles is often limited, however, by the high electrode
potentials required to initiate electron transfer from the substrate.
Various strategies, such as “cation pool” and flow-based methods,
have been employed to expand the nucleophile compatibility, but
functional groups on the amine-derived substrate remain
limited.[8,9] Indirect (i.e., mediated) electrolysis methods provide a
means to circumvent this issue.[3] The ET-PT-ET sequence
involved in traditional Shono oxidations is formally equivalent to a
hydride transfer. A mediator that reacts with substrate via
concerted hydride transfer could alleviate the requirement for a
high-potential electron transfer step, thereby permitting operation
at lower electrode potentials and increasing the functional group
compatibility. Herein, we demonstrate this concept through the
use of derivatives of the bicyclic aminoxyl ABNO (9-
azabicyclo[3.3.1]nonane N-oxyl) as the mediator. The resulting
methods show considerably improved scope and functional group
compatibility relative to conventional Shono conditions, as well as
previously reported indirect electrolysis methods.[10,11,12]
Poor functional groups tolerance
b) This work: Mediated electrolysis
(Hydride transfer)
R
R
R
H2O, [O]
Mediator
+
N
H
N
N
O
CO2R’
CO2R’
CO2R’
Low applied potential
Water as nucleophile
Good functional groups tolerance
Scheme 2. Limitations in conventional Shono oxidation.
R
N
R
N
Et4NOTs (0.17 M)
CH3CN/H2O (5:1)
Constant current @ 10 mA
undivided cell, Pt II Pt
OH
O
OMe
O
OMe
1a, R = 4-MeO-Phenyl
1b, R = H
n.d.
89%
500
400
300
200
100
0
1a
1b
anisole
OMe
The functional group limitations of Shono oxidations are
illustrated by the attempted a-oxygenation of the 4-(4-
methoxyphenyl)-piperidine carbamate 1a. When 1a was
subjected to conventional Shono oxidation conditions with water
OMe
N
N
O
OMe
O
OMe
1b
1a
anisole
[*]
Dr. F. Wang, Dr. M. Rafiee, Prof. Dr. S. S. Stahl
Department of Chemistry, University of Wisconsin-Madison,
Madison, Wisconsin 53706 (USA)
-100
0
0.4
0.8
E (v) vs. Fc/Fc+
1.2
1.6
E-mail: stahl@chem.wisc.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201803539
Angewandte Chemie International Edition
COMMUNICATION
Use of a hydride-transfer mediator could provide a means to
alleviate the functional-group incompatibility evident in Scheme 2.
To our knowledge, the only precedent for mediated Shono-type
oxidation of unactivated substrates, such as 1a, was reported by
Torii and coworkers, using a RuO2/Cl- dual-mediator system.[10]
Preliminary tests of this system, however, led to chlorination of
the methoxyarene ring rather than oxygenation of the nitrogen
heterocycle (see Supporting Information for details).
Oxoammonium reagents, derived from one-electron oxidation of
aminoxyls, have been used as oxidants for the a-functionalization
of activated (benzylic and allylic) carbamates and amides.[11,13]
These observations, together with recent studies of aminoxyl-
based mediators in electroorganic chemistry by us[ 14 ] and
others,[15,16,17] prompted us to consider whether aminoxyls could
mediate Shono-type a-oxidation of unactivated substrates with
water as the nucleophile (cf. Scheme 1b).[ 18 ] To test this
hypothesis, we initiated experiments with 1a as substrate and
evaluated a series of aminoxyls with different steric profiles and
redox potentials (Figure 1; redox potentials correspond to the one-
electron aminoxyl/oxoammonium redox couple). Constant current
conditions (3 mA) were employed, using a reticulated vitreous
carbon (RVC) anode and Pt wire counter electrode in an
undivided cell (see Supporting Information for full optimization
was recovered unreacted, even with 4-oxo-TEMPO as mediator.
These observations are consistent with the lack of reactivity with
oxidants such as TEMPO+ and Bobbitt’s salt.[13] The desired
reactivity was observed, however, with the less sterically hindered
bicyclic aminoxyls ABNO, PhCO2ABNO, and ketoABNO. Only low
yields were observed with the commercially available derivatives,
ABNO and ketoABNO. The majority of substrate (81%) was
recovered unreacted with ABNO. This low reactivity is attributed
to the lower redox potential and hydride acceptor ability of ABNO.
Somewhat improved yield was observed with ketoABNO (36%);
however, the reaction solution of ketoABNO and 1a was darkened
relative to solutions ketoABNO and other substrates (see below).
The origin of this observation is not known, but it may reflect
formation of a non-productive adduct between the electrophilic
ketoABNO+ species and the electron-rich aromatic ring (i.e., a
donor-acceptor interaction), which could hinder the desired
reactivity and/or lead to side reactions (only 32% of 1a was
recovered). The modified ABNO derivative, PhCO2ABNO, which
has a redox potential intermediate between ABNO and ketoABNO,
was then synthesized and tested as a mediator.[19] This aminoxyl
led to considerable improvement in the yield of 2a (62%, with 23%
recovery of 1a). The reaction proceeded smoothly at room
temperature in a simple undivided cell.
data).
The
results
showed
that
TEMPO
(2,2,6,6-
These bicyclic aminoxyl derivatives were then tested in
mediated electrolysis conditions with substrates bearing different
functional groups, and the results were compared with
conventional Shono oxidation conditions (Scheme 3). The Shono
conditions led to poor results in each case. For substrates 1c and
1d, the best yield was observed with PhCO2ABNO as mediator
(67 and 64%), while the best yield for 2e was obtained with
ketoABNO as the mediator (60%).
tetramethylpiperidine N-oxyl) and its derivatives were
insufficiently reactive to promote substrate oxidation, irrespective
of the aminoxyl redox potential. In each case, the reactivity
reported previously for a-functionalization of non-activated
carbamates with stoichiometric oxoammonium-based substrate
OMe
OMe
Scheme 3. Comparison of different a-functionalization conditions for
a series of different substrates.
mediator (60 mol%)
H2O (50 equiv)
NaClO4 (0.1 M), RT,
constant current @ 3 mA
CH3CN (2.0 mL)
F
N
N
O
N
OMe
O
N
N
O
OMe
O
OMe
2a
undivided cell
1a, 0.1 M
Pt
RVC
NHAc
OCOPh
O
Steric effect:
N
O
N
O
N
O
O
OMe
O
OMe
2d
O
OMe
N
O
N
O
N
O
N
O
2c
2e
PhCO2TEMPO
n.d.
TEMPO
n.d.
ACT
n.d.
oxoTEMPO
n.d.
Shono Ox.a
ABNOb
PhCO2ABNOc
ketoABNOd
22%
49%
67%
63%
n.d.
51%
64%
< 5%
5%
< 5%
< 5%
60%
active
non-active
mV vs Fc/Fc+
200
250
300
350
400
450
[a] Yields of hydroxylated products. [b] 40 equiv of H2O @ 3 mA, 40 mol% ABNO.
[c] 30 equiv of H2O @ 5 mA, 60 mol% PhCO2ABNO. [d] 50 equiv of H2O @ 5
mA, 60 mol% ketoABNO. 1H NMR yield was shown with mesitylene as internal
standard.
Oxidative effect:
H
O
OCOPh
N
O
N
N
O
O
PhCO2ABNO
62%
ABNO
ketoABNO
These results prompted us to examine the compatibility of the
mediated system toward diverse functional groups, and a
robustness screen[20] was conducted by testing the oxidation of
1b in the presence of various additives with PhCO2ABNO as
mediator (Table 1，see Supporting Information for an analogous
13%
36%
Figure 1. Reactions with different mediators (1H NMR yields with
mesitylene as internal standard).
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10.1002/anie.201803539
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COMMUNICATION
screen with ketoABNO). The data reveal that the reactions
proceed well in the presence of many different functional groups,
including several that are oxidatively sensitive. For example,
thiophene, benzothiophene, and indole derivatives and anisole
were tolerated under the mediated conditions, with >92% of the
additive recovered after bulk electrolysis. CV analysis of the
individual additives (see below Table 1) shows that none of these
functional groups is compatible with conventional Shono oxidation
conditions; each of the additives undergoes oxidation at potentials
below the potential of 1b. The results in Table 1 also draw
attention to the chemoselectivity of the reaction. For example,
substrate 1b undergoes selective conversion to 2b in the
mediator (Table 2). Good yields were obtained with substrates
bearing diverse functional groups, such as substituted arenes,
esters, ethers, ketones, halides and sulfonyl groups. Substituted
pyrrolidines also proved to be good candidates for the α-
oxygenation reaction, furnishing the desired products in improved
yields relative to those observed with the piperidine carbamate
substrates. Collectively, these results demonstrate the broadest
functional group compatibility reported to date for Shono-type
oxidations.
Table 2. Substrate scope for α-Oxygenation of Carbamates.[a,b]
PhCO2ABNO (A) or
presence
of
N-methyl-2-piperidone
(11)
and
1-
ketoABNO (B) (40-60 mol%)
R
R
(phenylsulfonyl)piperidine (12), both of which could potentially
undergo a-oxidation.
H2O (15-60 equiv)
N
N
O
NaClO4 (0.1 M), RT
CH3CN (2.0 mL)
O
OMe
O
OMe
1
2
Pt
Table 1. Robustness screen for mediated electrolysis with
RVC
PhCO2ABNO.[a]
OMe
F
N
N
OMe
O
N
N
O
PhCO2ABNO (60 mol%)
H2O (50 equiv), additive (1.0 equiv)
N
N
O
NaClO4 (0.1 M), RT
CH3CN (2.0 mL)
RVC Pt
O
OMe
O
OMe
N
O
OMe
O
N
O
N
O
1b
2b
yield of 2b; recovery of additive
O
OMe
O
OMe
O
OMe
Additives:
2a, 59% (A)
2c, 69% (A)
2d, 62% (A)
2e, 58% (B)
Br
Br
R
without
additive
Cl
O
Cl
S
N
OMe
S
SO2Ph
O
O2S
3
4
5
89%; > 99%
71%ꢀꢁꢂꢃꢄ
84%; > 99%
86%
Br
N
O
N
O
N
O
N
O
OMe
N
N
N
Me
O
OMe
O
OMe
O
OMe
O
OMe
Me
Br
S
S
2j, 61% (B)
2k, 83% (B)
2l, 83% (B)
2f, R = H, 81% (B)
2g, R = Cl, 62% (B)
2h, R = Br, 63% (B)
2i, R = F, 83% (B)
6
7
8
9
86%; > 99%
84%; > 99%
80%; > 99%
72%; 95%
RO
O
N
O
O
O
O
Me
O
OMe
N
NH2
76%; > 99%
N
N
R
O
OEt
2n, R = Bn, 85% (B)
2o, R = Me, 76% (B)
SO2Ph
12
83%; > 99%
89%; > 99%
O
OMe
Br
10
11
2q, R = H, 86% (B)
2r, R = F, 82% (B)
2s, R = Cl, 82% (B)
CV of different additives:
MeO
N
O
O
N
400
O
OMe
anisole
ketoABNO
O
OMe
300
5
2m, 58% (B)
2p, 93% (B)
3
1b
200
[a] These reactions were conducted with 0.2 mmol scale in 2 mL CH3CN (see
Supporting Information for conditions). [b] Isolated yield was shown.
PhCO2ABNO
4
100
0
-100
-200
Analysis of the reaction time course provided valuable, and
unexpected, insights into the reaction pathway. Formation of the
a-oxygenation products corresponds to net four-electron
oxidation of the carbamate substrates. The reaction is initiated by
one-electron oxidation of the aminoxyl mediator to generate an
oxoammonium species that can promote two-electron hydride-
transfer oxidation of the substrate, resulting in formation of the
hydroxylamine form of the mediator. Oxidation of this species at
the electrode will regenerate the oxoammonium species to allow
for further substrate oxidation. We anticipated that substrate-
derived iminium ion resulting from hydride transfer would be
0
0.4
0.8
E (v) vs. Fc/Fc+
1.2
1.6
[a] Constant current @ 3 mA with PhCO2ABNO as mediator.
Under the optimized conditions, a range of substituted
piperidine carbamate derivatives were tested for their ability to
undergo a-oxygenation with PhCO2ABNO or ketoABNO as the
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10.1002/anie.201803539
Angewandte Chemie International Edition
COMMUNICATION
trapped by water to generate a hemiaminal that could undergo the
second two-electron oxidation by the mediator to furnish the
desired product (Figure 2b, path A). The reaction time course with
1b as the substrate and ketoABNO as the mediator was analyzed,
and the data revealed build-up and decay of an intermediate
during the reaction (Figure 2a). Subsequent isolation and
characterization of the intermediate by 1H and 13C NMR
spectroscopy and high-resolution mass spectrometry revealed
this intermediate to be an adduct of the substrate and ketoABNO
(2b’), rather than the expected hemiaminal (Figure 2b). This
outcome is rationalized by the nucleophilicity of hydroxylamines
(and their tautomeric amine oxides),[21] and by the generation of
ketoABNO–H in direct proximity to the iminium ion in the hydride
transfer reaction. This species and the time course in Figure 2a
also accounts for the high mediator loading in these reactions, as
nearly all of the mediator is present in the form of 2b’ at the
maximum concentration of this species. Control experiments
suggest that this species undergoes negligible hydrolysis under
the reaction conditions. Therefore, we propose that formation of
2b forms via hydride transfer from the intermediate 2b' to
generate the iminium species 2b", which then undergoes
hydrolysis. A control experiment confirmed that 2b' undergoes
direct conversion to 2b in the presence of ketoABNO as a
mediator.
In summary, the results described herein represent the first
electrochemical Shono-type oxidation of unactivated cyclic amine
derivatives that show broad scope and functional group tolerance.
This advance has been achieved by use of an aminoxyl mediator
a) Time course of the reaction
ketoABNO (60 mol%), H2O (50 equiv)
N
N
O
NaClO4 (0.1 M), RT, @ 0.65 V vs Fc/Fc+
CH3CN (4.0 mL)
that undergoes electrochemical generation at
a potential
O
OMe
1b
O
OMe
approximately 1.0 V lower than is needed for direct one-electron
oxidation of the substrate. The potential needed for
oxoammonium generation is also much lower than the potentials
associated with outer-sphere ET oxidation of heterocycles and
other common substituents and functional groups. The concepts
illustrated in this study, specifically the redox-potential-lowering
ability of hydride transfer mediators, has significant implications
for the development of electrochemical synthetic methods that
can achieve broader functional-group tolerance. The mechanistic
insights gain from this study provide a foundation for ongoing
studies directed toward the development of improved mediated
electrolysis methods that operate with lower catalyst loading.
Pt
RVC
2b
100
1b
2b'
2b
80
60
40
20
0
0
2
4
6
8
10
time/h
Acknowledgements
b) Plausible mechanism
The authors thank Dr. A. J. J. Lennox and J. E. Nutting for helpful
discussions during the course of this project. Financial support
was provided from an SIOC fellowship (for FW), AbbVie, and the
NIH (R01 GM100143 for SSS). Spectroscopic instrumentation
was partially supported by the NIH (S10 OD020022) and the NSF
(CHE-1048642).
Anode
Cathode
O
H2, OH-
N
HO
N
N
OMe
B
O
-
B+H
O
Conflict of interest:
H2O
OMe
N
O
O
The authors declare no conflict of interest.
O
Keywords: Shono oxidation, Mediated electrolysis, Oxygenation,
OH
N
OMe
O
N
H2O
O
Carbamate, Hydride transfer, Aminoxyls
N
OMe
N
OMe
path A
O
O
O
O
path B
N
O
O
HO
O
N
O
H2O
N
N
N
O
2b
N
O
O
O
OMe
O
OMe
2b’
2b’’
N
HO
Figure 2. Reaction time course (a) and proposed mechanism (b).
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10.1002/anie.201803539
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COMMUNICATION
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[16]
For early precedents, see: a) M. F. Semmelhack, C. S. Chou, D. A.
Cortes, J. Am. Chem. Soc. 1983, 105, 4492; b) T. Inokuchi, S.
Matsumoto, S. Torii, J. Org. Chem. 1991, 56, 2416.
[6]
[17]
[18]
For a comprehensive review, see: J. E. Nutting, M. Rafiee, S. S. Stahl
Chem. Rev. 2018, submitted for publication.
[7]
[8]
a) T. Shono, T. Toda, N. Oshino, Drug Metab. Dispos. 1981, 9, 481. b)
T. Shono, T. Toda, N. Oshino, J. Am. Chem. Soc. 1982, 104, 2639.
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Yoshida, J. Am. Chem. Soc. 2001, 123, 7941; b) J.-i. Yoshida, S. Suga,
Chem. Eur. J. 2002, 8, 2650.
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Soc., Chem. Commun. 1979, 749.
[19]
For the synthesis of N-oxyl mediators, see: M. B. Lauber, S. S. Stahl,
ACS Catal. 2013, 3, 2612 and ref. 15c.
[9]
Modification of the substrate with an "electroauxiliary" provides a
strategy to enhance the substrate scope. For leading references, see ref.
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[20]
[21]
K. D. Collins, F. Glorius, Nat. Chem. 2013, 5, 597.
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This article is protected by copyright. All rights reserved.

10.1002/anie.201803539
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
O
Reaching your low potential: Use of
aminoxyls as hydride-transfer
mediators enables electrochemical a-
oxygenation of unactivated cyclic
carbamates at low electrode
potentials. This method greatly
expands the substrate scope beyond
conventional Shono oxidations.
Fei Wang, Mohammad Rafiee, Shannon
S. Stahl*
O
N
OMe
OMe
N
O
O
O
O
O
N
N
OMe
OH
N
OMe
Page No. – Page No.
O
N
H2
O
HO
O
N
O
Electrochemical Functional-Group-
Tolerant Shono-Type Oxidation of
Cyclic Carbamates Enabled by
Aminoxyl Mediators
Low Potential
Redox Mediator is
Compatible with
Functional Groups
Mediators
0.2 mA
Electron Rich
Cyclic
Functional Groups
Carbamates
0
0.4
0.8
1.2
1.6
E
(v) vs. Fc/Fc+
This article is protected by copyright. All rights reserved.