Electrochemically Enabled Intramolecular Aminooxygenation of Alkynes via Amidyl Radical Cyclization

Article abstract of DOI:10.1002/cjoc.201900500

An electrochemical synthesis of oxazol-2-ones and imidazol-2-ones has been developed via 5-exo-dig cyclization of propargylic carbamates- and ureas-derived amidyl radicals. The electrosynthesis relies on the dual function of 2,2,6,6-tetramethylpiperidin- 1-yl)oxyl (TEMPO) as a redox mediator for amidyl radical formation and an oxygen atom donor. The reactions are conducted under mild conditions using a simple setup and provide convenient access to functionalized oxazol-2-ones and imidazol-2-ones from readily available materials.

Full text of DOI:10.1002/cjoc.201900500

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Electrochemically Enabled Intramolecular Aminooxygenation of Alkynes via
Amidyl Radical Cyclization
Authors: Zhong-Wei Hou and Hai-Chao Xu*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.201900500.
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published online in Early View: http://dx.doi.org/10.1002/cjoc.201900500.
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Electrochemically Enabled Intramolecular Aminooxygenation of Alkynes
via Amidyl Radical Cyclization
Zhong-Wei Houa and Hai-Chao Xu*,a
a State Key Laboratory of Physical Chemistry of Solid Surfaces, iChEM, Key Laboratory of Chemical Biology of Fujian Province, and College of Chemistry and
Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China.
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion An electrochemical synthesis of oxazol-2-ones and imidazol-2-ones has been developed via 5-exo-dig
cyclization of propargylic carbamates- and ureas-derived amidyl radicals. The electrosynthesis relies on the dual function of TEMPO as a redox mediator
for amidyl radical formation and an oxygen atom donor. The reactions are conducted under mild conditions using a simple setup and provide convenient
access to functionalized oxazol-2-ones and imidazol-2-ones from readily available materials.
Background and Originality Content
Scheme 1 Electrochemical aminooxygenation of alkenes and alkynes
Nitrogen-centered radicals (NCRs) are versatile synthetic
work
Previous
a)
(ref. [8])
intermediates for organic synthesis and can participate in
reactions such as hydrogen atom transfer and addition to
π-systems.[1] Particularly, the addition reactions provide access to
nitrogen-containing compounds, which are prevalent in chemistry
and biology. Probably due to the importance of
nitrogen-containing compounds, addition reactions of NCRs have
been attracting increasing interests. Among the addition reactions
that have been investigated, reactions with alkynes are much less
common compared to those with alkenes.[2] Further expansion of
the synthetic utility of NCRs hinges on the development of
efficient methods for their formation from readily available
precursors.
Organic electrochemistry is emerging as a useful tool for
promoting radical reactions.[3] In this context, we have developed
several electrochemical methods for the generation of NCRs from
N–H precursors.[4] The electrochemically generated NCRs
participate in intramolecular cyclization reactions with arenes,[5]
alkenes[6] and alkynes[7] to afford various N-heterocycles.
Particularly, we have shown that TEMPO can serve as both a redox
mediator for amidyl radical formation and an oxygen atom donor
to achieve intramolecular alkene aminooxygenation.[8] In these
reactions, TEMPO is incorporated into the final product as an
alkoxyamine moiety, which can be cleaved reductively to a
hydroxyl group or oxidatively to a keto group. Herein, we report a
OH
Ph
N
O
O
N
Zn
O
Ph
Ph
O
NH
N
O
TEMPO
equiv)
O
O
O
Ph
N
m
-CPBA
O
(2.0
O
work
This
b)
R2
R2
R2
Ar
Ar
NH
Ar
N
O
N
O
TEMPO
equiv)
(1.5
MeCN/H2O
O
X
R1
X
R1
O
X
R1
=
X
NR
O,
Results and Discussion
We first selected carbamate 1 as a model substrate for
optimization of the electrolysis conditions. The electrochemical
reaction was carried out in an undivided cell equipped with a
reticulated vitreous carbon (RVC) anode and a platinum cathode
at a constant current of 5 mA (Table 1). Oxazol-2-one 2 was
isolated in 85% yield when the reaction was conducted at room
temperature for 1.2 h in the presence of 1.5 equiv of TEMPO and
2.0 equiv of CF3COONa in a mixed solvent of MeCN/H2O (11:1)
under argon atmosphere (entry 1). Electricity was indispensable
for success (entry 2). Reduction of the amount of TEMPO to 0.5
equiv (entry 3) or conducting the electrolysis without CF3COONa
(entry 4) resulted in a lower yield of 2. Other basic additives such
as Na2CO3 (entry 5), NaHCO3 (entry 6), NaOAc (entry 7) and
CF2ClCOONa (entry 8) failed to give better results. Moderate yield
of 2 was obtained when the electrolysis was performed in the
absence of nBu4NBF4 (entry 9) or under air atmosphere (entry
TEMPO-mediated,
electricity-driven
intramolecular
aminooxygenation reaction of alkynes. Unlike the reactions of
alkenes, these reactions of alkynes afford acyl-substituted
oxazolone and imidazolone products that do not contain
TEMPO-derived
alkoxyamine
moiety.
Oxazolones
and
imidazolones are useful synthetic intermediates and are also
structural motifs present in several bioactive compounds.[9]
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/cjoc.201900500
This article is protected by copyright. All rights reserved.

First author et al.
Report
10).
Scheme 2 Scope of oxazol-2-one synthesisa
Table 1 Optimization of reaction conditionsa
TEMPO 1.5
equiv)
R2
(
R2
O
Ph
CF COONa 2.0
equiv)
(
3
Ph
Ar
TEMPO 1.5
equiv)
equiv)
PMP
(
Ar
N
O
CF COONa 2.0
NH
PMP
O
(
3
N
O
n
NH
Bu4NBF4 0.5
O
equiv)
RT
mol-1
(
O
O
R1
H,
n
R1
Bu4NBF4 0.5
O
MeCN/H O
equiv)
(
(11:1),
2
O
iPr
O
iPr
MeCN/H O
RT
(11:1),
2
1.2 1.1 F
h,
1
2
"standard conditions"
=
=
=
=
=
=
3 R
85%
,
R
O
Entry
1
2
3
4
5
6
7
8
Deviation from standard conditions
None
no electricity
entry 1 but TEMPO (0.5 equiv)
entry 1 but no CF3COONa
entry 1 but Na2CO3 (2.0 equiv) as base
entry 1 but NaHCO3 (2.0 equiv) as base
entry 1 but NaOAc (2.0 equiv) as base
Yield b/%
85c
0 (99)
40 (34)
32
4
R
R
OPh, 75%
SMe, 83%
Me, 81%
,
,
N
5
Ph
Ph
6 R
,
N
O
O
7
R
81%
F,
Cl, 76%
,
O
N
O
O
8 R
,
iPr
=
9 R Br, 71%
,
iPr
31%b,c
12
,
28
36
65
73
70
67
X-ray of 3
=
=
10
R
R
68%
,
,
I,
1969894]
[CCDC
11
OCF3 80%
,
MeO
MeO
MeO
Cl
MeO
MeO
Br
entry 1 but CF2ClCOONa (2.0 equiv) as base
entry 1 but no nBu4NBF4
entry 1 but under air
F
9
10
Ph
Ph
N
Ph
N
O
aReaction conditions: RVC anode, Pt cathode, 1 (0.2 mmol), TEMPO (0.3
mmol), CF3COONa (0.4 mmol), nBu4NBF4 (0.1 mmol), MeCN (5.5 mL), H2O
N
N
O
O
O
O
O
O
O
O
O
O
iPr
O
iPr
iPr
iPr
1
(0.5 mL), argon, 5 mA, 1.2 h (1.1 F mol−1). bYield determined by H-NMR
73%c
16
,
13
,
87%
15
84%
,
14
,
71%
analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as
the internal standard, unreacted 1 in parenthesis. Isolated yield. PMP =
MeO
MeO
c
MeO
F
MeO
p-methoxyphenyl.
S
Ph
N
N
O
O
N
O
N
O
O
After the optimized reaction conditions were defined, we
investigated the substrate scope of the electrosynthesis (Scheme
2). The phenyl ring of the aniline moiety tolerated substituents of
diverse electronic properties, including electron-donating groups
such as OPh (4), SMe (5) and Me (6), halogens (F, Cl, Br, I; 7–10),
and electron-withdrawing groups such as OCF3 (11). The structure
of 3 was confirmed by single crystal X-ray diffraction studies.
2-Aminopyridine-derived substrate afforded the corresponding
oxazol-2-one 12 in 31% yield. Substrates with a disubstituted
N-aryl ring were also suitable for the electrochemical cyclization
reaction (13–15). While the reaction is compatible with
4-methoxyphenyl (16), 2-thiophenyl (17) or 3-fluorophenyl (18)
substituted alkynes, alkyl substituted alkynes failed to afford any
O
O
O
O
O
O
O
iPr
85%
tBu
iPr
Me
56%c
0%
20
57%
,
17
18
,
19
,
,
MeO
MeO
Ph
Ph
Ph
N
O
N
O
O
O
N
O
O
O
OH
Me
O
Me
70%
Ph
O
Me
89%d
23
X-ray of
1969895]
21
,
22
65%
,
23
,
[CCDC
aReaction conditions: Table 1, entry 1 unless otherwise mentioned. All
yields are isolated yields. bReaction with NaOAc (2.0 equiv) instead of
CF3COONa. cReaction for 4 h. dReaction for 2.5 h.
desired products (19). Furthermore, carbamates bearing
a
tert-butyl (20), methyl (21) or phenyl (22) group at the propargylic
position also reacted successfully to produce the desired
oxazol-2-ones. Interestingly, substate without propargylic proton
reacted to afford a hydroxyl oxazolidone (23).
Next, we applied the electrochemical strategy to the synthesis
of imidazol-2-ones from propargylic ureas (Scheme 3). Urea
substrates bearing 4-methoxy phenyl (24) and phenyl (25) groups
reacted to afford the corresponding imidazol-2-ones in 68% and
64% yields, respectively. 4-Chlorophenyl (26), 4-cyanophenyl (27)
and 3,5-dichlorophenyl (28) substituted ureas reacted successfully
under modified conditions with K2CO3 as the base at a constant
current of 10 mA. The substitutent on the linking nitrogen also
tolerated variation as demonstrated with a N-Ph urea (29).
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Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
Scheme 3 Scope of imidazol-2-one synthesisa
40
40
TEMPO 1.5
(
equiv)
equiv)
Ph
Ph
Ar
K2CO3 2.0
d
d
(
30
30
N
N
Ar
O
NH
O
n
Bu4NBF4 0.5
equiv)
RT
mol-1
(
iPr
e
e
O
N
iPr
MeCN/H O
(11:1),
2
R
20
20
R
2.5 4.6 F
h,
Cl
MeO
a, b, c
a, b, c
10
10
Ph
f
f
Ph
Ph
N
O
0
0
N
N
O
N
N
N
O
O
iPr
O
O
iPr
n
Bu
iPr
n
-10
-10
n
Bu
26
Bu
64%b
,
51%
0.4
0.4
0.6
0.6
0.8
0.8
1.0
1.0
25
68%b
,
24
,
NC
MeO
E / V vs SCE
E / V vs SCE
Cl
Cl
Ph
Ph
Figure 1 Cyclic voltammograms in MeCN, nBu4NBF4 (0.1 M). a:
TEMPO (3 mM). b: TEMPO (3 mM) + 30 (10 mM). c: b + CF3COONa
(10 mM). d: b + nBu4NOH (10 mM). e: 30 (10 mM) + nBu4NOH (10
mM). f: nBu4NOH (10 mM).
Ph
N
N
N
N
O
N
N
O
O
O
O
O
iPr
62%
iPr
64%
iPr
67%
n
n
Bu
Bu
Ph
27
,
28
,
29
,
Next, we performed a series of mechanistic experiments
aReaction conditions: urea (0.2 mmol), TEMPO (0.3 mmol), K2CO3 (0.4
mmol), nBu4NBF4 (0.1 mmol), MeCN (5.5 mL), H2O (0.5 mL), argon, 10 mA,
2.5 h (4.6 F mol−1). All yields are isolated yields. bReaction under the
conditions of Table 1, entry 1 for 4 h.
(Scheme 5). The oxidation of 30 was investigated with
−
oxoammonium salt (TEMPO+BF4 ) under electricity-free conditions
(Scheme 5a). While no reaction occurred in the presence of
CF3COONa, oxazolone 3 was formed in 24% along with hydroxy
ketone 31 in 62% when Cs2CO3 was employed as a base. These
results, together with the CV studies, clearly showed that a base
strong enough to deprotonate the carbamate was needed for the
aminooxygenation reaction to occur. The inferior results obtained
using stoichiometric oxidant also highlighted the advantage of our
electrochemical method. The alkyne substrates are known to
undergo base promoted hydroamidation reaction.[7c,10] For
example, propargyl carbamate 30 underwent efficient
hydroxide-promoted ionic cyclization to afford oxazolidinone 32 in
78% yield. However, electrolysis of 32 under the standard
conditions resulted in no oxazolone 3 and the recovery of 92% of
32 (Scheme 5b). These results suggested that 32 was not an
intermediate for the electrochemical synthesis of 3.
The practicality of our method was further demonstrated by
the gram scale reaction of 30 to give oxazolone 3 in 82% yield
(Scheme 4). Note that larger electrodes were employed to allow
the use of higher current to increase productivity.
Scheme 4 Gram-scale synthesis of oxazol-2-one 3
RVC
Pt
Ph
Ph
Ph
N
TEMPO 1.5
(
equiv)
Ph
O
O
NH
O
n
Bu4NBF4 0.5
O
equiv)
MeCN/H O
(
iPr
g)
O
iPr
CF COONa 2.0
(
equiv),
(11:1)
mol-1
F RT, 1.5 h,
,
)
3
2
450 mA
30
(1.4
82%
3,
(4.5
To shine light on the reaction mechanism, we first recorded
cyclic voltammograms (CVs) of TEMPO under different conditions
(Figure 1). The CVs of TEMPO did not change when either the
substrate 30 (curve b) or 30 together with CF3COONa was added
(curve c), suggesting that the neutral substrate 30 did not react
with anodically generated TEMPO+. However, a catalytic current
was observed in the presence of nBu4NOH, along with complete
disappearance of reduction current (curve d). A comparison of
curve d with curve e, the voltammogram of the conjugate base of
30, suggested the current increase of curve d was not due to the
oxidation of the substrate anion. These studies indicated that
effective electron transfer occurred between TEMPO+ and the
conjugate base of 30 but not the neutral 30.
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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This article is protected by copyright. All rights reserved.

First author et al.
Report
Scheme 5 Mechanistic experiments
Scheme 4 Proposed mechanism
cathode
e
anode
a)
TEMPO+BF4 1.5
Ph
Ph
equiv)
(
Ph
N
Ph
CF COONa 2.0
equiv)
(
3
Ph
O
O
NH
Ph
O
NH
O
n
Bu4NBF4 0.5
iPr
equiv)
RT, 1.2 h
(
OH
O
iPr
iPr
O
30
O
iPr
+
1/2 H2
MeCN/H O
(11:1),
2
30
3
reaction)
, 0%
(no
=
E
1.64
V)
(
p/2
e
Ph
TEMPO+BF4 1.5
Ph
equiv)
equiv)
(
Ph
Ph
Ph
N
Ph
N
Cs2CO3 2.0
H2O
(
Ph
Ph
O
+
O
N
O
N
O
NH
O
O
OH
O
n
TEMPO+
Bu4NBF4 0.5
equiv)
O
(
O
33
O
iPr
V)
iPr
O
iPr
MeCN/H O
RT, 1.2 h
(11:1),
2
=
E
0.71
(
p/2
30
=
3 24%
31
, 62%,
d.r. 10:1
,
Ph
b)
Ph
N
Ph
N
Ph
Ph
TEMPO
Ph
Ph
Ph
O
Ph
N
O
N
O
n
Bu NOH
mol%)
(11:1)
(10
4
N
O
TEMPO
O
Ph
O
iPr
O
O
NH
=
E
0.67 V)
O
iPr
standard
conditions
(
p/2
MeCN/H O
60 °C, 3 78%
h,
2
O
O
iPr
reaction)
iPr
35
34
O
iPr
32
3
, 0%
30
N
H
(no
38
Ph
[detected
HRMS]
Ph
Ph
N
Ph
N
Ph
Ph
N
by
O
N
O
O
O
(
Based on the above studies and previous reports,[8,11]
a
O
O
O
O
O
iPr
1.72 V)
iPr
iPr
3
possible mechanism for the electrochemical cyclization reaction
was proposed using carbamate 30 as a model substrate (Scheme
6). At the anode, TEMPO (Ep/2 = 0.67 V vs SCE) is oxidized through
single electron transfer (SET) to afford TEMPO+. Simultaneously,
the cathodic reduction of H2O forms H2 and HO−. The cathodically
generated base HO− deprotonates 30 (Ep/2 = 1.64 V vs SCE) to give
the nitrogen anion intermediate 33 (Ep/2 = 0.71 V vs SCE), which is
easily oxidized by TEMPO+ via SET to furnish nitrogen-centered
radical 34. The 5-exo-dig cyclization of 34 affords vinyl radical 35,
which is trapped by TEMPO to give tetrasubstituted alkene 36.
The sterically crowded alkene 36 undergoes N–O bond cleavage to
afford iminium 37 and 2,2,6,6-tetramethylpiperidine 38.[12] The
latter has been detected by high resolution mass spectrometry
(HRMS). Intermediate 37 undergoes proton loss to afford the final
oxazolone 3. For substrates that do not contain a propargylic
proton, reaction of the iminium intermediate with H2O affords a
hydration product (e.g. 23).
36
37
H
OH
=
E
p/2
Conclusions
In summary, we have developed
a TEMPO-mediated
electrochemical synthesis of functionalized oxazol-2-ones and
imidazol-2-ones through oxidative cyclization of propargylic
carbamates and ureas. In these reactions, TEMPO serves as both a
redox mediator to produce amidyl radicals and an oxygen-atom
donor.
Experimental
General procedures for the electrosynthesis:
A 10 mL
three-necked round-bottomed flask (Figure S1) was charged with
TEMPO (0.3 mmol, 1.5 equiv), the substrate (0.2 mmol, 1.0 equiv),
nBu4NBF4 (0.1 mmol, 0.5 equiv), and CF3COONa or K2CO3 (0.4
mmol, 2.0 equiv). The flask was equipped with a reticulated
vitreous carbon (100 PPI, 1 cm x 1 cm x 1.2 cm) anode and a
platinum plate (1 cm x 1 cm) cathode and then flushed with argon.
MeCN (5.5 mL) and H2O (0.5 mL) were added. The electrolysis was
carried out at room temperature using a constant current of 5 mA
or 10 mA until complete consumption of the substrate (monitored
1
by TLC or H NMR). The reaction mixture was concentrated under
reduced pressure and the residue was chromatographed through
silica gel eluting with ethyl acetate/hexane to give the desired
product.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
Electrochemical Arylation Reaction. Chem. Rev. 2018, 118,
6706-6765. (j) Sauer, G. S.; Lin, S., An Electrocatalytic Approach to
the Radical Difunctionalization of Alkenes. ACS Catal. 2018, 8,
5175-5187. (k) Nutting, J. E.; Rafiee, M.; Stahl, S. S.
Tetramethylpiperidine N-Oxyl (TEMPO), Phthalimide N-Oxyl (PINO),
and Related N-Oxyl Species: Electrochemical Properties and Their
Acknowledgement
The authors acknowledge the financial support of this
research from MOST (2016YFA0204100), NSFC (No. 21672178),
and Fundamental Research Funds for the Central Universities.
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(The following will be filled in by the editorial staff)
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Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
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Entry for the Table of Contents
Page No.
Electrochemically Enabled Intramolecular
Aminooxygenation of Alkynes via Amidyl
Radical Cyclization
R2
R2
R1
Ar
Ar
NH
N
X
O
TEMPO
equiv)
(1.5
MeCN/H2O
O
X
R1
O
=
X
NR
O,
An electrochemical synthesis of oxazol-2-ones and imidazol-2-ones has been developed via
5-exo-dig cyclization of amidyl radicals. The electrosynthesis relies on the dual functional of
TEMPO as a redox mediator for amidyl radical formation and an oxygen atom donor.
Zhong-Wei Hou and Hai-Chao Xu*
a Department, Institution, Address 1
E-mail:
c Department, Institution, Address 3
E-mail:
b Department, Institution, Address 2
E-mail:
Chin. J. Chem. 2018, template
© 2018 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
This article is protected by copyright. All rights reserved.