Electro-oxidative C-H azolation of quinoxalin-2(1H)-ones

Article abstract of DOI:10.1039/d1gc00861g

We have developed a practical, general protocol for direct C-H azolation reactions of quinoxalin-2(1H)-ones by electro-oxidative cross-coupling. These mild reactions proceed under metal-, oxidant-, and reagent-free conditions to provide synthetically useful azolated quinoxalin-2(1H)-ones. Furthermore, the reactions can be carried out with a pencil lead as an electrode and a 3 V battery as a power source, revealing the remarkable flexibility of this protocol.

Full text of DOI:10.1039/d1gc00861g

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Electro-oxidative C–H azolation of quinoxalin-2
(
1H)-ones†
Cite this: Green Chem., 2021, 23,
246
3
a
a
a
a
a
a
Kaikai Niu, Ling Ding, Pan Zhou, Yanke Hao, Yuxiu Liu,
and Qingmin Wang
Hongjian Song
Received 9th March 2021,
Accepted 13th April 2021
a,b
*
DOI: 10.1039/d1gc00861g
rsc.li/greenchem
11
We have developed a practical, general protocol for direct C–H and lead to the azolation of lactams (Scheme 1C). Soon after-
1
2
azolation reactions of quinoxalin-2(1H)-ones by electro-oxidative wards they have achieved the azolation reaction of sulfides.
cross-coupling. These mild reactions proceed under metal-, However, the direct use of an azole radical for electro-oxidative
oxidant-, and reagent-free conditions to provide synthetically C–H functionalization reactions of electron-deficient
1
3
useful azolated quinoxalin-2(1H)-ones. Furthermore, the reactions N-heterocycles like quinoxalin-2(1H)-ones
under electro-
can be carried out with a pencil lead as an electrode and a 3 V chemical conditions was challenging. Building on our previous
1
4
battery as a power source, revealing the remarkable flexibility of research in organic radical chemistry, we have now developed
this protocol.
a mild electrochemical protocol for direct C–H azolation of
quinoxalin-2(1H)-ones (Scheme 1D).
Pyrazoles are a synthetically useful class of heterocycles that
To optimize the reaction conditions, we chose 1-methyl-
quinoxalin-2(1H)-one (1a) and pyrazole (2a) as model sub-
strates (Table 1). We used graphite plates as electrodes, MeCN
1
have ubiquitous applications for drug discovery and medic-
2
3
4
5
inal, agricultural, organometallic, and materials chemistry.
The most straightforward and economical way to access these
n
as a solvent, and Bu NBF (2.0 equiv.) as an electrolyte, and
4
4
6
molecules is through direct S
example, C–H azolation reactions mediated by metals and
N
Ar-type C–H azolation. For
−2
the reaction was carried out at a current density of 10 mA cm
hypervalent iodine are useful for the generation of azolated
7
structural motifs. Moreover, visible-light-mediated photo-
redox catalysis provides an elegant approach for synthesizing
8
azolated arenes. The key step in this transformation is the oxi-
dation of an electron-rich arene to form a radical cation, which
subsequently undergoes a nucleophilic addition reaction with
a pyrazole (Scheme 1A).
Electrochemical oxidation is an attractive, green alternative
to chemical oxidation, which use electrons as a clean and
9
renewable reagent. Recent studies have revealed that electro-
chemical oxidation of phenols and azoles can generate the
corresponding radical intermediates, which can undergo
1
0
radical coupling to generate azolated arenes (Scheme 1B). In
addition, Lei et al. reported that an azole radical generated at
the anode can promote the production of an iminium cation
a
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin
3
00071, People’s Republic of China. E-mail: wangqm@nankai.edu.cn
b
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),
Tianjin 300071, People’s Republic of China
†
Electronic supplementary information (ESI) available. CCDC 2036666. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1gc00861g
Scheme 1 Methods for C–H azolation of arenes (Ts
p-toluenesulfonyl).
=
3246 | Green Chem., 2021, 23, 3246–3249
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a
Table 1 Optimization of the reaction conditions
in an undivided cell. Under these conditions, reaction for 8 h
in air furnished product 3a in 99% yield by H NMR
1
spectroscopy and 95% isolated yield (entry 1). Control experi-
n
ments indicated that electricity (entry 2) and Bu
4
NBF
4
(entries
3
–6) were critical. Evaluation of various solvents revealed
that MeCN was the best choice (entries 7–9). Decreasing
n
the amount of Bu
0–12).
Under the optimized conditions (Table 1, entry 1), we
4 4
NBF or 2a lowered the yield (entries
b
Entry
Variation from standard conditions
Yield (%)
1
c
1
2
3
4
5
6
7
8
9
None
No electricity
99 (95 )
0
explored the scope and generality of this electrochemical C–H
azolation reaction (Table 2). Quinoxalin-2(1H)-ones with
various substituents on the aromatic ring (methyl, fluoro,
chloro, bromo, methoxy, and trifluoromethyl) reacted with pyr-
azole (2a) to afford corresponding products 3a–3f in moderate
to good yields. The structure of 3a was confirmed by X-ray crys-
tallographic analysis. Disubstituted quinoxalin-2(1H)-ones also
proved to be good substrates, affording 3g–3j in reactions with
No electrolyte
0
n
Bu
Bu
4
NPF
NClO
as electrolyte
6
as electrolyte
14
83
70
12
43
37
75
40
67
n
4
4
as electrolyte
LiClO
4
MeOH as solvent
DCE as solvent
DMF as solvent
1.0 equiv. electrolyte
0.5 equiv. electrolyte
1.5 equiv. 2a
1
1
1
0
1
2
2
a. Quinoxalin-2(1H)-ones with an ethyl, butyl, benzyl, benzoyl
a
n
Standard reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), Bu
4
NBF
4
methyl, propargyl, allyl, or ethoxycarbonylmethyl group on the
nitrogen were also suitable substrates (3k–3q).
Pyrazoles 2 with a methyl, fluoro, chloro, bromo, iodo or
ethoxycarbonyl substituent reacted regioselectively with 1a to
(
2.0 equiv.), MeCN (acetonitrile, 5 mL), undivided cell with two graphite
2
−
2
electrodes (each 1.0 × 1.0 cm ), room temperature (r.t.), 10 mA cm
,
b
1
8
h. Yields were determined by H NMR spectroscopy with CH Br as
2 2
c
an internal standard. Isolated yield.
a
Table 2 Electro-oxidative C–H azolation of quinoxalin-2(1H)-ones
a
n
Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), Bu
4
NBF
4
(2.0 equiv.), MeCN (5 mL), undivided cell with two graphite electrodes (each 1.0 ×
2
−2
1
.0 cm ), room temperature (r.t.), 10 mA cm , 8 h. Isolated yields are reported.
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furnish a single isomer of the corresponding products (3r–3aa)
in moderate to good yields. Notably, triazole and 1H-benzotria-
zole substituents were also compatible with this protocol (3ab,
3
ac).
To demonstrate the practicality and utility of the electro-
chemical protocol, we devised an inexpensive setup for carry-
ing it out with a pencil lead as the electrode and a 3 V battery
1
5
as a power supply (Scheme 2A). With this setup, electro-
chemical reactions can be readily accomplished without the
need for complex equipment, thus allowing chemists who do
not have preparative devices to explore the utility of electro-
synthesis. Meanwhile, we also carried out a scaled-up reaction
(
(
Scheme 2B): reaction of 5.0 mmol of 1-methylquinoxalin-2
1H)-one (1a) with pyrazole (2a) under the standard conditions
afforded 3a in 84% yield under undivided flow cell
Scheme 2B). Notably, the reaction could be carried out easily
by direct electrolysis at constant voltage of 2.5
Scheme 2C).
Next, we elucidated the reaction mechanism by means of
(
a
V
(
the experiment depicted in Scheme 3. First, we found that the
electro-oxidative C–H azolation reaction was completely sup-
1
6
pressed by the radical scavengers
TEMPO (2,2,6,6-tetra-
methyl-piperidine N-oxide) and BHT (2,6-di-tert-butyl-4-methyl-
phenol). In addition, radical trapping product 3ad was
detected by high-resolution mass spectrometry (Scheme 3A).
Moreover,
when
1,1′-(1,2-ethenediyl)dibenzene
and
N-phenylmethacrylamide were subjected to electrolysis in the
Scheme 3 Mechanistic studies.
presence of pyrazole under the standard conditions, radical
trapping product 3ae (Scheme 3B) and radical relay product
3af (Scheme 3C) were detected by high-resolution mass spec-
trometry. These results indicate that a pyrazole radical was
formed. Furthermore, cyclic voltammetry showed that the oxi-
dation potentials of 1a and 2a were +1.61 and +1.51 V (vs.
3
AgNO 0.1 M in MeCN) respectively; that is, 2a was more easily
oxidized than 1a at the anode (Scheme 3D). The oxidation
peak of 2a indicates an oxidative pathway for pyrazole-radical
generation.
On the basis of the above-described results, a mechanistic
rationale for these electrocatalytic reactions is shown in
Scheme 4. First, single-electron oxidation of the pyrazole (2a)
at the anode followed by deprotonation forms nitrogen radical
I, which reacts with 1-methylquinoxalin-2(1H)-one (1a) to give
nitrogen radical II. Then II undergoes single-electron oxidation
to form nitrogen cation III, which undergoes deprotonation to
afford the product.
Scheme 2 Demonstration of the practicality of the electrochemical
protocol.
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Notes and references
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In summary, we have developed a practical, general protocol for
direct C–H azolation reactions of quinoxalin-2(1H)-ones. This
mild, sustainable protocol avoids the use of chemical oxidants
and releases only hydrogen. The reactions can be carried out
with a pencil lead and a 3 V battery, allowing chemists to capita-
lize on the flexibility and operational simplicity of electro-
chemical reactions. Further studies involving pyrazole radicals
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Acknowledgements
We are grateful to the National Natural Science Foundation of
China (21732002, 22077071) for generous financial support for
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This journal is © The Royal Society of Chemistry 2021
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