Electrochemical Dehydrogenative Cross-Coupling of Quinoxalin-2(1H)-ones with Amines for the Synthesis of 3-Aminoquinoxalinones

Article abstract of DOI:10.1002/adsc.201800989

An efficient protocol for the synthesis of 3-aminoquinoxalinones via the electrochemical dehydrogenative C-3 amination of quinoxalin-2(1H)-ones was developed. With aliphatic amines and azoles as the nitrogen sources, a series of 3-aminoquinoxalinones was

Full text of DOI:10.1002/adsc.201800989

Title: Electrochemical dehydrogenative cross-coupling of
quinoxalin-2(1H)-ones with amines for the synthesis of 3-
aminoquinoxalinones
Authors: Ke-Jing Li, Kun Xu, yongguo liu, Cheng-Chu Zeng, and
baoguo sun
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800989
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
VERY IMPORTANT PUBLICATION
Electrochemical Dehydrogenative Cross-Coupling of Quinoxalin-2(1H)-ones with
Amines for the Synthesis of 3-Aminoquinoxalinones
Ke-Jing Li,1 Kun Xu, 1 Yong-Guo Liu,2 Cheng-Chu Zeng*,1 and Bao-Guo Sun2
1 Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science
& Bioengineering, Beijing University of Technology, Beijing 100124, China.
Corresponding author: zengcc@bjut.edu.cn
2
Beijing Key Laboratory of Flavor Chemistry, Beijing Technology and Business
University, Beijing 100048, China
Abstract:
An efficient protocol for the synthesis of 3-aminoquinoxalinones via the
electrochemical dehydrogenative C-3 amination of quinoxalin-2(1H)-ones was
developed. With aliphatic amines and azoles as the nitrogen sources, a series of 3-
aminoquinoxalinones was obtained in up to 99% yield. This direct electrolytic method
avoids the use of transition metals and external oxidants, and represents an appealing
alternative for the synthesis of 3-aminoquinoxalinones.
Key words: quinoxalinone, direct electrolysis, dehydrogenative cross coupling,
oxidative amination
Graphic Abstract:
Introduction
Efficient synthesis of quinoxaline-2(1H)-ones has attracted much attention due to
their diverse biological properties and pharmacological properties.[1] In particular, the
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
3-aminoquinoxalinone motif is found widely in bioactive compounds, such as
antibacterial, antiviral, anticancer, anti-diabetic, and anti-inflammatory agents.[2]
Consequently, many synthetic strategies have been developed for the synthesis of 3-
aminoquinoxalinones, the most conventional approaches involving either the
construction of the quinoxalin-2(1H)-one heterocycle or the nucleophilic substitution
of quinoxalin-2(1H)-one derivatives bearing a halo or other leaving group.[3] The
oxidative functionalization of C-H bonds has emerged as an appealing method in
organic chemistry, since the prefunctionalization of C-H bonds is avoided. In this regard,
Gulevskaya et al. reported the first direct oxidative C-H amination of quinoxalin-2(1H)-
ones without the prefunctionalized steps.[4] This protocol is highly significant due to the
atom- and step-economy character, whereas an excess of strong oxidants, such as
KMnO4 or AgPy2MnO4, is required. Recently, Cui[5] and Phan[6] independently
reported the copper-catalyzed C-H amination of quinoxalin-2(1H)-ones for the
synthesis of 3-aminoquinoxalinones (Scheme 1). Despite the significant progress, only
limited examples for the synthesis of 3-aminoquinoxalinones via direct C-H amination
under metal-free conditions have been reported. More recently, Jain et al. successfully
developed an iodine-catalyzed synthesis of 3-aminoquinoxalinones (Scheme 1),[7]
wherein, 2 equiv of TBHP as the oxidant was necessary for this transformation. In view
of the pharmaceutical significance of 3-aminoquinoxalinones, a green method for the
synthesis of 3-aminoquinoxalinones is still highly desirable.
Organic electrosynthesis is regarded as a green and environmentally friendly way
to achieve C-H bonds functionalization, and it is revolutionizing the way of organic
synthesis.[8,9] In this context, electrochemical oxidative amination of C-H bonds has
been well documented by Xu,[10] Wang,[11] Ackermann,[12] Lei[13] and our group,[14] and
has even been reviewed recently by Kärkäs.[15] Nevertheless, the electrochemical C-H
amination of electron-deficient heterocyclic compounds is less well established.
In continuation of our interest in the electrochemical formation and cleavage of
chemical bonds,[14,16] herein, we report an intermolecular electrochemical cross-
coupling of quinoxalin-2(1H)-ones with aliphatic amines or azoles for the synthesis of
3-aminoquinoxalinones (Scheme 1). To the best of our knowledge, this is the first
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
example of C-H amination of quinoxalin-2(1H)-ones under electrolytic conditions. This
protocol features mild reaction conditions and wide range of substrates, avoiding the
utilization of transition metal catalysts and external oxidants. Moreover, owing to
constant current electrolysis (CCE) in undivided cell, the protocol is easy to scale up
for industrial setting.
Scheme 1. Oxidative amination of quinoxalin-2(1H)-ones
Results and discussion
We initiated our studies by using quinoxalinone, 1a, and morpholine, 2a, as model
substrates to identify the optimal reaction conditions. As shown in Table 1, when
constant current electrolysis of 1a and 2a was performed in an undivided cell equipped
with graphite electrodes using NaI as a mediator at room temperature, the desired
product 3a was isolated in 27% yield (entry 1). Encouraged by this result, different
solvents were screened. The results showed that DMF was the optimal solvent, while
other solvents such as MeOH, CH3CN, and aqueous 1,4-dioxane only led to trace
amount of product (entries 1 vs 2-5). Subsequent optimization revealed that NaBr as
the mediator could give the best yield of 26%, while other iodides and bromide as the
mediators gave lower yields (entries 7 vs 1, 6 and 8). Next, we turned our attention to
optimize the acid additives. When acetic acid was used as the acid additive, the yield
of 3a improved to 32% (entry 9). However, only trace amounts of 3a were detected
when using TsOH or solid acid Amberlyst-15(H)® as the additives, and most of the
starting material 1a was recovered (entries 10-11). Further studies showed that the
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
isolated yield of 3a was improved to 68% when the ratio of 1a and 2a was increased to
1:5 with a longer reaction time (10 h) (entry 13). Control experiment demonstrated that
the yield of 3a could be obtained in 73% yield in the absence of NaBr. Therefore, the
following optimization experiments were carried out under the direct electrolytic
conditions. It was observed that when the cathode material was changed from graphite
to platinum, not only did the yield of 3a increase to 81%, but the reaction time also
shortened to 7 hours (entry 15). This result is in accord with the low over-potential of
the Pt cathode for hydrogen evolution. In contrast, when Pt wire, glass carbon (GC) or
RVC were used as the cathode, the desired product 3a was obtained in trace amounts
and the starting material 1a was recovered completely (entries 15 vs 16, 17 and 18). In
addition, it was observed that an almost identical yield of 3a was produced at a current
density of 2 mA/cm2 (entry 19), but with longer reaction time than that proceeding at 4
mA/cm2. However, increasing the current density to 8 mA/cm2 resulted in lower yield
of 3a (entry 20). Further screening of conducting salts indicated that LiClO4 is superior
since 3a was obtained in lower yields when n-Bu4NBF4 or n-Bu4NPF6 were employed
as the electrolytes (entries 21-22). Notably, without electricity, 3a was not produced
(entry 23), thereby revealing that electricity plays an essential role for the cross-
dehydrogenative coupling reaction.
Table 1. Optimization of reaction conditions[a]
Entry 1a:2a
Mediator
(mol %)
NaI (50)
Solvent
Additive
(equiv.)
Electrodes
Yield
(%)[b]
21
1
2
3
4
5
6
7
8
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
DMF
CH3OH
-
-
-
-
-
-
-
-
C(+)/C(-)
C(+)/C(-)
C(+)/C(-)
C(+)/C(-)
C(+)/C(-)
C(+)/C(-)
C(+)/C(-)
C(+)/C(-)
NaI (50)
8
NaI (50)
CH3CN
Trace
Trace
Trace
13
NaI (50)
CH3CN/CH2Cl2=2:1
1,4-Dioxane/H2O=2:1
DMF
NaI (50)
NH4I (50)
NaBr (50)
NH4Br (50)
DMF
26
DMF
20
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
9
1:1.5
1:1.5
1:1.5
1:1.5
1:5
NaBr (50)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
HOAc(2)
TsOH(2)
A-15(H)®
HOAc(2)
HOAc(2)
HOAc(2)
HOAc(2)
HOAc(2)
HOAc(2)
HOAc(2)
HOAc(2)
HOAc(2)
HOAc(2)
HOAc(2)
HOAc(2)
C(+)/C(-)
32
Trace
Trace
52
10
NaBr (50)
C(+)/C(-)
C(+)/C(-)
C(+)/C(-)
C(+)/C(-)
C(+)/C(-)
C(+)/Pt(-)
Pt(+)/C(-)
GC(+)/Pt(-)
RVC(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
C(+)/Pt(-)
-
11
NaBr (50)
12c
13c
14c
15d
16d
17d
18d
19e
20f
21g
22h
23i
NaBr (50)
NaBr (50)
68
1:5
-
-
-
-
-
-
-
-
-
-
73
1:5
81
1:5
Trace
4
1:5
1:5
4
1:5
80
1:5
52
1:5
72
1:5
75
1:5
0
[a]
Reaction conditions: 1a (1 mmol), amine 2a in 8 mL of solvent, undivided cell,
current density of 4 mA/cm2, 0.1 M LiClO4 as conducting salt, rt, 6 h.
[b] Isolated yield.
[c] Reaction time was 10 h.
[d] Reaction time was shortened to 7 h.
[e] J = 2 mA/cm2, 10 h.
[f] J = 8 mA/cm2.
[g] 0.1 M n-Bu4NBF4 as conducting salt.
[h] 0.1 M n-Bu4NPF6 as conducting salt.
[i] No electricity.
With the optimal reaction conditions in hand, we then studied the scope and the
generality of the protocol by examining reactions of quinoxalinone 1a with a variety of
amines 2. As shown in Table 2, the corresponding products 3a-3m were obtained in up
to 99% yield under the electrochemical conditions. For six-membered cyclic amines,
such as morpholine, piperazine, piperidine and tetrahydroisoquinoline, the reactions
underwent smoothly to give the corresponding 3-aminoquinoxalinones 3b-3h in 21-81%
yields. When piperazine was employed as the nitrogen source, an electron-withdrawing
protecting group (3d) is beneficial for the yield compared with the electron-donating
protecting group (3c). When piperidine was used as the substrate, it was found that the
target products 3e-3g were obtained with similar yields regardless of the electron-
withdrawing or the electron-donating nature of substituents. In addition to six-
membered cyclic amines, seven-membered and five-membered cyclic amines were also
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
suitable nitrogen sources for this amination reaction, delivering products 3i and 3j in
41% and 69% yields, respectively. To demonstrate the generality of this methodology,
azoles as nitrogen sources were also tested. The results showed that azoles tolerated
well under the optimized reaction conditions, giving the corresponding products 3k and
3l in 49% and 99% yields, respectively. It is noteworthy that acyclic amine was also
tolerated well to give the corresponding products 3m in 70% yield. Unfortunately, the
protocol was not suitable for primary amines. For example, when cyclohexylamine or
aniline were subjected to reaction with 1a, the desired products, as well as the homo-
coupling product from 1a, were not detected. In addition, when aromatic aniline was
used as a substrate, the reaction mixture became dark quickly, which might result from
its polymerization.
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
Table 2. Substrate scope with the nitrogen source[a,b]
[a] Reaction conditions: 1a (1 mmol), 2 (5 mmol) in 8 mL of 0.1 M LiClO4/DMF, HOAc
(2.0 equiv.), undivided cell, room temperature, current density of 4 mA/cm2, graphite
as an anode and platinum net as a cathode.
[b] Isolated yield.
[c] Isolated yield based on the recovered 1a.
To further explore the potential of our methodology, the reaction of morpholine
2a with a variety of quinoxalinone 1 was investigated, and the results are summarized
in Table 3. It was found that the electronic character of the substituent on the aryl ring
has a great influence on the reaction. For example, when substituents on the aryl ring
were weaker electron-withdrawing groups, such as fluoro and chloro, moderate yields
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
of 3n-3o were obtained. However, when the substituents on the aryl ring were replaced
by electron-donating groups such as methyl and methoxy, the yields of 3p and 3r were
obtained in 31% and 33% yields, respectively. N-Substituted quinoxalinones such as
N-methyl-, N-acetyl-, and N-benzyl-protected derivatives also proceeded smoothly to
give the corresponding products 3s–u in moderate to high yields. Notably, other
heterocycles such as quinoxaline and coumarin did not work, and most of the starting
materials were recovered.
Table 3. Substrate scope with quinoxalinone[a,b]
[a] Reaction conditions: 1 (1 mmol), 2a (5 mmol) in 8 mL of 0.1 M LiClO4/DMF, HOAc
(2.0 equiv.), undivided cell, room temperature, current density of 4 mA/cm2, graphite
as an anode and platinum net as a cathode.
[b] Isolated yield.
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
The practicability of the protocol was demonstrated by a scale-up reaction. As
illustrated in Scheme 2, when 10 mmol of quinoxalinone 1a was allowed to react with
morpholine 2a under the standard condition, the direct amination product 3a was
afforded in 59% yield. Compounds 3 are important intermediates, which could be
further transformed to various quinoxaline derivatives via chlorinated intermediates
(Scheme 2).[17]
C(+)/Pt(-)
AcOH (2 equiv)
H
N
H
N
O
H
O
N
H N
O
+
0.1 M/LiClO4/DMF
J = 4 mA/cm2
N
N
undivided cell, rt
O
1a
2a
(50 mmol)
(10 mmol)
3a (59%)
H
N
H
R2
R1
Cl
N
ref. 17
ref. 17
N
R1
N
Scheme 2. Scaling up and possible transformation
As for the reaction mechanism of the oxidative amination of quinoxaline-2(1H)-
ones, both a nucleophilic addition (ionic mechanism) and a radical pathway are reported
in literatures.[12d,18] Therefore, it is safe to assume that our electrochemical version may
also proceed through ionic or radical pathways. As depicted in Scheme 3, the ionic
mechanism starts from nucleophilic addition of the substrate amine to protonated
quinoxaline-2(1H)-one, 1-H, giving intermediate A, which after anodic oxidation and
deprotonation affords product 3 (Pathway 1). In the radical pathway, the anodic
oxidation of amines forms nitrogen-centered radical B, which is intercepted by 1-H
giving intermediate C. Further anodic oxidation and deprotonation give the desired
products 3 (pathway 2). Simultaneously, proton is reduced at the cathode surface to
generate molecular hydrogen.
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Advanced Synthesis & Catalysis
Anodic reaction
R2
R2
N
R2
N
R2
N
Pathway 1
N
O
O
O
O
-2e, -2H
anode
NHR3R4
R1
R1
H
R1
R1
R3
N
H
NR3R4
N
N
- H
N
N
H
1-H
H
R4
3
1
A
R2
N
O
R1
-e, - 2H
anode
.
R3
N
R4
Pathway 2
N
H
.
H
-e, -H
NHR3R4
NR3R4
C
anode
B
Cathodic reaction
+ 2 e
cathode
H2
2 H
Scheme 3. Two possible pathways for the electrochemical oxidative amination of
quinoxaline-2(1H)-ones
To identify which pathway is predominant, control experiments were performed
and the results were summarized in Scheme 4. When the reaction of 1a and 2a was
repeated under standard conditions, but without electricity, the assumed intermediate A
was not detected and all the starting material 1a and 2a were recovered. Since the
generation of intermediate A is significantly essential for pathway 1, this observation
indicates that the ionic mechanism may not be involved. On the other hand, the
electrochemically oxidative amination of 1a with 2a under the standard conditions was
a little restrained and only 61% yield of 3a was isolated in the presence of 3.0 equiv of
1,1-diphenylethene, a radical trapping reagent. Cyclic voltammetry measurements were
also performed to understand the possible mechanism. As shown in Fig. 1, the oxidation
peak potential of 2a (1.30 V vs Ag/AgNO3 in 0.1 M in CH3CN, curve c) is much lower
than that of 1a (no peak potential in the range of more than 2.0 V vs Ag/AgNO3 in 0.1
M in CH3CN, curve b); therefore, amine 2a is more easily oxidized at the surface of the
anode. Moreover, the oxidation potential of the mixture of 1a with 2a is approximately
0.7 V lower than the oxidation potential of amine 2a, which indicates direct radical
transfer in the process. Based on these results and related literature,[12d,18] we suggest
that the electrochemical oxidative amination might involves a radical process, although
more evidence is required.
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
H
N
H
O
N
N
O
without passing charge
standard conditions
HN
O
+
(1)
N
H
N
O
A
1a (1.0 mmol)
not detected
H
N
H
O
N
3.0 equiv 1,1-diphenylethene
standard conditions
N
O
(2)
HN
O
+
N
N
O
3a (61% yield)
1a (1.0 mmol)
Scheme 4. Control Experiments
Fig. 1 Cyclic voltammograms of related compounds in 0.1 M LiClO4/DMF using glass
carbon as the working electrode, Pt wire, and Ag/AgNO3 (0.1 M in CH3CN) as the
counter and reference electrode, respectively, at a scan rate of 100 mV s−1: (a)
background, (b) 1a (5.0 mmol L−1), (c) 2a (5.0 mmol L−1), (d) 1a + 2a (1:1) (5.0 mmol
L−1).
Conclusion
In summary, we have developed oxidative C-H amination of quinoxalin-2(1H)-
ones under electrochemical conditions. With aliphatic amines and azoles as the nitrogen
sources, a variety of 3-aminoquinoxalinones were obtained in up to 99% yield.
Compared with the previous reports on 3-aminoquinoxalinone synthesis, this
electrochemically dehydrogenative cross-coupling method avoids the use of transition
metals and external oxidants, thus providing an appealing alternative for 3-
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
aminoquinoxalinone synthesis.
Experimental Section
Instruments and reagents
All melting points were measured with an electrothermal melting point apparatus
1
and are uncorrected. NMR spectra were recorded using a 400 MHz (400 MHz H
13
frequency, 100 MHz C frequency). Chemical shifts are given as δ values (internal
standard: TMS). Coupling constants are reported in Hz. The chemical shifts were
referenced to signals at 7.28 ppm. Proton coupling patterns were described as singlet
(s), doublet (d), triplet (t), quartet (q) and multiplet (m). All starting materials and
solvents were obtained from commercial sources and used without further purification.
Products were purified by chromatography on silica gel (petroleum ether/EtOAc). The
starting quinoxalin-2(1H)-ones were prepared according to known procedure.[19]
Typical procedure for the electrochemical synthesis of 3-aminoquinoxalinones
An undivided cell was equipped with a carbon anode (2.0×1.5 cm2) and a platinum
net (2.0×1.5 cm2) and connected to a DC regulated power supply. To the cell was added
the quinoxalinone (1.0 mmol), morpholine (5.0 mmol) and 8.0 mL of 0.1 M
LiClO4/DMF. The mixture was electrolyzed using constant current conditions (4
mA/cm2) at room temperature under magnetic stirring. When TLC analysis indicated
that the electrolysis was complete (witnessed by the disappearance of the
quinoxalinone), the solvent was removed under reduced pressure. The residue was
purified by column chromatography on silica gel to afford the desired pure product.
3-(Morpholin-4-yl)quinoxalin-2(1H)-one (3a)[5] White solid; 187 mg; Yield 81%;
m.p.: 204-205 oC; 1H NMR (400 MHz, CDCl3) δ 3.90 (t, J = 4.4 Hz, 4H), 4.06 (t, J =
4.8 Hz, 4H), 7.16-7.18 (m, 1H), 7.25-7.28 (m, 2H), 7.55-7.57 (m, 1H), 11.47 (s, 1H);
13C NMR (100 MHz, DMSO-d6) δ 47.2, 66.5, 114.8, 123.6, 125.2, 125.6, 129.8, 132.6,
151.5, 152.5.
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
3-(2,6-Dimethylmorpholino)quinoxalin-2(1H)-one (3b)[7] White solid; 135 mg;
Yield 52%; m.p.: 208-209 oC; 1H NMR (400 MHz, CDCl3) δ 1.30 (d, J = 6.4 Hz, 6H),
2.71-2.77 (m, 2H), 3.82-3.86 (m, 2H), 4.90 (d, J = 12.8 Hz, 2H), 7.15-7.17 (m, 1H),
7.24-7.26 (m, 2H), 7.55-7.57 (m, 1H), 11.34-11.40 (m, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 14.5, 47.3, 66.6, 110.1, 118.8, 120.4, 120.9, 125.0, 127.9, 146.5, 147.7.
3-(4-Methylpiperazin-1-yl)quinoxalin-2(1H)-one (3c)[20] White solid; 51 mg; Yield
21%; m.p.: 190-195 oC; 1H NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 2.65 (t, J = 4.8 Hz,
4H), 4.09 (s, 4H), 7.11-7.13 (m, 1H), 7.22-7.25 (m, 2H), 7.53-7.56 (m, 1H), 10.70 (br,
13
1H); C NMR (100 MHz, DMSO-d6): δ 45.7, 46.1, 54.7, 114.8, 123.6, 125.2, 125.6,
129.8, 132.7, 151.5, 152.5.
3-(4-Acetylpiperazin-1-yl)quinoxalin-2(1H)-one (3d)[7] Yellowish solid; 212 mg;
Yield 78%; m.p.: 230-231 oC; 1H NMR (400 MHz, CDCl3) δ 2.19 (s, 3H), 3.66 (t, J =
4.8 Hz, 2H), 3.82 (t, J = 4.8 Hz, 2H), 4.01-4.07 (m, 4H), 7.16-7.19 (m, 1H), 7.26-7.28
13
(m, 2H), 7.55-7.58 (m, 1H), 11.14 (s, 1H); C NMR (100 MHz, DMSO-d6) δ 21.7,
41.2, 45.9, 46.4, 46.8, 114.9, 123.6, 125.3, 125.6, 129.8, 132.6, 151.5, 152.5, 168.9.
3-(4-Metylpiperidin-1-yl)quinoxalin-2(1H)-one (3e)[6] White solid; 185 mg; Yield
76%; m.p.: 168-169 oC; 1H NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.4 Hz, 3H), 1.35-
1.45 (m, 2H), 1.68-1.74 (m, 1H), 1.78-1.82 (m, 2H), 3.00 (t, J = 12.4 Hz, 2H), 4.96 (d,
J = 12.8 Hz, 2H), 7.15-7.25 (m, 3H), 7.53-7.55 (m, 1H), 11.26-11.36 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 22.2, 31.1, 34.4, 47.0, 114.7, 123.5, 124.7, 125.4, 129.7, 133.0,
151.6, 152.6.
3-(4-Benzylpiperidin-1-yl)quinoxalin-2(1H)-one (3f)[7] Yellow solid; 226 mg; Yield
71%; m.p.: 170-171 oC ; 1H NMR (400 MHz, CDCl3) δ 1.42-1.51 (m, 2H), 1.81-1.91
(m, 3H), 2.62 (d, J = 6.8 Hz, 2H), 2.95 (t, J = 12.8 Hz, 2H), 5.00 (d, J = 12.8 Hz, 2H),
7.15-7.16 (m, 1H), 7.20-7.26 (m, 5H), 7.33 (t, J = 7.2 Hz, 2H), 7.53-7.55 (m, 1H), 11.36
(s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 27.5, 33.4, 38.0, 42.1, 110.0, 118.7, 120.0,
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
120.6, 121.5, 123.8, 124.7, 124.9, 128.2, 135.8, 146.9, 147.8.
Ethyl 1-(3-oxo-3,4-dihydroquinoxalin-2-yl)piperidine-4-carboxylate (3g) White
solid; 217 mg; Yield 72%; m.p.: 128-129 oC; 1H NMR (400 MHz, CDCl3) δ 1.27 (t, J
= 7.2 Hz, 3H), 1.71-1.91 (m, 3H), 2.15-2.18 (m, 1H), 2.75-2.80 (m, 1H), 3.17-3.23 (m,
1H), 3.33-3.38 (m, 1H), 4.20 (q, J = 7.2 Hz, 2H), 4.78 (d, J = 13.2 Hz, 1H), 5.00 (d, J
13
= 12.8 Hz, 1H), 7.19-7.26 (m, 3H), 7.54-7.57 (m, 1H), 11.56 (s, 1H); C NMR (100
MHz, DMSO-d6) δ 9.7, 19.5, 22.8, 36.4, 42.2, 43.7, 55.7, 110.0, 118.7, 120.2, 120.7,
125.0, 128.0, 146.9, 147.7, 168.7. HRMS (ESI) m/z calculated for C16H19O3N3 (M+H)+
302.1499, Found 302.1497.
3-(3,4-Dihydroisoquinolin-2(1H)-yl)quinoxalin-2(1H)-one (3h) Yellowish solid;
130 mg; Yield 47%; m.p.: 170-174 oC; 1H NMR (400 MHz, DMSO-d6) 2.94 (m, 2H)
(m, 2H), 4.16 (t, J = 5.6 Hz, 2H), 4.99 (s, 2H), 7.13-7.21 (m, 7H), 7.41-7.43 (m, 1H),
12.12 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 28.9, 44.6, 48.8, 114.8, 123.6, 124.9,
125.5, 126.4, 126.7, 126.9, 129.0, 129.7, 132.9, 134.7, 135.1, 151.4, 152.6. HRMS (ESI)
m/z calculated for C17H15ON3 (M+H)+ 278.1288, Found 278.1286.
3-(Azepan-1-yl)quinoxalin-2(1H)-one (3i) White solid; 100 mg; Yield 41%; m.p.:
183-184 oC; 1H NMR (400 MHz, CDCl3) δ 1.63-1.64 (m, 4H), 1.93 (s, 4H), 4.05 (t, J =
5.6 Hz, 4H), 7.07 (d, J = 7.6 Hz, 1H), 7.12-7.21 (m, 2H), 7.48 (d, J = 7.6 Hz, 1H), 10.95
(br, 1H); 13C NMR (100 MHz, DMSO-d6) δ 26.7, 28.8, 50.5, 114.5, 123.4, 123.7, 124.9,
129.2, 133.5, 150.5, 152.5. HRMS (ESI) m/z calculated for C14H17ON3 (M+H)+
244.1444, Found 244.1444.
3-(Pyrrolidin-1-yl)quinoxalin-2(1H)-one (3j)[7] Yellowish solid; 148 mg; Yield 69%;
m.p.: 204-205 oC; 1H NMR (400 MHz, CDCl3) δ 1.98 (s, 4H), 4.01 (br, 4H), 7.07-7.19
(m, 3H), 7.48 (d, J = 8.0 Hz, 1H), 11.32 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 25.5,
49.5, 114.5, 123.3, 124.0, 124.9, 127.8, 134.6, 149.3, 154.1.
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
3-(4-Methyl-1H-imidazol-1-yl)quinoxalin-2(1H)-one (3k) Yellow solid; 111 mg;
Yield 49%; m.p.: 190-195 oC; 1H NMR (400 MHz, DMSO-d6) δ 2.12 (s, 3H), 7.33-7.37
(m, 2H), 7.51-7.55 (m, 1H), 7.70 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 8.71 (s, 1H), 12.91
(s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 9.0, 115.6, 118.0, 124.3, 128.4, 129.1, 129.9,
131.0, 131.3, 131.9, 144.0, 151.1. HRMS (ESI) m/z calculated for C12H10ON4 (M+H)+
227.0927, Found 227.0929.
3-(1H-benzo[d][1,2,3]triazol-1-yl)quinoxalin-2(1H)-one (3l) Yellowish solid; 260
mg; Yield 99%; m.p.: 250-254 oC;1H NMR (400 MHz, DMSO-d6) δ 7.41-7.48 (m, 2H),
7.54 (t, J = 7.6 Hz, 1H), 7.68 (t, J = 7.6 Hz, 2H), 7.91 (d, J = 8.0 Hz, 1H), 8.05 (d, J =
8.0 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 13.12 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
δ 109.4, 111.3, 115.0, 119.7, 120.7, 124.3, 124.5, 125.9, 127.2, 128.2, 128.5, 140.3,
140.6, 146.6. HRMS (ESI) m/z calculated for C14H9ON5 (M+H)+ 264.0880, Found
264.0887.
3-[Benzyl(methyl)amino]quinoxalin-2(1H)-one (3m)[7] White solid; 186 mg; Yield
70%; m.p.: 170-171 oC; 1H NMR (400 MHz, CDCl3) δ 3.31 (s, 3H), 5.24 (s, 2H), 6.99
(d, J = 8.0 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.28-7.32 (m, 1H),
7.35-7.41 (m, 4H), 7.53 (d, J = 8.0 Hz, 1H), 11.48 (br, 1H); 13C NMR (100 MHz, CDCl3)
δ 38.1, 55.1, 114.6, 124.1, 124.5, 125.5, 127.1, 127.7, 128.3, 128.5, 133.7, 138.8, 150.8,
154.1.
6-Chloro-3-(morpholin-4-yl)quinoxalin-2(1H)-one (3n) Yellowish solid; 183 mg;
o
Yield 69%; m.p.: 268-271 C; 1H NMR (400 MHz, DMSO-d6) δ 3.70 (t, J = 4.8 Hz,
4H), 3.94 (br, 4H), 7.14-7.22 (m, 2H), 7.38 (d, J = 2.0 Hz, 1H), 12.23 (s, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 47.1, 66.5, 116.2, 124.4, 124.6, 127.3, 128.6, 133.8, 151.7,
152.3. HRMS (ESI) m/z calculated for C14H9ON2Cl (M+H)+ 266.0691, Found
266.0699.
6-Fluoro-3-(morpholin-4-yl)quinoxalin-2(1H)-one (3o)[7] White solid; 177 mg;
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
o
1
Yield 71%; m.p.: 237-238 C; H NMR (400 MHz, DMSO-d6) δ 3.70 (t, J = 4.4 Hz,
4H), 3.93 (d, J = 4.4 Hz, 4H), 7.01-7.03 (m, 1H), 7.12-7.17 (m, 2H), 12.17 (s, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 47.1, 66.6, 110.7 (d, JCF = 22.0 Hz), 112.3 (d, JCF = 24.0
Hz), 115.8 (d, JCF = 9.0 Hz), 126.4, 133.6 (d, JCF = 12.0 Hz), 151.8, 152.1, 158.7 (d,
JCF = 237.0 Hz).
6, 7-Dimethyl-3-morpholinoquinoxalin-2(1H)-one (3p)[5] White solid; 80 mg; Yield
31%; m.p.: 214-216 oC; 1H NMR (400 MHz, CDCl3) δ 2.32 (s, 3H), 2.33 (s, 3H), 3.88-
13
3.90 (m, 4H), 3.97-3.99 (m, 4H), 6.91 (s, 1H), 7.35 (s, 1H), 10.83 (s, 1H); C NMR
(100 MHz, DMSO-d6) δ 19.4, 19.8, 47.3, 66.5, 115.1, 126.1, 127.8, 130.7, 131.8, 134.1,
151.3, 152.5.
Methyl 2-morpholino-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (3q) and
methyl
2-morpholino-3-oxo-3,4-dihydroquinoxaline-7-carboxylate
(3q’)
Yellowish solid; 107 mg; Yield 37%; m.p.: 226-230 oC; 1H NMR for (3q) (400 MHz,
DMSO-d6) δ 3.71 (t, J = 4.8 Hz, 4H), 3.84 (s, 3H), 3.91-3.92 (m, 4H), 7.22 (d, J = 8.4
Hz, 1H), 7.73-7.77 (m, 1H), 7.91 (d, J = 1.2 Hz, 1H), 12.41 (s, 1H); 1H NMR for (3q’)
(400 MHz, DMSO-d6) δ 3.71 (t, J = 4.8 Hz, 4H), 3.84 (s, 3H), 4.01 (br, 4H), 7.41 (d, J
13
= 8.4 Hz, 1H), 7.67-7.70 (m, 1H), 7.73-7.77 (m, 1H), 12.27 (s, 1H); C NMR of 3q
and 3q’ (100 MHz, DMSO-d6) δ 47.1, 52.4, 66.5, 66.6, 114.9, 115.9, 124.2, 124.7,
125.1, 125.2, 125.6, 126.6, 129.3, 132.2, 133.5, 136.5, 151.6, 152.0, 152.4, 152.6, 166.3,
166.4. HRMS (ESI) m/z calculated for C14H15N3O4 (M+H)+ 290.1135, Found 290.1142.
6-Methoxy-3-morpholinoquinoxalin-2(1H)-one (3r) White solid; 86 mg; Yield 33%;
m.p.: 248-249 oC ;1H NMR for the mixture (400 MHz, DMSO-d6) δ 3.69-3.72 (m, 4H),
3.76 (s, 3H), 3.88-3.89 (m, 4H), 6.83 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 6.92 (d, J = 2.4 Hz,
1H), 7.09 (d, J = 8.8 Hz, 1H), 12.04 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 47.2,
55.8, 66.6, 108.2, 113.8, 115.6, 123.8, 133.4, 151.8, 152.0, 156.1. HRMS (ESI) m/z
calculated for C13H15N3O3 (M+H)+ 262.1186, Found 262.1189.
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
1-Methyl-3-morpholinoquinoxalin-2(1H)-one (3s)[7] White solid; 174 mg; Yield
71%; m.p.: 101-102 oC ; 1H NMR (400 MHz, CDCl3) δ 3.67 (s, 3H), 3.83-3.85 (m, 4H),
3.94-3.97 (m, 4H), 7.19 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.22-7.31 (m, 2H), 7.54 (dd,
13
J = 7.6 Hz, J = 1.6 Hz, 1H). C NMR (100 MHz, CDCl3) δ 29.3, 47.5, 67.0, 113.3,
123.8, 125.3, 126.8, 130.8, 133.0, 150.6, 152.1.
Ethyl 2-(3-morpholino-2-oxoquinoxalin-1(2H)-yl)acetate (3t)[5] White solid; 241
mg; Yield 76%; m.p.: 133-136 oC ; 1H NMR (400 MHz, CDCl3) δ 1.27 (t, J = 7.2 Hz,
3H), 3.83-3.85 (m, 4H), 3.96-3.98 (m, 4H), 4.25 (q, J = 7.2 Hz, 2H), 4.98 (s, 2H), 6.94-
13
6.99 (m, 1H), 7.22-7.26 (m, 2H), 7.54-7.58 (m, 1H). C NMR (100 MHz, CDCl3) δ
14.1, 43.8, 47.5, 61.9, 66.9, 112.7, 124.1, 125.4, 127.1, 130.0, 133.1, 150.2, 152.0,
167.3.
1-(3,5-Dimethylbenzyl)-3-morpholinoquinoxalin-2(1H)-one (3u) White solid; 279
mg; Yield 80%; m.p.: 135-139 oC ; 1H NMR (400 MHz, CDCl3) δ 2.25 (s, 6H), 3.85-
3.88 (m, 4H), 3.98-4.01 (m, 4H), 5.39 (s, 2H), 6.81 (s, 2H), 6.87 (s, 1H), 7.13-7.23 (m,
13
3H), 7.55-7.57 (m, 1H). C NMR (100 MHz, CDCl3) δ 21.4, 46.2, 47.7, 67.0, 114.3,
123.9, 124.4, 125.5, 126.9, 129.3, 130.4, 133.2, 135.4, 138.5, 150.8, 152.3. HRMS (ESI)
m/z calculated for C21H23N3O2 (M+H)+ 350.1863, Found 350.1855.
Acknowledgements
This work was supported by grants from the National Key Technology R&D Program
(2017YFB0307502) and the National Natural Science Foundation of China (No.
21472011). ZCC also thank financial support from the Open Project Program of Beijing
Key Laboratory of Flavor Chemistry, Beijing Technology and Business University
(BTBU)
The authors declare no competing financial interest.
Supporting Information Available: Copies of 1H NMR, 13C NMR spectral and HRMS.
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10.1002/adsc.201800989
Advanced Synthesis & Catalysis
References:
[1] a) S. A. Galal, S. H. M. Khairat, F. A. F. Ragab, A. S. Abdelsamie, M. M. Ali, S.
M. Soliman, J. Mortier, G. Wolber, H. I. E. Diwani, Eur. J. Med. Chem. 2014, 86, 122-
132; b) J. A. Willardsen, D. A. Dudley, W. L. Cody, L. Chi, T. B. McClanahan, T. E.
Mertz, R. E. Potoczak, L. S. Narasimhan, D. R. Holland, S. T. Rapundalo, J. J. Edmunds,
J. Med. Chem. 2004, 47, 4089-4099; c) M. Weïwer, J. Spoonamore., J. Q. Wei, B.
Guichard, N. T. Ross, K. Masson, W. Silkworth, S. Dandapani, M. Palmer, C. A.
Scherer, A. M. Stern, S. L. Schreiber, B. Munoz, ACS Med. Chem. Lett. 2012, 3, 1034-
1038; d) M. Imanishi, M. Sonoda, H. Miyazato, K. Sugimoto, M. Akagawa, S.
Tanimori, ACS. Omega. 2017, 2, 1875-1885.
[2] a) G. Moarbess, C. Deleuze-Masquefa, V. Bonnard, S. Gayraud-Paniagua, J. R.
Vidal, F. Bressolle, F. Pinguet, P. A. Bonnet, Bioorg. Med. Chem. Lett. 2008, 16, 6601-
6610; b) S. Hussain, S. Parveen, X. Hao, S. Z. Zhang, W. Wang, X. Y. Qin, Y. C. Yang,
X. Chen, S. J. Zhu, C. J. Zhu, B. Ma, Eur. J. Med. Chem. 2014, 80, 383-392; c) A. A.
Abu-Hashem, M. A. Gouda, F. A. Badria, Eur. J. Med. Chem. 2010, 45, 1976-1981; d)
R. V. Ghadage, P. J. Shirote, J. Chem. Pharm. Res. 2011, 3, 260-266.
[3] J. Dudash, Y. Z. Zhang, J. B. Moore, R. Look, Y. Liang, M. P. Beavers, M. P. Beavers,
B. R. Conway, P. J. Rybczynski, K. T. Demarest, Bioorg. Med. Chem. Lett. 2005, 15,
4790-4793.
[4] A. V. Gulevskaya, O. N. Burov, A. F. Pozharskii, M. E. Kletskii, I. N. Korbukova,
Tetrahedron. 2008, 64, 696-707.
[5] Y. Li, M. Gao, L. H. Wang, X. L. Cui, Org. Biomol. Chem. 2016, 14, 8428-8432.
[6] T. T. Hoang, T. A. To, V. T. T. Cao, A. T. Nguyen, T. T. Nguyen, N. T. S. Phan,
Catal. Commun. 2017, 101, 20-25.
[7] A. Gupta, M. S. Deshmukh, N. Jain, J. Org. Chem. 2017, 82, 4784-4792.
[8] For recent reviews, see: a) Y. Y. Jiang, K. Xu, C. C. Zeng, Chem. Rev. 2018, 118,
4485-4540; b) D. Pletcher, R. A. Green, R. C. D. Brown, Chem. Rev. 2018,118, 4573-
4591; c) J. I. Yoshida, A. Shimizu, R. Hayashi, Chem. Rev. 2018, 118, 4702-4730; d)
S. Tang, Y. C. Liu, A. W. Lei, Chem. 2018, 4, 27-45; e) C. Ma, P. Fang, T. S. Mei, ACS
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800989
Advanced Synthesis & Catalysis
Catal. 2018, 8, 7179-7189; f) M. Yan, Y. Kawamata, P. S. Baran, Chem. Rev. 2017, 117,
13230-13319; g) R. Francke, R. D. Little, Chem. Soc. Rev. 2014, 43, 2492-2521.
[9] For recent representative examples of electrochemical C-H functionalization, see:
a) Z. J. Wu, S. R. Li, H. Long, H. Z. Xu, Chem. Commun. 2018, 54, 4601-4604; b) M.
Y. Lin, K. Xu, Y. Y. Jiang, Y. G. Liu, B. G. Sun, C. C. Zeng, Adv. Synth. Catal. 2018,
360, 1665-1672; c) A. Shrestha, M. Lee, A. L. Dunn, M, S. Sanford, Org. Lett. 2018,
20, 204-207.
[10] a) H. B. Zhao, Z. J. Liu, J. S. Song, H. C. Xu, Angew. Chem. Int. Ed. 2017, 56,
12732-12735; b) F. Xu, Y. J. Li, C. Huang, H. C. Xu, ACS. Catal. 2018, 8, 3820-3824;
c) Z. W. Hou, Z. Y. Mao, Y. Y. Melcamu, X. Lu, Angew. Chem. Int. Ed. 2018, 57,
1636-1639.
[11] P. Qian, J. H. Su, Y. K. Wang, M. X. Bi, Z. G. Zha, Z. Y. Wang, J. Org. Chem.
2017, 82, 6434-6440.
[12] a) R. H. Mei, N. Sauermann, J. C. A. Oliveira, L. Ackermann, J. Am. Chem. Soc.
2018, 140, 7913-7921. b) N. Sauermann, T. H. Meyer, Y. A. Qiu, L. Ackermann, ACS
Catal. 2018, 8, 7086-7103. c) N. Sauermann, T. H. Meyer, L. Ackermann, Chem. Eur.
J. 2018, 24, 1-10. d) Y. A. Qiu, J. Struwe, T. H. Meyer, J. C. A. Oliveira, L. Ackermann,
Chem. Eur. J. 2018, 24, 12784-12789. e) N. Sauermann, R. H. Mei, L. Ackermann,
Angew. Chem. Int. Ed. 2018, 57, 5090-5094.
[13] a) L. Zeng, H. R. Li, S. Tang, X. L. Gao, Y. Deng, G. T. Zhang, C. W. Pao, J. L.
Chen, J. F. Lee, A. W. Lei, ACS Catal. 2018, 8, 5448-5453; b) X. L. Gao, P. Wang, L.
Zeng, S. Tang, A. W. Lei, J. Am. Chem. Soc. 2018, 140, 4195-4199; c) S. Tang, S. Y.
Wang, Y. C. Liu, H. J. Cong, A. W. Lei, Angew. Chem. Int. Ed. 2018, 57, 4737-4741.
d) J. W. Wu, Y. Zhou, Y. C. Zhou, C. W. Chiang, A. W. Lei, ACS Catal. 2017, 7, 8320-
8323.
[14] a) S. Liang, C. C. Zeng, H. Y. Tian, B. G. Sun, X. G. Luo, F. Z. Ren, J. Org. Chem.
2016, 81, 11565-11573; b) W. J. Gao, W. C. Li, C. C. Zeng, H. Y. Tian, L. M. Hu, R.
D. Little, J. Org. Chem. 2014, 79, 9613-9618.
[15] M. D. Kärkäs, Chem. Soc. Rev. DOI: 10.1039/c7cs00619e.
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800989
Advanced Synthesis & Catalysis
[16] a) Q. Q. Wang, K. Xu, Y. Y. Jiang, Y. G. Liu, B. G. Sun, C. C. Zeng, Org. Lett.
2017, 19, 5517-5520; b) M. H. Luo, Y. Y. Jiang, K. Xu, Y. G. Liu, B. G. Sun, C. C.
Zeng, Beilstein J. Org. Chem. 2018, 14, 499-505; c) S. Liang, C. C. Zeng, H. Y. Tian,
B. G. Sun, X. G. Luo, F. Z. Ren, Adv. Synth. Catal. 2017, 359, 1-10.
[17] S. Liu, Y. Huang, F. L. Qing, X. H. Xu, Org. Lett. 2018, 20, 5497-5501.
[18] J. W. Yuan, S. N. Liu, L. B. Qu, Adv. Synth. Catal. 2017, 359, 4197-4207.
[19] L. Sumunnee, C. Pimpasri, M. Noikham, S. Yotphan, Org. Biomol. Chem. 2018,
16, 2697-2704.
[20] R. A. Smits, H. D. Lim, A. Hanzer, O. P. Zuiderveld, E. Guaita, M. Adami, G.
Coruzzi, R. Leurs, I. J. P. D. Esch, J. Med. Chem. 2008, 51, 2457-2467.
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