Direct Introduction of Sulfonamide Groups into Quinoxalin-2(1H)-ones by Cu-Catalyzed C3-H Functionalization

Article abstract of DOI:10.1002/asia.202000916

Direct sulfonamidation of quinoxalin-2(1H)-one derivatives has been developed using a readily available Cu salt as the catalyst and inexpensive ammonium persulfate as the oxidant in moderate conditions. Owing to the feature of handy operation and good functional group tolerance, this method provides a convenient and efficient access to curative 3-sulfonamidated quinoxalin-2(1H)-one scaffolds.

Full text of DOI:10.1002/asia.202000916

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: The Direct Introduction of Sulfonamide Groups into
Quinoxalin-2(1H)-ones via Cu-Catalyzed C3-H Functionalization
Authors: Yushi Tan, Boyan Liu, Ya-Ping Han, Yuecheng Zhang, Hong-
Yu Zhang, and Jiquan Zhao
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Chemistry - An Asian Journal
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The Direct Introduction of Sulfonamide Groups into Quinoxalin-
(1H)-ones via Cu-Catalyzed C3-H Functionalization
2
[a]
[a]
[a]
[a]
[a]
[a]
Yushi Tan, Boyan Liu, Ya-Ping Han, Yuecheng Zhang, Hong-Yu Zhang* and Jiquan Zhao*
[
a]
Y. S. Tan, B. Y. Liu, Dr. Y.-P. Han, H.-Y. Zhang, Prof. Dr. Y. C. Zhang, J. Q. Zhao
School of Chemical Engineering and Technology, Hebei Provincial Key Lab of Green Chemical Technology & High Efficient Energy Saving, Tianjin Key
Laboratory of Chemical Process Safety
Hebei University of Technology
Tianjin 300130 (P. R. China)
E-mail: zhanghy@hebut.edu.cn; zhaojq@hebut.edu.cn
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: The direct sulfonamidation of quinoxalin-2(1H)-one
derivatives has been developed using a readily available Cu salt as
the catalyst and inexpensive ammonium persulfate as the oxidant in
moderate conditions. Owing to the feature of handy operation and
good functional group tolerance, this method provides a convenient
and efficient access to curative 3-sulfonamidated quinoxalin-2(1H)-
one scaffolds.
transformation
electrochemical method (Scheme 1a).
Yuan, Zhang and He groups respectively reported the C3-
amidation of quinoxalin-2(1H)-ones with a broad substrate scope
under moderate conditions (Scheme 1b).
engaged in the direct C3-H amination of quinoxalin-2(1H)-ones
utilizing TMSN as an amino source to synthesize primary 3-
adopting
a
visible-light-catalyzed
or
[
16e-f]
At the same time,
[
17]
Our group also
3
aminoquinoxalin-2(1H)-ones, which are important intermediates
for the synthesis of biologically active 3-N-substituted
[
18]
quinoxalinone derivatives (Scheme 1c).
All above brilliant
Introduction
achievements showed the superiority in high atom and step
economy, and featured excellent functional group tolerance with
good yields under readily accessible conditions. However, we
could not ignore that the introduction of sulfonamide groups into
the C3 position of quinoxalin-2(1H)-ones via direct C3-H
functionalization is still rare and challenging, taking into
consideration the importance of sulfonamide moiety in medicinal
chemistry. Therefore, we demonstrated the first example for C3-
H sulfonamidation of quinoxalin-2(1H)-ones with sulfonamide
under a facile and mild conditions (Scheme 1d).
Figure 1. Pharmacoactive quinoxaline or quinoxalin-2(1H)-one sulfonamides
Sulfonamides, especially quinoxaline or quinoxalin-2(1H)-one
sulfonamides, are privileged structural motif found in market
[
1]
drugs or pharmacologically active natural products (Figure 1).
As shown in Figure 1, Chloroquinoxaline Sulfonamide (CQS)
[2]
has been used in clinical trials for the treatment of solid tumors.
XL147, a potent phosphoinositide 3-kinase (PI3K) inhibitor, has
entered clinical trials as a promising anticancer drug candidate
[
3]
for targeted therapy. A series of 3-aminoquinoxalin-2(1H)-one
sulfonamides (compounds 1) as excitatory amino acid receptor
antagonists are useful for the treatment of anxiety, depression,
[
4]
epilepsy, Alzheimer’s disease or like. So, the efficient synthetic
means for introduction of sulfonamide groups into
(
hetero)aromatic rings have received widespread attention and
significant achievements in this field have been accomplished in
[
5-6]
the last several years.
On the other hand, the direct C3-H bond functionalizations of the
quinoxalin-2(1H)-ones have emerged as powerful tools to
[
7-14]
synthesize complex quinoxalin-2(1H)-one derivatives,
especially the 3-aminoquinoxalin-2(1H)-one derivatives. The
pioneering studies focused on oxidative cross-dehydrogenation
coupling of quinoxalin-2(1H)-ones with primary or secondary
amines as the nitrogen sources, and Gulevskaya, Cui, Jain or
Phan group independently reported the manganese, copper,
iodine or copper-organic framework catalytic systems for this
Scheme 1. Construction of C-N with quinoxalin-2(1H)-ones
[
15, 16a-d]
transformation (Scheme 1a).
Later, in view of green
chemistry, Wei and Zeng groups respectively improved this
1
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Chemistry - An Asian Journal
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Results and Discussion
conditions involved the use of 1a (0.3 mmol), 2.0 equivalents of
sulfonamide 2a, 10 mol % of Cu(PF
equivalents of (NH , and stirring in CH
0 °C under an argon atmosphere.
6
)·4CH
3
CN catalyst, 2.0
4
)
2
S
2
O
8
3
CN (3.0 mL) at
[
a]
Table 1. Selected reaction conditions optimization
5
Yield
Entry
catalyst
oxidant
(NH
T (°C)
[b]
(%)
1
2
3
-
-
-
4 2
) S
2
O
8
60
60
60
60
60
60
60
60
60
50
40
50
50
50
50
50
50
50
50
50
8
K
2
S
O
2 8
trace
trace
49
48
45
54
50
63
70
60
78
53
61
trace
22
trace
trace
trace
trace
Na
2
S
O
2 8
[
[
[
[
[
[
c]
c]
c]
c]
c]
c]
4
5
6
7
8
9
Cu(ClO
Cu(OTf)
Cu(BF )·4CH
4
2
) ·6H
2
O
(NH
(NH
(NH
(NH
(NH
(NH
(NH
(NH
(NH
(NH
4
)
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
2
2
2
2
2
2
2
2
2
O
8
8
8
8
8
8
8
8
8
8
2
4
)
4
)
4
)
4
)
4
)
4
)
4
)
4
)
4
)
O
O
O
O
O
O
O
O
O
4
3
CN
CuCl
CuI
Cu(PF
Cu(PF
Cu(PF
6
)·4CH
6
)·4CH
6
)·4CH
3
3
3
CN
CN
CN
[
[
c]
1
1
0
1
c]
1
2
Cu(PF
6
)·4CH
)·4CH
)·4CH
)·4CH
)·4CH
)·4CH
)·4CH
)·4CH
)·4CH
3
CN
[
d]
13
Cu(PF
Cu(PF
Cu(PF
Cu(PF
Cu(PF
Cu(PF
Cu(PF
Cu(PF
6
3
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
CN
1
1
1
4
5
6
6
6
6
6
6
6
6
Na
2
S
O
2 8
Scheme 2. Substrate scope of various quinoxalin-2(1H)-ones. General
conditions: (0.3 mmol), (0.6 mmol), Cu(PF )·4CH CN (10 mol %),
(NH (2.0 equiv.) and CH CN (3 mL), stirring under an argon
PhI(OAc)
2
[
e]
1
2
6
3
PIFA
[
f]
4
)
2
S
2
O
8
3
17
(NH
(NH
(NH
(NH
4 2
) S
4 2
) S
4 2
) S
4 2
) S
2
O
2
O
2
O
2
O
8
8
8
8
[
a]
[
g]
atmosphere about 12 hours; Yield of isolated product.
divided into seven parts and evenly added in 28 hours.
divided into three parts and evenly added in 12 hours.
(NH
4
)
2
S
2
O
8
was
(NH ) S O was
1
1
8
9
[
b]
[
h]
i]
4
2
2
8
[
20
With the optimal reaction conditions established, we investigated
the substrate scope of this transformation. Firstly, various
quinoxalin-2(1H)-one substrates were investigated, and the
results are summarized in Scheme 2. Several quinoxalin-2(1H)-
ones with N-substituted groups such as methyl, ethyl and methyl
acetate, could proceed smoothly and afford the corresponding
products in moderate to good yields (3a-3c). However,
quinoxalin-2(1H)-one without protecting group provided the
target molecule in a low yield of 37% (3d). The N-SEM protected
quinoxalin-2(1H)-one gave the expected product in 44% yield
[
a]
Unless specifically noted otherwise, reaction conditions are: 1a (0.3 mmol),
a (0.6 mmol), catalyst (10 mol %), oxidant (2.0 equiv.) and CH CN (3 mL),
Yield of isolated
2
3
[
b]
stirring under an argon atmosphere about 12 hours.
product.
catalyst.
equivalents Cs
present of 15 mol % 1,10-phen·H
bipyridine.
[
c]
[d]
In the present of 20 mol % catalyst.
In the present of 5 mol %
[f]
[
e]
[Bis(trifluoroacetoxy)iodo]benzene.
In the present of 2.0
[
g]
[h]
2 3
CO .
In the present of 2.0 equivalents KOAc.
In the
[
i]
2
O.
In the present of 15 mol % 2,2'-
Preliminary investigation was focused on the optimization of
reaction with 1-methylquinoxalin-2(1H)-one (1a) and N, 4-
dimethylbenzenesulfonamide (2a) as model substrates. Our
initial experiments were performed to screen various oxidants
under transition-metal-free condition. The expected product was
(
3e). The substrates bearing weak electron-donating, weak and
strong electron withdrawing groups such as methyl, halogen
fluoro, chloro and bromo) or nitro, cyano groups, matched the
(
obtained in 8%, when (NH
Table 1, entry 1). But the expected product was not obtained in
the case of K or Na (Table 1, entries 2-3). Next, we
continued to screen various copper salts as catalysts in the
presence of (NH as oxidant. Fortunately, the expected
product (3a) was obtained in 63% yield, When the
Cu(PF )·4CH CN was employed as catalyst (Table 1, entry 9).
2
And the other copper salts including Cu(ClO ·6H O, Cu(OTf) ,
4 2 2 8
) S O was used as the oxidant
reaction very well and offered the corresponding products in
moderate to good yields (3f-3o). Besides, the optimized
conditions were also applicable to 1-methylbenzo[g]quinoxalin-
(
2
S
2
O
8
2 2 8
S O
2(1H)-one and the corresponding product was obtained in 78%
4 2 2 8
) S O
yield. Motivated by these acceptable results of quinoxalin-2(1H)-
one derivatives, we further tested 2H-benzo[b][1,4]oxazin-2-one
and found that the target product was successfully isolated in a
moderate yield of 61% (3q).
6
3
4
)
2
2
Cu(BF
Cu(PF
4
)·4CH
)·4CH
3
CN, CuCl and CuI were less effective than
CN (Table 1, entries 4-9). Subsequently, the
Next, we continued to explore the substrate scope of N-
6
3
methyl sulfonamides (Scheme 3).
methylbenzenesulfonamides containing
A
series of N-
electron-donating
reaction was carried at different temperatures, and a yield of
0% of 3a was obtained at 50 °C (Table 1, entries 10-11). Next,
the loading of catalyst was evaluated and the result revealed
that 10% of Cu(PF )·4CH CN was suitable for the reaction with
the yield of 3a increasing to 78% (Table 1, entries 12-13).
Subsequently, diverse oxidants including Na , PhI(OAc)
and PIFA ([Bis(trifluoroacetoxy)iodo]benzene) were also tested
again and the results showed that (NH still was the most
appropriate oxidant among the aforementioned oxidants (Table
, entries 14-16). Finally, several bases (Cs CO , KOAc, etc.) or
N, N-bidentate ligands (1,10-phen·H O, 2,2'-Bipyridine, etc.)
7
groups (ethyl and methoxyl) reacted with 1-methylquinoxalin-
(1H)-one (1a) smoothly and gave the desired products in good
2
6
3
yields (3r-3t). And the substrates with the halogens (fluoro,
chloro and bromo) also afforded the target products in moderate
yields (3u-3w, 3y-3z). N-methylbenzenesulfonamide bearing
2
S
2
O
8
2
both
corresponding product in
Surprisingly, N-methylmethanesulfonamide
a
fluorine and
a
methyl group also offered the
moderate yield of 58% (3x).
matched the
4 2 2 8
) S O
a
1
2
3
transformation well and the expected product was received in
outstanding yield of 80% (3aa). Encouraged by the result of this
2
were further examined under the selected reaction conditions
exhibited in the entry 12, but did not lead to any improvement
(
simple
N-methylmethanesulfonamide,
we
test
L-N-
methylcamphorsulfonamide as a representative of complicated
Table 1, entries 17-20). In conclusion, optimized reaction
2
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Chemistry - An Asian Journal
10.1002/asia.202000916
FULL PAPER
substrate and obtained the corresponding product in 48% yield
regenerating the copper(I) catalyst A to complete the catalytic
(
3ab).
cycle.
Scheme 3. Substrate scope of various sulfonamides. General conditions: 1
.
(0.3 mmol), 2 (0.6 mmol), Cu(PF
6 3 4 2 2 8
) 4CH CN (10 mol %), (NH ) S O (2.0
equiv.) and CH CN (3 mL), stirring under an argon atmosphere about 12h;
3
[
a]
Yield of isolated product. (NH
added in 12 hours.
4 2 2 8
) S O was divided into three parts and evenly
Scheme 5. Plausible mechanism
After the investigation of substrate scope, two radical trapping
experiments were performed to gain the preliminary mechanism
insights of this sulfonamidation (Scheme 4). First, the reaction
did not occur when 2.0 equivalents of BHT (2,6-di-tert-butyl-p-
cresol) was added under standard reaction system as a radical
inhibitor. But a BHT-trapped adduct 4a was detected by LC-MS
To demonstrate the scalability of this protocol, a large-scale
reaction was performed and desired sulfonamidation product 3a
was obtained in 75% yield.
(
Scheme 4, Equation 1). Second, the reaction was partially
suppressed in the presence of 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) as the radical scavenger. Only 9% yield
of the target product was obtained and 79% of the starting
material 1a was recovered. Besides, TEMPO-trapped adduct 5a
was also observed (Scheme 2, Equation 2). These experiment
results implied that a single-electron-transfer (SET) might be
involved in this sulfonamidation.
Scheme 6. Large-scale experiment
Conclusion
In conclusion, the direct C-H sulfonamidation of quinoxalin-
2(1H)-ones
with
sulfonamides
via
C-H/N-H
cross-
dehydrogenation coupling has been developed. This method
provides a practical and convenient approach for introduction of
sulfonamide groups into the C3 position of quinoxalin-2(1H)-
ones, with readily available Cu salt as the catalyst and
inexpensive ammonium persulfate as the oxidant. In addition,
the transformation is operated in mild conditions with a wide
range of substrates, affording
interesting 3-sulfonamidated quinoxalin-2(1H)-one derivatives in
a number of medicinally
Scheme 4. Radical trapping experiments
moderate to excellent yields.
Based on the aforementioned results of radical trapping
[19]
experiments and previous literatures,
a plausible mechanism
Experimental Section
was proposed in scheme 5. Initially, the Cu(I) catalyst A reacts
2
-
with peroxydisulfate B to produce active Cu(II) species C, SO
4
•-
[19a-19b]
and SO
4
radical anion (D),
and D abstracts a hydrogen
General procedure for the sulfonamidation of quinoxalin-
2(1H)-ones
-
atom from sulfonamide 2a to generate HSO
4
and the
corresponding sulfonamide radical F. Subsequently, the
coordination of C with the nitrogen atom of the C=N bond in the
quinoxalin-2(1H)-one substrate leads to the polarization of the
An oven-dried Schlenk tube was charged with quinoxalin-2(1H)-
one
derivative
(1a)
(0.3
mmol),
N,
4-
[
19c-19d, 19g-19h]
C=N double bond and gives the active species E,
which undergoes an addition with the sulfonamide radical F to
dimethylbenzenesulfonamide (2a) (2.0 equiv., 0.6 mmol),
.
Cu(PF ) 4CH CN (0.1 equiv., 0.03 mmol) , (NH ) S O (2.0
6
3
4 2
2
8
[
19a-19b, 19g]
provide the key intermediate G.
Finally, the
equiv., 0.6 mmol) and a magnetic stirring bar, and then was
intermediate G goes through a single-electron transfer and
deprotonation in succession to afford the target product 3a, with
purged with argon for three times. Subsequently, anhydrous
CH CN (3mL) was added via syringe, and the mixture was
3
3
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Chemistry - An Asian Journal
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FULL PAPER
stirred at 50 °C in oil bath. The mixture was continued reaction
until the substrate was consumed (monitored by TLC, about 12
hour). After that, the reaction mixture was cooled to room
temperature, and the solvent was removed under reduced
pressure. The resulting residue was purified by flash column
chromatography on silica gel to afford the corresponding
sulfonamidation product (3a).
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[
7]
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Zhang, J. Zhao, Front. Chem. 2020, 8, 582.
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We acknowledge the financial support from the National Natural
Science Foundation of China (Grant No. 21776056), the Natural
Science Foundation of Hebei Province (CN) (Grant No.
B2018202253).
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Keywords: Radical reactions
•
Cross-coupling
•
C-H
functionalization • Quinoxalin-2(1H)-ones • Sulfonamide
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Entry for the Table of Contents
The first example of Cu-catalyzed C3-H sulfonamidation of quinoxalin-2(1H)-ones via C-H/N-H cross-dehydrogenation coupling. This
reaction tolerates various quinoxalin-2(1H)-ones and sulfonamides to afford 3-sulfonamidated quinoxalin-2(1H)-one derivatives.
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