Visible-light-induced C[sbnd]H arylation of quinoxalin-2(1H)-ones in H2O

Article abstract of DOI:10.1016/j.tetlet.2021.152841

An efficient visible-light-induced C[sbnd]H arylation of quinoxalin-2(1H)-ones in H₂O is developed, which has the advantages of mild reaction conditions, environmental friendliness and good functional group tolerance. This strategy provides a s

Full text of DOI:10.1016/j.tetlet.2021.152841

Tetrahedron Letters 66 (2021) 152841
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Visible-light-induced CAH arylation of quinoxalin-2(1H)-ones in H2O
Hanyang Bao a,1, Ziyun Lin a,1, Mengshi Jin a, Hongdou Zhang a, Jun Xu a, Bajin Chen b,
,
⇑
Wanmei Li a,
⇑
a College of Material Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 311121, China
b Transfar Zhilian Co., Ltd., Hangzhou, 311215, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient visible-light-induced CAH arylation of quinoxalin-2(1H)-ones in H2O is developed, which has
the advantages of mild reaction conditions, environmental friendliness and good functional group toler-
ance. This strategy provides a simple operation method to access various 3-aryl quinoxalin-2(1H)-ones in
moderate to good yields.
Received 2 December 2020
Revised 5 January 2021
Accepted 8 January 2021
Available online 2 February 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Photocatalysis
Deboronation
Arylation
Quinoxalin-2(1H)-ones
Radical process
Introduction
Nitrogen-containing heterocycles are significant structures fea-
tured in diverse pharmaceutical drug and biological compounds
[1]. Especially, C3-substituted quinoxalin-2-ones are important
pharmaceutical intermediates because of its biological activity
[2]. For instance, STK33 inhibitor [3], polymers [4], CFTR activators
and ALE2 inhibitors [1] have a 3-arylquinoxalin-2(1H)-one unit in
their molecular structures (Figure 1). Therefore, there is a great sig-
nificance of functionalization of quinoxalin-2(1H)-ones at C3
position.
Although in recent years, a number of methods for the forma-
tions of CAC [5], CAN [6], CAO [7], CAP [8] bonds from CAH func-
tionalization of quinoxalin-2(1H)-ones have been reported, there is
still a substantial interest in the formation of C(sp2)-C(sp2) bond in
order to introduce functional aryl groups into quinoxalin-2(1H)-
ones. In 2013, Alami and co-workers reported a palladium-cat-
alyzed oxidation with arylboronic acids, which provided a new
strategy for arylation of quinoxalin-2(1H)-ones (Scheme 1a) [9].
Zhang and coworkers reported a CAH arylation of quinoxalin-2
(1H)-ones using iodine(III) compounds as arylation reagent
(Scheme 1b) [10]. Qu’s group and Lee’s group reported an efficient
method to realize CAH arylation of quinoxalin-2(1H)-ones through
deamination of arylamine or arylhydrazines respectively
Fig. 1. Selecting structures of bearing 3-aryl-quinoxalin2(1H)-one.
(Scheme 1c, d) [11]. Reddy et al. performed the CAH arylation of
quinoxalin-2-one with Mn(OAc)3 and arylboronic acid at 120 °C
(Scheme 1e) [12]. Despite their utilities, the reported approaches
usually require transition metal, toxic organic solvent or high reac-
tion temperatures, failing to meet the demand of green chemistry
[13].
⇑
Corresponding authors.
E-mail addresses: 4437@etransfar.com (B. Chen), liwanmei@hznu.edu.cn (W. Li).
Photocatalysis has been considering as an ideal green chemistry
because of its advantages of environmental friendliness, mild
1
These authors contributed equally.
https://doi.org/10.1016/j.tetlet.2021.152841
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

H. Bao, Z. Lin, M. Jin et al.
Tetrahedron Letters 66 (2021) 152841
Scheme 1. Synthesis of 3-arylquinoxalin-2(1H)-ones.
Table 1
Screening of reaction conditions.a,b
Entry
Photocatalyst
Oxidant
Solvent
Yield(%)b
1
2
3
4
5
6
7
8
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Ru(bpy)3Cl3
Rhodamine B
Acid Red 94
–
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
oxone
DCE
27
24
NR
28
26
51
48
65
55
37
42
0
5
20
NR
45
5
22
DMSO
DMF
CH3CN
THF
DCE/H2Oc
CH3CN/H2Oc
H2O
9
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
TBHP
DTBP
PhI(TF(A)2
KHS2O8
(NH4)2S2O8
Na2S2O8
–
K2S2O8
K2S2O8
K2S2O8
K2S2O8
43
14
32d, 53e
45f, 62g
44h, 63i
12j
NR = No reaction.
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), oxidant (0.3 mmol), photocatalyst (3 mol%), solvent (2.0 mL), at room temperature under blue LED in air for 12 h.
b
c
d
e
f
Isolated yields.
Organic solvent/H2O (v/v = 1:1, 2.0 mL).
Oxidant (0.1 mmol).
Oxidant (0.4 mmol).
2a (0.2 mmol).
g
h
i
2a (0.6 mmol).
Eosin Y (1 mol%).
Eosin Y (5 mol%).
In the dark.
j
2

H. Bao, Z. Lin, M. Jin et al.
Tetrahedron Letters 66 (2021) 152841
Table 2
conditions, functional group tolerance and simple operation [14].
Based on our previous work of the CAH functionalization of N-con-
taining heterocycles [1b,15] and the concept of green chemistry,
herein, we developed a new strategy for the CAH arylation of
quinoxalin-2(1H)-ones with aryboronic acid in H2O through
photocatalysis.
Substrate scope of quinoxalin-2(1H)-ones.a,b
Results and discussion
We started our work with the reaction of 1-methylquinoxalin-2
(1H)-one 1(a) with phenylboronic acid 2(a) using Eosin Y as photo-
catalyst, K2S2O8 as oxidant in DCE under blue LEDs for 12 h. As
shown in Table 1, the desired product 3(a) was obtained in 27%
yield. Other organic solvents such as DMSO, DMF, CH3CN and
THF could not enhance the yield (Table 1, entry 2–5). To meet
the demand of green chemistry, H2O as co-solvent was added to
the reaction mixture (Table 1, entry 6–7). To our delight, the yield
was increased. The yield could be further enhanced to 65%, if H2O
was chosen as solvent (Table 1, entry 8). We think that the usage of
H2O enhanced the solubility of phenylboronic acid 2(a) and K2S2O8,
which was beneficial to the reaction. Further optimization in the
type and amount of photocatalysts and oxidants did not improve
the reaction yield (Table 1, entry 9–24).
With the optimized conditions in hand, we then evaluated the
scope of substituted quinoxalin-2(1H)-ones (1) with phenyl-
boronic acid 2(a) (Table 2). To our delight, quinoxalin-2(1H)-ones
with a variety of N-protecting groups, including methyl, ethyl, iso-
propyl, N-butyl, isopentyl, cyclohexylmethyl, could be transformed
into the desired products in good yield (3a-f). Notably, some sen-
sitive groups in the reaction, including alkenes, cyclopropyl and
ester, were well tolerated (3 g-i). However, when various substi-
tuted benzyl were employed as N-protecting groups (3j-q), the
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), K2S2O8 (0.3 mmol), Eosin Y
(3 mol%), H2O (2.0 mL), at room temperature under blue LED in air for 12 h.
b
Isolated yields.
Scheme 2. Gram-scale synthesis and control experiment.
3

H. Bao, Z. Lin, M. Jin et al.
Tetrahedron Letters 66 (2021) 152841
–NO2). The heterocycle-containing boronic acids were also
compatible, yielding the corresponding products (3am-ao) in
66–69% yields. Unfortunately, N-heteroarenes including quinoline,
isoquinoline, N-methylindole and aliphatic boronic acids such as
isopropylboric acid are not suitable for this reaction.
Table 3
Substrate scope of arylboronic acids.a,b
To demonstrate the application value of such method, the
gram-scale synthesis of C-3 arylated quinoxalin-2(1H)-ones (1)
was performed, providing the corresponding product in 62% yield
(Scheme 2a).
To elucidate the possible reaction pathway, a control reaction
was carried out (Scheme 2b). The reaction was inhibited when
2.0 equiv. of 2,2,6,6-tetramethyl-piperdin-1-oxyl (TEMPO) was
added. Furthermore, the adduct 4 was detected by HRMS. These
results indicated that a radical process was involved in the reac-
tion. The reaction could also be performed under nitrogen atmo-
sphere, to afford the corresponding product in 63% yield,
indicating that oxygen do not take part in the transformation
(Scheme 2c).
a
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), K2S2O8 (0.3 mmol), Eosin Y
(3 mol%), H2O (2.0 mL), at room temperature under blue LED in air for 12 h.
b
Isolated yields.
Based on the results and previous reports [14d,16], a possible
mechanism was proposed (Scheme 3). Firstly, Eosin
Y was
activated under irradiation of blue LED, which reduced the
K2S2O8 to generate radical I. Then the radical I reacted with
boronic acid 2(a) to produce aryl radical II, which subsequently
attacked quinoxalin-2(1H)-ones (1) to form nitrogen radical
intermediate III. The generated intermediate III underwent a 1,2-
hydrogen shift process to produce carbon radical IV, which was
oxidized by Eosin YÁ+ to form carbon cation V. The final product
3a was generated through a deprotonation process.
desired products were isolated in lower yields. This result might be
caused by the low solubility of N-benzyl quinoxalin-2(1H)-ones.
The N-aryl quinoxalin-2(1H)-one has been tested under the stan-
dard condition, and the corresponding product (3r) was obtained
in 53% yield. Quinoxalin-2(1H)-ones with methyl, fluorine, chlo-
rine, bromine and ester groups on the benzene ring were also com-
patible, giving the products (3 s-3y) in 43–55% yields. Further
investigation found that N-free protecting quinoxalinone was also
suitable for the transformation (3z).
Subsequently, a number of boronic acids (2) were tested with 1-
methylquinoxalin-2(1H)-one 1(a) under the standard condition
(Table 3). Phenyl boronic acid with electron-donating groups
(–CH3, –OCH3, -OPh) and halogen were compatible with the reac-
tion in a good yield (3aa-aj). Unfortunately, no desired product
(3ak, 3al) was observed If the substituents of phenyl boronic acids
were displaced with strong electron-withdrawing groups (–CF3,
Conclusion
In conclusion, we have developed a mild and green strategy for
CAH arylation of quinoxalin-2(1H)-ones in H2O through photo-
catalysis. Various substrates were well compatible under standard
condition, providing an environmentally benign route to construct
various 3-arylated quinoxalin-2(1H)-ones.
Scheme 3. Plausible mechanism.
4

H. Bao, Z. Lin, M. Jin et al.
Tetrahedron Letters 66 (2021) 152841
ACS Sustainable Chem. Eng. 7 (2019) 19993;
(f) J.-W. Yuan, J.-L. Zhu, B. Li, L.-Y. Yang, P. Mao, S.-R. Zhang, Y.-C. Li, L.-B. Qu,
Org. Biomol. Chem. 17 (2019) 10178;
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
(g) T.T. Hoang, T.A. To, V.T.T. Cao, A.T. Nguyen, T.T. Nguyen, N.T.S. Phan, Catal.
Commun. 101 (2017) 20.
[7] (a) Q. Yang, X. Han, J. Zhao, H.-Y. Zhang, Y. Zhang, J. Org. Chem. 84 (2019)
11417;
(b) S. Peng, D. Hu, J.-L. Hu, Y.-W. Lin, S.-S. Tang, H.-S. Tang, J.-Y. He, Z. Cao, W.-
M. He, Adv. Synth. Catal. 361 (2019) 5721;
Acknowledgement
(c) J. Zhou, P. Zhou, T. Zhao, Q. Ren, J. Li, Adv. Synth. Catal. 361 (2019) 5371;
(d) L. Zhao, L. Wang, Y. Gao, Z. Wang, P. Li, Adv. Synth. Catal. 361 (2019) 5363;
(e) J. Xu, H. Yang, H. Cai, H. Bao, W. Li, P. Zhang, Org. Lett. 21 (2019) 4698.
[8] (a) M. Gao, Y. Li, L. Xie, R. Chauvinabc, X. Cui, Chem. Commun. 52 (2016) 2846;
(b) Y. Kim, D.Y. Kim, Tetrahedron Lett. 59 (2018) 2443;
(c) J. Wang, J. Li, Y. Wei, J. Yang, C. Huo, Org. Chem. Front. 5 (2018) 3534;
(d) W.-P. Mai, J.-W. Yuan, J.-L. Zhu, Q.-Q. Li, L.R. Yang, Y.-M. Xiao, P. Mao, L.-B.
Qu, ChemistrySelect 4 (2019) 11066.
[9] A. Carrer, J. Brion, S. Messaoudi, M. Alami, Org. Lett. 15 (2013) 5606.
[10] K. Yin, R. Zhang, Org. Lett. 19 (2017) 1530.
[11] (a) J. Yuan, S. Liu, L. Qu, Adv. Synth. Catal. 359 (2017) 4197;
(b) S. Paul, J.H. Ha, G.E. Park, Y.R. Lee, Adv. Synth. Catal. 359 (2017) 1515.
[12] B. Ramesh, C.R. Reddy, G.R. Kumar, B.V.S. Reddy, Tetrahedron Lett. 59 (2018)
628.
[13] (a) Z. Cao, Q. Zhu, Y.-W. Lin, W.-M. He, Chin. Chem. Lett. 30 (2019) 2132;
(b) L.-H. Lu, Z. Wang, W. Xia, P. Cheng, B. Zhang, Z. Cao, W.-M. He, Chin. Chem.
Lett. 30 (2019) 1237.
[14] (a) C.K. Prier, D.A. Rankic, D.W.C. MacMillan, Chem. Rev. 113 (2013) 5322;
(b) J. Li, M. Kong, B. Qiao, R. Lee, X. Zhao, Z. Jiang, Nat. Common. 9 (2018) 2445;
(c) J.M.R. Narayanam, C.R.J. Stephenson, Chem. Soc. Rev. 40 (2011) 102;
(d) X. Li, M. Han, B. Wang, L. Wang, M. Wang, Org. Biomol. Chem. 17 (2019)
6612;
(e) L.-Y. Xie, S. Peng, L.-H. Yang, C. Peng, Y.-W. Lin, X. Yu, Z. Cao, Y.-Y. Peng, W.-
M. He, Green Chem. (2020), https://doi.org/10.1039/D0GC02844D.
[15] (a) C. Shen, A. Wang, J. Xu, Z. An, K.Y. Loh, P. Zhang, X. Liu, Chem 5 (2019)
1059;
This work was supported by the Natural Science Foundation of
Zhejiang Province (No. LY21B060009), National Innovation Train-
ing Program for College Students (No. 202010346017) and Hang-
zhou Normal University "Undergraduate Innovation Ability
Enhancement” Project (No. CX2020106).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152841.
References
[1] (a) X. Qin, X. Hao, H. Han, S. Zhu, Y. Yang, B. Wu, S. Hussain, S. Parveen, C. Jing,
B. Ma, C. Zhu, J. Med. Chem. 58 (2015) 1254;
(b) C. Shen, A. Wang, J. Xu, Z. An, K.Y. Loh, P. Zhang, X. Liu, Chem 5 (2019) 1059.
[2] (a) Q. Ke, G. Yan, J. Yu, X. Wu, Org. Biomol. Chem. 17 (2019) 5863;
(b) G.L. Douaron, L. Ferrié, J.E. Sepulveda-Diaz, M. Amar, A. Harfouche, B. Séon-
Méniel, R. Raisman-Vozari, P.P. Michel, B. Figadère, J. Med. Chem. 59 (2016)
6169.
[3] M. Weïwer, J. Spoonamore, J. 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. 3 (2012) 1034.
(b) J. Xu, K. Cheng, C. Shen, R. Bai, Y. Xie, P. Zhang, ChemCatChem 10 (2018)
965;
(c) B. Ying, J. Xu, X. Zhu, C. Shen, P. Zhang, ChemCatChem 8 (2016) 2604;
(d) C. Shen, M. Yang, J. Xu, C. Chen, K. Zheng, J. Shen, P. Zhang, RSC Adv. 7
(2017) 49436;
(e) J. Shen, J. Xu, L. Huang, Q. Zhu, P. Zhang, Adv. Synth. Catal. 362 (2020) 230;
(f) J. Xu, K. Du, J. Shen, C. Shen, K. Chai, P. Zhang, ChemCatChem 10 (2018)
3675;
(g) J. Xu, X. Zhu, G. Zhou, B. Ying, P. Ye, L. Su, C. Shen, P. Zhang, Org. Biomol.
Chem. 14 (2016) 3016;
[4] J. Quinn, C. Guo, L. Ko, B. Sun, Y. He, Y. Li, RSC Adv. 6 (2016) 22043.
[5] (a) W. Xue, Y. Su, K. Wang, R. Zhang, Y. Feng, L. Cao, D. Huang, Y. Hu, Org.
Biomol. Chem. 17 (2019) 6654;
(b) C. Jin, X. Zhuang, B. Sun, D. Li, R. Zhu, Asian J. Org. Chem. 8 (2019) 1490;
(c) J. Wang, B. Sun, L. Zhang, T. Xu, Y. Xie, C. Jin, Asian J. Org. Chem. 8 (2019)
1942;
(d) H. Zhang, J. Xu, M. Zhou, J. Zhao, P. Zhang, W. Li, Org. Biomol. Chem. 17
(2019) 10201;
(e) L.-Y. Xie, S. Peng, T.-G. Fan, Y.-F. Liu, M. Sun, L.-L. Jiang, X.-X. Wang, Z. Cao,
W.-M. He, Sci. Chin. Chem. 62 (2019) 460;
(f) L.-Y. Xie, Y.-S. Bai, X.-Q. Xu, X. Peng, H.-S. Tang, Y. Huang, Y.-W. Lin, Z. Cao,
W.-M. He, Green Chem. 22 (2020) 1720;
(g) Z. Yan, B. Sun, X. Zhang, X. Zhuang, J. Yang, W. Su, C. Jin, Chem.-Asian J. 14
(2019) 3344;
(h) P. Bao, F. Liu, Y. Lv, H. Yue, J.-S. Li, W. Wei, Org. Chem. Front. 7 (2020) 492;
(i) J. Wang, B. Sun, L. Zhang, T. Xu, Y. Xie, C. Jin, Org. Chem. Front. 7 (2020) 113;
(j) Z. Wei, S. Qi, Y. Xu, H. Liu, J. Wu, H.-S. Li, C. Xia, G. Duan, Adv. Synth. Catal.
361 (2019) 5490.
(h) J. Xu, H. Zhang, J. Zhao, Z. Ni, P. Zhang, B. Shi, W. Li, Org. Chem. Front. 7
(2020) 4031;
(i) J. Xu, H. Yang, L. He, L. Huang, J. Shen, W. Li, P. Zhang, Org. Lett. 23 (2021)
195.
[16] (a) L. Zhou, M.L. Hossain, T. Xiao, Chem. Rec. 16 (2016) 319;
(b) C. Xia, Z. Wei, Y. Yang, W. Yu, H. Liao, C. Shen, P. Zhang, Chem.-Asian J. 11
(2016) 360;
(c) S. Bertrand, A.H. Matthew, P.B. Eduardo, M. Paolo, Nature Chem. 11 (2019)
129;
(d) S. Mandal, T. Bera, G. Dubey, J. Saha, J.K. Laha, ACS Catal. 8 (2018) 5085;
(e) H. Yi, G. Zhang, H. Wang, Z. Huang, J. Wang, A.K. Singh, A. Lei, Chem. Rev.
117 (2017) 9016;
(f) C. Shen, M. Yang, J. Xu, C. Chen, K. Zheng, J. Shen, P. Zhang, RSC Adv. 7
(2017) 49436;
(g) G. Duret, R. Quinlan, P. Bisseret, N. Blanchard, Chem. Sci. 6 (2015) 5366;
(h) B. Li, P.H. Dixneuf, Chem. Soc. Rev. 42 (2013) 5744;
(i) M. Jouffroy, J. Kong, Chem. Eur. J. 25 (2019) 2217.
[6] (a) A. Gupta, M.S. Deshmukh, N. Jain, J. Org. Chem. 82 (2017) 4784;
(b) Q. Yang, Z. Yang, Y. Tan, J. Zhao, Q. Sun, H.-Y. Zhang, Y. Zhang, Adv. Synth.
Catal. 361 (2019) 1662;
(c) W. Wei, L. Wang, P. Bao, Y. Shao, H. Yue, D. Yang, X. Yang, X. Zhao, H. Wang,
Org. Lett. 20 (2018) 7125;
(d) Q. Yang, Y. Zhang, Q. Sun, K. Shang, H.-Y. Zhang, J. Zhao, Adv. Synth. Catal.
360 (2018) 4509;
(e) L.-Y. Xie, J.-L. Hu, Y.-X. Song, G.-K. Jia, Y.-W. Lin, J.-Y. He, Z. Cao, W.-M. He,
5