Copper catalyzed aerobic oxidative amination of 3,4-dihydroquinoxalin-2(1H)-ones

Article abstract of DOI:10.1016/j.tetlet.2021.153271

A copper catalyzed aerobic sp³ C[sbnd]H amination of 3,4-dihydroquinoxalin-2(1H)-ones is developed. This protocol provides a concise method to access 3-aminoquinoxalinone derivatives with good functional-group tolerances, utilizing primary and secondary aliphatic amines as nitrogen sources under mild and simple reaction conditions. It provides a practical approach to the synthesis of pharmaceutical active 3-aminoquinoxalinones.

Full text of DOI:10.1016/j.tetlet.2021.153271

Tetrahedron Letters 78 (2021) 153271
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper catalyzed aerobic oxidative amination of 3,4-dihydroquinoxalin-
2(1H)-ones
⇑
Shuocheng Wan, Jie Wang, Congde Huo
Gansu International Scientific and Technological Cooperation Base of Water-Retention Chemical Functional Materials, College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou, Gansu 730070, China
a r t i c l e i n f o
a b s t r a c t
A copper catalyzed aerobic sp3 CAH amination of 3,4-dihydroquinoxalin-2(1H)-ones is developed. This
protocol provides a concise method to access 3-aminoquinoxalinone derivatives with good functional-
group tolerances, utilizing primary and secondary aliphatic amines as nitrogen sources under mild and
simple reaction conditions. It provides a practical approach to the synthesis of pharmaceutical active
Article history:
Received 18 April 2021
Revised 5 June 2021
Accepted 20 June 2021
Available online 9 July 2021
3-aminoquinoxalinones.
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Aerobic
Amination
Oxidation
Copper
3
3
-Aminoquinoxalinones
,4-Dihydroquinoxalin-2(1H)-ones
Introduction
3-Aminoquinoxalin-2(1H)-one structure motif has been well
known as an important pharmacophore to possess various potent
biological activities, which has been wildly explored for therapeu-
tic applications. For examples, as shown in Scheme 2, compound I
(ataquimast) is applied as a tumor necrosis factor antagonist in the
treatment of chronic obstructive bronchopneumopathies [12];
Compound II is a PAS kinase modulator [13]; Compound III can
be used as a calcium channel blocker [14]; as well as compound
IV acts as a histamine-4 receptor antagonist [15].
Although we and others have developed an oxidative CAH func-
tionalization strategy to construct new CAC, CAP and CAO bond to
deliver 3-substituted 3,4-dihydro-1,4-benzoxazin-2-ones and 3,4-
dihydroquinoxalin-2(1H)-ones, we are still seeking more type of
chemical bond formation reaction of 3,4-dihydro-1,4-benzoxazin-
2-ones and 3,4-dihydroquinoxalin-2(1H)-ones. C A N bond forma-
tion reaction is one of the most fundamental pursuit in organic
synthesis. Encouraged by the pharmaceutical significance of 3-
aminoquinoxalinone moieties, we became interested in exploring
direct CAH amination of readily available 3,4-dihydroquinoxalin-
2(1H)-ones with following oxidative aromatization, which seems
3
,4-Dihydro-1,4-benzoxazin-2-ones and 3,4-dihydroquinox-
alin-2(1H)-ones (Scheme 1) as privileged nitrogen-heterocyclic
skeletons have attracted considerable attention due to their signif-
icant bio-activities and interesting chemical properties [1,2]. In
3
2
2
016, we for the first time developed an oxidative C(sp )–C(sp )
bond formation reaction to deliver 3-indolated 3,4-dihydro-1,4-
benzoxazin-2-ones [3]. Afterward, visible-light promoted versions
of this transformation were reported by the He group [4], the Lee
group [5], and the Vila group [6] respectively in 2018. And a
ionic-liquid variation was developed by the Sharifi group in 2020
[
7]. In 2017, we described an iron-catalyzed oxidative dehydro-
genative coupling reaction of 3,4-dihydro-1,4-benzoxazin-2-ones
3
3
with malonic esters or ketones to construct C(sp )–C(sp ) bonds
8]. In 2019, the Vila group described a copper-catalyzed aerobic
[
3
oxidative C(sp )–C(sp) bonds forming reaction of 3,4-dihydro-
quinoxalin-2(1H)-ones with terminal alkynes under visible-light
irradiation [9]. In 2018, we reported a copper catalyzed oxidative
phosphonation reaction of 3,4-dihydro-1,4-benzoxazin-2-ones
3
through an oxidative Pudovik reaction [10]. In 2020, the sp ACAH
peroxidation reaction of 3,4-dihydro-1,4-benzoxazin-2-ones and
a
straightforward pathway to construct complex 3-
3
,4-dihydroquinoxalin-2(1H)-ones was achieved by our group
aminoquinoxalinones.
under catalyst-free reaction conditions [11].
Herein, as a part of our research on oxidative dehydrogenative
CAH functionalization reactions, we reported an efficient oxidative
amination aromatization tandem reaction of 3,4-dihydroquinox-
alin-2(1H)-ones with primary and secondary aliphatic amines
⇑
Corresponding author.
E-mail address: huocongde@nwnu.edu.cn (C. Huo).
https://doi.org/10.1016/j.tetlet.2021.153271
040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
0

S. Wan, J. Wang and C. Huo
Tetrahedron Letters 78 (2021) 153271
O
2
atmosphere resulted in same efficiency (Scheme 3, entry 5).
2 2
The use of other solvents such as CH Cl (31%), MeCN (50%), EtOAc
(
(
26%) and EtOH (51%) was found to be less productive then DMSO
87%) (Scheme 3, entries 6–9). The variation of temperature sug-
gested that 60 °C was the best choice for the transformation
(Scheme 3, entries 10 and 11).
With the optimized reaction conditions in hand, the scope of
the oxidative amination/aromatization tandem reaction was
explored. Firstly, we applied the transformation to a range of 3,4-
dihydroquinoxalin-2(1H)-ones 1 using morpholine (2a) as the
reaction partner. Dihydroquinoxalinones (1a–f), including elec-
tron-donating or electron-withdrawing groups on the aromatic
ring, worked well in this reaction (Scheme 4, 3aa-3fa). Subse-
quently, a variety of secondary aliphatic amines ranging from cyc-
lic to acyclic derivatives were tested, and the corresponding
products were isolated in moderate to high yields (Scheme 4,
Scheme 1. CAH functionalization of 3,4-dihydro-1,4-benzoxazin-2-ones and 3,4-
dihydroquinoxalin-2(1H)-ones.
3
aa-3ae). After the successful demonstration of oxidative
Scheme 2. Examples of bio-active 3-aminoquinoxalinones.
enabled by aerobic copper catalysis. A range of 3-amino substi-
tuted quinoxalin-2(1H)-ones were obtained under simple and mild
reaction conditions.
Aliphatic amines are extremely valuable structural motifs in
natural products and biologically active molecules. This study
was initiated by investigating the reaction of 3,4-dihydroquinox-
alin-2(1H)-one 1a with morpholine 2a in DMSO under an air atmo-
sphere with Cu(OAc) as the catalyst. To our delight, as shown in
2
Scheme 3, when the mixture was heated at 60 °C for 24 h, the
desired product 3aa was isolated in 87% yield (Scheme 1, entry
1
). The use of other copper salts or iron salts was found to be less
effective (Scheme 3, entries 2–4). Changing the air atmosphere to
Scheme 4. Copper catalyzed aerobic amination aromatization tandem reaction of
a
a,b
a
Scheme 3. Screening of Reaction Conditions Reaction Conditions: 1a (0.2 mmol),
2
3,4-dihydroquinoxalin-2(1H)-ones
Reaction Conditions: 1 (0.2 mmol), 2
b
b
a (0.6 mmol), solvent (1 mL), 24 h. Isolated yields.
(0.6 mmol), DMSO (1 mL), 60 °C, air, 24 h. Isolated yields.
2

S. Wan, J. Wang and C. Huo
Tetrahedron Letters 78 (2021) 153271
amination of 3,4-dihydroquinoxalin-2(1H)-ones with secondary
amines, the reaction was further explored with primary amines.
A range of primary aliphatic and aromatic amines were found also
suitable substrates to give high yields of the corresponding 3-
aminoquinoxalinones (Scheme 4, 3af-3an). Moreover, an anti-
allergic medicinal molecule desloratadine was suitable substrate
in this transformation too (Scheme 4, 3ao). The scalability of the
reaction was confirmed by carrying out a gram-scale synthesis
starting from 1a and 2c. The desired product 3ac was obtained in
hydrogen abstraction process from intermediate A by Cu(II)OO
radical. Subsequently, nucleophilic addition of activated interme-
diate B with aliphatic amine 2a occurred to give intermediate C.
Finally, aromatization of intermediate C occurred under copper
catalyzed aerobic conditions to generate the desired product 3aa.
In summary, an efficient and practical copper catalyzed aerobic
3
oxidative C(sp )–H amination and the following aromatization of
3,4-dihydroquinoxalin-2(1H)-ones was developed, which provides
a possibility for the preparation of biologically active 3-amino-
quinoxalinone derivatives from readily available starting materi-
als. This amination reaction can be scaled up to gram level.
Exploration of more type of oxidative dehydrogenative CAH func-
tionalization reactions of 3,4-dihydroquinoxalin-2(1H)-ones and
3,4-dihydro-1,4-benzoxazin-2-ones are currently underway in
our laboratory.
6
8% yield (1.34 g) after 16 h of reaction time (Scheme 5).
To understand the mechanism of this transformation, several
control experiments were conducted. First of all, we observed that
the template reaction of 3,4-dihydroquinoxalin-2(1H)-one 1a with
morpholine 2a did not take place under argon atmosphere
(Scheme 6, rxn. 1). On the other hand, the reaction of 1a in the
absence of 2a under the standard reaction conditions was investi-
gated. quinoxalin-2(1H)-ones B was isolated in an excellent yield
Declaration of Competing Interest
(Scheme 6, rxn. 2). And the reaction of B with 2a under standard
reaction conditions was then investigated (Scheme 6, rxn. 2). The
desired product 3aa was obtained in a high yield. These results
indicate that the quinoxalin-2(1H)-ones B is involved as a key
intermediate and copper salt is the redox catalyst with air as termi-
nal oxidant.
On the basis of the findings of control experiments, a possible
mechanism is proposed in Scheme 6 (bottom half). The 3,4-dihy-
droquinoxalin-2(1H)-one 1a was first one-electron oxidized to
generate the radical cation intermediate A by copper (II) salt. The
iminium ion intermediate B could then be formed through a
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.
Acknowledgments
We thank the National Natural Science Foundation of China
(
21961033) for financially supporting this work.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153271.
H
N
N
O
N
2
Cu(OAc) (10 mol%)
+
HN
DMSO (2 mL)
N
H
N
H
O
o
Air, 60 C
References
1
a (1.05 g)
2c (2.84 g)
3ac (1.34 g)
[
1] (a) N. Zidar, D. Kikelj, Tetrahedron. 64 (2008) 5756–5761;
(b) B. Achari, S.B. Mandal, P.K. Dutta, C. Chowdhury, Synlett. 14 (2004) 2449–
a
Scheme 5. Scale-up experiment and Late-stage transformation .
2467;
(
(
c) F. Bihela, J.-L. Kraus, Org. Biomol. Chem. 1 (2003) 793–799;
d) R.L. Jarvest, S.C. Connor, J.G. Gorniak, L.J. Jennings, H.T. Serafinowska, A.
Westa, Bioorg. Med. Chem. Lett. 7 (1997) 1733–1738;
(e) A. Belattar, J.E. Saxton, J. Chem. Soc., Perkin Trans. 1 (1992) 1583–1585;
(f) K.S. Brown, C. Djerassi, J. Am. Chem. Soc. 86 (1964) 2451–2462;
(g) J. Rostoll-Berenguer, G. Blay, M.C. Muñoz, J.R. Pedro, C. Vila, Org. Lett. 21
(2019) 6011–6015;
H
N
O
Cu(OAc)
2
(10 mmol %)
N
N
O
+
HN
N
H
O
DMSO, 60
o
C , 24h, Ar
N
H
2a
1
a
3aa (0%)
(
8
h) J. Rostoll-Berenguer, G. Blay, J.R. Pedro, C. Vila, Org. Lett. 22 (20) (2020)
012–8017;
O
(i) A. Gupta, M.S. Deshmukh, N. Jain, J. Org. Chem. 82 (9) (2017) 4784–4792;
(j) W. Wei, L. Wang, O. Bao, Y. Shao, H. Yue, D. Yang, X. Yang, X. Zhao, H. Wang,
Org. Lett. 20 (22) (2018) 7125–7130;
O
H
N
N
O
Cu(OAc)
2
(10 mmol %)
o
N
HN
2a
N
N
H
N
H
O
N
H
O
DMSO, 60 C , 24h, air
(k) K. Li, K. Xu, Y. Liu, C. Zeng, B. Sun, Adv. Synth. Catal. 361 (2019) 1033.
3
aa (85%)
[2] (a) D. Iordanidou, Z.-T. Tryfon, C.G. Neochoritis, A. Dömling, I.N. Lykakis, ACS
Omega. 3 (2018) 16005–16013;
1
a
B (95%)
(
2
(
b) Y. Amano, T. Yamaguchi, E. Tanabe, Bioorg. Med. Chem. 22 (2014) 2427–
434;
c) Y. Yang, L. Zhao, B. Xu, L. Yang, J. Zhang, H. Zhang, J. Zhou, Bioorg. Chem. 68
(2016) 236–244;
d) S.A. Galal, A.S. Abdelsamie, S.M. Soliman, J. Mortier, G. Wolber, M.M. Ali, H.
[
Cu]
1/
O
2 2
O
H
2
O
2
H
2
(
Tokuda, N. Suzuki, A. Lida, R.A. Ramadan, H.I. El Diwani, Eur. J. Med. Chem. 69
(2013) 115–124;
(e) S. Tanimori, T. Nishimura, M. Kirihata, Bioorg. Med. Chem. Lett. 19 (2009)
4119–4121;
CuII
CuIIOOH
- H
O
HN
H
N
H
H
N
N
2a
-
e
.
(
f) R. Gitto, M.L. Barreca, L. De Luca, A. Chimirri, Expert Opin. Ther. Pat. 14
N
H
O
N
H
O
N
H
O
(2004) 1199–1213.
1
a
A
B
[
[
3] C. Huo, J. Dong, Y. Su, J. Tang, F. Chen, Chem. Commun. 52 (2016) 13341–13344.
4] G. Zhang, K. Yu, C. Zhang, Z. Guan, Y. He, Eur. J. Org. Chem. (2018) 525–531.
[5] P.S. Akula, B.-C. Hong, G.-H. Lee, RSC Adv. 8 (2018) 19580–19584.
[6] J. Rostoll-Berenguer, G. Blay, J.R. Pedro, C. Vila, Catalysts 8 (2018) 653.
[7] A. Sharifi, M. Moazami, M. Saeed Abaee, M. Mirzaei, J. Iran. Chem. Soc. 17
CuI
CuIIOO
Nucleophillic
Addition
O
2
O
O
N
H
N
N
N
Oxidative Aromatization
(
2020) 2471–2480.
[
8] J. Dong, W. Min, H. Li, Z. Quan, C. Yang, C. Huo, Adv. Synth. Catal. 359 (2017)
3940–3944.
N
H
O
N
H
O
3
aa
C
[9] J. Rostoll-Berenguer, G. Blay, J.R. Pedro, C. Vila, Synthesis. 52 (2020) 544–552.
10] J. Wang, J. Li, Y. Wei, J. Yang, C. Huo, Org. Chem. Front. 5 (2018) 3534–3537.
[
Scheme 6. Control experiments and proposed mechanism.
[11] J. Wang, X. Bao, J. Wang, C. Huo, Chem. Commun. 56 (2020) 3895–3898.
3

S. Wan, J. Wang and C. Huo
Tetrahedron Letters 78 (2021) 153271
[
12] L. Shi, W. Hu, J. Wu, H. Zhou, H. Zhou, X. Li, Mini-Rev. Med. Chem. 18 (2018)
92.
13] J.M. Mccall, D.L. Romero, R.C. Kelly, Heterocyclic compounds for the inhibition
of PASK. WO 2012119046A2, Sept 2012.
[14] P.K. Chakravarty, Y. Ding, J.L. Duffy, H. Pajouhesh, P.P. Shao, S. Tyagarajan, F. Ye,
Substituted aryl sulfone derivatives as calcium channel blockers. WO
2009045382A1, April 2009.
[15] J.P. Edwards, J.D. Venable, Quinoxaline compounds. US 20050070527A1,
March 2005.
3
[
4