Synthesis of (E)-Quinoxalinone Oximes through a Multicomponent Reaction under Mild Conditions

Article abstract of DOI:10.1021/acs.orglett.0c03918

Herein, a novel method for the gram-scale synthesis of (E)-quinoxalinone oximes through a multicomponent reaction under mild conditions is described. Such a transformation was performed under transition-metal-free conditions, affording (E)-oximes in a moderate-to-good yield through recrystallization. Our methodology demonstrates a successful combination of a Mannich-type reaction and radical coupling, providing a green and practical approach for the synthesis of potentially bioactive quinoxalinone-containing molecules.

Full text of DOI:10.1021/acs.orglett.0c03918

pubs.acs.org/OrgLett
Letter
Synthesis of (E)‑Quinoxalinone Oximes through a Multicomponent
Reaction under Mild Conditions
Jun Xu, Huiyong Yang, Lei He, Lin Huang, Jiabin Shen, Wanmei Li,* and Pengfei Zhang*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03918
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Herein, a novel method for the gram-scale synthesis of (E)-quinoxalinone oximes through a multicomponent reaction
under mild conditions is described. Such a transformation was performed under transition-metal-free conditions, affording (E)-
oximes in a moderate-to-good yield through recrystallization. Our methodology demonstrates a successful combination of a
Mannich-type reaction and radical coupling, providing a green and practical approach for the synthesis of potentially bioactive
quinoxalinone-containing molecules.
ximes are important structural motifs of many natural
products,1 molecular sensors,2 and medicines (Figure
des.10c Zhao’s group10d and Tang’s group10e each demon-
strated a new approach for the synthesis of α-trifluoromethyl
ethanone oximes through the three-component reaction of
unactivated alkenes, TBN, and Langlois’ reagent. Wang’s group
reported a method for the synthesis of α-sulfonylethanone
oximes through the tandem sulfonylation and oximation of
alkenes in 2017.10h Subsequently, the same group further
achieved a novel strategy toward α-sulfonylethanone oximes by
way of the TBN-mediated sulfonylation and oximation of
alkynes under a N2 atmosphere.10f More interestingly, Patel’s
group and Wan’s group each reported many useful methods for
the synthesis of cyclic oxime ethers or esters using alkenes and
TBN as starting materials.10l−o Although significant progress
has been made in the green synthesis of oximes, simple and
efficient methodologies still needed to be developed to
introduce an oximido group in organic molecules.
O
1).3 In addition, such useful synthons are prerequisites for the
Figure 1. Bioactive molecules containing an oxime moiety.
Quinoxalinones play an important role in the synthesis of
natural products11 and pharmaceutical12 as well as in materials
chemistry.13 Therefore, considerable research efforts have been
devoted to the modification of quinoxalinones through various
transformations (Scheme 1).14 Two-component reactions for
the synthesis of quinoxalinones are well-studied.15−19 Recently,
the development of multicomponent transformations20 for the
modification of quinoxalinones has attracted extensive interest
synthesis of nitriles,4 amides,5 amines,6 and other important
compounds.7 The common methods for the synthesis of
oximes usually require hydroxylamine, which can be formed in
situ through the oxidation of ammonia in the presence of a
peroxide.8 Another approach to prepare oximes involves the
reduction of nitro compounds.9 However, these two conven-
tional methods suffer from some disadvantages, such as low
yields and a lack of atom- and step-economy. To improve the
atom-and step-economy, much attention has recently been
paid to the synthesis of oximes through the difunctionalization
of unactivated alkenes or alkynes in which tert-butyl nitrite
(TBN) is commonly used as the oximido source.10 For
instance, the Patel group recently reported a visible-light-
induced difunctionalization of styrenes, providing a novel
strategy for the synthesis of N-hydroxybenzimidoyl cyani-
Received: November 26, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03918
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 1. Modification of Quinoxalinones by C−H
Functionalization
Table 1. Screening of Reaction Conditions
b
entry
variation from given conditions
none
no CH3SO3H
CH3SO3H was replaced with CH3CO2H
10.0 equiv of acetone was used
2.0 equiv of TBN was used
extended reaction time (12 h)
under a N2 atmosphere
yield (%)
1
2
3
4
5
6
7
8
82
0
trace
81
78
79
trace
80
10.0 mmol 1a was used
a
Reaction conditions are as follows: 1a (5.0 mmol), 2a (5.0 equiv),
CH3SO3H (25 mol %), and TBN (1.2 equiv) in an open flask at room
b
temperature for 6 h; TBN = tert-butyl nitrate. Isolated yields by
recrystallization.
because they conform with “Principle 2, Atom Economy” of
Green Chemistry.21 Our group recently reported a three-
component cascade reaction of quinoxalinones with olefins and
TMSN3, providing a useful method for the rapid synthesis of
quinoxalinone-containing organoazides.20a Wei’s group20b and
Studer’s group20c independently reported a three-component
reaction of quinoxalinones with olefins and fluoroalkylation
reagents. Koley et al.20d described a metal-free three-
component radical cascade reaction of quinoxalinones with
olefins and sulfinic acids. Although elegant, such trans-
formations are usually performed on a milligram-scale using
a large quantity of toxic solvents. In addition, they require
column chromatography for isolation, which not only greatly
reduces the synthesis efficiency but also adds to the
environmental load. Therefore, the development of more
green and efficient methods for the synthesis of quinoxalinone
derivatives is highly necessary in modern organic methodology
research.
reaction was performed under a N2 atmosphere (Table 1, entry
7). The yield of product 3 had no obvious change when the
quinoxalinone (1a) dose was increased to 10.0 mmol (Table 1,
entry 8).
With the optimal reaction conditions in hand, we next
explored the substrate scope of quinoxalinones for the
multicomponent reaction (Scheme 2). The reactivity of
various N-substituted quinoxalinones was first tested. A wide
range of N-substituents, such as methyl, ethyl, n-butyl, i-butyl,
i-pentyl, cyclopropylmethyl, cyclohexylmethyl, and ester, were
well-compatible with this reaction, affording the target
a,b
Scheme 2. Substrate Scope of Quinoxalinones
We are interested in developing green methodologies for
multicomponent transformations as part of our long-standing
interest in developing novel approaches for the modification of
N-containing heterocycles.17a,20a,22,23 We herein report a novel
method for the gram-scale synthesis of (E)-quinoxalinones
oximes from simple and inexpensive starting materials through
an easy-to-perform recrystallization method. We conducted
this transformation under transition-metal-free conditions,
affording green and practical access to various (E)-quinox-
alinone oximes in moderate-to-good yields.
The conditions of the multicomponent reaction were first
optimized by changing the catalysts, the starting-material dose,
the reaction time, and the atmosphere (Table 1 and the
Supporting Information). (E)-Quinoxalinone oxime (3) was
obtained in an 82% yield by performing the multicomponent
reaction of 1 (5.0 mmol), 2a (5.0 equiv), CH3SO3H (25 mol
%), and tert-butyl nitrite (TBN) (1.2 equiv) at room
temperature for 6 h (Table 1, entry 1). Crude NMR
experiments confirmed that there was no other stereoisomer.
No corresponding product was obtained in the absence of
CH3SO3H or when CH3SO3H was replaced with CH3CO2H
(Table 1, entries 2 and 3, respectively). The product yield
could not be improved by increasing the amount of starting
materials or extending the reaction time (Table 1, entries 4−
6). In addition, no target product was generated when the
a
Reaction conditions are as follows: 1 (10.0 mmol), 2 (5.0 equiv),
CH3SO3H (25 mol %), and TBN (1.2 equiv) in an open flask at room
b
c
temperature for 6 h. Isolated yields by recrystallization. Reaction
was performed on a 1 mmol scale.
B
https://dx.doi.org/10.1021/acs.orglett.0c03918
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
products (3−10) in good yields. To our delight, the sensitive
groups, including allyl and propargyl, also underwent the
reaction smoothly, affording the corresponding products (11
and 12, respectively) in moderate yields. A variety of substrates
bearing different substituted benzyl groups were examined, and
the corresponding (E)-quinoxalinones oximes (13−18) were
obtained in 55−69% yields. The multicomponent reactions of
TBN and acetone (2a) with quinoxalinones bearing both
electron-donating and electron-withdrawing substituent groups
at the C5-, C6-, or C7-position, afforded the corresponding
products (19−27) in 39−65% yields. The molecular structures
of compounds 18 and 20 were confirmed by X-ray crystallo-
graphic analysis (CCDC 2007883 and 2009728). To explain
the reason for the generation of the E-isomer, density
functional theory (DFT) calculations with wB97X-D24 were
carried out at the wB97xd/def2TZVPP/SMD(acetone)//
wB97xd/6-31G(d) levels of theory with the Gaussian 16
package. On the basis of our calculation, the E-isomer is more
stable than the Z-isomer by 1.2 kcal/mol. The computational
results are consistent with the experimental observations.
The substrate scope of methyl ketones for the multi-
component reaction was also investigated under the optimal
reaction conditions (Scheme 3). Methyl ketones containing
In this case, the generation of 49 is more favorable according
to Le Chatelier’s principle, which makes compound 28 the
main product. Indeed, product 51 was obtained in a low yield
of 28% by treating 1a with 3-pentanone. On the other hand,
acetophenone was been tested under standard conditions;
however, the poor conversion and selectivity of the reaction
mean the present methodology has no practical application
value to acetophenone derivatives. As described previously, the
quinoxalinone skeleton is common in many biologically
important molecules. Therefore, the synthesis of quinoxalinone
derivatives has received significant attention. The direct
structural modification of the quinoxalinone skeleton affords
a straightforward approach to such compounds. In addition,
the synthesis of hybrid molecules comprised of two bioactive
molecules has also attracted considerable attention because
such hybrid molecules may possess special biological activity.25
Hence, we selected some bioactive compounds, such as
raspberry ketone, vanillylacetone, nabumetone, and 5α-
dihydroprogesterone, to react with quinoxalinones through
oximation. To our delight, the corresponding hybrid molecules
(40−43, respectively) were obtained in 40−63% yields. The
successful implementation of the above-mentioned trans-
formations demonstrated that the proposed strategy has a
good application value in the synthesis of potentially bioactive
quinoxalinone-containing molecules.
a,b
Scheme 3. Substrate Scope of Methyl Ketones
Because oximes can be transformed to other useful
functional groups, a further transformation of (E)-quinox-
alinones oximes was performed. As shown in Scheme 4, the
cyano- or nitro-substituted quinoxalinones (44−45) and oxime
ether (46) were obtained in excellent yields when (E)-
quinoxalinone oxime (3) was used as the starting material.
Scheme 4. Further Transformation
a
Reaction conditions are as follows: 1a (10.0 mmol), 2 (2.0 equiv),
CH3SO3H (25 mol %), and TBN (1.2 equiv) in an open flask at room
A series of control experiments were performed to
understand the reaction mechanisms. First, intermediates 47
and 48 were obtained instead of the target product 3 when 2
equiv of radical scavengers 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) was added to the catalytic system, and the NO
radical was also captured (Scheme 5a). These experimental
results clearly reveal that a radical mechanism is responsible for
the reaction, but the generation of 47 and 48 may not involve a
radical pathway. Then, intermediate 48 was obtained in a 48%
yield when the reaction was performed without TBN (Scheme
5b), and the target product 3 was obtained in an 87% yield
when 48 was used as the substrate with TBN (Scheme 5c).
Furthermore, we used 47 as a starting material to investigate
the effect of the atmosphere on this transformation (Scheme
5d). The results showed that 48 was obtained in 66% and 68%
yields when the reaction was performed under an air or O2
b
c
temperature for 6 h. Isolated yields by recrystallization. For the
detailed reaction conditions, see the Supporting Information.
either long-chain alkyl or cycloalkyl could afford the
corresponding (E)-quinoxalinones oximes (28−39) in 55−
78% yields. It is worth mentioning that a small amount of
product 50 was obtained when using 2-butanone as substrate
(Scheme S1). We assume that there are two possible reasons
for the phenomena. First, while enolization of the more
substituted site is more favorable the steric hindrance is also
larger, which is of no advantage to the reaction. Second, the
reactions for the formations of 49 and 50 are competing
reactions since keto−enol tautomerism is a reversible reaction.
In addition, 49 can be further converted to target product 28.
C
https://dx.doi.org/10.1021/acs.orglett.0c03918
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 5. Control Experiments
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03918.
Experimental procedures and characterization data for
all compounds (PDF)
Accession Codes
CCDC 2007883 and 2009728 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Wanmei Li − College of Material, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China; Email: liwanmei@hznu.edu.cn
Pengfei Zhang − College of Material, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China; orcid.org/0000-0001-9859-0237;
Email: pfzhang@hznu.edu.cn
atmosphere, respectively; no product was generated under a N2
atmosphere. This result illustrates that product 47 is the
precursor of 48 and the O2 plays an important role in this
transformation.
Based on the results of the control experiments and previous
investigations,10,14,26 a plausible mechanism for the multi-
component reaction was proposed (Scheme 6). First, iminium
Authors
Jun Xu − College of Material, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China
Huiyong Yang − College of Material, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China
Scheme 6. Plausible Mechanism
Lei He − College of Material, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China
Lin Huang − College of Material, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China
Jiabin Shen − College of Material, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03918
Notes
ion A is generated through the protonation of substrate 1a.
Meanwhile, acetone 2a is transformed to the enol form (B)
under acidic conditions. Next, A reacts with B to afford 47.27
Then, 47 is converted to 48 through an oxidative dehydrogen-
ation process. Meanwhile, the homolysis of TBN affords tert-
butoxy (tBuO·) and nitroso (·NO) radicals. Subsequently, the
nitroso (·NO) radical attacks the CC bond of 48 to afford
intermediate E, which is then oxidized to intermediate F by
tert-butoxy (tBuO·). Finally, the target product is generated
through the isomerization of F.
In conclusion, this study describes a novel method for the
gram-scale synthesis of (E)-quinoxalinone oximes through a
multicomponent reaction. As demonstrated using the model
systems, we obtained (E)-oximes in moderate-to-good yields
when different substrates were used. Such methodology
provides a green and practical approach for the synthesis of
potentially bioactive quinoxalinone-containing molecules.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21871071) and the Natural Science Foundation of Zhejiang
Province (LY21B060009) for financial support.
REFERENCES
■
(1) (a) Hertiani, T.; Edrada-Ebel, R.; Ortlepp, S.; van Soest, R. W.
M.; de Voogd, N. J.; Wray, V.; Hentschel, U.; Kozytska, S.; Mu
̈
ller, W.
E. G.; Proksch, P. From anti-fouling to biofilm inhibition: new
cytotoxic secondary metabolites from two indonesian agelas sponges.
Bioorg. Med. Chem. 2010, 18, 1297−1311. (b) Liu, N.; Song, L.; Liu,
M.; Shang, F.; Anderson, Z.; Fox, D. J.; Challis, G. L.; Huang, Y.
Unique post-translational oxime formation in the biosynthesis of the
azolemycin complex of novel ribosomal peptides from streptomyces
sp. FXJ1.264. Chem. Sci. 2016, 7, 482. (c) Calcul, L. T.; Inman, W. D.;
D
https://dx.doi.org/10.1021/acs.orglett.0c03918
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Morris, A. A.; Tenney, K.; Ratnam, J.; McKerrow, J. H.; Valeriote, F.
A.; Crews, P. Additional insights on the bastadins: isolation of
analogues from the sponge ianthella cf. reticulata and exploration of
the oxime configurations. J. Nat. Prod. 2010, 73, 365. (d) Almeida, C.;
(6) (a) Dong, X.; Kita, Y.; Oestreich, M. Kinetic Resolution of α-
hydroxy-substituted oxime ethers by enantioselective Cu-H-catalyzed
Si-O coupling. Angew. Chem., Int. Ed. 2018, 57, 10728. (b) Hong, W.
P.; Iosub, A. V.; Stahl, S. S. Pd-catalyzed Semmler-Wolff reactions for
the conversion of substituted cyclohexenone oximes to primary
anilines. J. Am. Chem. Soc. 2013, 135, 13664. (c) Chu, Y.; Shan, Z.;
Liu, D.; Sun, N. Asymmetric reduction of oxime ethers promoted by
chiral spiroborate esters with an O3BN framework. J. Org. Chem.
2006, 71, 3998.
(7) (a) Fan, X.; Lei, T.; Chen, B.; Tung, C.-H.; Wu, L.-Z.
Photocatalytic C-C bond activation oxime ester for acyl radical
generation and application. Org. Lett. 2019, 21, 4153. (b) Trofimov,
B. A.; Schmidt, E. Y. Acetylenes in the superbase-promoted assembly
of carbocycles and heterocycles. Acc. Chem. Res. 2018, 51, 1117.
(c) Hughes, J. M. E.; Gleason, J. L. A concise enantioselective total
synthesis of (−)-virosaine A. Angew. Chem., Int. Ed. 2017, 56, 10830.
(d) Ge, J.-J.; Yao, C.-Z.; Wang, M.-M.; Zheng, H.-X.; Kang, Y.-B.; Li,
Y. Transition-metal-free deacylative cleavage of unstrained C(sp3)-
C(sp2) bonds: cyanide-free access to aryl and aliphatic nitriles from
ketones and aldehydes. Org. Lett. 2016, 18, 228. (e) Huang, H.; Cai,
J.; Deng, G.-J. O-acyl oximes: versatile building blocks for N-
heterocycle formation in recent transition metal catalysis. Org. Biomol.
Chem. 2016, 14, 1519. (f) Sukhorukov, A. Y.; Ioffe, S. L. Chemistry of
six-membered cyclic oxime ethers. Application in the synthesis of
bioactive compounds. Chem. Rev. 2011, 111, 5004. (g) Narasaka, K.;
Kitamura, M. Amination with oximes. Eur. J. Org. Chem. 2005, 2005,
4505.
(8) (a) MendezSanchez, D.; Lavandera, I.; Gotor, V.; Gotor-
Fernandez, V. Novel chemoenzymatic oxidation of amines into
oximes based on hydrolase-catalysed peracid formation. Org. Biomol.
Chem. 2017, 15, 3196. (b) Aakeroy, C. B.; Sinha, A. S.; Epa, K. N.;
Spartz, C. L.; Desper, J. A versatile and green mechanochemical route
for aldehyde-oxime conversions. Chem. Commun. 2012, 48, 11289.
(9) (a) Zhou, Q. F.; Zhang, K.; Cai, L.; Kwon, O. Phosphine-
catalyzed intramolecular cyclizations of α-nitroethylallenoates forming
(Z)-furanone oximes. Org. Lett. 2016, 18, 2954. (b) Cai, S.; Zhang, S.;
Zhao, Y.; Wang, D. Z. New approach to oximes through reduction of
nitro compounds enabled by visible light photoredox catalysis. Org.
Lett. 2013, 15, 2660.
(10) For reviews, see: (a) Dahiya, A.; Sahoo, A. K.; Alam, T.; Patel,
B. K. Tert-butyl nitrite (TBN), a multitasking reagent in organic
synthesis. Chem. - Asian J. 2019, 14, 4454. (b) Li, P.; Jia, X. Tert-butyl
nitrite (TBN) as a versatile reagent in organic synthesis. Synthesis
2018, 50, 711. For selected examples, see: (c) Alam, T.; Rakshit, A.;
Begum, P.; Dahiya, A.; Patel, B. K. Visible-light-induced difunction-
alization of styrenes: synthesis of N-hydroxybenzimidoyl cyanides.
Org. Lett. 2020, 22, 3728. (d) Lu, K.; Wei, X.; Li, Q.; Li, Y.; Ji, L.;
Hua, E.; Dai, Y.; Zhao, X. Synthesis of α-trifluoromethyl ethanone
oximes via the three-component reaction of aryl-substituted ethylenes,
tert-butyl nitrite, and the langlois reagent. Org. Chem. Front. 2019, 6,
3766. (e) Wu, Y.; Zhang, Y.; Yang, Z.; Jiao, J.; Zheng, X.; Feng, W.;
Zhang, M.; Cheng, H.; Tang, L. Dual roles of tert-butyl nitrite in the
transition metal- and external oxidant-free trifluoromethyloximation
of alkenes. ChemSusChem 2019, 12, 3960. (f) Wang, B.; Yan, Z.; Liu,
L.; Wang, J.; Zha, Z.; Wang, Z. TBN-mediated regio- and
stereoselective sulfonylation & oximation (oximosulfonylation) of
alkynes with sulfonyl hydrazines in EtOH/H2O. Green Chem. 2019,
21, 205. (g) Chu, X.-Q.; Ge, D.; Loh, T.-P.; Shen, Z.-L. Oxidant-
directed chemoselective sulfonylation and sulfonyloximation of
alkenes via cleaving the C-S bond in TosMIC. Org. Chem. Front.
2019, 6, 835. (h) Wang, B.; Tang, L.; Liu, L.; Li, Y.; Yang, Y.; Wang,
Z. Base-mediated tandem sulfonylation and oximation of alkenes in
water. Green Chem. 2017, 19, 5794. (i) Chen, F.; Zhou, N.-N.; Zhan,
J.-L.; Han, B.; Yu, W. Tert-butyl nitrite-mediated vicinal sulfoximation
of alkenes with sulfinic acids: a highly efficient approach toward α-
sulfonyl ketoximes. Org. Chem. Front. 2017, 4, 135. (j) Yang, J.; Liu,
Y.-Y.; Song, R.-J.; Peng, Z.-H.; Li, J.-H. Copper-mediated 1,2-
difunctionalization of styrenes with sodium arylsulfinates and tert-
butyl nitrite: facile access to α-sulfonylethanone oximes. Adv. Synth.
̈
Part, N.; Bouhired, S.; Kehraus, S.; Konig, G. M. Stachylines A-D
from the sponge-derived fungus stachylidium sp. J. Nat. Prod. 2011,
74, 21.
(2) (a) Sęk, J. P.; Kasprzak, A.; Bystrzejewski, M.; Poplawska, M.;
Kaszuwara, W.; Stojek, Z.; Nowicka, A. M. Nanoconjugates of
ferrocene and carbon-encapsulated iron nanoparticles as sensing
platforms for voltammetric determination of ceruloplasmin in blood.
Biosens. Bioelectron. 2018, 102, 490−496. (b) Huang, J.; Zhou, Z.;
Zhou, M.; Miao, M.; Li, H.; Hu, Q. Development of benzoxazole
deoxybenzoin oxime and acyloxylamine derivatives targeting innate
immune sensors and xanthine oxidase for treatment of gout. Bioorg.
Med. Chem. 2018, 26, 1653. (c) Huixiang, W.; Danqun, H.; Yanan, Z.;
Na, M.; Jingzhou, H.; Miao, L.; Caihong, S.; Changjun, H. A non-
enzymatic electro-chemical sensor for organophosphorus nerve agents
mimics and pesticides detection. Sens. Actuators, B 2017, 252, 1118.
(d) Dong, J.; Hou, J.; Jiang, J.; Ai, S. Innovative approach for the
electrochemical detection of non-electroactive organophosphorus
pesticides using oxime as electroactive probe. Anal. Chim. Acta
2015, 885, 92.
(3) (a) Motaleb, M. A.; Selim, A. A. Dioximes: synthesis and
biomedical applications. Bioorg. Chem. 2019, 82, 145. (b) Lin, G.; Bai,
X.; Duan, W.; Cen, B.; Huang, M.; Lu, S. High value-added
application of sustainable natural forest product α-pinene: synthesis of
myrtenal oxime esters as potential KARI inhibitors. ACS Sustainable
Chem. Eng. 2019, 7, 7862. (c) He, Y.; Xue, H.; Zhang, W.; Wang, L.;
Xiang, G.; Li, L.; Shang, X. Discovery of a series of ruthenium(II)
derivatives with α-dicarbonylmonoxime as novel inhibitors of cancer
cells invasion and metastasis. J. Organomet. Chem. 2017, 842, 82.
(d) Miyawaki, S.; Hirokami, Y.; Kinami, K.; Hoshino, M.; Minehira,
D.; Miyamoto, D.; Nash, R. J.; Fleet, G. W.J.; Adachi, I.; Toyooka, N.;
Kato, A. Strategy for designing selective α-l-rhamnosidase inhibitors:
synthesis and biological evaluation of l-DMDP cyclic isothioureas.
Bioorg. Med. Chem. 2017, 25, 107. (e) Choi, S.-J.; Lee, J.-E.; Jeong, S.-
Y.; Im, I.; Lee, S.-D.; Lee, E.-J.; Lee, S. K.; Kwon, S.-M.; Ahn, S.-G.;
Yoon, J.-H.; Han, S.-Y.; Kim, J.-I.; Kim, Y.-C. 5,5′-Substituted
Indirubin-3′-oxime derivatives as potent cyclin-dependent kinase
inhibitors with anticancer activity. J. Med. Chem. 2010, 53, 3696.
(f) Katakawa, K.; Kitajima, M.; Aimi, N.; Seki, H.; Yamaguchi, K.;
Furihata, K.; Harayama, T.; Takayama, H. Structure elucidation and
synthesis of lycoposerramine-B, a novel oxime-containing lycopodium
alkaloid from lycopodium serratum thunb. J. Org. Chem. 2005, 70,
658.
(4) (a) Ding, R.; Liu, Y.; Han, M.; Jiao, W.; Li, J.; Tian, H.; Sun, B.
Synthesis of nitriles from primary amides or aldoximes under
conditions of a catalytic swern oxidation. J. Org. Chem. 2018, 83,
12939. (b) Sun, D.; Kitamura, E.; Yamada, Y.; Sato, S. Efficient
formation of nitriles in the vapor-phase catalytic dehydration of
aldoximes. Green Chem. 2016, 18, 3389. (c) Rapeyko, A.; Climent, M.
́
J.; Corma, A.; Concepcion, P.; Iborra, S. Nanocrystalline CeO2 as a
highly active and selective catalyst for the dehydration of aldoximes to
nitriles and one-pot synthesis of amides and esters. ACS Catal. 2016,
6, 4564. (d) Zhang, X.; Sun, J.; Ding, Y.; Yu, L. Dehydration of
aldoximes using PhSe(O)OH as the pre-catalyst in air. Org. Lett. 2015,
17, 5840.
(5) (a) Xu, Y.; Hu, W.; Tang, X.; Zhao, J.; Wu, W.; Jiang, H.
Palladium-catalyzed Csp2−H carbonylation of aromatic oximes:
selective access to benzo[d][1,2]oxazin-1-ones and 3-methyleneisoin-
dolin-1-ones. Chem. Commun. 2015, 51, 6843. (b) Crochet, P.;
Cadierno, V. Catalytic synthesis of amides via aldoximes rearrange-
ment. Chem. Commun. 2015, 51, 2495. (c) Ramon, R. S.; Bosson, J.;
Diez-Gonzalez, S.; Marion, N.; Nolan, S. P. Au/Ag-cocatalyzed
aldoximes to amides rearrangement under solvent- and acid-free
conditions. J. Org. Chem. 2010, 75, 1197. (d) Furuya, Y.; Ishihara, K.;
Yamamoto, H. Cyanuric chloride as a mild and active Beckmann
rearrangement catalyst. J. Am. Chem. Soc. 2005, 127, 11240.
E
https://dx.doi.org/10.1021/acs.orglett.0c03918
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Catal. 2016, 358, 2286. (k) Prateeptongkum, S.; Jovel, I.; Jackstell, R.;
Vogl, N.; Weckbecker, C.; Beller, M. First iron-catalyzed synthesis of
oximes from styrenes. Chem. Commun. 2009, 1990. (l) Sau, P.;
Rakshit, A.; Alam, T.; Srivastava, H. K.; Patel, B. K. Tert-butyl nitrite
mediated synthesis of 1,2,4-oxadiazol-5(4H)-ones from terminal aryl
alkenes. Org. Lett. 2019, 21, 4966. (m) Chen, R.; Zhao, Y.; Fang, S.;
Long, W.; Sun, H.; Wan, X. Coupling reaction of Cu-based carbene
and nitroso radical: a tandem reaction to construct isoxazolines. Org.
Lett. 2017, 19, 5896. (n) Sau, P.; Santra, S. K.; Rakshit, A.; Patel, B. K.
Tert-butyl nitrite-mediated domino synthesis of isoxazolines and
isoxazoles from terminal aryl alkenes and alkynes. J. Org. Chem. 2017,
82, 6358. (o) Sau, P.; Rakshit, A.; Modi, A.; Behera, A.; Patel, B. K.
Three sequential C-N bond formations: tert-butyl nitrite as a N1
synthon in a three component reaction leading to imidazo[1,2-
a]quinolines and imidazo[2,1-a]isoquinolines. J. Org. Chem. 2018, 83,
1056.
(11) (a) Mamedov, A.; Zhukova, N. A. Chapter 1-progress in
quinoxaline synthesis (part 2). Prog. Heterocycl. Chem. 2013, 25, 1.
(b) Akins, P. T.; Atkinson, R. P. Glutamate AMPA Receptor
Antagonist Treatment for Ischaemic Stroke. Curr. Med. Res. Opin.
2002, 18, s9−s13.
(12) (a) Shi, L.; Hu, W.; Wu, J.; Zhou, H.; Zhou, H.; Li, X.
Quinoxalinone as a privileged platform in drug development. Mini-
Rev. Med. Chem. 2018, 18, 392. (b) Carta, A.; Piras, S.; Loriga, G.;
Paglietti, G. Chemistry, biological properties and SAR analysis of
quinoxalinones. Mini-Rev. Med. Chem. 2006, 6, 1179.
(13) (a) Peng, C.; Ning, G.-H.; Su, J.; Zhong, G.; Tang, W.; Tian,
B.; Su, C.; Yu, D.; Zu, L.; Yang, J.; Ng, M.-F.; Hu, Y.-S.; Yang, Y.;
Armand, M.; Loh, K. P. Reversible multi-electron redox chemistry of
π-conjugated N-containing heteroaromatic molecule-based organic
cathodes. Nat. Energy 2017, 2, 17074. (b) Quinn, J.; Guo, C.; Ko, L.;
Sun, B.; He, Y.; Li, Y. Pyrazino[2,3-g]quinoxaline-2,7-dione based π-
conjugated polymers with affinity towards acids and semiconductor
performance in organic thin film transistors. RSC Adv. 2016, 6, 22043.
(14) Ke, Q.; Yan, G.; Yu, J.; Wu, X. Recent advances in the direct
functionalization of quinoxalin-2(1H)-ones. Org. Biomol. Chem. 2019,
17, 5863.
(15) For C−C cross-couplings of quinoxalinones, see: (a) Xie, L.-Y.;
Bai, Y.-S.; Xu, X.-Q.; Peng, X.; Tang, H.-S.; Huang, Y.; Lin, Y.-W.;
Cao, Z.; He, W.-M. Visible-light-induced decarboxylative acylation of
quinoxalin-2(1H)-ones with α-oxo carboxylic acids under metal-,
strong oxidant- and external photocatalyst-free conditions. Green
Chem. 2020, 22, 1720. (b) Bao, P.; Liu, F.; Lv, Y.; Yue, H.; Li, J.-S.;
Wei, W. Visible-light-promoted acridine red catalyzed aerobic
oxidative decarboxylative acylation of α-oxo-carboxylic acids with
quinoxalin-2(1H)-ones. Org. Chem. Front. 2020, 7, 492. (c) Wang, J.;
Sun, B.; Zhang, L.; Xu, T.; Xie, Y.; Jin, C. Transition-metal-free direct
C-3 cyanation of quinoxalin-2(1H)-ones with ammonium thiocyanate
as the “CN” source. Org. Chem. Front. 2020, 7, 113. (d) Xu, J.; Zhang,
H.; Zhao, J.; Ni, Z.; Zhang, P.; Shi, B.; Li, W. Photocatalyst-, metal-
and additive-free, direct C-H arylation of quinoxalin-2(1H)-ones with
aryl acyl peroxides induced by visible light. Org. Chem. Front. 2020, 7,
4031. (e) Yan, Z.; Sun, B.; Zhang, X.; Zhuang, X.; Yang, J.; Su, W.;
Jin, C. Construction of C(sp2)-C(sp3) bond between quinoxalin-
2(1H)-ones and N-hydroxyphthalimide esters via photocatalytic
decarboxylative coupling. Chem. - Asian J. 2019, 14, 3344.
(f) Zhang, H.; Xu, J.; Zhou, M.; Zhao, J.; Zhang, P.; Li, W. The
visible-light-triggered regioselective alkylation of quinoxalin-2(1H)-
ones via decarboxylation coupling. Org. Biomol. Chem. 2019, 17,
10201. (g) Xie, L.-Y.; Peng, S.; Fan, T.-G.; Liu, Y.-F.; Sun, M.; Jiang,
L.-L.; Wang, X.-X.; Cao, Z.; He, W.-M. Metal-free C3-alkoxycarbo-
nylation of quinoxalin-2(1H)-ones with carbazates as ecofriendly ester
sources. Sci. China: Chem. 2019, 62, 460. (h) Liu, L. X.; Pan, N.;
Sheng, W.; Su, L.; Liu, L.; Dong, J. Y.; Zhou, Y. B.; Yin, S. F. Visible
light-induced regioselective decarboxylative alkylation of the C(sp2)-
H bonds of non-aromatic heterocycles. Adv. Synth. Catal. 2019, 361,
4126. (i) Zhang, W.; Pan, Y.-L.; Yang, C.; Chen, L.; Li, X.; Cheng, J.-
P. Metal-free direct C-H cyanoalkylation of quinoxalin-2(1H)-ones by
organic photoredox catalysis. J. Org. Chem. 2019, 84, 7786. (j) Xie, L.-
Y.; Jiang, L.-L.; Tan, J.-X.; Wang, Y.; Xu, X.-Q.; Zhang, B.; Cao, Z.;
He, W.-M. Visible-light-initiated decarboxylative alkylation of
quinoxalin-2(1H)-ones with phenyliodine(III) dicarboxylates in
recyclable ruthenium(II) catalytic system. ACS Sustainable Chem.
Eng. 2019, 7, 14153. (k) Hong, G.; Yuan, J.; Fu, J.; Pan, G.; Wang, Z.;
Yang, L.; Xiao, Y.; Mao, P.; Zhang, X. Transition-metal-free
decarboxylative C3-difluoroarylmethylation of quinoxalin-2(1H)-
ones with α,α-difluoroarylacetic acids. Org. Chem. Front. 2019, 6,
1173. (l) Wang, L.; Liu, H.; Li, F.; Zhao, J.; Zhang, H.-Y.; Zhang, Y.
Copper-catalyzed C3-H difluoroacetylation of quinoxalinones with
ethyl bromodifluoroacetate. Adv. Synth. Catal. 2019, 361, 2354.
(m) Jin, C.; Zhuang, X.; Sun, B.; Li, D.; Zhu, R. Merging visible-light
photoredox and organoamine catalysis for the C-3 difluoroalkylation
of quinoxalin-2(1H)-ones. Asian J. Org. Chem. 2019, 8, 1490. (n) Xue,
W.; Su, Y.; Wang, K.-H.; Cao, L.; Feng, Y.; Zhang, W.; Huang, D.;
Hu, Y. Phenyliodonium diacetate mediated carbotrifluoromethylation
of quinoxalin-2(1H)-ones. Asian J. Org. Chem. 2019, 8, 887.
(o) Wang, J.; Sun, B.; Zhang, L.; Xu, T.; Xie, Y.; Jin, C. Visible-
light-induced trifluoromethylation of quinoxalin-2(1H)-ones under
photocatalyst-free conditions. Asian J. Org. Chem. 2019, 8, 1942.
(p) Wei, W.; Wang, L.; Yue, H.; Bao, P.; Liu, W.; Hu, C.; Yang, D.;
Wang, H. Metal-free visible-light-induced C-H/C-H cross-dehydro-
genative-coupling of quinoxalin-2(H)-ones with simple ethers. ACS
Sustainable Chem. Eng. 2018, 6, 17252. (q) Liu, S.; Huang, Y.; Qing,
F.-L.; Xu, X.-H. Transition-metal-free decarboxylation of 3,3,3-
trifluoro-2,2-dimethylpropanoic acid for the preparation of C(CF3)-
Me2-containing heteroarenes. Org. Lett. 2018, 20, 5497. (r) Hu, L.;
Yuan, J.; Fu, J.; Zhang, T.; Gao, L.; Xiao, Y.; Mao, P.; Qu, L. Copper-
catalyzed direct C-3 benzylation of quinoxalin-2(1H)-ones with
methylarenes under microwave irradiation. Eur. J. Org. Chem. 2018,
2018, 4113. (s) Fu, J.; Yuan, J.; Zhang, Y.; Xiao, Y.; Mao, P.; Diao, X.;
Qu, L. Copper-catalyzed oxidative coupling of quinoxalin-2(1H)-ones
with alcohols: access to hydroxyalkylation of quinoxalin-2(1H)-ones.
Org. Chem. Front. 2018, 5, 3382. (t) Yuan, J.; Fu, J.; Yin, J.; Dong, Z.;
Xiao, Y.; Mao, P.; Qu, L. Transition-metal-free direct C-3 alkylation of
quinoxalin-2(1H)-ones with ethers. Org. Chem. Front. 2018, 5, 2820.
(u) Yin, K.; Zhang, R. Mild and direct C-H arylation of quinoxalin-
2(1H)-ones with aryldiazonium salts under metal-free conditions.
Synlett 2018, 29, 597. (v) Ramesh, B.; Reddy, C. R.; Kumar, G. R.;
Reddy, B. V. S. Mn(OAc)3*2H2O promoted addition of arylboronic
acids to quinoxalin-2-ones. Tetrahedron Lett. 2018, 59, 628.
(w) Wang, L.; Zhang, Y.; Li, F.; Hao, X.; Zhang, H.-Y.; Zhao, J.
Direct C-H trifluoromethylation of quinoxalin-2(1H)-ones under
transition-metal-free conditions. Adv. Synth. Catal. 2018, 360, 3969.
(x) Yuan, J.-W.; Fu, J.-H.; Liu, S.-N.; Xiao, Y.-M.; Mao, P.; Qu, L.-B.
Metal-free oxidative coupling of quinoxalin-2(1H)-ones with
arylaldehydes leading to 3-acylated quinoxalin-2(1H)-ones. Org.
Biomol. Chem. 2018, 16, 3203. (y) Yin, K.; Zhang, R. Transition-
metal-free direct C-H arylation of quinoxalin-2(1H)-ones with
diaryliodonium salts at room temperature. Org. Lett. 2017, 19,
1530. (z) Yuan, J.; Liu, S.; Qu, L. Transition metal-free direct C-3
arylation of quinoxalin-2(1H)-ones with arylamines under mild
conditions. Adv. Synth. Catal. 2017, 359, 4197.
(16) For C−N cross-couplings of quinoxalinones, see: (a) Xie, L.-Y.;
Hu, J.-L.; Song, Y.-X.; Jia, G.-K.; Lin, Y.-W.; He, J.-Y.; Cao, Z.; He,
W.-M. Visible-light-initiated cross-dehydrogenative coupling of
quinoxalin-2(1H)-ones and simple amides with air as an oxidant.
ACS Sustainable Chem. Eng. 2019, 7, 19993. (b) Yuan, J.-W.; Zhu, J.-
L.; Li, B.; Yang, L.-Y.; Mao, P.; Zhang, S.-R.; Li, Y.-C.; Qu, L.-B.
Transition-metal free C3-amidation of quinoxalin-2(1H)-ones using
selectfluor as a mild oxidant. Org. Biomol. Chem. 2019, 17, 10178.
(c) Yang, Q.; Yang, Z.; Tan, Y.; Zhao, J.; Sun, Q.; Zhang, H.-Y.;
Zhang, Y. Direct C(sp2)-H amination to synthesize primary 3-
aminoquinoxalin-2(1H)-ones under simple and mild conditions. Adv.
Synth. Catal. 2019, 361, 1662. (d) Yang, Q.; Zhang, Y.; Sun, Q.;
Shang, K.; Zhang, H.-Y.; Zhao, J. [3 + 2] Cyclization of
azidotrimethylsilane with quinoxalin-2(1H)-ones to synthesize
tetrazolo[1,5-a]quinoxalin-4(5H)-ones. Adv. Synth. Catal. 2018, 360,
4509. (e) Wei, W.; Wang, L.; Bao, P.; Shao, Y.; Yue, H.; Yang, D.;
F
https://dx.doi.org/10.1021/acs.orglett.0c03918
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Yang, X.; Zhao, X.; Wang, H. Metal-free C(sp2)-H/N-H cross-
dehydrogenative coupling of quinoxalinones with aliphatic amines
under visible-light photoredox catalysis. Org. Lett. 2018, 20, 7125.
(f) Hoang, T. T.; To, T. A.; Cao, V. T. T.; Nguyen, A. T.; Nguyen, T.
T.; Phan, N. T. S. Direct oxidative C-H amination of quinoxalinones
under copper-organic framework catalysis. Catal. Commun. 2017, 101,
20. (g) Gupta, A.; Deshmukh, M. S.; Jain, N. Iodine-catalyzed C-N
bond formation: synthesis of 3-aminoquinoxalinones under ambient
conditions. J. Org. Chem. 2017, 82, 4784.
(17) For C−O cross-couplings of quinoxalinones, see: (a) Xu, J.;
Yang, H.; Cai, H.; Bao, H.; Li, W.; Zhang, P. Transition-metal and
solvent-free oxidative C-H fluoroalkoxylation of quinoxalinones with
fluoroalkyl alcohols. Org. Lett. 2019, 21, 4698. (b) Zhou, J.; Zhou, P.;
Zhao, T.; Ren, Q.; Li, J. (Thio)etherification of quinoxalinones under
visible-light photoredox catalysis. Adv. Synth. Catal. 2019, 361, 5371.
(c) Peng, S.; Hu, D.; Hu, J.-L.; Lin, Y.-W.; Tang, S.-S.; Tang, H.-S.;
He, J.-Y.; Cao, Z.; He, W.-M. Metal-free C3 hydroxylation of
quinoxalin-2(1H)-ones in water. Adv. Synth. Catal. 2019, 361, 5721.
(d) Zhao, L.; Wang, L.; Gao, Y.; Wang, Z.; Li, P. Visible-light-induced
alkoxylation of quinoxalin-2(1H)-ones with alcohols for the synthesis
of heteroaryl ethers. Adv. Synth. Catal. 2019, 361, 5363. (e) Yang, Q.;
Han, X.; Zhao, J.; Zhang, H.-Y.; Zhang, Y. Direct C3 alkoxylation of
quinoxalin-2(1H)-ones with alcohols via cross-dehydrogenative
coupling under catalyst-free conditions. J. Org. Chem. 2019, 84,
11417.
(18) For C−P cross-couplings of quinoxalinones, see: (a) Mai, W.-
P.; Yuan, J.-W.; Zhu, J.-L.; Li, Q.-Q.; Yang, L. R.; Xiao, Y.-M.; Mao,
P.; Qu, L.-B. Selectfluor-mediated direct C-H phosphonation of
quinoxalin-2(1H)-ones under base and transition-metal free con-
ditions. ChemistrySelect 2019, 4, 11066. (b) Wang, J.; Li, J.; Wei, Y.;
Yang, J.; Huo, C. Copper-catalyzed oxidative phosphonation of 3,4-
dihydro-1,4-benzoxazin-2-ones. Org. Chem. Front. 2018, 5, 3534.
(c) Kim, Y.; Kim, D. Y. Visible light photoredox-catalyzed
phosphorylation of quinoxalin-2(1H)-ones. Tetrahedron Lett. 2018,
59, 2443. (d) Gao, M.; Li, Y.; Xie, L.; Chauvin, R.; Cui, X. Direct
phosphonation of quinoxalin-2(1H)-ones under transition-metal-free
conditions. Chem. Commun. 2016, 52, 2846.
(19) For C−S cross-couplings of quinoxalinones, see: (a) Xie, L.-Y.;
Chen, Y.-L.; Qin, L.; Wen, Y.; Xie, J.-W.; Tan, J.-X.; Huang, Y.; Cao,
Z.; He, W.-M. Visible-light-promoted direct C-H/S-H cross-coupling
of quinoxalin-2(1H)-ones with thiols leading to 3-sulfenylated
quinoxalin-2(1H)-ones in air. Org. Chem. Front. 2019, 6, 3950.
(b) Teng, Q.-H.; Yao, Y.; Wei, W.-X.; Tang, H.-T.; Li, J.-R.; Pan, Y.-
M. Direct C-H sulfenylation of quinoxalinones with thiols under
visible-light-induced photocatalyst-free conditions. Green Chem. 2019,
21, 6241.
(20) For multicomponent reactions of quinoxalinones, see: (a) Shen,
J.; Xu, J.; Huang, L.; Zhu, Q.; Zhang, P. Hypervalent iodine(III)-
promoted rapid cascade reaction of quinoxalinones with unactivated
alkenes and TMSN3. Adv. Synth. Catal. 2020, 362, 230. (b) Meng, N.;
Wang, L.; Liu, Q.; Li, Q.; Lv, Y.; Yue, H.; Wang, X.; Wei, W. Metal-
free trifluoroalkylation of quinoxalin-2(1H)-ones with unactivated
alkenes and langlois’ reagent. J. Org. Chem. 2020, 85, 6888. (c) Zheng,
D.; Studer, A. Photoinitiated three-component α-perfluoroalkyl-β-
heteroarylation of unactivated alkenes via electron catalysis. Org. Lett.
2019, 21, 325. (d) Dutta, H. S.; Ahmad, A.; Khan, A. A.; Kumar, M.;
Raziullah; Koley, D. Metal free benzylation and alkylation of
quinoxalin-2(1H)-ones with alkenes triggered by sulfonyl radical
generated from sulfinic acids. Adv. Synth. Catal. 2019, 361, 5534. For
other multicomponent reactions, see: (e) Yang, L.; Wan, J.-P. Ethyl
lactate-involved three-component dehydrogenative reactions: biomass
feedstock in diversity-oriented quinoline synthesis. Green Chem. 2020,
22, 3074. (f) Yu, S.; Chen, J.; Liu, G.; Lei, J.; Hu, W.; Qiu, H. A
gold(i)-catalysed chemoselective three-component reaction between
phenols, α-diazocarbonyl compounds and allenamides. Chem.
Commun. 2020, 56, 1649. (g) Shi, T.; Teng, S.; Wei, Y.; Guo, X.;
Hu, W. Synthesis of spiro[2,3-dihydrofuran-3,3′-oxindole] derivatives
via a multi-component cascade reaction of α-diazo esters, water,
isatins and malononitrile/ethyl cyanoacetate. Green Chem. 2019, 21,
4936. (h) Lv, X.; Kang, Z.; Xing, D.; Hu, W. Cu(I)-catalyzed three-
component reaction of diazo compound with terminal alkyne and
nitrosobenzene for the synthesis of trifluoromethyl dihydroisoxazoles.
Org. Lett. 2018, 20, 4843. (i) Wan, J.-P.; Zhou, Y.; Liu, Y.; Sheng, S.
Metal-free oxidative carbonylation on enaminone C = C bond for the
cascade synthesis of benzothiazole-containing vicinal diketones. Green
Chem. 2016, 18, 402. (j) Jiang, L.; Jin, W.; Hu, W. Double C-H
functionalization of indoles via three-component reactions/CuCl2-
catalyzed aerobic dehydrogenative coupling for the synthesis of
polyfunctional cyclopenta[b]indoles. ACS Catal. 2016, 6, 6146.
(k) Wan, J.-P.; Cao, S.; Liu, Y. A metal- and azide-free multi-
component assembly toward regioselective construction of 1,5-
disubstituted 1,2,3-triazoles. J. Org. Chem. 2015, 80, 9028.
(l) Sapuppo, G.; Wang, Q.; Swinnen, D.; Zhu. Copper-catalyzed
three-component synthesis of 5-acetamidoimidazoles from carbodii-
mides, acyl chlorides and isocyanides. Org. Chem. Front. 2014, 1, 240.
(m) Guo, X.; Hu, W. Novel multicomponent reactions via trapping of
protic onium ylides with electrophiles. Acc. Chem. Res. 2013, 46, 2427.
(21) (a) Cao, Z.; Zhu, Q.; Lin, Y.-W.; He, W.-M. The concept of
dual roles design in clean organic preparation. Chin. Chem. Lett. 2019,
30, 2132. (b) Lu, L.-H.; Wang, Z.; Xia, W.; Cheng, P.; Zhang, B.; Cao,
Z.; He, W.-M. Sustainable routes for quantitative green selenocyana-
tion of activated alkynes. Chin. Chem. Lett. 2019, 30, 1237.
(22) (a) Shen, C.; Wang, A.; Xu, J.; An, Z.; Loh, K. Y.; Zhang, P.;
Liu, X. Recent advances in the catalytic synthesis of 4-quinolones.
Chem. 2019, 5, 1059. (b) Xu, J.; Du, K.; Shen, J.; Shen, C.; Chai, K.;
Zhang, P. Copper(II)-catalyzed selective para amination of arylamine
with pyrazole by C-H functionalization. ChemCatChem 2018, 10,
3675. (c) Xu, J.; Cheng, K.; Shen, C.; Bai, R.; Xie, Y.; Zhang, P.
Coordinating activation strategy-induced selective C-H trifluorome-
thylation of anilines. ChemCatChem 2018, 10, 965. (d) Shen, C.;
Yang, M.; Xu, J.; Chen, C.; Zheng, K.; Shen, J.; Zhang, P.
Iodobenzene-catalyzed synthesis of aryl sulfonate esters from
aminoquinolines via remote radical C-O cross-coupling. RSC Adv.
2017, 7, 49436. (e) Xu, J.; Shen, C.; Zhu, X.; Zhang, P.; Ajitha, M. J.;
Huang, K.; An, Z.; Liu, X. Remote C-H activation of quinolines
through copper-catalyzed radical cross-coupling. Chem. - Asian J.
2016, 11, 882. (f) Xu, J.; Zhu, X.; Zhou, G.; Ying, B.; Ye, P.; Su, L.;
Shen, C.; Zhang, P. Copper(II)-catalyzed C5 and C7 halogenation of
quinolines using sodium halides under mild conditions. Org. Biomol.
Chem. 2016, 14, 3016.
(23) (a) Shen, C.; Shen, H.; Yang, M.; Xia, C.; Zhang, P. A novel d-
glucosamine-derived pyridyl-triazole@palladium catalyst for solvent-
free mizoroki-heck reactions and its application in the synthesis of
axitinib. Green Chem. 2015, 17, 225. (b) Shen, C.; Xu, J.; Yu, W.;
Zhang, P. A highly active and easily recoverable chitosan@copper
catalyst for the C-S coupling and its application in the synthesis of
zolimidine. Green Chem. 2014, 16, 3007.
(24) Chai, J. D.; Head-Gordon, M. Long-range corrected hybrid
density functionals with damped atom-atom dispersion corrections.
Phys. Chem. Chem. Phys. 2008, 10, 6615.
(25) Naresh, V. V.; Kumari, Y. B.; Sridhar, M.; Raju, A. R.; Rao, A. S.
Synthesis and biological evaluation of 1,3,4-oxadiazole fused
resveratrol derivatives as anticancer agents. Asian J. Chem. 2020, 32,
1967.
(26) (a) Yi, H.; Zhang, G.; Wang, H.; Huang, Z.; Wang, J.; Singh, A.
K.; Lei, A. Recent advances in radical C-H activation/radical cross-
coupling. Chem. Rev. 2017, 117, 9016. (b) Tang, S.; Liu, K.; Liu, C.;
Lei, A. Olefinic C-H functionalization through radical alkenylation.
Chem. Soc. Rev. 2015, 44, 1070.
(27) (a) Huo, C.; Wu, M.; Jia, X.; Xie, H.; Yuan, Y.; Tang, J. Aerobic
oxidative Mannich reaction promoted by catalytic amounts of stable
radical cation salt. J. Org. Chem. 2014, 79, 9860. (b) Chen, W.; Seidel,
D. The redox-Mannich reaction. Org. Lett. 2014, 16, 3158. (c) Nikam,
S. S.; Sahasrabudhe, A. D.; Shastri, R. K.; Ramanathan, S. A facile
synthesis of (2-oxo-1,2-dihydroquinoxalin-3-yl)-methyl ketones and
(quinoxalin-2-yl)-methyl ketones. Synthesis 1983, 1983, 145.
G
https://dx.doi.org/10.1021/acs.orglett.0c03918
Org. Lett. XXXX, XXX, XXX−XXX