Copper-Catalyzed Direct Carbamoylation of Quinoxalin-2(1H)-ones with Hydrazinecarboxamides Under Mild Conditions

Article abstract of DOI:10.1002/ejoc.201901858

A direct C–H bond carbamoylation of quinoxalin-2(1H)-ones with hydrazinecarboxamides has been developed. This reaction provides a series of 3-carbamoylquinoxalin-2(1H)-one derivatives in moderate to good yields under mild conditions with a broad range of

Full text of DOI:10.1002/ejoc.201901858

A Journal of
Accepted Article
Title: Copper-Catalyzed Direct Carbamoylation of Quinoxalin-2(1H)-
Ones with Hydrazinecarboxamides under Mild Conditions
Authors: Xianglong Chu, Yujuan Wu, Haigen Lu, and Chen Ma
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901858
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901858
Supported by

10.1002/ejoc.201901858
European Journal of Organic Chemistry
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper-Catalyzed Direct Carbamoylation of Quinoxalin-2(1H)-
Ones with Hydrazinecarboxamides under Mild Conditions
Xianglong Chu,a Yujuan Wu,a Haigen Lu,a Bingchuan Yangb* and Chen Maa*
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
In view of their remarkable importance, the direct
functionalization of C3 position of quinoxalin-2(1H)-one
has been extensively studied in recent organic synthesis,
for instance (Scheme 1a), etherification,[8] amination,[9]
alkylation,[10] benzylation,[11] arylation,[12] acylation,[13]
Abstract:
A
direct C-H bond carbamoylation of
quinoxalin-2(1H)-ones with hydrazinecarboxamides has
been developed. This reaction provides a series of 3-
carbamoylquinoxalin-2(1H)-one derivatives in moderate to
good yields under mild conditions with a broad range of
substrates and functional group tolerance. The present
methodology affords a convenient and practical access to
pharmaceutically active 3-carbamoylquinoxalin-2(1H)-one
derivatives.
phosphonation,[14]
trifluoromethylation.[15]
Although
remarkable achievements have been obtained, the direct
C3-H carbamoylation of quinoxalin-2(1H)-ones remains
scarce. Due to importance of the 3-carbamoylquinoxalin-
2(1H)-one derivatives, the development of a direct and
simple method for synthesis of 3-carbamoylated
quinoxalin-2(1H)-one derivatives is still highly desirable.
The quinoxalin-2(1H)-one derivatives have attracted
tremendous attention due to pharmaceutically important
molecules[1] and outstanding biological properties.[2]
Morever, 3-carbamoylquinoxalin-2(1H)-one derivative as
an important pharmacophore has shown numerous
signifigance biological properties.[3] Examples include the
c-Met kinase inhibitors,[4] small-molecule HCV
inhibitors,[5] PDE4 inhibitors[6] and anti-cancer properties[7]
(Figure 1).
Figure 1. Pharmaceutically active 3-carbamoylquinoxalin-
2(1H)-one derivatives.
Scheme 1. Synthesis of 3-functionalized quinoxalin-
2(1H)-one derivatives.
Amide bond linkage is one of the most essential unit
omnipresent in many organic molecules including
proteins,[16] natural alkaloids,[17] fine chemicals and
pharmaceuticals.[18] About 60% of reactions (including 7.2%
of peptide synthesis and 50% of amide-bond coupling)
belong to amide bond formation in current medicinal
chemistry according to litreature (2014) reported.[19] It is
notable that carboxamide is the most abundant functional
group in pharmaceutical structure, more than 25% drug
[a]
[b]
Dr. Xianglong Chu, Yujuan Wu, Haigen Lu, Dr. Bingchuan Yang* and
Prof. Dr. Chen Ma*
school of Chemistry and Chemical Engineering, Shandong University,
Jinan, 250100, P R China
E-mail: chenma@sdu.edu.cn
School of Chemistry and Chemical Engineering, Liaocheng University,
Liaocheng, 252059, PR China
E-mail: yangbingchuan@lcu.edu.cn
Supporting information for this article is given via a link at the end of
the document.
1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901858
European Journal of Organic Chemistry
molecules contain at least one amide functional group.[20]
In classical amide-bond formation, the activation of
carboxylic acid or employment of novel catalyst is usually
necessary.[21] However, there are several drawbacks in the
classic synthetic methods of amides, including too much
reaction waste, requirement of prefunctionalized starting
materials, harsh reaction conditions and limited substrate
scope. In additation, it has always been difficult to
synthesize sterically hindered amide. Therefore, the
developement of novel and efficient synthetic methods for
the direct formation of 3-carbamoylated quinoxalin-2(1H)-
one derivatives is in high demand. In continuation of our
previous efforts on direct C-H bond functionalization,[22]
we herein report our recent work on direct carbamoylation
of quinoxalin-2(1H)-ones with hydrazinecarboxamides by
a N-acyl radical process (scheme 1b), this protocol features
without the necessary for pre-activation of reactant, broad
substrate scope and moderate to good yields. To the best of
our knowledge, direct carbamoylation on the C3 position
of quinoxalin-2(1H)-one has not been reported.
It is worthy to be noticed that sterically hindered amides
can be smoothly introduced at C3 position of quinoxalin-
2(1H)-one in our reaction system.
for this transformation (Table 1, entry 2), and the copper
was much more effective than iodine (Table 1, entry 3).
Various copper catalysts were then investigated, and CuI
exhibited the best effciency to afford 3aa in 56% yield
(Table 1, entries 4-7). The subsequent screening of
oxidants showed that among the various oxidants
(dibenzoyl peroxide (BPO), tert-butyl peroxybenzoate, di-
t-butyl peroxide and (NH4)2S2O8), BPO showed the best
efficiency (Table 1, entries 8-11). Finally, other solvents
(DMSO: H2O, dioxane, DMF, toluene) were used instead
of DMSO, giving a decreased yield of 3aa (Table 1, entries
12-15). Thus, we chose 1a (0.2 mmol), 2a (3.0 equiv.) 10
mol% of CuI and 3 equivalent of BPO in 1.5 mL DMSO at
100 oC for 18 hours as the optimal reaction conditions.
Table 2. Synthesis of the products 3aa–3ar. [a],[b]
Table 1. Optimization of quinoxalin-2(1H)-
ones with hydrazinecarboxamides.[a], [b]
entry [Cu]
[O]
solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
yield, %[b]
31
‐
Trace
47
38
40
56
70
1
2
CuBr
‐
TBHP
TBHP
TBHP
3
I2
4
Cu(OAc)2•H2O TBHP
5
6
7
CuCl
Cu(OAc)2
CuI
TBHP
TBHP
TBHP
BPO
TBPB
DTBP
(NH4)2
S2O8
8
CuI
9
CuI
29
‐
10
CuI
11
12
CuI
CuI
DMSO
‐
DMSO/H2
O = 2:1
Dioxane
DMF
BPO
39
13
14
15
CuI
CuI
CuI
BPO
BPO
BPO
27
‐
20
Toluene
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.5 mmol), [Cu]
o
(0.02 mmol), [O] (0.6 mmol), solvent (1.5 mL), 100 C, 18
h.
[b] Isolated yield.
Initially, we selected 1-methylquinoxalin-2(1H)-one (1a)
[a] Unless specifically noted otherwise, reaction conditions:
1a (0.2 mmol), 2a (0.5 mmol), CuI (0.02 mmol), BPO (0.6
mmol), solvent (1.5 mL), 100 oC, 18 h.
as
a
model
substrate
to
react
with
N-
phenylhydrazinecarboxamide (2a) in the presence of 10
mol% of CuBr, 3 equivalent of tert-butyl hydroperoxide
(TBHP) in DMSO at 100 oC. To our delight, the desired 4-
methyl-3-oxo-N-phenyl-3,4-dihydroquinoxaline-2-
carboxamide product (3aa) was obtained in 31% yield
(Table 1, entry 1). The catalyst was proven to be essential
[b] Isolated yield.
With the optimized reaction conditions in hand, we
explored the reaction of 2a with various quinoxalin-2(1H)-
2
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901858
European Journal of Organic Chemistry
ones under the standard conditions. The results were
shown in Table 2. First, we investigated the substitution at
R1 with R2 = CH3. A series of quinoxalin-2(1H)-ones with
different electronic properties smoothly underwent the
reaction, the corresponding compounds were obtained in
60-86% yields (Table 2, 3aa-3ae). Generally, electron-
withdrawing substituents on the aromatic ring has positive
effect on the yield. It is worth mentioning that strong
position, the corresponding product 3bg was obtained in 76%
yield. We were pleased to see that sterically hindered
amides was successfully introduced at C3 position of
quinoxalin-2(1H)-one (3bh-3bi). In addition, N-aliphatic
group substrate (N-cyclohexylhydrazinecarboxamide)
proceed smoothly to give the desired compound 3bj in 62%
yield. Finally, the π-extended aromatic 2ak provided the
expected product 3bk in 60% yield.
conjugated
aromatic
system
such
as
1-
To provide further insight into the reaction system, we
peformed the reaction in the presence 3 equiv. of BHT or
TEMPO under the standard conditions. The transformation
was completely inhibited (Scheme 2). This result indicated
that the reaction may proceed via a radical pathway.
methylbenzo[g]quinoxalin-2(1H)-one provided the desired
product 3af in a yield of 48%. We next studied the
compatibility with N-substituted quinoxalinones with R1 =
H. To our delight, various N-substituted quinoxalinones
were well compatible in this reaction system. We observed
that N-protected aliphatic groups such as N-propyl, N-butyl,
N-cyclohexylmethyl, N-esteryl, N-2-oxo-2-phenylethyl, N-
allylic, N-cinnamyl and N-benzyl were all suitable for this
reaction, providing the desired products in moderate to
good yield. In addition, N-phenyl quinoxalinone proceeded
smoothly to give the corresponding product 3ar in 72%
yield.
Scheme 2. Control experiments.
On the basis of the control experiments and literature
Table 3. Synthesis of the products 3ba–3bk.[a],[b]
reports,[11],[12],[23] we proposed
a
plausible reaction
mechanism (Scheme 3). The benzoyl radical is generated
via homolysis or copper-catalyzed decomposition of
dibenzoyl peroxide. Radical intermediate 4 was generated
by
the
single-electron
transfer
between
N-
phenylhydrazinecarboxamide (2a) and RO●. The stepwise
single-electron transfer and deprotonation forms radical
intermediate 7 with the release of molecular nitrogen. The
addition of 7 to the 1a affords radical intermediate 8,
which is further oxidized by Cu (II) to form nitrogen cation
intermediate 9. Finally, desired compound 3aa is obtained
by the deprotonation of 9.
Scheme 3. Presumptive reaction mechanism.
[a] Unless specifically noted otherwise, reaction conditions:
1a (0.2 mmol), 2a (0.5 mmol), CuI (0.02 mmol), BPO (0.6
mmol), solvent (1.5 mL), 100 oC, 18 h.
[b] Isolated yield.
Further, we studied the scope of carbamoylation of
quinoxalin-2(1H)-ones reaction by investigating a wide
variety of N-substitued hydrazinecarboxamide compounds
(Table 3). The substituents (R3) on the N-phenyl was first
investigated. Both electon-withdrawing groups (4-Cl, 4-Br,
4-F) and electron-donating groups (4-methoxy, 4-methyl,
4-tert-butyl) afforded the desired compound 3ba-3bf in
good yield. When the substituent was present in ortho-
In conclusion, an efficient and simple method for
synthesis of 3-carbamoylated quinoxalin-2(1H)-ones base
on copper-catalyzed direct carbamoylation of quinoxalin-
2(1H)-ones at C3 position has been reported. This process
exhibits good functional group tolerance with a broad
substrate scope and provides an efficient method for the
introduction sterically hindered amides at C3 position of
quinoxalin-2(1H)-one. This method features cheap catalyst
3
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901858
European Journal of Organic Chemistry
and without the necessary for pre-activation of reactant.
Our research also provides a novel and efficient synthetic
method for the formation of amide on α,β-unsaturated
compound. Our future work will extend this efficient
functionalization strategy to other α,β-unsaturated bonds.
[3] a) T. Harayama, Y. Tezuka, T. Taga, F. Yoneda, J.
Chem. Soc., Perkin Trans. 1 1987, 75. b) J. B.
Townsend, F. Shaheen, R. Liu, K. S. Lam, J. Comb.
Chem. 2010, 12, 700. c) J. Unitt, M. Fagura, T. Phillips,
S. King, M. Perry, A. Morley, C. MacDonald, R.
Weaver, J. Christie, S. Barber, R. Mohammed, M. Paul,
A. Cook, A. Baxter, Bioorg. Med. Chem. Lett. 2011, 21,
2991.
Experimental Section
[4] J. Liu, D. Yang, X. Yang, M. Nie, G. Wu, Z. Wang, W.
Li, Y. Liu, P. Gong, Bioorg. Med. Chem. 2017, 25,
4475.
General Procedure for the carbamoylation of
Quinoxalin-2(1H)-ones
[5] Q. Zhong, R. Liu, G. Liu, Mol. Diversity 2015, 19, 829.
A
round-bottomed flask was charged with 1-
[6] C. De Savi, R. J. Cox, D. J. Warner, A. R. Cook, M. R.
Dickinson, A. McDonough, L. C. Morrill, B. Parker, G.
Andrews, S. S. Young, P. S. Gilmour, R. Riley, M. S.
Dearman, J. Med. Chem. 2014, 57, 4661.
methylquinoxalin-2(1H)-one (1a) (0.2 mmol, 0.0320 g), N-
phenylhydrazinecarboxamide (2a) (0.5 mmol, 0.0756 g),
BPO (0.6 mmol, 0.1453 g), CuI (0.02 mmol, 0.0038 g) and
o
DMSO (1.5 mL). Then, the mixture was stirred at 100 C
under air until the reaction was completed (monitored by
TLC). The cooled reaction mixture was added with ethyl
acetate (20 mL) and and saturated aqueous NaCl (20 mL),
then filtered by sintered funnel. The remaining aqueous
was extracted with ethyl acetate (20 mL×3). The combined
organic layers were dried with Na2SO4 and evaporated
under vacuum to afford the residue. The residue was
purified by column chromatography (silica gel) with
petroleum ether/ethyl acetate (3: 1) to obtain pure product
3aa as a yellow solid (70% yield).
[7] Y. Usuki, K. Mitomo, N. Adachi, X. Ping, K.-I. Fujita,
O. Sakanaka, K. Iinuma, H. Iio, M. Taniguchi, Bioorg.
Med. Chem. Lett. 2005, 15, 2011.
[8] J. Zhou, P. Zhou, T. Zhao, Q. Ren, J. Li, Adv. Synth.
Catal. 2019, 361, 5371.
[9] a) A. Gupta, M. S. Deshmukh, N. Jain, J. Org. Chem.
2017, 82, 4784. b) W. Wei, L. Wang, P. Bao, Y. Shao,
H. Yue, D. Yang, X. Yang, X. Zhao, H. Wang, Org.
Lett. 2018, 20, 7125.
[10] J. Yuan, J. Fu, J. Yin, Z. Dong, Y. Xiao, P. Mao, L. Qu,
Org. Chem. Front. 2018, 5, 2820-2828.
Acknowledgements
[11] L. Hu, J. Yuan, J. Fu, T. Zhang, L. Gao, Y. Xiao, P.
We are grateful to the National Science Foundation of China (No.
21572117), the Shandong Key Research Program (Nos.
2019JZZY021015,2019GHY112053) for their financial support.
We also are grateful to the Analytical Center for Structural
Constituent and Physical Property of Core Facilities Sharing
Platform, Shandong University for their technology and services
support.
Mao, L. Qu, Eur. J. Org. Chem. 2018, 30, 4113.
[12] a) K. Yin, R. Zhang, Org. Lett. 2017, 19, 1530. b) J.
Yuan, S. Liu, L. Qu, Adv. Synth. Catal. 2017, 359,
4197.
[13] a) J. Yuan, J. Fu, S. Liu, Y. Xiao, P. Mao, L. Qu, Org.
Biomol. Chem. 2018, 16, 3203. b) X. Zeng, C. Liu, X.
Wang, J. Zhang, X. Wang, Y. Hu, Org. Biomol. Chem.
2017, 15, 8929.
References
[1] a) L. Shi, H. Zhou, J. Wu, X. Li, Mini-Rev. Org. Chem.
2015, 12, 96. b) A. Carta, S. Piras, G. Loriga, G.
Paglietti, Mini-Rev. Med. Chem. 2006, 6, 1179. c) M.
Patel, R. J. McHugh, B. C. Cordova, R. M. Klabe, S.
Erickson-Viitanen, G. L. Trainor, J. D. Rodgers, Bioorg.
Med. Chem. Lett. 2000, 10, 1729. d) J. Son, J. Zhu, P.
Phuan, O. Cil, A. P. Teuthorn, C. K. Ku, S. Lee, A. S.
Verkman, M. J. Kurth, J. Med. Chem. 2017, 60, 2401
[14] M. Gao, Y. Li, L. Xie, R. Chauvin, X. Cui, Chem.
Commun. 2016, 52, 2846.
[15] L. Wang, Y. Zhang, F. Li, X. Hao, H. Zhang, J. Zhao,
Adv. Synth. Catal. 2018, 360, 3969.
[16] a) J. D. Majmudar, H. B. Hodges-Loaiza, K. Hahne, J.
L. Donelson, J. Song, L. Shrestha, M. L. Harrison, C. A.
Hrycyna, R. A. Gibbs, Bioorg. Med. Chem. 2012, 20,
283. b) V. Vagenende, T. Ching, R. Chua, N.
Thirumoorthi, P. Gagnon, ACS Appl. Mater. Interfaces
2013, 5, 4472. c) N. A. Biok, A. D. Passow, C. Wang,
C. A. Bingman, N. L. Abbott, S. H. Gellman,
Biochemistry 2019, 58, 4821.
[2] a) M. Patel, R. J. McHugh, B. C. Cordova, R. M. Klabe,
S. Erickson-Viitanen, G. L. Trainor, J. D. Rodgers,
Bioorg. Med. Chem. Lett. 2000, 10, 1729. b) J. Dudash,
Y. Zhang, J. B. Moore, R. Look, Y. Liang, M. P.
Beavers, B. R. Conway, P. J. Rybczynski, K. T.
Demarest, Bioorg. Med. Chem. Lett. 2005, 15, 4790. c)
J. Miyashiro, K. W. Woods, C. H. Park, X. Liu, Y. Shi,
E. F. Johnson, J. J. Bouska, A. M. Olson, Y. Luo, E. H.
Fry, V. L. Giranda, T. D. Penning, Bioorg. Med. Chem.
Lett. 2009, 19, 4050. d) Y. Zou, X. Qin, X. Hao, W.
Zhang, S. Yang, Y. Yang, Z. Han, B. Ma, C. Zhu,
Bioorg. Med. Chem. Lett. 2015, 25, 3924.
[17] a) C. E. Puerto Galvis, V. V. Kouznetsov, J. Org. Chem.
2019, 84, 15294. b) M. M. Pompeo, J. H. Cheah, M.
Movassaghi, J. Am. Chem. Soc. 2019, 141, 14411. c) T.
Che, Y. Wang, Z. Huang, J. Tan, Z. Huang, S. Chen,
Molecules 2018, 23, 493. d) M. D. Patil, G. Grogan, H.
Yun, ChemCatChem 2018, 10, 4797.
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901858
European Journal of Organic Chemistry
[18] a) L. Wang, Y. Zhang, F. Li, X. Hao, H. Zhang, J. Zhao, [22] a) Z. Zhang, C. Xie, X. Tan, G. Song, L. Wen, H. Gao,
Adv. Synth. Catal. 2018, 360, 3969. b) Handoko, S.
Satishkumar, N. R. Panigrahi, P. S. Arora, J. Am. Chem.
Soc. 2019, 141, 15977. c) T. Nanjo, E. C. de Lucca, M.
C. White, J. Am. Chem. Soc. 2017, 139, 14586. d) K.
Tani, B. M. Stoltz, Nature 2006, 441, 731
C. Ma, Org. Chem. Front. 2015, 2, 942. b) X. Chu, T.
Duan, X. Liu, L. Feng, J. Jia, C. Ma, Org. Biomol.
Chem. 2017, 15, 1606. c) H. Liu, T. Zhai, S. Ding, Y.
Hou, X. Zhang, L. Feng, C. Ma, Org. Chem. Front.
2016, 3, 1096.
[19] D. G. Brown, J. Bostrom, J. Med. Chem. 2016, 59, [23] a) X. Li, M. Fang, P. Hu, G. Hong, Y. Tang, X. Xu,
4443.
Adv. Synth. Catal. 2014, 356, 2103. b) X. Xu, Y. Tang,
X. Li, G. Hong, M. Fang, X. Du, J. Org. Chem. 2014,
79, 446. c) T. Taniguchi, Y. Sugiura, H. Zaimoku, H.
Ishibashi, Angew. Chem., Int. Ed. 2010, 49, 10154.
[20] A. K. Ghose, V. N. Viswanadhan, J. J. Wendoloski, J.
Comb. Chem. 1999, 1, 55.
[21] a) E. Valeur, M. Bradley, Chem. Soc. Rev. 2009, 38,
606. b) H. Lundberg, F. Tinnis, N. Selander, H.
Adolfsson, Chem. Soc. Rev. 2014, 43, 2714. c) F. de
Azambuja, T. N. Parac-Vogt, ACS Catal. 2019, 9,
10245. d) T. Narendar Reddy, A. Beatriz, V.
Jayathirtha Rao, D. Pires de Lima, Chem. - Asian J.
2019, 14, 344. e) K. Hollanders, B. U. W. Maes, S.
Ballet, Synthesis 2019, 51, 2261. f) U. Dutta, A. Deb, D.
W. Lupton, D. Maiti, Chem. Commun. 2015, 51, 17744.
g) A. V. A. Gholap, S. Maity, C. Schulzke, D. Maiti, A.
R. Kapdi, Org. Biomol. Chem. 2017, 15, 7140.
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901858
European Journal of Organic Chemistry
Entry for the Table of Contents
Copper-Catalyzed Direct Carbamoylation of Quinoxalin-2(1H)-Ones with Hydrazinecarboxamides under Mild Conditions
Xianglong Chu, Yujuan Wu, Haigen Lu, Bingchuan Yang* and Chen Ma*
An efficient and simple method for synthesis of 3-carbamoylated quinoxalin-2(1H)-ones base on copper-catalyzed direct carbamoylation
of quinoxalin-2(1H)-ones at C3 position has been reported, This process provides a series of 3-carbamoylquinoxalin-2(1H)-one
derivatives in moderate to good yields under mild conditions with good functional group tolerance. Our work provide a novel and efficient
synthetic method for the formation of amide.
Key Topic*: Carbamoylation; Quinoxalin-2(1H)-ones; C-H bond activation
Institute and/or researcher Twitter usernames: ((optional))
6
This article is protected by copyright. All rights reserved.