Aerobic oxidation of β-dicarbonyls into vicinal tricarbonyls by Cu(II) salts for one-pot synthesis of quinoxalines

Article abstract of DOI:10.1016/j.tetlet.2017.03.071

Vicinal tricarbonyl intermediates are directly synthesized from β-dicarbonyls with the aid of Cu(II) salts and air, and they are further condensed with phenylene diamine to produce a range of quinoxalines in moderate to good yields in one-pot reaction.

Full text of DOI:10.1016/j.tetlet.2017.03.071

Accepted Manuscript
Aerobic oxidation of β –dicarbonyls into vicinal tricarbonyls by Cu(II) salts for
one-pot synthesis of quinoxalines
Xu Han, Tao Lei, Xiu-Long Yang, Lei-Min Zhao, Bin Chen, Chen-Ho Tung,
Li-Zhu Wu
PII:
S0040-4039(17)30393-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.071
TETL 48772
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 February 2017
21 March 2017
23 March 2017
Please cite this article as: Han, X., Lei, T., Yang, X-L., Zhao, L-M., Chen, B., Tung, C-H., Wu, L-Z., Aerobic
oxidation of β –dicarbonyls into vicinal tricarbonyls by Cu(II) salts for one-pot synthesis of quinoxalines,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.03.071
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Aerobic oxidation of β–dicarbonyls into
vicinal tricarbonyls by Cu(II) salts for one-
pot synthesis of quinoxalines
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Xu Han, Tao Lei, Xiu-Long Yang, Lei-Min Zhao, Bin Chen, Chen-Ho Tung, and Li-Zhu Wu∗

1
Tetrahedron Letters
journal homepage: www.els evier.com
Aerobic oxidation of β–dicarbonyls into vicinal tricarbonyls by Cu(II) salts for one-
pot synthesis of quinoxalines
Xu Han, Tao Lei, Xiu-Long Yang, Lei-Min Zhao, Bin Chen, Chen-Ho Tung, and Li-Zhu Wu∗
Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry & University of Chinese Academy of
Sciences, the Chinese Academy of Sciences, Beijing 100190, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Vicinal tricarbonyl intermediates are directly synthesized from β–dicarbonyls with the aid of Cu
(II) salts and air, and they are further condensed with phenylene diamine to produce a range of
quinoxalines in moderate to good yields in one-pot reaction.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
β–Dicarbonyls
Vicinal tricarbonyls
Quinoxalines
Cu(II) salt
Aerobic oxidation
Introduction
Quinoxalines are a kind of important nitrogen-containing
heterocycle due to their significant pharmacological and
biological properties (Scheme 1).1-7 National Cancer Institute
(Bethesda, MD), for example, showed that compounds (I and II)
have in vitro anticancer activity.8 Min Teng and co-workers
reported that compound III, served as the hGLP-1 receptor
agonist, is the most potent and efficacious compound in their is
the most potent and efficacious compound in their system.9 Over
Scheme 2. Different synthetic approaches toward vicinal
tricarbonyl compounds
the past decades, various synthetic strategies to construct this
skeleton have been reported.10-19 Among these strategies, vicinal
tricarbonyl intermediate is the most common one to treat with
phenylene diamine.20
In order to construct this key intermediate,21-26 two approaches
are put forward. One is a two-step procedure, i.e. β–dicarbonyls
or other substrates are firstly employed to construct α-functional
β-dicarbonyls and then followed by oxidation.27-39 The other is
that β-dicarbonyls are directly oxidized by strong oxidations,
such as Dess–Martin periodinane (DMP),40 2-iodoxybenzoic acid
(IBX),41 iodosobenzene (PhIO),42 SeO2,43 cerium ammonium
nitrate (CAN)44 or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
Scheme1. Several quinoxaline-containing active
moleculars
———
∗ Corresponding author Tel.: (+86) 010–82543580; fax: (+86) 010–82543580; e-mail: lzwu@mail.ipc.ac.cn

2
Tetrahedron
Table 1. Optimization of the reaction conditiona
reaction (Table 1, entry 3 and entries 6 –12). Temperature also
played a vital role in this reaction. When the temperature
decreased from 50 oC to 40 oC, inferior result was obtained
(Table 1, entry 13). At last, we reduced the amount of catalyst
and found 10 mol % of Cu(II) salt was adequate for this
conversion (Table 1, entries 14 and 15).
entry
catalyst
Cu(OTf)2
solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1,4-dioxane
DCM
yield (%)b
1
51
0
With the optimized reaction conditions in hand (Table1, entry
14), we explored the scopes of this conversion (Table 2). Both
electron-donating and electron-withdrawing substitution at the
phenyl ring of the benzoyl group could be tolerated in this system.
The substrates of p-methyl, p-methoxyl p-fluoro, p-bromo even
p-nitro substituted smoothly reacted with benzene-1,2-diamine,
giving moderate to good yields (Table 2, 3b–3f). Other
heterocyclic aromatic substrates were also suitable for our
system. When ethyl 3-(furan-2-yl)-3-oxopropanoate (1g) and
ethyl 3-oxo-3-(thiophen-2-yl) propanoate (1h) separately reacted
with benzene-1,2-diamine (2a) in standard conditions, relevant
products were achieved with the yield of 63% and 60% (Table 2,
3g and 3h). Moreover, aliphatic β-keto ester could also proceed
to generate corresponding quinoxaline (Table 2, 3i). Afterward,
we investigated the scope of R2. Apart from ethyl benzoylacetate
3a, butyl, cyclohexyl, benzyl benzoylacetate and β-ketoamide
generated the corresponding products with moderate yields
2
Cu(CH3CN)4PF6
3
Cu(NO3)2·2.5H2O
Zn(NO3)2 ·6H2O
Fe(NO3)3·9H2O
72
0
4
5
0
6
Cu(NO3)2·2.5H2O
Cu(NO3)2·2.5H2O
Cu(NO3)2·2.5H2O
Cu(NO3)2·2.5H2O
Cu(NO3)2·2.5H2O
Cu(NO3)2·2.5H2O
Cu(NO3)2·2.5H2O
Cu(NO3)2·2.5H2O
Cu(NO3)2·2.5H2O
Cu(NO3)2·2.5H2O
0
7
0
8
toluene
DMSO
CH3OH
THF
0
9
0
10
11
12
13c
14d
15e
0
0
DMF
0
CH3CN
CH3CN
CH3CN
47
72
57
Table 2. Synthesis of quinoxaline derivativesa
aReaction was carried out with 0.1 mmol ethyl benzoylacetate and catalyst in
2 mL solvent in air for 1 h and then 0.2 mmol benzene-1,2-diamine was
added and reacted for 2 h at room temperature.
bYields were determined by 1H-NMR analysis using diphenylmethanol as an
internal standard.
cStep I at 40 oC.
dAmount of catalyst is 10 mol%.
e
Amount of catalyst is 5 mol%.
(DDQ)/2,2,6,6-tetramethyl
piperidin-1-oxyl
(TEMPO)45.
However, the tedious synthesis strategies or the use of strong
oxidation reagents undoubtedly increase the cost of reactions and
restrict the sequent reacions in synthetic chemistry, which are not
satisified with requirement of green chemistry and atom
economy. Searching for a mild and green procedure is timely.
Herein, we report a direct strategy that is able to convert β–
dicarbonyls to vicinal tricarbonyl intermediates using catalytic
amount of Cu(II) salts in air without strong oxidation.
Subsequently, these intermediates are condensed with benzene-
1,2-diamine to form quinoxaline derivatives in one pot. This
efficiently and atom-economically synthetic strategy can tolerate
a wide scope of functional groups from moderate to good yields
(Scheme 2).
Results and discussion
In our initial investigation, we used ethyl benzoylacetate (1a)
and benzene-1,2-diamine (2a) as model substrates (Table 1). 1a
(0.1 mmol) and Cu(OTf)2 (20 mol %) were stirred in 2 mL
CH3CN at 50 oC in air for 1 h, and then 2a (0.2 mmol) was added
into the above system. After the reaction completed, 51% yield of
3a was obtained (Table 1, entry 1). Based on this result, we
optimized the reaction conditions. When Cu(OTf)2 was replaced
by other salts, such as Cu(CH3CN)4PF6, Cu(NO3)2·2.5H2O,
Zn(NO3)2·6H2O and Fe(NO3)3·9H2O (Table 1, entries 2–5), the
reaction was inefficient except for Cu(NO3)2·2.5H2O that could
improve the yield to 72%. The optimization of solvents indicated
that acetonitrile was the only appropriate solvent towards our
a Reaction was carried out on 0.1 mmol β-dicarbonyl substrate, 10 mol %
Cu(NO3)2•2.5H2O, in 2 mL CH3CN, at 50 oC, in open flask for 1 h, then
followed by the addition of 0.2 mmol various 1,2-phenylene diamine
substrate at room temperature for 2 h. The isolated yield was based on 1.
b The reaction was carried out at 50 oC for 3 h, followed by the addition of 0.2
mmol benzene-1,2-diamine at room temperature for 3 h.
c The pyrazino[2,3-b]pyrazine-2,3-diamine was dissolved in 2 mL CH3OH
then added into system.

3
noted that there was an equilibrium between 4a and 6a. Keto
form 4a and hydrate form 6a of vicinal tricarbonyl intermediate
further reacted with 2a to form quinoxaline.
Conlusion
In summary, we have disclosed a direct, atom-economical,
and environment-friendly method for the synthesis of vicinal
tricarbonyl intermediate. Many functional groups could be
tolerated in our system and various quinoxalines with moderate
to good yields have been synthesised in virture of our strategy.
As compared with those reported two approaches, the greatest
advantage of our system is the mild oxidation of β-dicarbonyls to
form vicinal tricarbonyl intermediates in situ catalysed by
commercial Cu(II) salts. The whole procedure is accomplished in
air without strong oxidants. The further investigation of the
aerobic oxidation method to construct significant heterocyclic
compounds is undergoing in our lab.
Scheme 3. Control experiments
(Table 2, 3j–3n). As for 3i and 3m, a part of starting materials
was decomposed in our systerm leading to the low yields. At the
same time, various 1,2-phenylene diamines were used to react
with ethyl benzoylacetate (1a). The quinoxaline derivated from
4-fluoro substrate was isolated with two isomers in the ratio of
1:3 (Table 2, 3o and 3o'). Other symmetric disubstituted 1,2-
diaminobenzene, such as difluoro, dichloro, dimethyl, dimethoxy
and naphthalene, could generate the desired products with 58%–
74% yields (Table 2, 3p–3t). Heteroaromatic diamine pyrazine-
2-3-diamine could produce final product in 33% yield. Since the
low solubility of starting material in acetonitrile, tricarbonyl
intermediate was not able to react with diamine efficiently. Yet
diethyl malonate could not be converted into the relevant
tricarbonyl intermediate by this method.
Acknowledgments
Financial support for this research from the Ministry of
Science and Technology of China (2013CB834804,
2014CB239402 and 2013CB834505), the National Natural
Science Foundation of China (21390404 and 91427303), the
Strategic Priority Research Program of the Chinese Academy of
Science (XDB17030200) and the Chinese Academy of Sciences
is gratefully acknowledged.
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Highlights
1、 Direct oxidation of β–dicarbonyls into vicinal tricarbonyl intermediates was
reported.
2、 Inexpensive Cu (II) salt served as catalyst.
3、 Air acted as oxidant.
4、 A range of quinoxalines have been synthesized in one-pot reaction.