Cu(II)-catalyzed synthesis of quinoxalines from o-phenylenediamines and nitroolefins

Article abstract of DOI:10.1016/j.tetlet.2012.11.127

An easy and efficient copper-catalyzed reaction for the synthesis of quinoxalines from o-phenylenediamines and nitroolefins is developed. This reaction could proceed well without additional base and be applied to various available substrates with a one-step synthetic procedure in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2012.11.127

Tetrahedron Letters 54 (2013) 1627–1630
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cu(II)-catalyzed synthesis of quinoxalines from o-phenylenediamines
and nitroolefins
Yongxin Chen a,b, Kangning Li a,b, Mingming Zhao a,b, Yuanjiao Li a,b, Baohua Chen a,b,
⇑
a State Key Laboratory of Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
b Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An easy and efficient copper-catalyzed reaction for the synthesis of quinoxalines from o-phenylenediam-
ines and nitroolefins is developed. This reaction could proceed well without additional base and be
applied to various available substrates with a one-step synthetic procedure in moderate to good yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 20 September 2012
Revised 19 November 2012
Accepted 27 November 2012
Available online 7 December 2012
Keywords:
Quinoxalines
Copper-catalyzed
o-Phenylenediamines
Nitroolefins
Introduction
(A) Genaral strategy
NH2
NH2
O
The quinoxaline core is one of the most important N-heterocy-
cles that display a wide range of biological activities, such as anti-
viral, antibacterial, and anti-inflammatory.1 In addition, it has
tremendous applications as useful dyes,2 precursors of pharmaco-
logical active compounds,3 and electroluminescent materials.4
During the last decades, great progress has been made to success-
fully construct this motif.5 The traditional methods for assembling
these heterocycles are highly dependent on using diketones as the
key intermediates and the direct condensation of o-phenylenedi-
amines with diketones (Scheme 1A).6 However, most of them re-
quired toxic oxidants, an excess amount of bases, high
temperature, and functionalized substrates.
N
N
R
R
M
O
O
R
(B)
Previous work in our group
NH2
N
N
Ph
NH2
Ph
NH2
N
N
Ph
CHO
NH2
Recently, we have revealed copper-catalyzed synthesis of quin-
oxalines with o-phenylenediamine and terminal alkyne in the
presence of bases.7 Subsequent to this discovery, arylacetaldehy-
des were reported as a suitable coupling partner for synthesis of
quinoxalines under metal-free conditions (Scheme 1B).8 These sys-
tems all showed a broad scope and high efficiency under mild con-
ditions, but bases were also required. As a part of our continuing
study on the quinoxaline derivations, we reported a novel and effi-
cient way of synthesizing quinoxalines via CuBr2-catalyzed from o-
phenylenediamine and nitroolefins without additional base
(Scheme 1C).
(C)
This work
NH2
NH2
Scheme 1. Synthesis of Quinoxaline Derivatives.
N
Ph
NO2
R
N
R
Results and discussion
At the outset of our study, (E)-(2-nitroprop-1-en-1-yl)benzene
(1a) and o-phenylenediamine (2a) were chosen as model sub-
strates to optimize the reaction conditions (Table 1). 3aa were ob-
tained in 46% yield with CuBr2 (10%) as catalyst in DMF at 110 °C
⇑
Corresponding author.
E-mail address: chbh@lzu.edu.cn (B. Chen).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.127

1628
B. Chen et al. / Tetrahedron Letters 54 (2013) 1627–1630
Table 1
Table 2
Optimization of the reaction conditionsa
Reactions of various nitroolefins (1) with o-phenylenediamine (2a)a
NH2
NO2
NH2
NH2
N
Ph
N
N
R2
R3
CuBr2(10%)
Catalyst
NO2
R2
C2H5OH,110oC
Solvent,T
NH2
N
R3
1a
2a
3aa
2a
3
1
Entry
Catalyst (%)
Solvent
T (°C)
Yieldb (%)
Entry
R2
C6H5 (1a)
R3
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
CuBr2 (10)
CuBr2 (10)
CuBr2 (10)
CuBr2 (10)
CuBr2 (10)
CuBr2 (10)
CuBr (10)
CuCl2 (10%)
Cu(OAc)2 (10)
CuO (10)
FeCl3 (10)
CuBr2 (5)
CuBr2 (20)
CuBr2 (10)
CuBr2 (10)
—
DMF
DMSO
PhMe
110
110
110
110
110
110
110
110
110
110
110
110
110
80
46
70
69
61
90
76
40
81
10
38
79
83
91
75
80
Trace
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
90
77
80
86
77
81
62
64
71
35
42
42
38
63
45
0
4-MeC6H4 (1b)
4-OMeC6H4 (1c)
4-OHC6H4 (1d)
4-ClC6H4 (1e)
4-BrC6H4 (1f)
4-NO2C6H4 (1g)
4-CNC6H4 (1h)
4-CF3C6H4 (1i)
2-OMeC6H4 (1j)
2-ClC6H4 (1k)
2-BrC6H4 (1l)
2-NO2C6H4 (1m)
3-ClC6H4 (1n)
2,4-DiClC6H3 (1o)
2-furyl (1p)
CH3CN
C2H5OH
CH3OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
130
110
C6H5 (1q)
0a/40c
a
Conditions: 1a (0.25 mmol), 2a (0.25 mmol), catalyst (10 mol %), solvent (2 mL),
a
4 h.
Conditions: 1 (0.25 mmol), 2a (0.25 mmol), CuBr2 (10 mol %), C2H5OH (2 mL),
110 °C, 4 h.
b
Isolated yields after column chromatography.
b
Isolated yields after column chromatography.
DMSO (2 mL) as solvent was used.
c
(Table 1, entry1). The yield of 3aa11 increased to 90% when C2H5OH
was used as the solvent, while other solvents showed no better ef-
fects on the promotion of this reaction (Table 1, entries 1–6). Sub-
sequently, we investigated the reaction using other iron and
copper salts as catalyst, but all gave inferior results compared to
CuBr2 (Table 1, entries 7–11). It was worth noting that reducing
the catalyst loading decreased the yield significantly, while
increasing the loading did not improve the yield (Table 1, entries
12–13). Furthermore, the yield was found to decrease with the
temperature changed to 80 or 130 °C (Table 1, entries 14–15).
Table 3
Reactions of (E)-(2-nitroprop-1-en-1-yl)benzene (1a) with substituted o-diamines (2)a
NO2
NH2
NH2
R1
N
N
N
N
CuBr2(10%)
C2H5OH,110oC
R1
Ph R1
Ph
3
4
2
1a
Entry
R1
Product
Yieldb (%)
N
N
N
1
4-Me (2b)
65
N
3ab:4ab=1.8:1
N
O
O
N
N
2
4-OMe (2c)
53
N
3ac:4ac=2.1:1

B. Chen et al. / Tetrahedron Letters 54 (2013) 1627–1630
1629
Table 3 (continued)
Entry
R1
Product
Yieldb (%)
N
Cl
N
N
3
4
5
4-Cl (2d)
86
N
Cl
Br
3ad:4ad=1.3:1
N
N
N
4-Br (2e)
89
Br
N
3ae:4ae=1.1:1
N
O2N
N
N
4-NO2 (2f)
61
93
N
O2N
3af:4af=1.9:1
3ag
6
4,5-DiCl (2g)
a
Conditions: 1a (0.25 mmol), 2 (0.25 mmol), CuBr2 (10 mol %), C2H5OH (2 mL), 110 °C, 4 h.
Isolated yields after column chromatography.
b
Additionally, only a trace amount of the product was observed in
the absence of CuBr2 (Table 1, entry 16).
failed to afford the desired reaction (Table 2, entry 16). (E)-(2-
nitrovinyl)benzene gave a lower yield in DMSO, probably because
of instability of substrate (Table 2, entry 17).
Under the optimized reaction conditions, a series of nitroolefins
were investigated to establish the scope and limitations of this pro-
cess (Table 2). To our delight, a wide range of substituted groups of
nitroolefins all gave the desired products in moderate to good
yields, which include methyl, methoxyl, hydroxyl, chloro, or cyano
groups, et al. The electron-rich nitroolefins showed better reactiv-
ities and gave higher yields than electron-deficient ones. Substitu-
tion at 2-position of nitroolefins had a significant impact on yields
and resulted in lower yields (Table 2, entries 10–13, 15). However,
substitution at 3-position of nitroolefins had only a slight impact
on yield (Table 2, entry 14). Besides, (E)-2-(2-nitrovinyl)furan
The reaction scope was also investigated with respect to the
other coupling partner 2 (Table 3). Generally, most of the sub-
strates provided moderate to good yields. Higher yields were ob-
tained with electron-withdrawing substituents on the aromatic
ring. It should be pointed out that poor regioselectivities were
observed in this transformation. The ratio of isomers varied from
1.1:1 to 2.1:1, confirmed by 1H NMR and 13C NMR. The structure
of 3af was unambiguously determined by X-ray crystallography
(Fig. 1). Unfortunately, coupling of (E)-(2-nitroprop-1-en-1-
yl)benzene (1a) with 1,2-diaminoanthracene-9,10-dione and
Figure 1. X-ray structure of 3af.

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B. Chen et al. / Tetrahedron Letters 54 (2013) 1627–1630
NH2
NH2
2a
H
H
H
NO2
N
N
N+
O
-e-
-H
OH
Cu2+
OH
OH
NH2
N
O
NH2
N
O
NH2
N
O
Cu+
A
1a
B
C
HNO
-H
N
N
N
-H2O
-HNO
OH
OH
N
H
N
N
H
N
N
H
OH
O
3aa
E
D
Scheme 2. Proposed mechanism.
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dure, probably because of electronic effect of 1,2-diaminoanthra-
cene-9,10-dione and configuration of cyclohexane-1,2-diamine.
To gain an insight into the mechanism of the above mentioned
process, the following control experiment was performed. 3aa was
also obtained in 88% yield via reaction of 1a with 2a under N2 pro-
tected conditions. Thus, we speculated the NO2 group was the ter-
minal oxidant in this process.
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Based on the above results, a tentative reaction mechanism is
illustrated in Scheme 2. The substrate 1a initially reacts with 2a
to produce the Michael addition intermediate A, which can be
one-electron oxidized by copper(II) to form radical cation B. Next,
C is generated from B through hydrogen abstraction with oxida-
tion, and then D is formed by proton elimination.9 Finally, proton
transfer and intramolecular cyclization followed by elimination
of H2O and HNO from the intermediate E afford the desired prod-
uct 3aa.10
Conclusions
In summary, we have demonstrated a novel Cu-catalyzed proto-
col for synthesis of quinoxaline without additional base. This sys-
tem could be applied to various available substrates with a one-
step synthetic procedure in moderate to good yields. The proce-
dure is a simple, economical, and environmentally friendly proto-
col for the synthesis of quinoxalines.
7. Wang, W.; Shen, Y.; Meng, X.; Zhao, M.; Chen, Y.; Chen, B. Org. Lett. 2011, 13,
4514.
Acknowledgment
8. Song, J.; Li, X.; Chen, Y.; Zhao, M.; Dou, Y.; Chen, B. Synlett 2012, 2416.
9. (a) Yan, R.-L.; Yan, H.; Ma, C.; Ren, Z.-Y.; Gao, X.-A.; Huang, G.-S.; Liang, Y.-M. J.
Org. Chem. 2012, 77, 2024; (b) Li, C.-J. Acc. Chem. Res. 2009, 42, 335.
10. (a) Kundu, D.; Samim, M.; Majee, A.; Hajra, A. Chem. Asian J. 2011, 6, 406; (b)
Shiraishi, H.; Nishitani, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 1998, 63, 6234;
(c) Maiti, S.; Biswas, S.; Jana, U. J. Org. Chem. 2010, 75, 1674.
We are grateful to the project sponsored by the Project of Na-
tional Science Foundation of PR China (No. J11003307)
Supplementary data
11. General procedure for the copper (II)-catalyzed synthesis of 3aa: Nitroolefins 1
(0.25 mmol), o-Phenylenediamines 2 (0.25 mmol), CuBr2 (5.6 mg, 10 mmol%),
and C2H5OH (2 mL) were added to a flask with a magnetic stirring bar. The
resulting mixture was stirred at 110 °C for 4 h. After cooling to room
temperature, the mixture was diluted with ethyl acetate and filtered. The
filtrate was removed under reduced pressure to get the crude product, which
was further purified by silica gel chromatography to give product 3aa. The
identity and purity of the products were confirmed by 1H and 13C NMR
spectroscopic analysis. White solid; mp 44–46 °C; 1H NMR (300 MHz, CDCl3) d
8.13–8.09 (m, 1H), 8.07–8.03 (m, 1H), 7.76–7.73 (m, 2H), 7.72–7.63 (m, 2H),
7.56–7.50 (m, 3H), 2.78 (s, 3H). 13C NMR (75 MHz, CDCl3) d 154.8, 152.4, 141.1,
140.9, 138.9, 129.6, 129.1, 129.1, 128.9, 128.8, 128.5, 128.2, 24.3.
Supplementary data(detailed experimentals for all compounds
including 1H and 13C NMR spectral assignments, and elemental
analysis) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2012.11.127.
References and notes
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