Synthesis of quinoxaline derivatives catalyzed by PEG-400

Article abstract of DOI:10.1016/j.cclet.2009.12.015

Polyethylene glycol (PEG) was found to be an effective catalyst for the condensation of 1,2-diamines with 1,2-dicarbonyl compounds to afford the corresponding quinoxaline derivatives in excellent yields under mild reaction conditions.

Full text of DOI:10.1016/j.cclet.2009.12.015

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 395–398
www.elsevier.com/locate/cclet
Synthesis of quinoxaline derivatives catalyzed by PEG-400
*
Xia Zhong Zhang, Jin Xian Wang , Yong Jun Sun, Hong Wen Zhan
Institute of Chemistry, Department of Chemistry, Northwest Normal University, Lanzhou 730070, China
Received 17 August 2009
Abstract
Polyethylene glycol (PEG) was found to be an effective catalyst for the condensation of 1,2-diamines with 1,2-dicarbonyl
compounds to afford the corresponding quinoxaline derivatives in excellent yields under mild reaction conditions.
#
2009 Jin Xian Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: PEG-400; Quinoxaline derivatives; 1,2-Diamines; 1,2-Dicarbonyl compounds
Quinoxalines are very important compounds due to their wide spectrum of biological activities behaving as
anticancer [1], antibacterial [2], and activity as kinase inhibitors [3]. Besides these, they are well known for their
application in rigid subunits in macro cyclic receptors [4], electroluminescent materials [5], organic semiconductors
[
6] and DNA cleaving agents [7]. Considering the significant applications in the fields of medicinal, industrial and
synthetic organic chemistry, there has been tremendous interest in developing efficient methods for the synthesis of
quinoxalines. Improved methods have been reported via a condensation process catalyzed by Pd(OAc) [8], MnO [9],
2
2
CAN [10], manganese octahedral molecular sieves [11], task-specific ionic liquid [12], Bismuth(III) [13] and so on.
Although great success has been obtained, many of these processes suffer from drawbacks such as drastic reaction
conditions, low product yields, tedious work-up procedures, using toxic metal salts as catalysts, long reaction time and
relatively expensive reagents. Hence, the search for the better method, especially the readily available and green
catalysts, is still being actively pursued.
As a non-toxic, inexpensive, thermally stable, recoverable and biologically acceptable reagent, polyethylene glycol
PEG) represents a very attractive medium for organic reactions [14]. To the best of our knowledge, the synthesis of
(
quinoxaline using PEG-400 as catalyst has not so far been reported. In our continuous search for developing new
processes using PEG as catalyst or solvent [15], in this paper, we wish to report a green and efficient method for the
synthesis of quinoxaline derivatives in good to excellent yields by the condensation of 1,2-diamines with 1,2-
dicarbonyl compounds catalyzed by PEG-400.
At the beginning of this work, the condensation reaction of 4-nitroenzene-1,2-diamine with benzil was employed as
the model reaction to screen the suitable reaction conditions (Table 1). Among different catalysts and PEG species
(Table 1, entries 1–11), we found PEG-400 was the best catalyst for the reaction. Furthermore, we studied the effect of
temperature on the yields of the reaction (Table 1, entries 11–14), lowering or elevating the reaction temperature had
*
Corresponding author.
E-mail address: wangjx@nwnu.edu.cn (J.X. Wang).
1001-8417/$ – see front matter # 2009 Jin Xian Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.12.015

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X.Z. Zhang et al. / Chinese Chemical Letters 21 (2010) 395–398
Table 1
a
Optimized conditions via the condensation of benzil and 4-nitroenzene-1,2-diamine. .
b
Yield (%)
Entry
Catalyst
HCl
Temperature (8C)
Time (min)
1
2
3
4
5
6
7
8
9
110
110
110
110
110
110
110
110
110
110
110
90
240
240
240
100
100
100
100
50
20
32
35
41
43
55
52
75
71
85
95
70
85
95
H
2
SO
4
CH
3
COOH
FeCl
ZnCl
CoCl
NiCl
3
2
2
2
PEG-2000
PEG-10000
PEG-600
PEG-400
PEG-400
PEG-400
PEG-400
50
1
1
1
1
1
0
1
2
3
4
50
50
100
100
50
100
120
a
Reaction conditions: 4-nitroenzene-1,2-diamine (1.0 mmol), benzyl (1.0 mmol), and catalyst (0.15 mmol) stirring at the appropriate temperature
for the indicated time.
b
Isolated yields.
Table 2
Synthesis of quinoxalines using different 1,2-diamines and 1,2-diketones.
2
b
Yield (%)
Entry
Amines
R
Products
Time (min)
Mp (8C)
Found
Lit.
1
2
3
4
5
6
7
8
9
Benzene-1,2-diamine
Ph
2a
2b
2c
2d
2e
2f
10
50
45
30
30
15
30
45
60
60
15
15
20
15
25
100
95
93
95
98
92
95
96
93
94
90
93
90
92
92
129–130
190–191
146
126–127 [10]
187 [16]
4-Nitrobenzene-1,2-diamine
(3,4-Diminophenyl)-(phenyl)methanone
5-Bromopyridine-2,3-diamine
4-Methylbenzene-1,2-diamine
Cyclohexane-1,2-diamine
Ph
Ph
150–151 [17]
149–150 [18]
109–110 [16]
167–169 [19]
183–184 [20]
142 [21]
Ph
150–151
112
Ph
Ph
170–171
185–186
146
Benzene-1,2-diamine
2-Py
2-Py
2-Py
2-Py
2-Py
2g
2h
2i
4-Methylbenzene-1,2-diamine
4-Nitrobenzene-1,2-diamine
(3,4-Diminophenyl)-(phenyl)methanone
Cyclohexane-1,2-diamine
191
193 [21]
10
11
12
13
14
15
2j
164–166
188–189
93
–
2k
2l
4-Methylbenzene-1,2-diamine
4-Nitrobenzene-1,2-diamine
Benzene-1,2-diamine
CH
CH
CH
CH
3
3
3
3
91 [22]
2m
2n
2o
136–137
108
134–135 [23]
104–106 [24]
127 [25]
(3,4-Diminophenyl)-(phenyl)methanone
124
a
Reaction conditions: 1,2-diamine (2 mmol), 1,2-dicarbonyl compound (2 mmol) and PEG-400 (0.3 mmol) stirring at 110 8C for the indicated time
26].
[
b
Isolated yields.

X.Z. Zhang et al. / Chinese Chemical Letters 21 (2010) 395–398
397
no positive effect, and 110 8C is the best temperature. Further study with varying PEG-400 equivalents revealed that
.15 eq. of PEG-400 is necessary to obtain high yield of the condensation product and the higher amount of the catalyst
did not increase the yield noticeably. Thus, it is clear that the condensation reaction carried out in the presence of PEG-
0
4
00 (15% mmol) at 110 8C showed the highest conversion, and this was chosen as the optimized condition.
Thus, under the optimized reaction conditions, we examined the substrate scope of this reaction by using various
,2-diamines and 1,2-dicarbonyl compounds, and the results are summarized in Table 2. We first tried the reactions of
1
benzil with various 1,2-diamines (Table 2, entries 1–6). From Table 1, it can be seen that diamines with either electron-
withdrawing groups or electron-donating groups gave the corresponding products in excellent yields. But substrates
bearing electron-withdrawing groups gave lower yields than substrates bearing electron-donating groups (Table 2,
entries 2–5). For example, 4-methylbenzene-1,2-diamine gave higher yield than 4-nitrobenzene-1,2-diamine.
Alicyclic 1,2-diamines could also react smoothly under our conditions (Table 2, entry 6). Similarly, when benzil was
0
replaced by 2,2 -pyridil, the desired quinoxalines were also obtained in good yields (Table 2, entries 7–11). Further
studies indicated that biacetyl also provide the corresponding quinoxalines in high yields (Table 2, entries 12–15).
In summary, we have described the first example of the use of PEG-400 as a catalyst for the synthesis of
quinoxalines under mild and solvent-free conditions. PEG-400 is an effective and environmentally benign catalyst and
it can be applied to the condensation reactions of 1,2-diamines and 1,2-dicarbonyl compounds. Furthermore, excellent
yields, mild reaction conditions, short reaction times and easy work-up procedures make this a green, facile and
superior method for the synthesis of quinoxalines.
Acknowledgments
The work was supported by the Natural Science Foundation of China (No. 20272047, 20572086), the Gansu
Natural Science Foundation of China (No. 0308RJZA-100) and Key Laboratory of Eco-Environment-Related
Polymer Material (Northwest Normal University), Ministry of the Education of China.
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X.Z. Zhang et al. / Chinese Chemical Letters 21 (2010) 395–398
4
extracted with ethyl acetate. The upper layers were decanted, combined, dried over anhydrous MgSO and was concentrated under vacuo to
afford the crude product. The product was recrystallized from acetone or purified by column chromatography on silica gel using petroleum
1 13
ether–ethyl acetate as the eluent to give the analytically pure product. All products were well characterized using MP, IR, H NMR, C NMR
and MS. The new compounds were also characterized by elemental analysis. The spectral data for some products were given below ꢀ2j, pale
ꢀ
1
1
3
yellow solid; MP (8C): 164–166. IR (y/cm ): 3078, 2935, 1854, 1613, 1550, 1440, 1284, 1059, 977, 764, 692; H NMR (400 MHz, CDCl ): d
1
3
8
.59 (s, 1H), 8.40–8.31 (m, 4H), 8.05–8.02 (m, 1H), 7.97–7.80 (m, 5H), 7.67–7.63 (m, 1H), 7.54 (t, J = 6.8 Hz, 2H), 7.29–7.24 (m, 2H);
C
3
NMR (100 MHz, CDCl ): d 195.7, 157.0, 156.9, 154.1, 153.6, 148.7, 142.9, 140.1, 138.8, 137.0, 136.8, 136.7, 132.9, 132.5, 130.4, 130.1,
+
29.9, 128.5, 124.3, 124.2, 123.3, 123.2. MS m/z (%): 387 (M -1, 84), 105 (54), 77 (100). Anal. Calcd. for C25
1
1
7
4
H
1
N
4
O: C, 77.30; H, 4.15; N,
ꢀ1
4.42. Found: C, 77.72; H, 4.05; N, 14.71. 2k, white solid; MP (8C): 188–189. IR (y/cm ): 3043, 2925, 1585, 1427, 1390, 1178, 1150, 995,
1
3
92; H NMR (400 MHz, CDCl ): d 8.46–8.45 (m, 2H), 7.69–7.65 (m, 2H), 7.60–7.58 (m, 2H), 7.27–7.17 (m, 2H), 3.11 (s, 4H), 2.17–1.99 (m,
1
H); C NMR (100 MHz, CDCl
3
+
3
): d 157.1, 151.6, 149.0, 136.2, 124.3, 122.6, 77.2, 31.9, 22.7. MS m/z (%): 289 (M , 100), 77 (26). Anal.
18 4
Calcd. for C18H N : C, 74.46; H, 6.25; N, 19.30. Found: C, 74.72; H, 6.05; N, 19.91.