Microwave-assisted synthesis of quinoxaline derivatives using glycerol as a green solvent

Article abstract of DOI:10.1007/s11172-013-0171-5

A rapid, efficient, and reliable catalyst-free procedure for the synthesis of quinoxaline derivatives in glycerol under focused microwave irradiation was developed. The reaction proceeded in glycerol without any catalyst making this methodology valuable from both economic and environmental viewpoints.

Full text of DOI:10.1007/s11172-013-0171-5

Russian Chemical Bulletin, International Edition, Vol. 62, No. 5, pp. 1244—1247, May, 2013
1244
Microwaveꢀassisted synthesis of quinoxaline derivatives
using glycerol as a green solvent
W.ꢀJ. Zhou,a X.ꢀZh. Zhang,a X.ꢀB. Sun,a B. Wang,a J.ꢀX. Wang,b and L. Baic
aKey Laboratory of Fruit Waste Treatment and Resource Recycling of the Sichuan Provincial College
and College of Chemistry and Chemical Engineering, Neijiang Normal University,
2341577 Neijiang, Sichuan, China.
Eꢀmail: zhouwj@njtc.edu.cn; wangbi05@163.com
bInstitute of Chemistry and Chemical Engineering, Northwest Normal University,
730070 Lanzhou, China
cInstitute of Green Chemistry Experiment and Teaching, Lanzhou City University,
730000 Lanzhou, China
A rapid, efficient, and reliable catalystꢀfree procedure for the synthesis of quinoxaline
derivatives in glycerol under focused microwave irradiation was developed. The reaction proꢀ
ceeded in glycerol without any catalyst making this methodology valuable from both economic
and environmental viewpoints.
Key words: microwave irradiation, glycerol, 1,2ꢀdiamines, 1,2ꢀdicarbonyl compounds,
quinoxalines.
Solvents are daily used in numerous industrial processꢀ
by MnO2,8 ceric ammonium nitrate,9 reusable polyanilineꢀ
sulfate salt catalyst,10 cupric sulfate pentahydrate,11
manganese octahedral molecular sieves,12 ionic liquid
[TMPSA]•HSO4 (trimethylꢀ3ꢀsulfopropylammonium),13
and etc. Although great success was achieved, many of
these methods suffer from such drawbacks as drastic reꢀ
action conditions, low product yields, tedious work up
procedures, requirements of relatively expensive reagents
and toxic metal catalysts. Therefore, the search for more
environmentally friendly routes to quinoxalines employing
the atom economy concept is a matter of current interest.
Recently, microwaveꢀassisted organic synthesis beꢀ
came a valuable tool of organic and combinatorial (paralꢀ
lel synthesis) chemistry.14 Employing this technique,
a number of chemical transformations were successfully imꢀ
plemented.15 In contrast to conventional heating (stanꢀ
dard oil bath), microwave dielectric heating dramatically
increases the reaction rate giving rise to more efficient and
high yield syntheses while saving time and resources.16 As
compared with conventional synthetic methods, focused
microwave heating in a sealed vessel is known to reduce
side reactions and sharply decrease the reaction time thus
improving the selectivity of the reaction, increasing yields
and purity of the products, and decreasing the amounts of
the solvents used as well.17
es for the separation of the synthesized products, as reacꢀ
tion media and diluents. Solvents are responsible for
a major part of wastes and environmental pollution, hence
their proper selection is a key parameter in the chemical
reaction design. Over recent years, due to safety reasons
and environmental concerns, reduction of costs and the
simplicity of the process, many studies have been devoted
to the search for new environmentally friendly green solꢀ
vents.1—3 Glycerol is a major byꢀproduct generated in the
biodiesel industry. It is abundant, biodegradable, cheap,
nonꢀtoxic, and nonꢀflammable solvent with a very high
boiling point (290 C).4 Glycerol is highly polar solvent
immiscible with hydrocarbons and ethers therefore it can
offer a sustainable medium for both biphasic catalysis and
the product isolation by liquid—liquid extraction. Due to
unique properties, glycerol meets the requirements of the
green solvent concept,5 thus prompting us to extend its
use in organic synthesis. Quinoxaline derivatives are an
important class of nitrogenꢀcontaining heterocycles. Quinꢀ
oxaline fragment is found in a large number of natural
products and biologically active compounds possessing
antiꢀinflammatory, antiviral, antiprotozoal, antibacterial,
anticancer, antiulcer properties and kinase inhibitor acꢀ
tivity.6 A wide range of biological activity and, hence,
a possibility of broad applications stimulate tremendous
interest in developing of an efficient methods for synthesis
of quinoxaline derivatives.7 Thus, the improved methods
were reported involving condensation reactions catalyzed
To the best of our knowledge, the microwaveꢀassisted
synthesis of quinoxaline derivatives in glycerol is not so far
reported. In continuation of our studies on the developꢀ
ment of efficient procedures for green chemistry,18 we reꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1244—1247, May, 2013.
1066ꢀ5285/13/6205ꢀ1244 © 2013 Springer Science+Business Media, Inc.

Microwaveꢀassisted synthesis of quinoxalines
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 5, May, 2013
1245
Scheme 1
port herein the use of glycerol as the green solvent for the
microwaveꢀassisted synthesis of quinoxaline derivatives in
the yields from good to excellent by the condensation of
1,2ꢀdiamines with 1,2ꢀdicarbonyl compounds.
Results and Discussion
Reagents and conditions: glycerol, microwave heating.
To find out how temperature and microwave radiation
power affect the yields of quinoxaline derivatives, we first
studied the condensation of 1,2ꢀdiaminobenzene (1a) with
benzil (2a) in glycerol using CEM Focused MicrowaveTM
Synthesis System (Scheme 1, Table 1). The data obtained
indicate that at 90 C and low microwave radiation power
(W), the yields of the target product 3a are low (Table 1,
entries 1—2). The yield of quinoxaline 3a (at constant
temperature of 90 C) increases with the increase in miꢀ
crowave radiation power to 200 W, but further increase in
the radiation power (to 220 W) decreases the yield of 3a
(cf. entries 1—4). Note that at constant microwave radiaꢀ
tion power, elevation of the reaction temperature to 100 C
does not virtually affect the yield of quinoxaline 3a (entry 5),
whereas a decrease in the temperature to 80 C considerꢀ
ably decreases the yield of 3a (entry 6). Thus, the temperꢀ
ature of 90 C and the microwave radiation power of 200 W
can be considered as the optimal conditions for the conꢀ
densation of compounds 1a and 2a. This reaction was also
carried out under reflux using conventional heating (oil
bath) and heating in the improved domestic microwave
oven, which enables refluxing but without control the
reaction temperature,19 gives the unsatisfactory results
(entries 7—9).
1a—c, 4 and 5 with 1,2ꢀdicarbonyl compounds 2a—c unꢀ
der the optimized conditions (Scheme 2, Table 2). Data
given in Table 2 indicates that the majority of the subꢀ
strates afford quinoxalines 3 in yields from good to excelꢀ
lent. The reactions of diketone 2a with aromatic 1,2ꢀdiꢀ
amines 1b—d bearing either electronꢀwithdrawing or elecꢀ
tronꢀdonating 4ꢀsubstituent lead to the corresponding
products 3 in high yields. Further studies indicate that the
alicyclic 1,2ꢀdiamine, cyclohexaneꢀ1,2ꢀdiamine (5), also
smoothly reacts under these conditions to give the target
compound 7 in 83% yield (entry 15). Aliphatic 1,2ꢀdiꢀ
ketone, butaneꢀ2,3ꢀdione (2b), reacts with 1,2ꢀdiamines
similarly affording the corresponding quinoxaline derivaꢀ
tives 3e—h and 6b in high yields (entries 5—8, 14). In the
case of 2,2´ꢀpyridil (2c), the selected reaction conditions
Scheme 2
In order to demonstrate a general character of this
procedure, we performed the reactions of 1,2ꢀdiamines
Table 1. Reaction condition optimization for the condensation
of 1,2ꢀdiaminobenzene (1) with benzil (2)a
Entry
W/W
T/C
t/min
Yield (%)b
1
2
3
4
5
6
7c
8c
9e
100
150
200
220
200
200
200
600
—
90
90
90
90
100
80
—
10
10
3
3
3
3
3
3
8 ч
30
52
93
89
95
80
—
45
80
d
—
90
R = H (1a), 4ꢀNO2 (1b), 4ꢀC(O)Ph (1c), 4ꢀMe (1d)
R´ = Ph (2a, 6a), Me (2b, 6b), 2ꢀpyridyl (2c)
a Reaction conditions: 1,2ꢀdiaminobenzene (1.0 mmol), benzil
(1.0 mmol), glycerol (2 mL), focused microwave irradiation
(CEM Focused MicrowaveTM Synthesis System).
b Isolated yield.
c Reactions were performed in an improved reflux microwave oven.
d Traces amounts of compound 3a was obtained.
e The reaction was performed under conventional heating (oil
bath) with stirring.
Comꢀ
pound 3
R
R´
Comꢀ
pound 3
g
h
i
j
k
l
R
R´
a
b
c
d
e
f
H
4ꢀNO2
4ꢀC(O)Ph
4ꢀMe
H
Ph
Ph
Ph
Ph
Me
Me
4ꢀC(O)Ph
4ꢀMe
H
4ꢀNO2
4ꢀC(O)Ph 2ꢀpyridyl
4ꢀMe 2ꢀpyridyl
Me
Me
2ꢀpyridyl
2ꢀpyridyl
4ꢀNO2

1246
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 5, May, 2013
Zhou et al.
Table 2. Synthesis of quinoxalines 3a—l, 6a,b, and 7 by the
condensation of 1,2ꢀdiamines 1a—d, 4, and 5 with 1,2ꢀdiꢀ
ketones 2a—ca
Table 4. Recyclability of glycerol on the example of
the synthesis of quinoxaline 3aa
Entry
Cycle
t/min
Yield (%)b
Entry 1,2ꢀDiamine 1,2ꢀDiketone Product t/min Yield (%)b
1
2
3
4
1
2
3
4
3
3
4
6
93
85
61
24
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
4
2a
2a
2a
2a
2b
2b
2b
2b
2c
2c
2c
2c
2a
2b
2a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
6a
6b
7
3
5
8
4
3
5
8
4
3
5
8
4
6
5
2
93
94
93
95
90
89
88
91
92
87
86
91
90
89
83
a Reaction conditions: 1,2ꢀdiamine 1a (1.0 mmol),
1,2ꢀdiketone 2a (1.0 mmol), glycerol (2 mL), microꢀ
wave irradiation power of 200 W, temperature of 90 C.
b Isolated yield.
9
The recyclability of glycerol was investigated on the
example of condensation of 1,2ꢀdiaminobenzene (1a) with
benzil (2a) at microwave radiation power of 200 W and
temperature of 90 C (Table 4). After the end of each
cycle, the reaction mixture was cooled to room temperaꢀ
ture and extracted with ethyl acetate (3×10 mL). The upper
layer (glycerol) was separated, charged with substrates 1a
and 2a, and subjected to the next run. The data in Table 4
show poor recyclability of glycerol.
In summary, we developed an efficient protocol for the
synthesis of quinoxaline derivatives in glycerol under foꢀ
cused microwave irradiation. Glycerol is found to be an
efficient and environmentally benign medium. After prodꢀ
uct isolation, glycerol can be recovered and reused twice.
Moreover, due to the high product yields, mild reaction
conditions, short reaction time, and convenient work up
procedure, this approach can be regarded as a green, facile,
and efficient method for the synthesis of quinoxaline deꢀ
rivatives.
10
11
12
13
14
15
4
5
a Reaction conditions: 1,2ꢀdiamine (1.0 mmol), 1,2ꢀdiketone
(1.0 mmol), glycerol (2 mL), microwave radiation power of 200 W
(in the case when both substrate were solids) and 10 W (in the
case when one of the substrates was liquid); temperature of 90 C.
b Isolated yield.
are mild to affect the pyridine ring nitrogen atom and the
condensation proceeds smoothly to give quinoxazolines
3i—k in 86—92% yields (entries 9—12).
This method can also be used for the synthesis of other
heterocycles. Thus, the condensation of benzaldehyde with
2ꢀsubstituted anilines 8a—c leads to benzoxazole (9a), benzꢀ
imidazole (9b), and benzothiazole (9c) (Scheme 3, Table 3).
Experimental
Scheme 3
Synthesis of quinoxaline derivatives (general procedure).
A mixture of 1,2ꢀdiamine (1.0 mmol), 1,2ꢀdiketone (1.0 mmol),
and glycerol (2.0 mL) (Sichuan Province Huaxing Technology
Co., China) was placed in a 10ꢀmL glass tube equipped with
a magnetic stir bar, the vessel was sealed with a rubber septum and
placed inside a CEM microwave oven (CEM Focused Microꢀ
waveTM Synthesis System, CEM Corp., USA). The reaction mixꢀ
ture was irradiated at microwave power ranged from 100 to 220 W,
the temperature was ramped from room temperature to 80, 90 or
100 C (see Tables 1 and 2). After completion of the reaction,
the mixture was cooled to room temperature, diluted with water
(10 mL), and extracted with ethyl acetate (2×10 mL). The orꢀ
ganic layer was dried with anhydrous MgSO4, the solvent was
evaporated in vacuo. Silica gel column chromatography (elution
with light petroleum—acetone, 10 : 1) of the residue afforded
pure product.
X = NH (a), O (b), S (c)
Reagents and conditions: glycerol, microwave heating.
Table 3. Microwaveꢀassisted synthesis of comꢀ
pounds 9a—c by the condensation of substituted
anilines 8a—c with benzaldehyde
Aniline
t/min
T/C
Yield (%)
Compounds 9a—c were obtained similarly from 8a—c and
benzaldehyde (see Table 3).
8a
8b
8c
3
3
4
110
110
100
91
92
92
This work was financially supported by Sichuan Province
Education Office (project Nos 12ZB074 and 13ZB0002).

Microwaveꢀassisted synthesis of quinoxalines
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 5, May, 2013
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Received May 3, 2012;
in revised form September 27, 2012