Silica sulfuric acid (SSA)/polyethylene glycol (PEG) as a recyclable system for the synthesis of quinoxalines and pyrazines

Article abstract of DOI:10.1080/00397911.2010.517894

An efficient and facile method has been developed for the condensation of 1,2-diamines with-hydroxyketones in polyethylene glycol (PEG) to quinoxalines and pyrazines with good yields in the presence of silica sulfuric acid (SSA). The important features of the methodology are simple operations, environmentally friendliness, and no requirement for metal catalysts. Additionally, the catalyst system (SSA/PEG) could be recovered easily and reused.

Full text of DOI:10.1080/00397911.2010.517894

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Silica Sulfuric Acid (SSA)/Polyethylene
Glycol (PEG) as a Recyclable System
for the Synthesis of Quinoxalines and
Pyrazines
a
a
a
a
Tieqiang Huang , Danna Jiang , Jiuxi Chen , Wenxia Gao
,
a b
a
Jinchang Ding
& Huayue Wu
a
College of Chemistry and Materials Engineering, Wenzhou
University , Wenzhou , China
b
Wenzhou Vocational and Technical College , Wenzhou , China
Published online: 26 Jul 2011.
To cite this article: Tieqiang Huang , Danna Jiang , Jiuxi Chen , Wenxia Gao , Jinchang Ding &
Huayue Wu (2011) Silica Sulfuric Acid (SSA)/Polyethylene Glycol (PEG) as a Recyclable System
for the Synthesis of Quinoxalines and Pyrazines, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 41:22, 3334-3343, DOI:
10.1080/00397911.2010.517894
To link to this article: http://dx.doi.org/10.1080/00397911.2010.517894
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1
Synthetic Communications , 41: 3334–3343, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.517894
SILICA SULFURIC ACID (SSA)/POLYETHYLENE
GLYCOL (PEG) AS A RECYCLABLE SYSTEM FOR THE
SYNTHESIS OF QUINOXALINES AND PYRAZINES
1
Tieqiang Huang, Danna Jiang, Jiuxi Chen, Wenxia Gao,
1
1
1
1
,2
Jinchang Ding, and Huayue Wu
1
1
College of Chemistry and Materials Engineering, Wenzhou University,
Wenzhou, China
2
Wenzhou Vocational and Technical College, Wenzhou, China
GRAPHICAL ABSTRACT
Abstract An efficient and facile method has been developed for the condensation of 1,2-dia-
mines with a-hydroxyketones in polyethylene glycol (PEG) to quinoxalines and pyrazines
with good yields in the presence of silica sulfuric acid (SSA). The important features of the
methodology are simple operations, environmentally friendliness, and no requirement for
metal catalysts. Additionally, the catalyst system (SSA=PEG) could be recovered easily
and reused.
Keywords Pyrazines; quinoxalines; recyclable catalyst; silica sulfuric acid
INTRODUCTION
Quinoxaline derivatives have become increasingly noticed in the past few years
because they are an important class of heterocycles with a wide range of pharmaco-
[1]
logical and biological activities. Moreover, the pyrazine ring system is also a useful
[2]
structural element in medicinal chemistry. In light of this significance, a variety of
[
synthetic strategies have been developed for the preparation of quinoxalines and
3]
[
4]
pyrazines. Oxidative cyclization of a-hydroxy ketones with 1,2-diamines is not a
common method but an alternative one. Generally, it can be catalyzed in the
[
5]
presence of various promoting agents, such as CuCl , FeMPA, TiO =2,2,6,6-
[6]
2
2
[7]
[8]
tetramethylpiperidinyloxy (TEMPO), MnO2, ceric ammonium nitrate (CAN),
[9]
Received May 6, 2010.
Address correspondence to Jiuxi Chen or Huayue Wu, College of Chemistry and Materials
Engineering, Wenzhou University, Wenzhou 325035, China. E-mail: jiuxichen@wzu.edu.cn;
huayuewu@wzu.edu.cn
3
334

SSA/PEG AS RECYCLABLE CATALYST
3335
[
10]
[11]
Pd(OAc) - or RuCl (PPh ) -TEMPO,
2
ecular sieves,
HgI2,
as well as promoted by microwave technology.
and manganese octahedral mol-
[13]
2
3 3
[12]
Although these
methods are suitable for certain synthetic conditions, many of these procedures
are associated with one or more disadvantages such as long reaction time, use of haz-
ardous organic solvents, and harsh reaction conditions, which leaves scope for
further development of new environmentally clean syntheses.
Silica sulfuric acid (SSA), an easily available reagent, has been used for various
[
14]
organic functional group transformations either as reagent or as catalyst,
but it
has not been carefully studied as a catalyst in the synthesis of quinoxalines and pyr-
azines until now.
As part of current studies on the development of green and efficient organic
[
15]
methodologies,
synthesis of quinoxaline and pyrazine derivatives from a-hydroxyketones and
,2-diamines catalyzed by SSA in poly ethylene glycol (PEG).
we herein report a green, simple, and practical method for the
1
RESULTS AND DISCUSSION
Our initial efforts were directed toward the catalytic evaluation of SSA for the
synthesis of quinoxalines and pyrazines. A blank reaction was carried out using ben-
zoin (1a) and 1,2-diaminobenzene (2a) in EtOH, which resulted in no quinoxaline
derivative after 2 h (Table 1 entry 1). The same reaction using SSA in EtOH afforded
the desired quinoxaline in 62% yield (Table 1, entry 2). Encouraged by this promising
a
Table 1. Effects of solvents on the reaction of benzoin with 1,2-diaminobenzene
ꢀ
b
Entry
Catalyst
Solvent
Temp. ( C)
Yield (%)
c
1
2
3
4
5
6
7
8
9
None
SSA
SSA
SSA
SSA
SSA
SSA
SSA
SSA
SSA
EtOH
EtOH
80
80
NR
62
71
90
77
66
69
H
2
O
100
120
80
PEG-400
CH CN
3
1,4-Dioxane
DMSO
100
120
120
120
120
d
PEG-400
PEG-400
PEG-400
80
82
e
f
1
0
90
a
All the reactions were performed using benzoin 1a (0.5 mmol), 1,2-diaminobenzene 2a
1.0 mmol), and 300 mg of SSA for 2 h.
(
b
Isolated yield.
NR, no reaction.
c
d
100 mg of catalyst.
e
200 mg of catalyst.
f
400 mg of catalyst.

3336
T. HUANG ET AL.
result, we next planned to determine the influence of solvent on the catalytic property
of the model reaction. Clearly, PEG-400 stands out as the solvent of choice, with its
fast conversion and good yield (Table 1, entry 8), so we chose to perform this reac-
tion in PEG-400. In addition, we also studied the influence of the amount of catalyst
on the reaction yields. Decreasing the amount of catalyst (Table 1, entries 8 and 9) in
the system reduced the yield slightly. The amount of catalyst (300 mg) was sufficient,
and excessive amount of catalyst did not increase the yield remarkably (Table 1,
entry 10).
With the optimized conditions in hand, the reactions of various a -hydroxyke-
tones with different 1,2-diamines were examined to explore the scope and generality
of this present protocol for the synthesis of various quinoxalines (3) and pyrazines
(
5), and the results are summarized in Tables 2 and 3.
As shown in Table 2, we investigated the influence of electronic factors of
1,2-diamine on the reaction results. It was observed that the reaction of 1,2-diamine
bearing an electron-donating group (-Me) on the benzene ring, such as
a
Table 2. Synthesis of quinoxalines using SSA in PEG
b
Entry
a-Hydroxyketone
1,2-Diamine
Product
Yields (%)
1
2
90
81
c
3
4
51
85
81
5
6
7
75
c
52
8
83
a
All the reactions were performed using a-hydroxyketone 1 (0.5 mmol), aromatic 1,2-diamine 2
ꢀ
(
1.0 mmol), and 300 mg of SSA in PEG-400 (5 mL) at 120 C for 2 h.
b
Isolated yield.
The reaction was carried out for 6 h.
c

SSA/PEG AS RECYCLABLE CATALYST
3337
a
Table 3. Synthesis of pyrazines using SSA in PEG
b
Entry
a-Hydroxyketone
1,2-Diamine
Product
Yields (%)
1
2
3
75
72
82
4
5
76
75
6
81
a
All the reactions were performed using a-hydroxyketone 1 (0.5 mmol), aliphatic 1,2-diamine
ꢀ
(
1.0 mmol), and 300 mg of SSA in PEG-400 (5 mL) at 120 C for 6 h.
b
Isolated yield.
4
-methylbenzene-1,2-diamine (2b) and 4,5-dimethylbenzene-1,2-diamine (2d) with
a-hydroxyketones, was examined, and the corresponding products 3b, 3d, 3f, and
h were obtained in good yields (Table 2, entries 2, 4, 9, and 11). However, the pres-
3
ence of an electron-withdrawing group on the benzene ring decreased the reactivity
of the substrate. For instance, 1,2-diamines containing electron-withdrawing group
(
PhC=O) such as benzoyl on the benzene ring, such as 4-benzoylbenzene-1,2-
diamine (2c), afforded the corresponding products 3c and 3g in moderate yields
(Table 2, entries 3 and 7), which showed an obvious electronic effect.
On the other hand, we examined the synthesis of pyrazines from the reaction of
aliphatic 1,2-diamines with a -hydroxyketones. As shown in Table 3, compared with
the aromatic 1,2-diamines, the reaction of most aliphatic 1,2-diamines, with
a-hydroxyketones required a longer reaction time. It is worth mentioning that
a-hydroxyketones can react with aliphatic 1,2-diamines, resulting in the formation
of pyrazines (5) in good yields, which can react in poor yields or result in the forma-
[
8]
tion of dihydropyrazines as reported in the literature.
The catalyst SSA works under heterogeneous conditions and can easily be pre-
pared from readily available ClSO H and silica gel, which can conveniently be
3
[
14e]
handled and removed from the reaction mixture.
Thus, we investigated the recy-
cling of SSA in the subsequent condensation reaction, for example, the reaction of
benzoin (1a) and 1,2-diaminobenzene (2a). As shown in Scheme 1, SSA could be
reused five times (with the yields of the corresponding product being 90%, 87%,
8
5%, 82%, and 80%, respectively).

3338
T. HUANG ET AL.
Scheme 1. Reusing SSA.
In conclusion, we have developed an efficient and facile synthesis of quinoxa-
lines and pyrazines catalyzed by SSA in PEG-400. Compared to previous reported
methodologies, the present protocol features simple operations, no requirement
for metal catalysts, reusability of the catalyst, and an environmentally benign pro-
cess. Further investigations on the reaction mechanism, scope, limitations, and bio-
logical activity evaluation of these new classes of compounds are under way.
EXPERIMENTAL
Melting points were recorded on digital melting-point apparatus WRS-1B and
are uncorrected. Infrared (IR) spectra were recorded on a Bruker Equinox55 spec-
trometer. Mass spectra were measured with Thermo Finnigan LCQ-Advantage.
1
13
H NMR and C NMR spectra were recorded on a Varian Mercury Plus-300 instru-
ment using CDCl as the solvent with tetramethylsilane (TMS); as an internal stan-
3
dard at room temperature. Chemical shifts are given in d relative to TMS; the
coupling constants J are given in hertz (Hz). Elemental analysis was determined
on a Carlo-Erba 1108 instrument. All reactions were conducted using standard
Schlenk techniques. Column chromatography was performed using EM silica gel
6
0 (300–400 mesh).
General Procedure for the Preparation of SSA
A 500-mL suction flask was used. It was equipped with a constant-pressure
dropping funnel containing chlorosulfonic acid (23.3 g, 0.2 mol) and gas inlet tube
for conducting HCl gas over an adsorbing solution (i.e., water). It was charged with
6
0.0 g of silica gel. Chlorosulfonic acid was added dropwise over a period of 30 min
at room temperature. HCl gas evolved from the reaction vessel immediately. After
the addition was complete, the mixture was shaken for 30 min. A white solid (silica
sulfuric acid) of 76.0 g was obtained.
General Procedure for the Preparation of Quinoxalines and
Pyrazines
1
0.5 mmol) and SSA (300 mg) in PEG-400 (5 mL), and the mixture was stirred at
,2-Diamines (1 mmol) were added slowly to a mixture of a a-hydroxyketone
(
ꢀ
120 C for 2 or 6 h. The reaction was monitored by thin-layer chromatography
TLC). After completion of the reaction, water (10 mL) was added, and the mixture
(
was extracted with ethyl acetate (3 ꢁ 10 mL). The organic layer was washed with

SSA/PEG AS RECYCLABLE CATALYST
3339
brine (3 ꢁ 10 mL), dried over anhydrous Na SO , and concentrated. The product
2
4
was separated and purified by column chromatography on silica gel (300–400 mesh)
using an ethyl acetate=petrol mixture as the eluent to afford a pure product. After
extraction with ethyl acetate, the catalyst in the aqueous phase was concentrated
ꢀ
in an oven at 130 C for 6 h, and the solution of the recovered SSA and PEG could
be reused in the next reaction batch. When necessary, the products were purified by
recrystallizion with ethanol.
Characterization Data of All the Products
ꢀ ꢀ
[16]
1
,3-Diphenylquinoxaline (3a). Solid, mp 128–129 C (lit. 130–131 C). H
2
NMR (300 MHz, CDCl ): d ¼ 7.34–7.36 (6H, m), 7.53–7.55 (4H, m), 7.74–7.78 (2H,
3
1
3
m), 8.18–8.21 (2H, m). C NMR (75 MHz, CDCl ) d ¼ 128.3, 128.8, 129.2, 129.8,
3
þ
1
23.0, 139.0, 141.2, 153.4. MS (ESI) m=z (%): 283 ([M þ 1] , 100).
ꢀ
-Methyl-2,3-diphenylquinoxaline (3b). Solid, mp 117–118 C (lit.
[16]
6
ꢀ
1
1
7
15–117 C). H NMR (300 MHz, CDCl ): d ¼ 2.62 (s, 3H), 7.32–7.35 (m, 6H),
3
1
3
.50–7.53 (m, 5H), 7.96 (s, 1H), 8.07 (d, J ¼ 8.55 Hz, 1H). C NMR (75 MHz,
CDCl ) d ¼ 21.9, 127.6, 127.6, 127.9, 127.9, 128.0, 128.2, 128.6, 128.7, 129.9,
3
þ
1
1
32.3, 139.2, 139.7, 140.5, 141.3, 152.6, 153.3. MS (ESI) m=z (%): 297 ([M þ 1] ,
00).
ꢀ
-Benzoyl-2,3-diphenylquinoxaline (3c). Solid, mp 138–139 C (lit.
[17]
6
ꢀ
1
1
40–142 C). H NMR (300 MHz, CDCl ): d ¼ 7.34–7.40 (m, 6H), 7.51–7.57 (m,
3
6
H), 7.63 (d, J ¼ 7.26 Hz, 1H), 7.91 (d, J ¼ 7.41 Hz, 2H), 8.28 (s, 2H), 8.54 (s, 1H).
1
3
C NMR (75 MHz, CDCl ) d ¼ 111.8, 128.3, 128.5, 129.1, 129.3, 129.7, 129.8,
3
1
1
29.8, 129.9, 130.1, 132.4, 132.8, 137.2, 138.3, 138.6, 138.6, 140.2, 143.0, 154.6,
55.1, 195.8. MS (ESI) m=z (%): 387 ([M þ 1] , 100).
þ
ꢀ
,7-Dimethyl-2,3-diphenylquinoxaline (3d). Solid, mp 174–176 C (lit.
[16]
6
ꢀ
1
1
7
1
1
77–179 C). H NMR (300 MHz, CDCl ): d ¼ 2.54 (6H, s), 7.34–7.37 (6H, m),
3
1
3
.52–7.56 (4H, m), 7.96 (2H, s). C NMR (75 MHz, CDCl ) d ¼ 20.4, 127.9,
3
þ
28.2, 128.5, 129.9, 139.4, 140.2, 140.5, 152.5. MS (ESI) m=z (%): 311 ([M þ 1] ,
00).
ꢀ
[18]
ꢀ
1
131 C). H
2
,3-Di(2-furyl)quinoxaline (3e). Solid, mp 134–136 C (lit.
NMR (300 MHz, CDCl ): d ¼ 6.55 (s, 2H) 6.66 (d, J ¼ 3.34 Hz, 2H), 7.72 (dd,
3
1
3
J ¼ 6.33, 3.41 Hz, 2H), 7.61 (s, 2H), 8.12 (dd, J ¼ 6.33, 3.41 Hz, 2H). C NMR
(
(
75 MHz, CDCl ) d ¼ 111.9, 113.0, 129.1, 130.4, 140.6, 142.6, 144.2, 150.8. MS
3
þ
ESI) m=z (%): 263 ([M þ 1] , 100).
ꢀ
,3-Di(2-furyl)-6-methylquinoxaline (3f). Solid, mp 118–121 C (lit.
[17]
2
ꢀ
1
1
7
16–118 C). H NMR (300 MHz, CDCl ): d ¼ 2.55 (s, 3H), 6.52–6.53 (m, 2H),
3
.88 (s, 1H), 6.60 (d, J ¼ 3.44 Hz, 2H), 7.53 (d, J ¼ 8.59 Hz, 1H), 7.59 (d, J ¼ 0.65 Hz,
1
3
Hz, 2H), 7.99 (d, J ¼ 8.57 Hz, 1H). C NMR (CDCl , 75 MHz) d ¼ 21.9, 111.8,
3
1
1
11.8, 112.5, 112.8, 113.0, 127.9, 128.6, 132.7, 139.0, 140.7, 141.0, 141.8, 142.5,
43.9, 144.1, 150.9. MS (ESI) m=z (%): 277 ([M þ 1] , 100).
þ
ꢀ
-Benzoyl-2,3-di(2-furyl)quinoxaline (3g). Solid, mp 135–137 C (lit.
[17]
6
ꢀ
1
1
32–134 C). H NMR (300 MHz, CDCl ): d ¼ 6.58–6.61 (m, 2H), 6.74–6.77 (m,
3

3340
T. HUANG ET AL.
2
H), 7.52–7.67 (m, 5H), 7.87–7.90 (m, 2H), 8.25 (d, J ¼ 0.74 Hz, 2H), 8.48 (s, 1H).
1
3
C NMR (75 MHz, CDCl ): d ¼ 112.0, 112.2, 113.6, 114.2, 128.5, 129.5, 130.0,
3
1
1
30.2, 132.2, 132.8, 137.1, 138.5, 139.5, 142.4, 143.4, 143.9, 144.5, 144.8, 150.4,
50.5, 195.6. MS (ESI) m=z (%): 367 ([M þ 1] , 100).
þ
ꢀ
[19]
2
,3-Di(2-furyl)-6,7-dimethylquinoxaline (3h). Solid, mp 131–133 C (lit.
1
ꢀ
1
1
34–136 C). H NMR (300 MHz, CDCl ): d ¼ 2.43 (s, 6 H), 6.50 (dd, J ¼ 3.3,
3
1
3
.73 Hz, 2 H), 6.57 (d, J ¼ 3.21, 2 H), 7.57 (s, 2 H), 7.83 (s, 2 H). C NMR
(
75 MHz, CDCl ): d ¼ 20.4, 111.8, 112.3, 128.1, 139.5, 141.1, 141.7, 143.8, 151.0.
3
þ
MS (ESI) m=z (%): 291 ([M þ 1] , 100).
ꢀ
[20]
ꢀ
1
119–120 C). H
2
,3-Diphenylpyrazine (5a). Solid, mp 121–122 C (lit.
NMR (300 MHz, CDCl ): d ¼ 7.28–7.34 (m, 6H), 7.45–7.49 (m, 4H), 8.59 (s, 2H).
3
1
3
C NMR (75 MHz, CDCl ): d ¼ 128.3, 128.7, 129.6, 138.6, 142.1, 152.8. MS (ESI)
3
þ
m=z (%): 233 ([M þ 1] , 100).
ꢀ
[21]
ꢀ
88–89 C).
5
-Methyl-2,3-diphenylpyrazine (5b). Solid, mp 91–92 C (lit.
1
H NMR (300 MHz, CDCl ): d ¼ 2.66 (s, 2H), 7.27–7.31 (m, 6H), 7.42–7.47 (m,
3
1
3
4
1
2
H), 8.48 (s, 1H). C NMR (75 MHz, CDCl ): d ¼ 21.3, 128.2, 128.2, 128.3,
3
28.5, 129.6, 129.7, 138.7, 138.8, 141.9, 149.7, 151.2, 151.6. MS (ESI) m=z (%):
47 ([M þ 1] , 100).
þ
[
22]
2
,3-Diphenyl-5,6,7,8-tetrahydroquinoxaline
1
(5c).
Solid,
mp
ꢀ
1
7
1
52–155 C. H NMR (300 MHz, CDCl ): d ¼ 1.99–2.01 (m, 4H), 3.09 (m, 4H),
3
1
3
.28–7.31 (m, 6H), 7.42–7.45 (m, 4H). C NMR (75 MHz, CDCl ): d ¼ 22.8, 31.8,
3
þ
28.1, 128.2, 129.7, 139.0, 149.5, 150.5. MS (ESI) m=z (%): 287 ([M þ 1] , 100).
ꢀ
[23]
ꢀ
1
81 C). H NMR
2
,3-Di(2-furyl)pyrazine (5d). Solid, mp 78–80 C (lit.
(
2
300 MHz, CDCl ): d ¼ 6.52–6.69 (m, 4H), 7.54–7.55 (m, 2H), 8.50 (d, J ¼ 1.7 Hz,
3
1
3
H). C NMR (75 MHz, CDCl ): d ¼ 111.8, 112.1, 112.3, 141.7, 143.8, 150.4. MS
3
þ
(ESI) m=z (%): 213 ([M þ 1] , 100).
[24]
ꢀ
1
Solid, mp 62–65 C. H NMR
2,3-Di(2-furyl)-6-methylpyrazine (5e).
(
300 MHz, CDCl ): d ¼ 2.59 (s, 3H), 6.46–6.59 (m, 4H), 7.49–7.52 (m, 2H), 8.35 (s,
3
1
3
1
1
1
H). C NMR (75 MHz, CDCl ): d ¼ 21.4, 111.5, 111.7, 111.7, 112.1, 139.2,
3
þ
40.9, 141.8, 143.4, 143.7, 150.5, 150.6, 151.3. MS (ESI) m=z (%): 227 ([M þ 1] ,
00).
[
25]
2
,3-Di(2-furyl)-5,6,7,8-tetrahydroquinoxaline
1
(5f).
Solid,
mp
ꢀ
1
4
3
50–151 C. H NMR (300 MHz, CDCl ): d ¼ 1.90–1.95 (m, 4H), 2.97–3.02 (m,
3
1
3
H), 6.44–6.49 (m, 4H), 7.49–7.50 (m, 2H). C NMR (75 MHz, CDCl ): d ¼ 22.6,
3
þ
1.8, 111.3, 111.6, 139.2, 143.3, 150.7, 150.8. MS (ESI) m=z (%): 267 ([M þ 1] , 100).
ACKNOWLEDGMENTS
We are grateful to the National Key Technology Research and Development
Program (No. 2007BAI34B00), the Natural Science Foundation of Zhengjiang
Province (No. Y4080107), and the Technology Innovation Foundation of Zhejiang
Province (No. 2010R424014) for financial support.

SSA/PEG AS RECYCLABLE CATALYST
3341
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