Graphite catalyzed green synthesis of quinoxalines

Article abstract of DOI:10.1016/j.tetlet.2012.12.041

A new simple approach using environmentally benign, cheap, and easily recyclable graphite as a heterogeneous catalyst for the synthesis of quinoxalines is described. A library of pharmacologically interesting diphenylquinoxalines is prepared by the double condensation of substituted benzils, phenanthrene-9,10-dione, and benzoin with aromatic diamines in 71-93% yields at room temperature in ethanol. Aliphatic diamines gave corresponding dihydropyrazines from substituted benzils in 72-92% yields.

Full text of DOI:10.1016/j.tetlet.2012.12.041

Tetrahedron Letters 54 (2013) 1003–1007
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Graphite catalyzed green synthesis of quinoxalines
⇑
Hari K. Kadam, Salman Khan, Rupesh A. Kunkalkar, Santosh G. Tilve
Department of Chemistry, Goa University, Taleigao Plateau, Goa 403206, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new simple approach using environmentally benign, cheap, and easily recyclable graphite as a
heterogeneous catalyst for the synthesis of quinoxalines is described. A library of pharmacologically
interesting diphenylquinoxalines is prepared by the double condensation of substituted benzils,
phenanthrene-9,10-dione, and benzoin with aromatic diamines in 71–93% yields at room temperature
in ethanol. Aliphatic diamines gave corresponding dihydropyrazines from substituted benzils in
72–92% yields.
Received 17 September 2012
Revised 10 December 2012
Accepted 12 December 2012
Available online 19 December 2012
Keywords:
Graphite
Ó 2012 Elsevier Ltd. All rights reserved.
Green chemistry
Quinoxalines
Quinoxalines are an important class of nitrogen containing het-
erocycles exhibiting diverse biological properties. They exhibit
antibacterial, antiviral, anthelmintic, anti-inflammatory, kinase
inhibitory, and anticancer activity.1 For example, NCG555879-
012a acts as BRCA1 inhibitor. Quinoxaline moiety is also present
in biologically active natural products like Izumiphenazine C2b
and Echinomycin2c (Fig. 1). In addition to their medicinal proper-
ties, they are also used in dyes and semiconductors.1
Over the years several catalysts and reagents are reported for
the synthesis of quinoxalines like CAN,3a sulfamic acid,3b IBX,3c
CuSO4Á5H2O,3d polyaniline sulfate,3e amidosulfonic acid,3f PTSA,3g
Mn octahedral molecular sieves,3h ionic liquid (Hbim)BF4,3i
Ga(OTf)3,3j SnCl2,3k montmorillonite K-10,3l DMSO-PdI2,3m oxalic
acid,3n Bi(III),3o Zr(DS)4,3p ZrO2 mixed metal oxide,3q silica bonded
S-sulfonic acid,3r ZnI2,3s silica supported SbCl3,3t NbCl5,3u amber-
lyte-15,3v I2,3w Ru/C,3x etc.
we herein report a highly efficient graphite catalyzed double con-
densation method for the synthesis of quinoxalines. The method
O
N
N
N
O
HN
O
N
O
NH
O
N
O
O
S
N
O
S
O
O
N
N
NH
NH
O
O
Echinomycin
HOOC
CH3
N
NH
N
N
N
Recently, many new methods are also reported like clayzic,4a
silica gel,4b Zr(IV) modified silica gel,4c alumina,4d DABCO,4e
Sm(OTf)2,4f PEG-400 in MW,4g PEG–water,4h glycerol,4i silica
sulfuric acid in PEG,4J CeCl3Á7H2O in glycerin,4k FeCl3 with morpph-
oline,4l triethylamine/O2,4m Ga(ClO4)3,4n and PTSA/H2O.4o Catalyst-
free process like reactions using MW5a and grinding5b are also
reported. Many of these methods have disadvantages like using
strong acidic condition; require heating condition, or use of transi-
tion metals to obtain good yields. Presently, appreciated synthetic
methods are those using environmentally harmless reagents, recy-
clable catalysts, and energy efficient processes.
O
O
N
N
O
NCGC55879-01
OH
Izumiphenazine C
Figure 1. Biologically important quinoxalines.
R1
R1
O
O
H2N
N
N
GRAPHITE
C
C
C
C
R2
Continuing our interest in the synthesis of heterocycles using
+
H2N
R2
tandem reaction,6a,b green catalyst,6c,d and solvent-free synthesis,6e
Ethanol, r.t.
R1
R1
1a
2a
3a
⇑
Corresponding author. Tel.: +91 832 6519317; fax: +91 832 2452886.
E-mail address: stilve@unigoa.ac.in (S.G. Tilve).
Scheme 1. Graphite catalyzed synthesis of quinoxalines.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.041

1004
H. K. Kadam et al. / Tetrahedron Letters 54 (2013) 1003–1007
Table 1
has advantages of ambient reaction condition, environmentally
acceptable solvent, high yields, simple work-up, and easy catalyst
recovery and reusability.
Optimization of graphite concentration
Entry
Graphite (equiv)
Time (min)
Yielda (%)
Graphite a form of carbon, though abundantly and cheaply
available benign chemical, has found very few applications in or-
ganic synthesis, for example, in Friedel–Crafts acylation,7a alkyl-
ation,7b and for conversion of aldehyde to nitriles.7c The benign
nature and abundant availability of it prompted us to explore its
potential use in organic synthesis. We visualized that it could be
used for the rapid double condensation of o-phenylenediamine
with 1,2-diketones to form quinoxalines.
1
2
3
4
5
6
7
20
10
5
2
0.5
0
30
60
60
60
300
900
24 h
86
89
90
92
42
Trace
20
51b
a
Benzil (1 mmol), o-phenylenediamine (1 mmol), graphite, ethanol (10 mL),
stir, rt.
b
As quinoxalines are medicinally important compounds, ethyl
alcohol was chosen as a solvent due to its lower toxicity. For initial
Water (10 mL) was used as solvent.
Table 2
Synthesis of quinoxalines via Scheme 1a
Entry
Diketone 1
Diamine 2
productc
3
Time (h)
Yieldb (%)
H2N
N
N
O
O
C
C
H2N
1
1
92
2a
3a
1a
H2N
H3C
O
O
O
H3C
O
N
N
H2N
O
O
2
2.5
79
H3C
H3C
2a
3b
1b
O
O
H2N
O
O
O
N
N
H2N
3
3
86
O
2a
1c
3c
N
O
O
H2N
H2N
O
Ph
Ph
4
O
N
3.5
77
2b
1a
3d
O
O
H2N
H2N
H3C
H3C
O
O
H3C
O
N
N
Ph
O
O
Ph
O
5
18
77
H3C
2b
3e
1b
O
O
O
O
O
O
O
H2N
H2N
N
N
Ph
Ph
6
24
80
2b
O
3f
1c

H. K. Kadam et al. / Tetrahedron Letters 54 (2013) 1003–1007
1005
Table 2 (continued)
Entry
Diketone 1
Diamine 2
productc
3
Time (h)
Yieldb (%)
H2N
O
O
N
N
H2N
NO2
7
8
86
NO2
2c
1a
3g
H2N
H2N
H3C
O
O
O
H3C
O
N
N
NO2
O
O
8
12
10
0.5
81
87
93
H3C
H3C
NO2
2c
1b
3h
O
O
H2N
H2N
O
O
O
N
NO2
9
O
N
NO2
2c
2a
3i
1c
H2N
H2N
O
N
N
10
O
1d
3j
N
O
O
H2N
H2N
O
O
Ph
Ph
11
1
88
N
2b
3k
1d
1d
H2N
H2N
O
O
N
N
NO2
12
12
71
2c
NO2
3l
O
H2N
H2N
N
O
0d
N
N
H
24
45
13
12d
N
H
1e
2a
3m
H2N
H2N
O
O
N
2d
14
1
92
N
1a
3n
(continued on next page)

1006
H. K. Kadam et al. / Tetrahedron Letters 54 (2013) 1003–1007
Table 2 (continued)
Entry
Diketone 1
Diamine 2
productc
3
Time (h)
Yieldb (%)
H2N
O
O
N
N
H2N
CH3
15
1
81
CH3
2e
1a
3o
N
H2N
H2N
O
O
2f
16
2.5
72
N
1a
3p
H2N
H2N
H3C
O
O
O
H3C
O
N
O
O
2f
17
3
86
H3C
H3C
N
1b
3q
H2N
H2N
O
N
N
12
45
64d (21e)
64d (21e)
2a
OH
18
3a
1f
a
Reaction condition: diketone (1 mmol), diamine (1 mmol), graphite (2 mmol), ethanol (10 mL), stir rt.
Isolate yield.
b
c
Products confirmed based on their 1H NMR, 13C NMR, DEPT, and elemental analysis/LCMS (Supplementary data).
Graphite (5 mmol), diamine (1.2 mmol), 80 °C.
d
e
2-(2-aminophenylimino)-1,2-diphenylethanol 3r.
GRAPHITE
GRAPHITE
Table 3
Reusability of catalysta
H
O
H
H
N
Yieldb (%)
O
O
Cycle
Time (min)
HN
C
C
-2H2O
C
C
O
H
0
1
2
3
4
5
6
60
60
90
120
150
150
150
92
92
90
89
88
88
88
3a
HN
H
N
H
GRAPHITE
GRAPHITE
Scheme 2. Probable mechanism illustrating role of graphite in reaction.
a
Benzil (1 mmol), o-phenylenediamine (1 mmol), graphite (2 mmol), ethanol
(10 mL), stir, rt.
b
Isolated yield.
electron deficient diamines (2b–c) took a longer time to react
due to +I effect and ÀI effect, respectively. The method could also
be successfully extended to phenanthrene-9,10-dione 1d for syn-
thesizing corresponding dibenzophenazines (entry 10–12).
When isatin 1e was used as dicarbonyl compound, after pro-
longed heating (entry 13), only 12% of product formation was ob-
served. This may be due to the less reactive amide carbonyl
group in isatin. When aliphatic amines were used corresponding
dihydropyrazines were obtained (entries 14–17) in good yields.
Further scope of this graphite catalyzed condensation process
was tested with 2-hydroxyketone, benzoin (entry 18). Reasonable
formation of product 3a was observed along with 2-(2-aminophe-
nylimino)-1,2-diphenylethanol 3r, only under reflux condition
using 5 equiv of graphite.
condensation studies between benzil 1a and o-phenylenediamine
2a (Scheme 1), excess of graphite (20 equiv) was used. This gave
quinoxaline 3a in 86% yield in 30 min. at room temperature. Hav-
ing observed the catalytic acceleration effect of graphite, we slowly
reduced the amount of graphite for optimization studies (Table 1).
It was observed that 2 equiv of graphite (entry 4) gave maximum
yield (92%) after 1 h. Hence, this condition was chosen for further
studies. Further decrease in graphite concentration resulted in
decreasing its efficacy.
Using this protocol,8 a library of quinoxalines (Table 2) was syn-
thesized. It was observed that electron rich diketones (1b–c) and

H. K. Kadam et al. / Tetrahedron Letters 54 (2013) 1003–1007
1007
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The separation of catalyst was very easy as mere filtration
through an ordinary filter paper and drying (100 °C) was sufficient
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and fairly reproducible yields were obtained up to 7 consecutive
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Though the role of graphite has not been clearly understood, a
speculative mechanism for product formation is proposed
(Scheme 2).
In conclusion, an efficiently recoverable, environment friendly,
and cheap graphite catalyst is demonstrated for the condensation
of diketones with o-phenylenediamine to give quinoxalines in
excellent yield at ambient condition.
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Acknowledgments
Authors gratefully acknowledge the Department of Science and
Technology (DST) and the Council for Scientific and Industrial Re-
search (CSIR), New Delhi for financial support. H.K.K. thanks CSIR,
New Delhi for award of NET Senior Research Fellowship.
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Supplementary data
Supplementary data (1H NMR, 13C NMR and DEPT spectra of all
the products) associated with this article can be found, in the on-
line version, at http://dx.doi.org/10.1016/j.tetlet.2012.12.041.
8. General procedure: Diketone (1 mmol), diamine (1 mmol), and graphite
(2 mmol) were mixed in a 50 mL round bottom flask and ethanol (10 mL) was
added. The reaction mixture was stirred vigorously at room temperature
(monitored by TLC). On completion, the mixture was filtered through an
ordinary filter paper and catalyst was washed with ethanol (10 mL). Organic
layer was concentrated to give crude solid product which on recrystallization
with ethanol/water (8:2) afforded analytically pure product. Structures of new
compounds were confirmed based on their 1H NMR, 13C NMR, DEPT data, and
elemental analysis.
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(2,3-Bis(3-methoxyphenyl)quinoxalin-6-yl)(phenyl)methanone 3e: Pale yellow
solid; mp 138–139 °C; 1H NMR (400 MHz, CDCl3,d ppm): 3.71 (3H, s), 3.73
(3H, s), 6.94 (2H, t, J = 8.0 Hz), 7.07–7.14 (4H, m), 7.26 (2H, q, J = 8.0 Hz), 7.53
(2H, t, J = 8.0 Hz), 7.64 (1H, t, J = 8.4 Hz), 7.91 (2H, d, J = 8.0 Hz), 8.28 (2H, s), 8.54
(1H, s); 13C NMR (100 MHz, CDCl3,d ppm): 55.30 (CH3), 55.31 (CH3), 114.66 (CH),
114.77 (CH), 115.52 (CH), 115.66 (CH), 122.25 (CH), 122.38 (CH), 128.55
(2 Â CH), 129.46 (2 Â CH), 129.75 (CH), 129.94 (CH), 130.17 (2 Â CH), 132.48
(CH), 132.88 (CH), 137.15 (Cq), 138.34 (Cq), 139.81 (Cq), 139.85 (Cq), 140.15
(Cq), 142.95 (Cq), 154.42 (Cq), 154.96 (Cq), 159.50 (2 Â Cq), 195.83 (Cq);
elemental analysis (calcd C = 78.01, H = 4.97, N = 6.27%) observed C = 77.65,
H = 4.75, N = 5.90%.
2,3-Bis(3-methoxyphenyl)-4a,5,6,7,8,8a-hexahydroquinoxaline 3q: White solid;
mp 136–137 °C; 1H NMR (400 MHz, CDCl3,d ppm): 1.42 (2H, t, J = 10.0 Hz),
1.62–1.64 (2H, m), 1.90 (2H, d, J = 8.0 Hz), 2.50 (2H, d, J = 14.0 Hz), 2.83 (2H, t,
J = 4.0 Hz), 3.69 (6H, s), 6.83 (2H, d, J = 8.0 Hz), 6.91 (2H, d, J = 8.0 Hz), 6.99 (2H,
s), 7.12 (2H, t, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3,d ppm): 25.43 (CH2), 33.49
(CH2), 55.24 (CH3), 59.55 (CH), 112.59 (CH), 115.91 (CH), 120.64 (CH), 129.15
(CH), 139.13 (Cq), 159.34 (Cq), 159.56 (Cq); elemental analysis (calcd C = 75.83,
H = 6.94, N = 8.04%) observed C = 75.57, H = 7.10, N = 7.81%.