Silica-gel-catalyzed efficient synthesis of quinoxaline derivatives under solvent-free conditions

Article abstract of DOI:10.1080/00397910903576685

Quinoxaline derivatives have been prepared in good to excellent yields using silica gel as catalyst from various 1,2-diketones and 1,2-diamines under solvent-free conditions for the first time. The advantages of this method are short reaction time, reaction simplicity, convenient workup procedure, and purification of compounds by a nonchromatographic method.

Full text of DOI:10.1080/00397910903576685

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Silica-Gel–Catalyzed Efficient Synthesis
of Quinoxaline Derivatives Under
Solvent-Free Conditions
Ganesh Chandra Nandi a , Subhasis Samai a , Ram Kumar a & M. S.
Singh a
a Faculty of Science, Department of Chemistry, Banaras Hindu
University, Varanasi, India
Published online: 13 Jan 2011.
To cite this article: Ganesh Chandra Nandi , Subhasis Samai , Ram Kumar & M. S. Singh (2011) Silica-
Gel–Catalyzed Efficient Synthesis of Quinoxaline Derivatives Under Solvent-Free Conditions, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:3, 417-425, DOI: 10.1080/00397910903576685
To link to this article: http://dx.doi.org/10.1080/00397910903576685
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Synthetic Communications1, 41: 417–425, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903576685
SILICA-GEL–CATALYZED EFFICIENT SYNTHESIS OF
QUINOXALINE DERIVATIVES UNDER
SOLVENT-FREE CONDITIONS
Ganesh Chandra Nandi, Subhasis Samai, Ram Kumar, and
M. S. Singh
Faculty of Science, Department of Chemistry, Banaras Hindu University,
Varanasi, India
Quinoxaline derivatives have been prepared in good to excellent yields using silica gel as
catalyst from various 1,2-diketones and 1,2-diamines under solvent-free conditions for the
first time. The advantages of this method are short reaction time, reaction simplicity, con-
venient workup procedure, and purification of compounds by a nonchromatographic method.
Keywords: 1,2-Diamines; 1,2-diketones; quinoxaline; silica gel
The quinoxaline and its derivatives constitute a very important, privileged class of
nitrogen-containing heterocyclic compounds that shows various biological activities
such as antiviral,[1] anti-inflammatory, antiprotozoal,[2] antihelmintic,[3] anticancer,[4]
antimalarial,[5] and antidepressant[6] activities. Quinoxaline derivatives are present in
different antibiotics such as echinomycin, levomycin, and actinoleutin,[7] which
inhibit the growth of Gram-positive bacteria. Beside its biological activities, it is used
in the synthesis of organic semiconductors,[8] dyes,[8c] and electroluminescent materi-
als.[9] Over the years, numerous synthetic strategies have been developed for the
preparation of quinoxaline derivatives. Among them, the most common methods
are the condensation of the 1,2-diketones and 1,2-aryldiamines at refluxing tempera-
ture in ethanol, benzene, or in acetic acid.[10] Different catalysts have also been used
for the synthesis of quinoxaline moieties such as iodine,[11] polyaniline sulfate salt,[12]
montmorillonite K-10,[13] InCl3,[14] MnCl2,[15] CuSO4 ꢀ 5H2O,[16] Zn=L-proline,[17]
ceric ammonium nitrate (CAN),[18] iodoxybenzoic acid (IBX),[19] Ga(OTf)3, and
NH4X.[20] Beside these condensation methods, oxidative coupling of epoxides and
ene-1,2-diamines catalyzed by Bi(0),[21] heteroannulation of nitroketene
N,S-aryliminoacetals with POCl3,[22] from a-hydroxy ketones via a tandem oxidation
process using Pd(OAc)2 or RuCl2-(PPh3)3-TEMPO,[23] as well as MnO2[24] have been
reported. Moreover, quinoxaline derivatives have also been prepared without any
catalyst under microwave heating.[25]
Received October 10, 2009.
Address correspondence to M. S. Singh, Faculty of Science, Department of Chemistry, Banaras
Hindu University, Varanasi 221005, India. E-mail: mssinghbhu@yahoo.co.in
417

418
G. C. NANDI ET AL.
Most of these methods suffer from one or more drawbacks such as high
temperature, poor yield, long reaction time, use of hazardous solvent, critical pro-
duct isolation procedure, and use of expensive catalysts, so a generalized method still
remains an ongoing challenge. In recent days, solvent-free syntheses have attracted
the attention of chemists because they are environmentally benign processes. As part
of our continued interest[26] in the development of solvent-free synthesis, herein we
report a new synthetic strategy for the preparation of quinoxaline derivatives cata-
lyzed by silica gel under solvent-free conditions. Silica gel has been effectively used
in organic synthesis not only as a simple medium but also as a mild acid catalyst
or as an accelerator. It is easily separable from the product because of its insolubility
in organic solvents. Previously, silica gel has been used in many reactions such as
selective allylation of aldehyde with tetrabutyltin,[27] selective C-S bond formation,
and synthesis of benzochromene.[28] Silica-gel-supported catalysts such as SiO2=
[29]
FeCl3, SiO2=BF3, SiO2=NaHSO4, and SiO2=H2SO4
have also been widely used
in various kinds of organic transformations. It is inexpensive, ecofriendly, and easily
available and can be easily separated out from the product.
RESULTS AND DISCUSSION
The new synthetic routes to quinoxaline derivatives are outlined in Schemes 1
and 2. The reactions of 1,2-diketones and 1,2-diamines were carried out in the pres-
ence of silica gel via a grinding process. The reaction proceeds at room temperature
(Scheme 1) or under heating (Scheme 2), depending upon the nature of the 1,2-dike-
tones. To realize the generality and versatility of the reaction condition, different
substituted 1,2-diamines and aliphatic as well as aromatic 1,2-diketones were taken.
For optimization of the reaction condition, silica gel was taken in different ratios, and
it was observed that for 1 mmol of the reactant 1.0 g silica gel provides the maximum
yield in the shortest time. Use of less than 1.0 g silica gel for 1 mmol of the reactant
requires a longer time to complete for both the methods. As shown in Table 1, when
1,4-dibromo-2,3-butanedione is treated with various 1,2-diamines, all reactions pro-
ceeded efficiently at room temperature and the desired quinoxalines were obtained in
excellent yields within short reaction times. However, the corresponding quinoxaline
unit of 2,3-diaminopyridine (Table 1, entry 3f) is obtained in less yield (30%).
When benzil was used as 1,2-diketone (Scheme 2), the progress of the reaction
was slow. Even after 1 h of grinding, the reaction was not complete and only 30%
conversion to product was achieved. Then the reaction mixture was heated at
100ꢁC for the stipulated time to get the quinoxaline derivatives in good yields.
The results obtained are given in detail in Table 2. Whether the substituent is
Scheme 1. Synthesis of quinoxalines from 1,4-dibromo-2,3-diketone with 1,2-diamines.

EFFICIENT SYNTHESIS OF QUINOXALINE DERIVATIVES
419
Scheme 2. Synthesis of quinoxalines from benzil with 1,2-diamines.
electron-withdrawing or electron-donating in the 1,2-diamine does not affect the
yield, which is an advantage of the reaction.
In conclusion, we have developed a facile and efficient method for the syn-
thesis of quinoxalines by the reaction of 1,2-diketones and 1,2-diamino compounds
in the presence of silica gel under solvent-free conditions. The method is equally
Table 1. Reaction of 1,4-dibromo-2,3-diketone with 1,2-diamines
Entry
3a
1,2-Diamine
Product
Time (min)
Yield (%)
85
20
3b
3c
3d
17
20
20
87
80
83
3e
20
84
3f
20
25
30
83
3g

420
G. C. NANDI ET AL.
Table 2. Reaction of benzil with 1,2-diamines
Entry
6a
1,2-Diamine
Product
Time (min)
Yield (%)
94
45
6b
6c
6d
60
45
65
96
88
97
6e
70
97
6f
45
75
83
80
6g
efficient for aromatic, aliphatic, and heterocyclic diamines and also for both
aromatic and aliphatic diketonic compounds. Both the electron-withdrawing and
electron-donating substituent in the 1,2-diamine shows equal ease in this transform-
ation. The advantages of this new strategy are short reaction time, excellent yield,
low cost, reaction simplicity, and purification of compounds by nonchromato-
graphic methods. Finally, it is in agreement with the green chemistry protocols.
EXPERIMENTAL
General
All reagents were purchased from Merck, Aldrich, CDH, and Fluka and
used without further purification. The silica gel G used as catalyst for thin-layer
chromatography (TLC) was obtained from Merck. NMR spectra were recorded
on a Jeol AL 300 Fourier transform (FT) NMR spectrometer. The infrared (IR)
spectra were recorded on a Varian 3100 FT-IR spectrophotometer. CHN analyses

EFFICIENT SYNTHESIS OF QUINOXALINE DERIVATIVES
421
were performed on an Exeter Analytical model CE-400 CHN analyzer. All the reac-
tions were monitored by TLC using precoated sheets of silica gel G=UV-254 0.25 mm
thick (Merck 60 F254). Melting points were determined with a Buchi B-540 melting-
point apparatus and are uncorrected.
General Procedure for Preparation of Quinoxaline Derivatives (3a–g)
A mixture of 1,2-dicarbonyl (1 mmol), 1,2-diamine (1 mmol), and 1.0 g of silica
gel were taken in a mortar and ground with a pestle thoroughly at room temperature
for 15 min. After the completion of the reaction, CHCl3 was added to dissolve the
product. Silica gel was filtered off, and the solvent was evaporated under vacuum
to give the crude products, which were crystallized from ethanol. The products have
been characterized by spectral and elemental analysis.
Physical and Spectral Data of the Products
2,3-Bis-bromomethyl-quinoxaline (3a). Mp 153 ꢁC. IR (KBr) nmax (cmꢂ1):
3053, 2924, 1610, 1125. 1H NMR (300 MHz, CDCl3): d 8.08 (dd, J ¼ 3.6 Hz, 6.3 Hz,
2H), 7.81 (dd, J ¼ 3.6 Hz, 6.3 Hz, 2H), 4.92 (s, 4H). 13C NMR (75 MHz, CDCl3): d
150.7, 141.4, 130.8, 128.9, 30.4. Anal. calcd. for C10H8Br2N2: C, 38.01; H, 2.55, N,
8.87. Found: C, 38.10; H, 2.65; N, 8.92.
2,3-Bis(bromomethyl)-6-methylquinoxaline (3b). Mp 126–127 ꢁC. IR
(KBr) nmax (cmꢂ1): 3055, 2925, 1612, 1341, 1120, 698. 1H NMR (300 MHz, CDCl3):
d 7.96 (d, J ¼ 8.7 Hz, 1H), 7.83 (s, 1H), 7.63 (d, J ¼ 8.7 Hz, 1H), 4.90 (s, 4H), 2.59 (s,
3H). 13C NMR (75 MHz, CDCl3): d 150.5, 149.6, 141.6, 141.5, 139.9, 133.1, 128.4,
127.7, 30.6, 30.5, 21.8. Anal. calcd. for C11H10Br2N2: C, 40.03; H, 3.05; N, 8.49.
Found: C, 39.85; H, 2.91; N, 8.15.
2,3-Bis-bromomethyl-6-chloro-quinoxaline (3c). Mp 150–151 ꢁC. IR
1
(KBr) nmax (cmꢂ1): 3051, 2924, 1590. H NMR (300 MHz, CDCl3): d 8.07 (s, 1H),
8.01 (d, J ¼ 8.7 Hz, 1H), 7.75 (d, J ¼ 8.7 Hz, 1H), 4.89 (s, 4H). 13C NMR
(75 MHz, CDCl3): d 151.8, 150.9, 141.7, 139.9, 136.8, 131.8, 130.1, 127.9, 30.1,
30.0. Anal. calcd. for C10H7Br2ClN2: C, 34.27, H, 2.01, N, 7.99. Found: C, 34.30;
H, 2.12; N, 8.09.
2,3-Bis-bromomethyl-6-nitro-quinoxaline (3d). Mp 116–117 ꢁC. IR (KBr)
1
nmax (cmꢂ1): 3056, 1603, 1180. H NMR (300 MHz, CDCl3): d 8.97 (s, 1H), 8.57 (d,
J ¼ 9.0 Hz, 1H), 8.24 (d, J ¼ 9.3 Hz, 1H), 4.94 (s, 2H), 4.93 (s, 2H). 13C NMR
(75 MHz, CDCl3): d 154.0, 153.3, 148.3, 143.7, 140.3, 130.7, 125.2, 124.1, 29.6,
29.5. Anal. calcd. for C10H7Br2N3O2: C, 33.27; H, 1.95; N, 11.64. Found: 33.20;
H, 1.92; N, 11.65.
(2,3-Bis-bromomethyl-quinoxalin-6-yl)-phenyl-methanone
(3e). Mp
120–121 ꢁC. IR (KBr) nmax (cmꢂ1): 3052, 1654, 1600, 1438. H NMR (300 MHz,
CDCl3): d 8.42 (s, 1H), 8.25–8.17 (m, 2H), 7.88 (d, J ¼ 7.2 Hz, 2H), 7.68–7.51 (m,
3H), 4.94 (s, 2H), 4.92 (s, 2H). 13C NMR (75 MHz, CDCl3): d 195.3, 152.6, 152.0,
143.1, 140.6, 139.2, 136.8, 133.0, 131.8, 130.7, 130.0, 129.5, 128.5, 30.0. Anal. calcd.
for C17H12Br2N2O: C, 48.60; H, 2.88; N, 6.67. Found: C, 48.62; H, 2.98; N, 6.53.
1

422
G. C. NANDI ET AL.
2,3-Bis-bromomethyl-pyrido[2,3-b]pyrazine (3f). Mp 106–107 ꢁC. IR
(KBr) nmax (cmꢂ1): 3052, 1592, 1542. 1H NMR (300 MHz, CDCl3): d 9.18 (d,
J ¼ 8.1 Hz, 1H), 8.49 (d, J ¼ 8.1 Hz, 1H), 7.81 (dd, J ¼ 3.3 Hz, 7.5 Hz, 1H), 4.97 (s,
2H), 4.95 (s, 2H); 13C NMR (75 MHz, CDCl3): d 153.1, 152.0, 149.8, 141.2, 141.0,
135.2, 123.5, 31.0, 30.9. Anal. calcd. for C9H7Br2N3: C, 34.10; H, 2.23; N, 13.26.
Found: C, 34.08; H, 2.15; N, 13.22.
5,6-Bis-bromomethyl-pyrazine-2,3-dicarbonitrile (3g). Mp 107 ꢁC. IR
1
(KBr): nmax (cmꢂ1): 2240, 1742, 1383. H NMR (300 MHz, CDCl3): d 4.74 (s, 4H);
13C NMR (75 MHz, CDCl3): d 155.3, 131.8, 112.2, 30.9. Anal. calcd. for C8H4Br2N4:
C, 30.41; H, 1.28; N, 17.73. Found: C, 30.45; H, 1.39; N, 17.92.
General Procedure for Preparation of Quinoxaline Derivatives (6a–g)
A mixture of 1,2-dicarbonyl (1 mmol), 1,2-diamine (1 mmol), and 1.0 g of silica
gel were taken in a mortar and ground with a pestle thoroughly at room temperature
for 1 h. Then the reaction mixture was heated at 100 ꢁC for 1 h. CHCl3 was added to
dissolve the product, silica gel was filtered off, and the solvent was evaporated under
vacuum to obtain the crude products, which were crystallized from ethanol. The
products have been characterized by spectral and elemental analyses.
Physical and Spectral Data of the Products
2,3-Diphenyl-quinoxaline (6a). Mp 130–131 ꢁC. IR (KBr) nmax (cmꢂ1):
1
3055, 2925, 1546, 1344, 767. H NMR (300 MHz, CDCl3): d 8.20 (dd, J ¼ 3.6 Hz,
6.3 Hz, 2H), 7.79 (dd, J ¼ 3.6 Hz, 6.3 Hz, 2H), 7.53–7.50 (m, 4H), 7.35–7.33 (m,
6H). 13C NMR (75 MHz, CDCl3): d 153.4, 141.1, 139.0, 129.9, 129.8, 129.1, 128.7,
128.2. Anal. calcd. for C20H14N2: C, 85.08; H, 5.00; N, 9.92. Found: C, 84.95; H,
4.82; N, 9.75.
6-Methyl-2,3-diphenyl-quinoxaline (6b). Mp 115–116 ꢁC. IR (KBr) nmax
(cmꢂ1): 3051, 2921, 1690, 1621, 1503. 1H NMR (300 MHz, CDCl3): d 8.10 (d,
J ¼ 8.4 Hz, 1H), 7.84 (s, 1H), 7.68 (dd, J ¼ 3.6 Hz, 6.3 Hz, 1H), 7.53–7.50 (m, 4H),
7.34–7.26 (m, 6H). 13C NMR (75 MHz, CDCl3): d 153.8, 153.0, 143.1, 138.9,
138.5, 138.0, 134.4, 130.9, 130.4, 129.9, 129.7, 129.0, 128.1, 126.2, 126.0, 21.9. Anal.
calcd. for C21H16N2: C, 85.11; H, 5.44; N, 9.45. Found: C, 85.19; H, 5.34; N, 9.72.
6-Chloro-2,3-diphenyl-quinoxaline (6c). Mp 122–123 ꢁC. IR (KBr) nmax
1
(cmꢂ1): 3053, 2915, 1599, 1546. H NMR (300 MHz, CDCl3): d 8.17 (s, 1H), 8.11
(d, J ¼ 8.7 Hz, 1H), 7.72 (dd, J ¼ 2.1 Hz, 9 Hz, 1H), 7.51–7.49 (m, 4H), 7.35–7.32
(m, 6H). 13C NMR (75 MHz, CDCl3): d 154.1, 153.5, 141.3, 139.6, 138.6, 138.5,
135.5, 130.8, 130.3, 129.8, 129.7, 129.0, 128.9, 128.2, 127.9. Anal. calcd. for
C20H13ClN2: C, 75.83; H, 4.14; N, 8.84. Found: C, 75.95; H, 4.21; N, 8.85.
6-Nitro-2,3-diphenylquinoxaline (6d). Mp 193–195 ꢁC. IR (KBr) nmax (cmꢂ1):
1
3031, 2921, 1617, 1497, 1358, 1100, 692, 662. H NMR (300 MHz, CDCl3): d 9.07
(s, 1H), 8.54 (dd, J ¼ 2.1 Hz, 9.0 Hz, 1H), 8.30 (d, J ¼ 9.0 Hz, 1H), 7.57–7.54 (m,
4H), 7.42–7.34 (m, 6H). 13C NMR (75 MHz, CDCl3): d 156.2, 155.6, 147.8,
143.5, 139.9, 138.0, 137.9, 130.7, 129.8, 129.7, 129.7, 129.5, 128.4, 125.5, 123.2.

EFFICIENT SYNTHESIS OF QUINOXALINE DERIVATIVES
423
Anal. calcd. for C20H13N3O2: C, 73.38; H, 4.00; N, 12.84. Found: C, 73.45; H,
4.07; N, 12.87.
(2,3-Diphenyl-quinoxalin-6-yl)-phenylmethanone (6e). Mp 147–148 ꢁC.
1
IR (KBr) nmax (cmꢂ1): 3053, 1660, 1600, 1438. H NMR (300 MHz, CDCl3): d
8.58 (s, 1H), 8.34–8.26 (m, 2H), 8.00 (d, J ¼ 5.7 Hz, 2H), 7.70–7.30 (m, 13 H). 13C
NMR (75 MHz, CDCl3): d 195.7, 155.0, 154.5, 142.9, 140.1, 138.6, 138.5, 138.2,
137.1, 132.7, 130.0, 129.8, 129.7, 129.6, 129.2, 129.1, 128.4, 128.3. Anal. calcd for
C27H18N2O: C, 83.92; H, 4.69; N, 7.25. Found: C, 84.03; H, 4.81; N, 7.23.
2,3-Diphenyl-pyrido[2,3-b]pyrazine (6f). Mp 144–145 ꢁC. IR (KBr) nmax
1
(cmꢂ1): 3056, 1591, 1545, 1433. H NMR (300 MHz, CDCl3): d 9.17 (d, J ¼ 4.2 Hz,
1H), 8.53 (dd, J ¼ 1.8 Hz, 8.4 Hz, 1H), 7.73–7.54 (m, 5H), 7.40–7.30 (m, 6H). 13C
NMR (75 MHz, CDCl3): d 156.2, 154.6, 154.0, 149.7, 138.4, 138.0, 137.9, 136.0,
130.1, 129.7, 129.3, 129.2, 128.3, 128.0, 125.1. Anal. calcd for C19H13N3: C, 80.54;
H, 4.62; N, 14.83. Found: C, 80.59; H, 4.79; N, 14.95.
5,6-Diphenyl-pyrazine-2,3-dicarbonitrile (6g). Mp 209–210 ꢁC. IR (KBr)
1
nmax (cmꢂ1): 3063, 2230, 1675, 1595. H NMR (300 MHz, CDCl3): d 7.54–7.33 (m,
ArH); 13C NMR (75 MHz, CDCl3): d 155.5, 135.1, 131.1, 129.7, 128.8, 128.4,
113.1. Anal. calcd. for C18H10N4: C, 76.58; H, 3.57; N, 19.85. Found: C, 76.69; H,
3.68; N, 19.93.
ACKNOWLEDGMENTS
G. C. N. and and S. S. are thankful to the Council of Scientific and Industrial
Research, New Delhi, for financial assistance in the form of Senior research fellow-
ships. Ram Kumar is thankful to M. D. LLC, USA.
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