An effective microwave-induced iodine-catalyzed method for the synthesis of quinoxalines via condensation of 1,2-diamines with 1,2-dicarbonyl compounds

Article abstract of DOI:10.3390/molecules15064207

A microwave-induced iodine-catalyzed simple, rapid and convenient synthesis of different types of quinoxalines via condensation of 1,2-diamines with 1,2-dicarbonyl compounds has been accomplished with an excellent yield.

Full text of DOI:10.3390/molecules15064207

Molecules 2010, 15, 4207-4212; doi:10.3390/molecules15064207
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
An Effective Microwave-Induced Iodine-Catalyzed Method for
the Synthesis of Quinoxalines via Condensation of 1,2-Diamines
with 1,2-Dicarbonyl Compounds
Debasish Bandyopadhyay, Sanghamitra Mukherjee, Robert R. Rodriguez and Bimal K. Banik *
Department of Chemistry, The University of Texas-Pan American, 1201 West University Drive,
Edinburg, TX 78541, USA
*
Author to whom correspondence should be addressed; E-Mail: banik@panam.edu;
Tel.: +1-956-380-8741; Fax: +1-956-384-5006.
Received: 28 March 2010; in revised form: 14 May 2010 / Accepted: 9 June 2010 /
Published: 9 June 2010
Abstract: A microwave-induced iodine-catalyzed simple, rapid and convenient synthesis
of different types of quinoxalines via condensation of 1,2-diamines with 1,2-dicarbonyl
compounds has been accomplished with an excellent yield.
Keywords: iodine; microwave; quinoxalines; amines; dicarbonyl compounds
1
. Introduction
A quinoxaline moiety serves as the nucleus for the synthesis of several biologically active
compounds including antitumor [1], antimycobacterial [2] and antidepressant [3] drugs. Some
antibiotics, such as levomycin, actinoleutin and echinomycin also contain a quinoxaline scaffold and
these are known to inhibit the growth of Gram positive bacteria [4] and are active against various
transplantable tumors [5]. As a part of our ongoing research leading to the synthesis of novel
anticancer drugs [6–11] we became interested in the development of a new, efficient and practical
method to synthesize quinoxalines.
Although diverse methods for the synthesis of substituted quinoxalines are described in the
literature [12,13], the most common method for their preparation is a condensation reaction between a
1,2-diamine and 1,2 dicarbonyl compound. Clearly, all while these methods have extended the scope
for the synthesis of this type of heterocycles, they have limitations in some of the following areas: low

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yield, long reaction time, difficult product isolation procedure and use of toxic metal catalysts as well
as hazardous solvents. In this paper, we describe an automated microwave-assisted extremely rapid
iodine-catalyzed method for the synthesis of substituted quinoxalines in high yields in aqueous ethanol
via the diamine-dicarbonyl compound condensation route (Scheme 1).
Scheme 1. Microwave-induced iodine-catalyzed synthesis of quinoxalines.
2
. Results and Discussion
Our group has reported the synthesis and biological evaluation of various β-lactams as novel
anticancer agents [6–11]. The synthesis of β-lactams through imines requires a dicarbonyl compound
and an amine. We have been conducting research on imines for the last 20 years. Our study suggests
that condensation of 1,2-diamino compounds and 1,2 dicarbonyl compounds in the presence of a mild
acidic reagent will lead to the synthesis of quinaxolines (Scheme 1). This hypothesis has been tested by
reacting several diamines with various dicarbonyl compounds in the presence of iodine (catalytic
amount, 5 mol %) in ethanol/water (1:1) using a microwave-induced method. The model reaction
between o-phenylenediamine and phenylglyoxal monohydrate in the presence of iodine as catalyst
using microwave irradiation has been performed in different solvent systems (Table 1). However, best
2
results were obtained when EtOH/H O (1:1) was used as solvent.
Table 1. Reaction between o-phenylene diamine and phenylglyoxal monohydrate in the
presence of iodine (5 mol %) in different solvents under microwave irradiation.
Entry
Solvent
Methanol
Time (min.)
Yield (%)
1
2
3
4
5
6
7
8
3
41
65
48
27
36
38
72
99
Ethanol
3
Tetrahydrofuran
Dichloromethane
THF/Water (1:1)
Water
5
3
5
5
3
Acetonitrile
Ethanol/Water (1:1)
30 sec.

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Next the reaction conditions were tested with a variety of 1,2-diamines and 1,2-dicarbonyl
compounds. In all cases the reaction was completed within 2–3 minutes at 50 °C in a CEM microwave
and the corresponding quinoxalines were isolated in excellent yields (Table 2).
Table 2. Synthesis of quinoxalines via condensation of 1,2-diamines with 1,2-dicarbonyl
compounds with iodine as the catalyst in water/ethanol (1:1) under microwave induces
reaction (Scheme 1).
a
Entry
Amine
Dicarbonyl
Compounds
MWI
(Power/temp/time)
300 watts
Product
Yield (%)
1
5
0°C
0 sec
300 watts
0 °C
0 sec
300 watts
0 °C
0 sec
300 watts
0 °C
5 sec
300 watts
99
90
92
95
98
86
90
85
95
3
2
3
4
5
6
7
8
9
5
3
5
3
5
4
50 °C
1
min
300 watts
50 °C
1
min
300 watts
0 °C
.5 min
300 watts
0 °C
0 sec
300 watts
0 °C
.5 min
5
1
5
3
NH2
5
NH2
2
10
300 watts
50 °C
87
2
min

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Table 2. Cont.
Entry
Amine
Dicarbonyl
Compounds
MWI
(Power/temp/time)
300 watts
Product
Yield
a
(%)
11
12
13
50 °C
92
2
min 15 sec
300 watts
N
N
50 °C
93
—
45 sec
300 watts
50 °C
No reaction
5
min
without catalyst
isolated yield.
a
The reaction proceeded equally well irrespective of the nature of substituents (chloro, nitro and
methoxy groups) present in the amino component. The reaction between 1,2-diamines and 1,2
dicarbonyl compounds does not proceed at all without iodine (Entry 13).
3. Experimental Section
3
.1. General
Melting points were determined in a Fisher Scientific electrochemical Mel-Temp* manual melting
point apparatus (Model 1001) equipped with a 300°C thermometer. Elemental analyses (C, H, N) were
conducted using the Perkin-Elmer 2400 series II elemental analyzer, their results were found to be in
good agreement (± 0.2%) with the calculated values for C, H, N. FT-IR spectra were registered on a
1
13
Bruker IFS 55 Equinox FTIR spectrophotometer as KBr discs. H-NMR (300 MHz) and C-NMR
75.4 MHz) spectra were obtained at room temperature with JEOL Eclipse-300 equipment using TMS
as internal standard and CDCl as solvent. Analytical grade chemicals (Sigma-Aldrich incorporation)
(
3
were used throughout the project. Deionized water was used for the preparation of all aqueous
solutions.
3.2. General procedure for the synthesis of quinoxalines
The diamine (1 mmol) and the dicarbonyl compound (1 mmol) were dissolved in ethanol/water (1:1, 1 mL). A
catalytic amount (5 mol%) of iodine was added and the mixture was irradiated using a CEM microwave (50 °C and
power level 300 µ) as described in Table 2. The reaction was monitored by TLC. After the completion of the reaction,
dichloromethane (10 mL) was added to the reaction mixture and it was then washed successively with 5% sodium
thiosulphate solution (2 mL) and brine (2 mL). The organic layer was dried with anhydrous sodium sulfate and
concentrated. Quinoxalines were found to be. No column chromatography was needed for the purification of the

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products and pure products (~95% by proton NMR) were isolated through crystallization (dichloromethane-hexane).
Compounds obtained from entries 5, 6 and 9–11 (Table 2) were previously reported [13-15]. The remaining
compounds (entries 1–4, 7, 8 and 12, Table 2) have been characterized by IR, NMR and mass spectral data. Our
products gave satisfactory spectral and mp data matching with the reported values. We also carried out a reaction of
benzil and ortho-phenylenediamine in absence of iodine (entry 13) following the published procedure [14]. However,
no reaction took place at 50 °C without catalyst, even after 5 minutes of microwave irradiation; thus suggesting a
lowering of the activation energy in the presence of the catalyst that also reduces the possibility of product loss due to
partial charring.
4. Conclusions
In conclusion, the iodine-catalyzed microwave-induced quinoxaline synthesis as described herein is
very simple, environmentally friendly and extremely rapid and affords high (almost quantitative)
yields. Our method is versatile since aliphatic and aromatic amino compounds can be used in this
reaction and these substrates all produce quinoxalines with remarkable success.
Acknowledgements
We gratefully acknowledge the funding support from National Cancer Institute (NIH/NCI-P20,
Grant# 5P20CA138022-02).
References
1.
Hazeldine, S.T.; Polin, L.; Kushner, J.; Paluch, J.; White, K.; Edelstein, M.; Palomino, E.; Corbett,
T.H.; Horwitz, J.P. Design, Synthesis, and Biological Evaluation of Analogues of the Antitumor
Agent, 2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic Acid (XK469). J. Med. Ch em.
2001, 44, 1758–1776.
2.
3.
4.
Seitz, L.E.; Suling, W.J.; Reynolds, R.C. Synthesis and Antimycobacterial Activity of Pyrazine
and Quinoxaline Derivatives. J. Med. Chem. 2002, 45, 5604–5606.
Badran, M.M.; Botros, S.; El-Gendy, A.A.; Abdou, N.A.; El-Assi, H.; Salem, A. Part I: novel
quinoxaline derivatives of biological interest. Bull. Pharm. Sci. 2001, 24, 135–144.
Bailly, C.; Echepare, S.; Gago, F.; Waring, M.J. Recognition elements that determine affinity and
sequence-specific binding to DNA of 2QN, a biosynthetic bis-quinoline analogue of echinomycin.
Anti Canc. Drug Des. 1999, 14, 291–303.
5
.
.
Sato, K.; Shiratori, O.; Katagiri, K. Mode of action of quinoxaline antibiotics. Interaction of
quinomycin A with deoxyribonucleic acid. J. Antibiot. 1967, 20, 270–276.
6
Becker, F.F.; Banik, B.K. Polycyclic aromatic compounds as anticancer agents: synthesis and
biological evaluation of some chrysene derivatives. Bioorg. Med. Chem. Lett.
877–2880.
1998, 8,
2
7.
Becker, F.F.; Mukhopadhyay, C.; Hackfeld, L.; Banik, I.; Banik, B.K. Polycyclic aromatic
compounds as anticancer agents: synthesis and biological evaluation of dibenzofluorene
derivatives. Bioorg. Med. Chem. 2000, 8, 2693–2699.

Molecules 2010, 15
4212
8
.
.
Banik, B.K.; Becker, F.F. Polycyclic aromatic compounds as anticancer agents. 4. Structure-
activity relationships of chrysene and pyrene derivatives. Bioorg. Med. Chem. 2001, 9, 593–605.
Banik, B.K.; Becker, F.F. Synthesis, electrophilic substitution and structure-activity relationship
studies of polycyclic aromatic compounds towards the development of anticancer agents. Curr.
Med. Chem. 2001, 8, 1513–1533.
9
1
1
1
0. Banik, B.K.; Becker, F.F.; Banik, I. Synthesis of anticancer β-lactams: Mechanism of action.
Bioorg. Med. Chem. 2004, 12, 2523–2528.
1. Banik, I.; Becker, F.F.; Banik, B.K. Stereoselective Synthesis of β-Lactams with Polyaromatic
Imines: Entry to New and Novel Anticancer Agents. J. Med. Chem. 2003, 46, 12–15.
2. Kamal, A.; Reddy, K.L.; Devaiah, V.; Shankaraiah, N.; Rao, M.V. Recent advances in the solid-
phase combinatorial synthetic strategies for the quinoxaline, quinazoline and benzimidazole based
privileged structures. Mini Rev. Med. Chem. 2006, 6, 71–89.
1
3. Srinivas, C.; Kumar, C.N.S.S.P.; Rao, V.J.; Palaniappan, S. Efficient, convenient and reusable
polyaniline-sulfate salt catalyst for the synthesis of quinoxaline derivatives. J. Mo l. Catal. A:
Chem. 2007, 265, 227–230.
1
4. Zhou, J.F.; Gong, G.X.; Zhi, S.J.; Duan, X.L. Microwave- assisted catalyst-free and solvent-free
method for the synthesis of quinoazlines. Synth. Commun. 2009, 39, 3743–3754.
5. More, S.V.; Sastry M.N.V.; Yao C.-F. Cerium (IV) ammonium nitrate (CAN) as a catalyst in tap
water: A simple, proficient and green approach for the synthesis of quinoxalines. Green Chem.
1
2
006, 8, 91-95.
Sample Availability: Samples of the compounds (mg quantity) are available from the authors.
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