Citric acid: An efficient and green catalyst for rapid one pot synthesis of quinoxaline derivatives at room temperature

Article abstract of DOI:10.1016/j.cclet.2010.11.002

The condensation of o-phenylenediamines with 1,2-dicarbonyl compounds in the presence of citric acid afforded the corresponding quinoxaline derivatives in higher yields at room temperature in ethanol, and most of the reactions were completed in less than 1 min.

Full text of DOI:10.1016/j.cclet.2010.11.002

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 389–392
www.elsevier.com/locate/cclet
Citric acid: An efficient and green catalyst for rapid one pot
synthesis of quinoxaline derivatives at room temperature
Radhakrishnan Mahesh a, Arghya Kusum Dhar a, Tara Sasank T.V.N.V. a,
Sappanimuthu Thirunavukkarasu b, Thangaraj Devadoss a,
*
a Birla Institute of Technology & Science, Pilani, Rajasthan -333031, India
b Orchid Chemicals and Pharmaceutical Ltd., Sholinganallur, Chennai -600119, India
Received 10 June 2010
Available online 17 January 2011
Abstract
The condensation of o-phenylenediamines with 1,2-dicarbonyl compounds in the presence of citric acid afforded the
corresponding quinoxaline derivatives in higher yields at room temperature in ethanol, and most of the reactions were completed
in less than 1 min.
# 2010 Thangaraj Devadoss. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Quinoxalins; Citric acid; o-Phenylenediamines; 1,2-Dicarbonyl compounds; Green catalyst
Quinoxaline derivatives are important heterocyclic compounds for medicinal chemists, since it has wide range of
therapeutic uses; acting as antimicrobial [1], antiinflammatory [2], antimalarial [3], anticancer [4], antidepressant [5],
etc. besides these therapeutic uses, it also serves as an intermediate in various organic dyes [6], efficient
electroluminescent materials [7] and organic semiconductors [8]. Because of these reasons, it remains attractive for an
organic chemist to develop new synthetic methods for the preparation of quinoxaline derivatives.
Several synthetic routes have been developed for the synthesis of quinoxaline derivatives which includes;
condensation of o-phenylenediamines with 1,2-dicarbonyl compounds [9], oxidative cyclization of o-phenylene-
diamines with a-hydroxyketones [10] or ketones [11], 1,4 addition of 1,2-diamine to diazabutadienes [12], oxidative
coupling of epoxides with ene-1,2-diamines [13], cyclic-oxidation of phenacyl bromides with 1,2-diamines by
HClO4ÁSiO2 [14] and by using solid phase synthesis [15] and so on. Traditionally, quinoxaline derivatives are
synthesized from o-phenylenediamines by condensing it with 1,2-dicarbonyl compounds under refluxing condition
(2–12 h) in acetic acid or ethanolic medium and the obtained yields are between 35 and 85% [16]. Using Lewis acid
catalysts (I2, InCl3) [17]. Nowadays the above mentioned reaction is being carried out under room temperature and the
obtained yields are varying from good to excellent. Further, by employing microwave irradiation, quinoxaline
derivatives are synthesized in quantitative yields [18]. However, the critical product isolation procedure, long reaction
time and harsh conditions of the above mentioned methods, limit their use in sustainable chemistry.
* Corresponding author.
E-mail address: tdevadoss@gmail.com (T. Devadoss).
1001-8417/$ – see front matter # 2010 Thangaraj Devadoss. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.11.002

[()TD$FIG]
390
R. Mahesh et al. / Chinese Chemical Letters 22 (2011) 389–392
NH2
NH2
O
O
Ph
Ph
N
Ph
Ph
Citric acid (10 mol%)
EtOH, rt,
<1 min., 94%
N
1
3a
2
Scheme 1.
Recently, Heravi et al. [19] and More et al. [20] reported greener methods for the synthesis of quinoxaline
derivatives in green solvents (EtOH/H2O), using copper sulphate pentahydrate and cerium (IV) ammonium nitrate as
catalysts, respectively. Though the above mentioned methods are greener in approach for small scale synthesis, but the
toxic nature of these catalysts (copper sulphate a mutagenic agent and cerium (IV) ammonium nitrate a skin corrosive,
irritant and mild explosive; owning to the oxidizing property) restricts their use in large scale or long term synthesis.
Very recently, Zhang et al. [21] used PEG-400 as a green catalyst for the synthesis of quinoxaline derivatives,
unfortunately reactions had taken longer time and furthermore harsh condition was also employed to accomplish the
condensation. The drawbacks of these existing methods clearly emphasize the need of new methods for the rapid and
greener of synthesis quinoxaline derivatives. Keeping these aspects in mind, efforts were focused to develop green
chemistry for quinoxaline synthesis with respect to both solvent and catalyst. Herein, we report a rapid and green
synthetic approach for the synthesis of quinoxaline derivatives from o-phenylenediamines and 1,2-dicarbonyl
compounds in the presence of nontoxic, cheap and edible citric acid as a catalyst in ethanolic medium. To the best of
our knowledge, citric acid has not been used as a catalyst for quinoxaline synthesis and as well as for any other organic
reaction transformation [22].
1. Results and discussion
In a model condensation reaction, o-phenylenediamine and benzil were stirred at room temperature in the presence of
catalytic amount of citric acid anhydrous (10 mol%) in ethanolic medium (Scheme 1). To our surprise, the reaction was
completed in less than 1 min (TLC). In order to evaluate the optimum concentration of citric acid required for this
condensation, thereactionwascarriedoutundervaryingconcentrationsofcitricacidviz. 1,3,5and12 mol%, inwhichwe
found that 3 mol% of citric acid is sufficient to do efficient transformation of this reaction; further increment in catalyst
amount did not improve the yield and the rate of reaction. Next, we performed a blank reaction, by omitting citric acid; the
reaction was not completed even after 2 h at room temperature, revealing the catalytic role of citric acid in condensation.
To study the effects of solvent, ethanol was replaced with several solvents (Table 1). This study suggested that, polar
solvents such as methanol, acetonitrile are equal to ethanol to carry out this condensation in the presence of citric acid.
However, ethanol was considered as the best solvent because of it greener in nature for further studies.
Having reaction conditions are optimized, to evaluate this methodology, various o-phenylenediamines were
condensed with benzil in the presence of citric acid (3 mol%) at room temperature (Table 2, entries 1–8) in ethanol. An
Table 1
Screened solvents for the condensation of o-phenylenediamine with benzila.
S. No.
Solvent
Time
<1 min
% Yieldb
1
2
3
4
5
6
7
8
9
Ethanol
94
93
84
94
77
78
74
NR
74
Methanol
<1 min
90 min
Water
Acetonitrile
Dimethylformamide
Dimethylsulphoxide
Tetrahydrofuran
Toluene
<1 min
5 min
60 min
<1 min
>180 min
80 min
Dichloromethane
NR, not recorded.
a
Reaction conditions: o-phenylenediamines (1 mmol), 1,2-dicarbonyl compounds (1 equiv.) and citric acid (3 mol%) were stirred with 2 mL of
solvent at room temperature.
b
Yields refers to isolated pure product.

R. Mahesh et al. / Chinese Chemical Letters 22 (2011) 389–392
391
Table 2
Synthesis of quinoxaline derivatives using citric acida
Entry
Amine
1,2-Dicarbonyl compound
Product
Time (min)
Yieldb
%
1
<1
94
90
[TD$INLINE]
[DT$INLE]
[DT$INLE]
2
<1
[TD$INLINE]
[DT$INLE]
[DT$INLE]
3
4
1
1
79
79
[TD$INLINE]
[DT$INLE]
[DT$INLE]
[TD$INLINE]
[DT$INLE]
[DT$INLE]
5
10
86
[TD$INLINE]
[DT$INLE]
[DT$INLE]
6
7
8
90
<1
5
86
88
75
[TD$INLINE]
[DT$INLE]
[DT$INLE]
[TD$INLINE]
[DT$INLE]
[DT$INLE]
[TD$INLINE]
[DT$INLE]
[DT$INLE]
9
<1
<1
90
88
[TD$INLINE]
[DT$INLE]
[DT$INLE]
10
[TD$INLINE]
[DT$INLE]
[DT$INLE]
11
<1
94
[TD$INLINE]
[DT$INLE]
[DT$INLE]
12
13
<1
<1
86
85
]
[TD$INLE]
[DT$INLE]
[TD$INLINE]
[DT$INLE]
[DT$INLE]
14
<1
83
[DT$INLE]
[TD$INLINE]
[DT$INLE]
a
Reaction conditions: o-phenylenediamines (1 mmol), 1,2-dicarbonyl compounds (1 equiv.) and citric acid (3 mol%) were stirred with ethanol
(2 mL) at room temperature.
b
Yields refers to isolated pure product.

392
R. Mahesh et al. / Chinese Chemical Letters 22 (2011) 389–392
introduction of methyl group on o-phenylenediamine, an electron releasing substituent, did not alter the reaction time
and not much difference was observed in the yield (entry 2). o-Phenylenediamines bearing electron withdrawing
substituents (entries 3–6 and 8) decreased the rate of reaction notably, the nitro substituent (entry 6) and the obtained
yields were also low as compared to no substituent on the o-phenylenediamine. Further, we extended our study by
replacing benzil with other 1,2-dicarbonyl compounds such as diethyl ketomalonate (entries 9–11) and pyruvic acid
(entries 12–14). Regarding the rate of reaction, the last two 1,2-dicarbonyls did not discriminate the electron releasing
or withdrawing group(s) presence on the o-phenylenediamine for the condensation, which indicated the high reactivity
of the carbonyl group. The Bronsted acid nature of citric acid, promotes the reaction by involving in both nucelophilic
addition as well as in dehydration steps.
2. Conclusion
The mild reaction conditions, short duration of reaction time, simple isolation procedure and eco-friendly nature of
citric acid as a catalyst, will make this method become an attractive greener technique for the construction of
quinoxalines and notably similar molecules, compared to the existing methods.
Acknowledgments
The work was supported by the University Grants Commission (UGC), New Delhi, India.
References
[1] M.M. Badran, K.A.M. Abouzid, M.H.M. Hussein, Arch. Pharm. Res. 26 (2003) 107.
[2] R.A. Smits, H.D. Lim, A. Hanzer, et al. J. Med. Chem. 51 (2008) 2457.
[3] J. Guillon, P. Grellier, M. Labaied, et al. J. Med. Chem. 47 (2004) 1997.
[4] P. Sanna, A. Carta, M. Loriga, et al. Farmaco 54 (1999) 161.
[5] R. Sarges, H.R. Howard, R.G. Browne, J. Med. Chem. 33 (1990) 2240.
[6] N.D. Sonawane, D.W. Rangnekar, J. Heterocycl. Chem. 39 (2002) 303.
[7] K.R. Justin Thomas, M. Velusamy, J.T. Lin, et al. Chem. Mater. 17 (2005) 1860.
[8] S. Dailey, J.W. Feast, R.J. Peace, et al. J. Mater. Chem. 11 (2001) 2238.
[9] S.Y. Kim, K.H. Park, Y.K. Chung, Chem. Commun. 10 (2005) 1321.
[10] E. Harms, Org. Process Res. Dev. 8 (2004) 666.
[11] C.S. Cho, W.X. Ren, S.C. Shim, Tetrahedron Lett. 48 (2007) 4665.
[12] D. Aparicio, O.A. Attanasi, P. Filippone, et al. J. Org. Chem. 71 (2006) 5897.
[13] S. Antoniotti, E. Dun˜ach, Tetrahedron Lett. 43 (2002) 3971.
[14] B. Das, K. Venkateswarlu, K. Suneel, et al. Tetrahedron Lett. 48 (2007) 5371.
[15] (a) Z. Wu, N.J. Ede, Tetrahedron Lett. 42 (2001) 8115;
(b) S.K. Singh, P. Gupta, S. Duggineni, et al. Synlett 14 (2003) 2147.
[16] D.J. Brown, in: E.C. Taylor, P. Wipf (Eds.), The Chemistry of Heterocyclic Compounds, John Wiley & Sons, New Jersey, 2004.
[17] (a) S.V. More, M.N.V. Sastry, C.C. Wang, et al. Tetrahedron Lett. 46 (2005) 6345;
(b) P. Hazarika, P. Gogoi, D. Konwar, Synth. Commun. 37 (2007) 3447.
[18] J.F. Zhou, G.X. Gong, K.B. Shi, et al. J. Chin. Chem. Lett. 20 (2009) 672.
[19] M.M. Heravi, S. Taheri, K. Bakhtiari, et al. Catal. Commun. 8 (2007) 211.
[20] S.V. More, M.N.V. Sastry, C.F. Yao, Green Chem. 8 (2006) 91.
[21] X.Z.J. Zhang, X.Y. Wang, J. Sun, et al. Chin. Chem. Lett. 21 (2010) 95.
[22] General procedure: A mixture of o-phenylenediamine (1 mmol), 1,2-dicarbonyl compound (1 equiv.) and citric acid (3 mol%) in ethanol was
stirred at room temperature. The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction,
ethanol was removed under vacuum. The obtained masses were stirred with crushed ice for the period of 10 min, filtered and dried under
vacuum. The synthesized compounds were characterized by spectral analysis. Selected compounds analytical data: 2,3-Diphenyl-6-
(trifluoromethyl)quinoxaline (3e): yield: 86%; mp: 130–132 8C; 1H NMR (CDCl3, 400 MHz): d 8.50 (s, 1H), 8.30 (d, 1H, J = 8.72 Hz),
7.95 (dd, 1H, J = 8.72 Hz), 7.55 (m, 4H), 7.42 (m, 6H): IR (KBr, cmÀ1); 3062, 2962, 2900, 1625, 1544, 1500, 1444, 1329, 837, 808, 770 and
649; MS (ESI); m/z 351 (M+1)+. Ethyl 6,7-dimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxylate (3j): yield: 88%; mp: 197–198 8C; 1H NMR
(CDCl3, 400 MHz): d 12.57 (s, 1H, D2O exchangeable), 7.70 (s, 1H), 7.26 (d, 1H), 4.57 (q, 2H, J = 13.6 Hz), 2.41 (s, 3H), 2.36 (s, 3H), 1.50 (t,
3H, J = 13.6 Hz): IR (KBr, cmÀ1); 3305, 2976, 2866, 2819, 2787, 2731, 1747, 1658, 1548, 1494, 1444, 1367,1271, 1232, 1101, 925 and 584;
MS (ESI): m/z 247 (M+1)+. 3-Methylquinoxalin-2(1H)-one (3l); yield: 86%; mp: 236–238 8C; 1H NMR (DMSO-d6, 400 MHz): d 12.18 (s, 1H,
D2O exchangeable), 7.72 (d, 1H), 7.44 (dd, 1H), 7.31(m, 1H), 7.26 (m, 1H), 2.59 (s, 3H); IR (KBr, cmÀ1); 3341, 3052, 3000, 2974, 2960, 2899,
2841,1672, 1566, 1485, 1433, 1371, 893, 754, 694, 599 and 586; MS (ESI): m/z 161 (M+1)+.