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Chinese Chemical Letters 20 (2009) 171–174

www.elsevier.com/locate/cclet

Development of mild and efficient method for synthesis of

substituted flavones using oxalic acid catalyst
Abhay S. Zambare a, Jaiprakash N. Sangshetti a,
Nagnnath D. Kokare a,b, Devanand B. Shinde a,*
a
Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004, MS, India
b
New Drug Discovery, Wocckhardt Research Centre, Aurangabad 431210, MS, India
Received 18 July 2008

Abstract
Oxalic acid has been used as a catalyst for intramolecular cyclisation of 2-hydroxychalcones to form flavones in good yields. The
efficiency of the catalyst was proved with a variety of substrates ranging from electron-deficient to electron-rich aryl aldehydes and
2-hydroxychalcone.
# 2008 Devanand B. Shinde. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Keywords: Aromatic aldehydes; 2-Hydroxychalcone; Oxalic acid; Flavones

Flavones are an important class of compounds belonging to the flavonoid group that occur naturally in fruits,
vegetables, nuts, seeds, flowers, and barks [1–3]. They are an integral part of the human diet and have been reported to
exhibit a wide range of biological effects [4–11]. Flavone and its derivatives are important intermediates in the
synthesis of anticancer, anti-inflammatory, antibacterial, and anti-AIDS drugs [12]. Also antiproliferative,
antifungal, antiviral, anti-inflammatory, antioxidant, and cardiovascular effects of flavones have been reported in
literature [13].
The methodology most widely used to prepare flavones involves the isomerization of appropriately substituted 2-
hydroxy chalcones, in turn obtained by an aldol condensation reaction between a 2-hydroxyacetophenone and an
aldehyde. These cyclizations have been carried out under numerous conditions using acids [14], bases [15], silica gel
[16], heat [17], light [18], electrolysis [19], Ni/Zn/K halides [20] and others [21]. Other alternative procedures to
synthesize flavones include oxidation of flavon-4-ol [22]. Reacting benzaldehydes with 1-(2-hydroxyphenyl)-3-
phenyl propane-1,3-diones in basic medium [23] and transformation of 3-bromo-1-phenylprop-2-ynyl aryl ethers in
the presence of mercury(II) trifluoroacetate [24].
However, some of these previous methods have suffered from one or more drawbacks like high temperature
requirement, highly acidic conditions, longer reaction time and the use of mercury(II) trifluoroacetate for preparation
of compounds that limit their uses [24]. Therefore, the development of new method for efficient synthesis of flavones is

* Corresponding author.
E-mail address: dbshinde.2007@rediffmail.com (D.B. Shinde).

1001-8417/$ – see front matter # 2008 Devanand B. Shinde. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2008.10.042
172 A.S. Zambare et al. / Chinese Chemical Letters 20 (2009) 171–174

strongly desirable. The use of oxalic acid as a catalyst is increasing due to its acidic character. Oxalic acid and oxalates
are abundantly present in many plants so it has green approach.
In continuation of our ongoing research for the development of simple and efficient methods for the synthesis of
various heterocyclic compounds [26] herein, we have presented a novel, mild and efficient method for synthesis of
flavones using oxalic acid as the catalyst.

1. Experimental
1
H NMR spectra were recorded on a 400 MHz Varian-Gemini spectrometer and are reported as parts per million
(ppm) downfield from a tetramethylsilane internal standard. The following abbreviations are used; singlet (s), doublet
(d), triplet (t), quartet (q), multiplate (m) and broad (br). Mass spectra were taken with Micromass-QUATTRO-II of
WATER mass spectrometer. HPLC was performed using Zorbax SB-C18 reverse phase column (0.46  25 cm) on
Shimadzu instrument equipped with an automatic injector with UV–PDA detector. Detection was carried out at
254 nm. The mobile phase consists of 0.05% TFA and acetonitrile (1:1, V/V). The products were eluted at flow rate of
1 mL/min using isocratic method. Flash column chromatography was performed with 300–400 mesh silica gel and
analytical thin layer chromatography was performed on precoated silica gel plates (60F-254) with system (v/v)
indicated. Melting points were determined in capillary tubes and are uncorrected.

1.1. General procedure

A mixture of oxalic acid (10 mol%), 2-hydroxychalcone (40 mmol) was dissolved in ethanol (20 mL). The reaction
mixture was heated at 80 8C until the reaction is complete (TLC). The reaction mixture was then cooled to room
temperature and poured on ice–water (50 mL) to obtain the solid precipitated. The mixture was filtered off on a
Buckner funnel, washed with water and dried to give the corresponding flavones.
All synthesized compounds were characterized with 1H NMR and mass. Also the melting points were recorded
and compared with those of corresponding literature melting points and found to be in agreement with literature
values. The representative analytical data for 2-(4-methoxyphenyl)-4H-chromen-4-one (4e) off white solid
mp 158–159 8C; 1H NMR (400 MHz, CDCl3, d ppm): 3.88 (s, 3H, OCH3), 6.97 (s, 1H), 6.99 (d, 2H,
J = 8.61 Hz), 7.37 (m, 1H), 7.52 (d, 1H, J = 8.7 Hz), 7.65 (m, 1H), 7.85 (d, 2H, J = 8.6 Hz), 8.2 (d, 1H,
J = 8.1 Hz).m/z = 252 [M+].

2. Results and discussion

The reaction conditions were standardized for the cyclisation of 2-hydroxychalcone (3a) (Scheme 1) in different
solvents using various mol% of oxalic acid catalyst (Table 1). The reaction was continued until completion as
monitored by TLC and also by GC. The yield of flavone 4a is 95% (Table 2).
The reaction was equally effective for both aldehydes bearing electron-withdrawing or electron-donating groups
giving moderate to better yield. The HPLC purity of synthesized compounds was between 95.8–98.8%.
In conclusion, using 10 mol% oxalic acid catalyst, flavones and its derivatives were efficiently synthesized with
moderate to excellent yields from 2-hydroxychalcones which were prepared from 2-hydroxyaceto-phenone and
aromatic aldehydes. The advantages of the reported method are the cheap and easily available catalyst, shorter reaction
time and better yields.

Scheme 1. Synthesis of flavones using 2-hydroxyacetophenone and aromatic aldehydes and 10 mol% oxalic acid catalyst.
 A.S. Zambare et al. / Chinese Chemical Letters 20 (2009) 171–174 173

Table 1
Optimization of reaction conditions for synthesis of flavones using 10 mol% oxalic acid catalyst.
Solvent Reaction time (h) Yield (%)
Acetonitrile 12 85
THF 10 88
Methanol 6.5 92
Ethanol 6 95

Table 2
Synthesis flavones using 2-hydroxyacetophenone and aromatic aldehyde, and 10 mol% oxalic acid catalyst.
Product Aldehydes Reaction time (h) Yield (%)* Melting points (8C)
Found Reported [25]
4a Benzaldhyde 6 95 96–97 94–95
4b 4-Nitrobenzaldhyde 6.5 94 155–156 155
4c 4-Chlorobenzaldhyde 6 95 184–185 185
4d 4-Methylbenzaldehyde 6 92 110–111 112
4e 4-Methoxybenzaldehyde 6.5 92 158–159 156–157
4f 4-Hydroxybenzaldehyde 6.5 92 269–270 269–270
4g 3,4-Dimethoxybenzaldehyde 7 93 175–176 178
4h 2-Chlorobenzaldehyde 8 91 121–122 119
4i 2-Methoxybenzaldehyde 8 91 129–130 128–129
4j 2-Hydroxybenzaldehyde 8 91 209–210 209–211
*
Yields are of pure isolated compounds.

Acknowledgments

The authors are grateful to Head Dr. D.B. Shinde, Department of Chemical Technology, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad 43100 (MS), India for providing the laboratory facility.

References

[1] V.M. Malikov, M.P. Yuldashev, Chem. Nat. Compd. 38 (2002) 358.
[2] C.W. Huck, C.G. Huber, K.H. Ongania, G.K. Bonn, J. Chromatogr. A (2000) 453.
[3] T. Nagao, F. Abe, J. Kinjo, H. Okabe, Biol. Pharm. Bull. 7 (2002) 875.
[4] M.J. Chan-Bacab, L.M. Pena-Rodriguez, Nat. Prod. Rep. 18 (2001) 674.
[5] J.B. Harborne, Nat. Prod. Rep. 16 (1999) 509.
[6] J.H. Wu, X.H. Wang, Y.H. Yic, K.H. Lee, Bioorg. Med. Chem. Lett. 13 (2003) 1813.
[7] F. Perez-Vizcaino, M. Ibarra, A.L. Cogolludo, J. Duarte, F. Zaragoza-Arnaez, L. Moreno, G. Lopez-Lopez, J.J. Tamargo, Pharmacol. Exp. Ther.
301 (2002) 66.
[8] (a) I. Sanchez, F. Gomez-Garibay, J. Taboada, B.H. Ruiz, Phytother. Res. 14 (2000) 89;
(b) E.A. Bae, M.J. Han, M. Lee, D.H. Kim, Biol. Pharm. Bull. 23 (2000) 1122.
[9] N. Matsuo, K. Yamada, K. Yamashia, K. Shoji, M. Mori, M. Sugano, In vitro Cell Dev., Biol. 106 (1996) 787.
[10] A. Jain, M.C. Martin, N. Praveen, N.U. Khan, J.H. Parish, S.M. Hadi, Phytother. Res. 13 (1999) 609.
[11] J. Yamada, Y. Tomita, Biosci. Biotechnol. Biochem. 58 (1994) 2197.
[12] C. Pouget, C. Fagnere, J.P. Basly, G. Habrioux, A.J. Chulia, Bioorg. Med. Chem. Lett. 12 (2002) 1059.
[13] T.C. Wang, I.L. Chen, P.J. Lu, C.H. Wong, C.H. Liao, K.C. Tsiao, K.M. Chang, Y.L. Chen, C.C. Tzeng, Bioorg. Med. Chem. 13 (2005) 6045.
[14] (a) P.L. Cheng, P. Fournari, J. Tirouet, Bull. Soc. Chim. Fr. (1963) 2248;
(b) L. Reichel, G. Proksch, Ann. Chem. 745 (1971) 59;
(c) G. Nabaei-Bidhendi, N.R. Bannerjee, J. Indian Chem. Soc. 67 (1990) 43.
[15] (a) D.D. Keane, K.G. Marathe, W.I. Sullivan, E.M. Philbin, R.M. Simons, P.C. Teague, J. Org. Chem. 35 (1970) 2286;
(b) L. Reichel, F.G. Weber, Pharmazie 30 (1975) 195;
(c) C.P. Dutta, L.P.K. Roy, Indian J. Chem. 13 (1975) 425.
[16] N.K. Sangawan, B.S. Varma, K.S. Dhindsa, Chem. Ind. (London) (1984) 271.
[17] (a) T.M. Harris, R.L. Carney, J. Am. Chem. Soc. 89 (1967) 6734;
(b) Y. Hoshino, N. Takeno, Bull. Chem. Soc. Jpn. 59 (1986) 2903.
174 A.S. Zambare et al. / Chinese Chemical Letters 20 (2009) 171–174

[18] (a) F.R. Stermitz, J.A. Adamovics, J. Geigert, Tetrahedron 31 (1975) 1593;
(b) R. Matsushima, H. Kageyama, J. Chem. Soc., Perkin Trans. 2 (1985) 743.
[19] Z. Sanicanin, I. Tabakovic, Tetrahedron Lett. 27 (1986) 407.
[20] S.M. Ali, J. Iqbal, M.J. Ilyas, Chem. Res. (S) (1984) 236.
[21] (a) H.Y. Chen, K.D. Dykstra, E.T. Birzin, K. Frisch, W. Chan, Y.T. Yang, R.T. Mosley, F. DiNinno, S.P. Rohrer, J.M. Schaer, M.L. Hammond,
Bioorg. Med. Chem. Lett. 14 (2004) 1417;
(b) B.M. Choudary, K.V.S. Ranganath, J. Yadav, M.L. Kantam, Tetrahedron Lett. 46 (2005) 1369.
[22] (a) V.K. Bhatia, H.G. Krishnamurthy, R. Madhav, T.R. Seshadri, Tetrahedron Lett. (1968) 3859;
(b) M. Flammang, D. Frederic, Acad. Sci. Ser. C 286 (1978) 721;
(c) D. Jyotsna, A.V.S. Rao, Indian J. Chem. 26B (1987) 877.
[23] S.J. Joglekar, S.D. Samant, Tetrahedron Lett. 29 (1988) 241.
[24] R.S. Subramanian, K.K. Balasubramanian, J. Chem. Soc. Chem. Commun. (1990) 1469.
[25] (a) S.R. Sarda, M.Y. Pathan, V.V. Paike, P.R. Pachmase, W.N. Jadhav, R.P. Pawar, ARKIVOC (2006) 43;
(b) S.C. Bhrara, A.C. Jaw, T.R. Seshaixu, Tetrahedron 21 (1965) 963;
(c) D. Nagarathnam, M. Cushman, Tetrahedron 47 (1991) 5071;
(d) K. Hemanth Kumar, P.T. Perumal, Tetrahedron 63 (2007) 9531;
(e) N. Ahmed, H. Ali, J.E. Vancier, Tetrahedron Lett. 46 (2005) 253.
[26] (a) N.D. Kokare, R.R. Nagawade, V.P. Rane, D.B. Shinde, Synthesis 4 (2007) 766;
(b) S.A. Kotharkar, M.R. Jadhav, R.R. Nagawade, S.S. Bahekar, D.B. Shinde, Lett. Org. Chem. 2 (2005) 398;
(c) S.S. Bahekar, D.B. Shinde, Tetrahedron Lett. 45 (2004) 7999;
(d) S.S. Bahekar, S.A. Kotharkar, D.B. Shinde, Mendeleev Commun. (2004) 2.