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Research Paper

An Improved and Eco-Friendly Method for the Synthesis of Flavanone by the Cyclization of 2-Hydroxy Chalcone

using Methane Sulphonic Acid as Catalyst

Pramod Kulkarni1, Pradip Wagh1 and Pudukulathan Zubaidha1*

1School of Chemical Sciences, S.R.T.M. University, Nanded 431606 (MS) India Tel. No. +912462229518 Fax: +912462229245

*1E-Mail: pzubaidha20001@yahoo.co.in

Abstract

Flavanones are important biosynthetic precursors for the synthesis of flavones, isoflavones, flavonols and dihydroflavonols. The flavanone skeleton is present in a wide range of synthetic and naturally occurring products exhibiting various interesting pharmacological activities. The present paper describes the use of methane sulphonic acid as an efficient organocatalyst for the synthesis of substituted flavanones from 2-Hydroxy Chalcones in good yields and in short reaction time. The catalytic efficiency of methane sulphonic acid in cyclization of chalcones to flavanones has been demonstrated with a variety of substrates bearing electrondeficient to electron rich groups on chalcones and the yields obtained are higher than the reported methods with triflluoroacetic acid / mineral acids. Methane sulphonic acid is an inexpensive, safe, eco-friendly acid catalyst with low LD50. The present protocol could find wide spread application in the synthesis of flavanones bearing free hydroxyl groups on the aromatic moiety. At the same time the methodology would be useful for the synthesis of naturally occurring bioactive flavanones.

Keywords: Methane Sulphonic Acid, 2-Hydroxy Chalcone, Flavanone, Cyclization, Acetic acid

1. Introduction

Flavanones (2,3-dihydro-2-phenyl-4H-1-benzo-pyran-4-one derivatives) are the main biosynthetic precursors for major flavonoids such as flavones or isoflavones and for two important flavonoid intermediates: the flavan-4-ols (biosynthetic precursors for the formation of 3-deoxyanthocyanins) and the dihydroflavonols (biosynthetic intermediates in the formation of catechins, flavonols, anthocyanins and proanthocyanidins) (Heller & Forkmann, 1988; Haslam, 1993 and Mann, 1994). The flavanone skeleton is present in a wide range of synthetic or naturally occurring products exhibiting various interesting pharmacological activities (Bertram, 1989; Pathak et al, 1991; Spilkova & Hubik, 1992 and Manach et al, 1996). Flavanones widely distributed in nature, continue to attract attention due to their ample range of biological activities (like hypotensive, antifungal,

antibacterial, antitumoral) (Middleton & Kandaswami, 1994; Harborne & Williams, 2001; Nijveldt et al, 2001; Wang et al, 2001 and Heim et al, 2002).

The cyclization of chalcones to Flavanones has been reported using acids (Reichel & Proksch, 1973 and Chaturvedi et al, 1992 ), bases (Keane et al, 1970; Nabaei-Bidhendi & Bannerjee, 1990 and Wurm & Schnetzer, 1992), silica gel (Bagade et al, 1991), heat (Harris & Carney, 1967 and Hoshino & Takeno, 1986), light (Stermitz et al 1975; Matsushima & Kageyama, 1985; Pandey et al, 1987 and Maki et al, 1988), electrolysis (Sanicanin & Tabakovic, 1986), Cobalt (II) Schiff-base complexes (Maruyama et al, 1989), zeolites (Climent et al, 1995),L-Proline (Chandrasekhar et al, 2005) and microwave conditions (Sagreraa & Seoane, 2005) but the

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obtained yields are often moderate and sometimes poor. The acid catalyzed cyclization can be carried out by refluxing the chalcone in acetic acid or also in ethanol or other suitable solvent in the presence of an acid catalyst such as H3PO4 (Sagrera et al, 1998). Flavanones can also be obtained from precursors other than chalcones, namely by (i) reacting 3-chloro-2,3-dihydro-3-nitro-2-phenyl-4H-1-benzopyran-4-ones with tributyl tin hydride and 2,2-azobisisobutyronitrile (Dauzonne & Monneret, 1997) (ii) treating 3-bromo-1-phenyl prop-2-ynil aryl ethers with mercury (II) trifluroroacetate (Subramanian & Balasubramanian, 1990) (iii) oxidizing flavan-4-ols (Bhatia et al, 1968) (iv) treating 1-(2-hydroxyphenyl)-3-phenyl-propane-1,3-diones with benzaldehydes (Joglekar & Samant, 1988).

Methane sulphonic acid is a clear colourless liquid available as a 70% solution in water and anhydrous form. The structure of methane sulphonic acid lends itself to many catalytic reactions, due to its high acid strength (PKa = -1.9) and low molecular weight (96.0 g/mol). Further it is easy to handle methane sulphonic acid as liquid and can be recyclized. The other attributes includes low LD50 and it is biodegradable forming sulphate and CO2. Methane sulphonic acid is considered to be natural product and is part of the natural sulfur cycle (Commarieua et al, 2002). Also as a Bronsted acid it has been widely used to catalyze wide

variety of reaction and as solvent for condensation and rearrangement reaction (Sharghi, 1998; Kaboudin, 1999 and Leleti et al, 2007).

Therefore, there is scope to develop a new method for the synthesis of flavanone by using an inexpensive, safe, simple and eco-friendly catalyst i.e. methane sulphonic acid. To, the best of our knowledge, there is no report on the use of methane sulphonic acid as catalyst for the cyclization of 2-hydroxy chalcone into flavanone.

2. Experimental

All purchased chemicals were of analytical grade and used without further purification. Melting point is determined by open capillary method and uncorrected. The 1H NMR spectra were obtained on a Bruker DRX-300 Avance instrument using CDCl3 as solvent and TMS as internal standard at 300MHz.

2.1. General Procedure for Cyclization of 2-Hydroxy-chalcone to Flavanone

A mixture of 2-hydroxy chalcones (1.0 mM), catalytic amount of methane sulphonic acid (10 mol %) in acetic acid was subjected to reflux for 2 hours. Workup with water afforded flavanone as solid which was filtered off and purified by column chromatography using ethyl acetate: petroleum ether (9:1) as eluent to get pure product.

The hydroxy flavanone was purified by column chromatography using MeOH: CHCl3.

3. Results and Discussion

When refluxed in acetic acid in the presence of methane sulphonic acid, chalcones (I) were transformed into equilibrium mixture containing (I a) and isomeric flavanone (II a), in 2 hours, the latter being the predominant component ( Scheme 1). To study the effect of solvent on equilibrium ratio, the reaction was performed in various solvents such as acetic acid, ethanol, DMF and DMSO. The reaction proceeds well in acetic acid compared to other solvents. The results are shown in Table 1.

OH

O

R4R3

R2R1

O

O

R4R3

R2R1

1 2

CH3SO3H

Acetic acidReflux

R2

R2

R1

R2

Scheme 1. Synthesis of Flavanone by using Methane Sulphonic Acid Catalyst

Table 1. Effect of Solvent on Cyclization of 2-Hydroxychalcone to Flavanone Catalyzed by Methane Sulphonic Acida

Sr.No. Solvent Temperature % Yieldb

1 Acetic acid 110 89 2 Ethanol 70 50 3 DMF 140 40 4 DMSO 140 No Reaction

aReaction Condition: 2-hydroxychalcone (1mmole), Methane Sulphonic Acid

b(10% v/v) in Solvent : Isolated Yield

Further the scope of the reaction was studied with substituted chalcones prepared by varying the substrates on B ring from electron donating groups to withdrawing groups. The results are presented in Table 2. As obvious from the results, the Cyclization of chalcones proceeds well to afford flavanones in good yield. As expected electron donating groups facilitate the cyclization to afford the corresponding flavanone in good yield while electron withdrawing groups and steric effects render the cyclization slow leading to moderate yield of flavanone. In next step the scope of reaction was examined by subjecting substituted ring A chalcone with 5-hydroxy, 7-hydroxy, 5,7-dihydroxy which undergo cyclization easily, giving good yields of corresponding flavanones. By using this

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methodology we have synthesised 5-hydroxyflavanone, 4-chloro-7-hydroxyflav-anone, 4-methoxy-7-hydroxyflava-none, 5,7-dihydroxyfla-vanone, and 4-methoxy-5,7-hydro-xyflavanone.

A possible reaction mechanism for the intramolecular oxa-Michael addition in 1a, promoted by Bronsted acid, as given by Johnsons group, is outlined in Scheme 2 (Ellis et al, 1982 and 1983). The carbonyl oxygen of 1a accepts

Table 2. Cyclization of 2-Hydroxy Chalcone to Flavanone Catalyzed by Methane Sulphonic Acida

Entry Chalcone (1) R1 R2 R3 R4 R5 R6 Flavanone (2) Time (hrs) %Yield 1 1a H H H H H H 2a 2 89 2 1b H H H OMe OMe OMe 2b 1.45 86 3 1c H H H H Cl H 2c 2.30 82 4 1d H H H H CH3 H 2d 2.10 80 5 1e H H H OMe H H 2e 2.25 73 6 1f H H H OMe H OMe 2f 2.15 78 7 1g H H OMe H H OMe 2g 2 75 8 1h H H CH3 H H CH3 2h 2.40 69 9 1i H H Cl H Cl H 2i 2.45 65

10 1j H H H H Br H 2j 2.30 73 11 1k H H Cl H H H 2k 2.30 68 12 1l H H H H F H 2l 3 82 13 1m OH OH H H H H 2m 1.5 64 14 1n OH H H H Cl H 2n 1.45 73 15 1o H H H NO2 H H 2o 1.20 79 16 1p H OH H H OMe H 2p 1.05 76 17 1q H OH H H Cl H 2q 1.40 71 18 1r H H H H OMe H 2r 1.35 85 19 1s H H H OMe OMe H 2s 1.50 82 20 1t H H H H NO2 H 2t 3.15 62 21 1u H H OMe OMe H H 2u 3.40 76 22 1v OH H H OMe OMe H 2v 3.50 73 23 1w OH OH H H OMe H 2w 3.45 72

a Reaction Condition : 2-Hydroxychalcone (1 mmole), Methane Sulphonic Acid (10% v/v) in Solvent b : Isolated Yield

O

OH H+

O+

OH

HOH

OH+

OH

OH

+

H+

H+

OH

O

O

O

I

IIIII

Scheme 2. Possible Reaction Mechanism in the Presence of Bronsted Acid

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proton from the Bronsted acid to give the protonated form of I and canonical form II undergoes ring closure to give the enol form III of 2a.

4. Conclusion

In conclusion, here in we report simple and an efficient method for the synthesis of flavanone from 2-hydroxychalcone by the use of methane sulphonic acid an inexpensive and safe acid catalyst. This protocol will be a good addition to the most recent environmentally friendly methods reported for the synthesis of flavanones. This protocol is also useful for the synthesis of phloroglucinol type flavanone. Other advantages of this method are high yield and shorter reaction time compare to other reaction conditions. Merits of this method over trifluroacetic acid and mineral acid are that 1) this acid is biodegradable and can be recycled while trifluroacetic acid is not biodegradable 2) example reported with trifluroacetic acid includes only methoxy group while this method is applicable to all types of functional groups.

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