Title of Invention

"A PROCESS FOR THE PREPARATION OF 2-ARYL- 4-HYDROXY-CYCLOPENT-2-EN-1-ONES"

Abstract

The present invention relates to a process for the preparation of 2-aryl-4-hydroxy-cyclopent-2-en-l-ones of the formula (1). More particularly it relates to a process for the preparation of 2-aryl(substituted)-4-hydroxy-cyclopent-2-en-l-ones of the formula (1) from the corresponding aryl (substituted) furyl methanol having formula (2) wherein R1to R5 are each independently selected from the group consisting of hydrogen, azido, cyano, carboxymethyl, methoxy, methyl, thiomethyl, halo and nitro. The 2-aryl (substituted)-4-hydroxy-cyclopent-2-en-l-ones and their derivatives are useful intermediates in the synthetic organic chemistry and can be used for synthesis of biologically active compounds. Some of the 2,3-diaryl-4-substituted cyclopent-2-en-l-one derivatives have demonstrated remarkable cytotoxic activity against a variety of human cancer cell lines

Full Text

The present invention relates to a process for the preparation of 2-aryl-4-hydroxy-cyclopent-2-en-l-ones of the formula (1). More particularly it relates to a process for the preparation (Figure Removed) of 2-aryl(substituted)-4-hydroxy-cyclopent-2-en-l-ones of the formula (1) from the corresponding aryl (substituted) furyl methanol having formula (2) wherein RI to R5 are each independently selected from the group consisting of hydrogen, azido, cyano, carboxymethyl, methoxy, methyl, thiomethyl, halo and nitro. (Figure Removed) The 2-aryl (substituted)-4-hydroxy-cyclopent-2-en-l-ones and their derivatives are useful intermediates in the synthetic organic chemistry and can be used for synthesis of biologically active compounds. Some of the 2,3-diaryl-4-substituted cyclopent-2-en-l-one derivatives have demonstrated remarkable cytotoxic activity against a variety of human cancer cell lines In the prior art the preparation of 2-aryl(substituted)-4-hydroxy-cyclopent-2-en-l-one of the formula (1) from the corresponding aryl(substituted) furyl methanol having formula (2) have been reported in two steps involving double rearrangement. The first rearrangement is effected by zinc chloride, formic acid, polyphosphoric acid, p-toluenesulfonic acid etc. followed by second rearrangement using alumina, chloral etc. Recently, a single step conversion was reported using water as solvent. It was observed that these conditions did not give the expected products in case of highly substituted aryl groups. Some of the related references are: R. A. Ellision, Synthesis, 397-412 (1973); G. Stork, C. Kowalski, G. Garcia, J. Am. Chem. Soc. 97, 3258 (1975); G. Piancatelli, A. Scettri, and S. Barbadoro, Tet. Lett. 39, 3555-3558 (1976); G. Piancatelli and A. Scettri, Tet. Lett. 13, 1131-1134 (1977); G. Piancatelli, A. Scettri, G. David and M. D. Auria, Tetrahedron 34, 2775-2778 (1978); A. Scettri, G. Piancatelli, M. D. Auria and G. David, Tetrahedron 35, 135-138 (1979); P. W. Collins, S. W. Kramer and G. W. Gullikson, J. Med. Chem. 30, 1952-1955 (1987); P. W. Collins, S. W. Kramer, A. F. Gasiecki, R. M. Weier, P. H. Jones, G. W. Gullikson, R. G. Bianchi, and R. F. Bauer, J. Med. Chem. 30, 193-197 (1987); M. D. Auria, Heterocycles, 52, 185-194 (2000). The present invention therefore provides for the preparation of 2-aryl(substituted)-4-hydroxy-cyclopent-2-en-l-ones of the formula (1) wherein R1 to R5 are each independently hydrogen, azido, cyano, carboxymethyl, methoxy, methyl, thiomethyl, halo or nitro from the corresponding aryl(substituted) furyl methanol having formula (2) wherein R1 to R5 are each independently hydrogen, azido, cyano, carboxymethyl, methoxy, methyl, thiomethyl, halo, or nitro in one step and high yields. The main object of the present invention is therefore to provide a process for the preparation of 2-aryl(substituted)-4-hydroxy-cyclopent-2-en-l-ones as an intermediate for the synthesis of 2,3-diaryl-4-substituted cyclopent-2-en-l-one derivatives. Accordingly the present invention provides a process for the preparation of 2-aryl(substituted)-4-hydroxy-cyclopent-2-en-l-ones of formula (1) whereinR1 to R5 are each independently selected from the group consisting of hydrogen, azido, cyano, carboxymethyl, methoxy, methyl, thiomethyl, halo and nitro which comprises, mixing a solution of aryl furfuryl alcohol of formula (2) and ZnCl2 in a mixture of dioxan and water, refluxing the above said reaction mixture for a period till complete disappearance of the starting material, cooling the said reaction mixture to an ambient temperature and acidifying by adding dilute acid selected from the group of hydrochloric acid, sulfuric acid and ammonium chloride to maintain pH at 1, extracting the resultant reaction product with an organic solvent as herein described, washing the organic layer extract with water followed by brine and drying over drying agent, concentrating the organic layer under reduced pressure and purifying the residue by known method to obtain the said product. (Formula Removed) In an embodiment of the present invention the reaction mixture is refluxed preferably for a period of 15 to 25 hrs. In an another embodiment of the present invention the acid used for acidification is selected from the group consisting of hydrochloric acid, sulfuric acid and ammonium chloride, preferably dilute hydrochloric acid. In yet another embodiment the solvent used for extraction is selected from the group consisting of chloroform, dichloromethane, ethylene dichloride or ethyl acetate or diethyl ether. In still another embodiment the drying agent used is selected from sodium sulphate and magnesium sulphate. In still another embodiment the yield obtained of 2-aryl (substituted)-4-hydroxy- cyclopent-2-en-l-ones of the formula (1) is 85-90%. The process of the present invention is described by the following examples which are illustrative only and should not be construed as limit to the scope of the present invention in any manner. Example 1 Preparation of substituted furfuryl alcohols of the formula 2 : General procedure : Magnesium (1.68 g, 70 mmol) was taken in three neck R.B. flask equipped with reflux condensor, and 100 ml ether followed by dibromoethane (9.5 g, 51.02 mmol) were added with stirring at 0°C under nitrogen atmosphere. Stirring was continued till all magnesium reacted, then ether was removed under vacuum till slurry was formed (A). In another single neck R.B. flask furan (4.76 g, 70 mmol) in tetrahydrofuran (100 m with ice-salt mixture, n-butyllithium (2M, 35 ml, 70 mmol) was added dropwise, and stirred at 0°C for 45 min (B). Fury lithium thus prepared in flask (B) was added to cold mixture in (A) through cannula, stirred at 0°C for 5 min, brought to room temperature and stirred at room temperature for 1.5 h and then cooled to -20°C (dry ice + CC14). Substituted benzaldehyde (51.02 mmol) in tetrahydrofuran (50 ml) was added and stirred at -20°C for 4 h (monitored by TLC). After completion of reaction the mixture was quenched with saturated ammonium chloride solution. The mixture was allowed to warm to room temperature. Solvent was removed under reduced pressure and residue extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated to dryness under reduced pressure using rotary evaporator. The crude residue was purified by column chromatography using silica gel (petroleum ether : acetone as eluents) to collect pure compounds of the formula (2). Example 2 Preparation of 2-(3,4,5-trimethoxyphenyI)-4-hydroxy-cyclopent-2-en-l-one: A solution of aryl furfuryl alcohol i.e. compound of the formula (2) wherein Rj and RS are H and R2, R3 and R4 are OCH3 (25 g, 94.69 mmol) and ZnCl2 (51.26 g, 378.7 mmol) in dioxan (309 ml) and water (206 ml) was refluxed for 24 h at which time TLC analysis indicated the complete disappearance of starting material. The mixture was brought to room temperature, acidified to pH 1 with dilute HC1 and extracted with ethyl acetate. Organic layer was washed with water, followed by brine and dried over sodium sulphate. The organic layer was concentrated under reduced pressure using rotary evaporator and chromatographed on silica gel column to collect the required 2-(3,4,5-trimethoxyphenyl)-4-hydroxy-cyclopent-2-en-l-one (21.25 g, 85%). Example 3 Preparation of 2-phenyl-4-hydroxy-cyclopent-2-en-l-one: A solution of aryl furfuryl alcohol i.e. compound of the formula (2) wherein R\ to Rsare H (0.30 g, 1.72 mmol) and ZnCl2 (0.940 g, 6.88 mmol) in dioxan (6.2 ml) and water (4.6 ml) was refluxed for 24 h at which time TLC analysis indicated the complete •n. disappearance of starting material. The mixture was brought to room temperature, acidified to pH 1 with dilute HC1 and extracted witlt ethyl acetate. Organic layer was washed with water, followed by brine and dried over sodium sulphate. The organic layer was concentrated under reduced pressure using rotary evaporator and chromatographed on silica gel column to collect the required 2-phenyl-4-hydroxy-cyclopent-2-en-l-one (0.268g, 89%). Example 4 Preparation of 2-(4-methoxyphenyl)-4-hydroxy-cyclopent-2-en-l-one: A solution of aryl furfuryl alcohol i.e. compound of the formula (2) wherein R,, R2, R4, R5 are H and R3 is OMe (2.10 g, 10.29 mmol) and ZnCl2 (5.60 g, 41.16 mmol) in dioxan (25.36 ml) and water (16.88 ml) was refluxed for 24 h at which time TLC analysis indicated the complete disappearance of starting material. The mixture was brought to room temperature, acidified to pH 1 with dilute HC1 and extracted with ethyl acetate. Organic layer was washed with water, followed by brine and dried over sodium sulphate. The organic layer was concentrated under reduced pressure using rotary evaporator and chromatographed on silica gel column to collect the required 2-(4-methoxy -phenyl)-4-hydroxy-cyclopent-2-en-l-one (1.89 g, 90%). Example 5 Preparation of 2-(4-thiomethylphenyl)-4-hydroxy-cyclopent-2-en-l-one: A solution of aryl furfuryl alcohol i.e. compound of the formula (2) wherein RI, R2, Rj, R5 are H and R3 is SMe (0.40 g, 1.81 mmol) and ZnCl2 (0.98 g, 7.27 mmol) in dioxan (6.88 ml) and water (5.1 ml) was refluxed for 24 h at which time TLC analysis indicated the complete disappearance of starting material. The mixture was brought to room temperature, acidified to pH 1 with dilute HC1 and extracted with ethyl acetate. Organic layer was washed with water, followed by brine and dried over sodium sulphate. The organic layer was concentrated under reduced pressure using rotary evaporator and purified by column chromatography to collect the required 2-(4-thiomethyl phenyl)-4-hydroxy-cyclopent-2-en-l-one (0.239 g, 60%). Example 6 Preparation of 2-(3-chlorophenyl)-4-hydroxy-cyclopent-2-en-l-one: A solution of aryl furfuryl alcohol i.e. compound of the formula (2) wherein R2 is Cl and RI, R3, R» and R5 are H (0.50 g, 2.40 mmol) and ZnCJf (1.30 g, 9.6 mmol) in dioxan (8.6 ml) and water (6.4 ml) was refluxed for 24 h. The reaction mixture was brought to room temperature, acidified to pH 1 with dilute HC1 and extracted with ethyl acetate. Organic layer was washed with water, followed by brine and dried over sodium sulphate. The organic layer was concentrated under reduced pressure using rotary evaporator and purified by column chromatography to collect the required 2-(-3-chloro phenyl)-4-hydroxy-cyclopent-2-en-1 -one (0.256 g, 70%). Example 7 Preparation of 2-(2,3-dichloro phenyl)-4-hydroxy-cyclopent-2-en-l-one : A solution of aryl furfuryl alcohol i.e. compound of the formula (2) wherein Rj, R2 are Cl and R3, RA, RS are H (0.50 g, 2.06 mmol) and ZnCl2 (1.12 g, 8.2 mmol) in dioxan (7.38 ml) and water (5.5 ml) was refluxed for 24 h. The reaction mixture was brought to room temperature, acidified to pH 1 with dilute HC1 and extracted with ethyl acetate. Organic layer was washed with water, followed by brine and dried over sodium sulphate. The organic layer was concentrated under reduced pressure using rotary evaporator and purified by column chromatography to collect the required 2-(2,3-dichlorophenyl)-4-hydroxy-cyclopent-2-en-l-one (0.135 g, 51% ). Example 8 Preparation of 2-(3-nitrophenyl)-4-hydroxy-cyclopent-2-en-l-one: A solution of aryl furfuryl alcohol i.e. compound of the formula (2) wherein R2 is N02 and Ri, R3, R4 and R5 are H (0.50 g, 2.28 mmol) and ZnCl2 (1.23 gm, 9.12 mmol) in dioxan (8.17 ml) and water (6.0 ml) was refluxed for 24 h . The reaction mixture was brought to room temperature, acidified to pH 1 with dilute HC1 and extracted with ethyl acetate. Organic layer was washed with water, followed by brine and dried over sodium sulphate. The organic layer was concentrated under reduced pressure using rotary evaporator and purified by column chromatography to collect the required 2-(3-nitro phenyl)-4-hydroxy-cyclopent-2-en-l-one (0.170 g, 49%). on the basis of recovery of starting material. Example 9 Preparation of 2-(3-nitro-4-methoxyphenyl)-4-hydroxy-cyclopent-2-en-l-one: A solution of aryl furfuryl alcohol i.e. compound of the formula (2) wherein R2 is NO2, R3 is OMe and Ri, R4 and R5 are H (11.50 g, 4.9 mmol) and ZnCl2 (25.67 g, 1.87 mmol) in dioxan (160 ml) and water (130 ml) was refluxed for 20 h . The reaction mixture was brought to room temperature, acidified to pH 1 with dilute HC1 and extracted with ethyl acetate. Organic layer was washed with water, followed by brine and dried over sodium sulphate. The organic layer was concentrated under reduced pressure using rotary evaporator and purified by column chromatography to collect the required 2-(3-nitro-4-methoxyphenyl)-4-hydroxy-cyclopent-2-en-1-one (5.75 g, 50%). Example 10 Preparation of 2-(3-fcrt.-butyldimethylsilyloxy-4-methoxyphenyl)-4-hydroxy-cyclopent-2-en-l-one: A solution of aryl furfuryl alcohol i.e. compound of the formula (2) wherein R2 is tert.-butyldimethylsilyloxy, RI is OMe and RI, R* and RS are H (6.0 g, 17.96 mmol) and ZnCl2 (10.06 g, 73.97 mmol) in dioxan (90 ml) and water (70 ml) was refluxed for 22 h . The reaction mixture was brought to room temperature, acidified to pH 1 with dilute HC1 and extracted with ethyl acetate. Organic layer was washed with water, followed by brine and dried over sodium sulphate. The organic layer was concentrated under reduced pressure using rotary evaporator and purified by column chromatography to collect the required 2-(3-ter^-butyldimethylsilyloxy-4-methoxyphenyl)-4-hydroxy-cyclopent-2-en-1 -one (4.5 g, 75%). Example 11 Preparation of 2-(3-methoxymethyloxy-4-methoxyphenyl)-4-hydroxy-cyclopent-2-en-l-one: A solution of aryl furfuryl alcohol i.e. compound of the formula (2) wherein R2 is methoxymethyloxy, R3 is OMe and RI, R4 and R5 are H (6.0 g, 17.96 mmol) and ZnCl2 (10.06 g, 73.97 mmol) in dioxan (90 ml) and water"(70 ml) was refluxed for 22 h. The reaction mixture was brought to room temperature, acidified to pH 1 with dilute HC1 and extracted with ethyl acetate. Organic layer was washed with water, followed by brine and dried over sodium sulphate. The organic layer was concentrated under reduced pressure using rotary evaporator and purified by column chromatography to collect the required 2-(3-methoxymethyloxy-4-methoxyphenyl)-4-hydroxy-cyclopent-2-en-1 -one (0.6g, 60%) Advantages of the present invention 1. The process involved in the present invention is a single step process for the preparation of 2-aryl(substituted)-4-hydroxy-cyclopent-2-en-l-ones of formula (1) and therefore is economical and time saving as compare to prior art process. 2. The process involved in the present invention results in the production of high yield of 2-aryl(substituted)-4-hydroxy-cyclopent-2-en-1 -ones. We claim 1. A process for the preparation of 2-aryl(substituted)-4-hydroxy-cyclopent-2-en-l-ones of formula (1) wherein R1 to R5 are each independently selected from the group consisting of hydrogen, azido, cyano, carboxymethyl, methoxy, methyl, thiomethyl, halo and nitro which comprises, mixing a solution of aryl furfuryl alcohol of formula (2) and ZnCl2 in a mixture of dioxan and water, refluxing the above said reaction mixture for a period till complete disappearance of the starting material, cooling the said reaction mixture to an ambient temperature and acidifying by adding dilute acid selected from the group of hydrochloric acid, sulfuric acid and ammonium chloride to maintain pH at 1, extracting the resultant reaction product with an organic solvent as herein described, washing the organic layer extract with water followed by brine and drying over drying agent, concentrating the organic layer under reduced pressure and purifying the residue by known method to obtain the said product. (Formula Removed) 2. A process as claimed in claims 1, wherein the reaction mixture is refluxed preferably for a period of 15 to 25 hrs. 3. A process as claimed in claims 1&2, wherein the acid used for acidification is preferably dilute hydrochloric acid. 4. A process as claimed in claims 1-3, wherein the organic solvent used for extraction is selected from the group consisting of chloroform, dichloromethane, ethylene dichloride, ethyl acetate or diethyl ether. 5. A process as claimed in claims 1-4, wherein the drying agent used is selected from sodium sulphate and magnesium sulphate. 6. A process as claimed in claims 1-5, wherein the yield obtained of 2-aryl (substituted)-4-hydroxy-cyclopent-2-en-l-ones of the formula (1) is 85-90%. 7. A process for the preparation of 2-aryl, (substituted)-4-hydroxy-cyclopent-2-en-l-ones of the formula (I), substantially as herein described with reference to the examples accompanying this specification.

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799-DEL-2002-Abstract-(21-08-2008).pdf

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