2,3-Dihydroxybutanedioic Acid → 4-(4-Chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enal

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Reaction Steps

760 mg (2.67 mmol) of 1,1′-bi-2-naphthol are admixed with 2.68 ml (1.34 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred at room temperature for an hour. 5.07 g (28.1 mmol) of 3-chloro-2-fluoro-6-(1-methyleneethyl)anisole and 3.25 ml (26.7 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 17 hours. After it has cooled it is immediately purified by column chromatography on silica gel (pentane/diethyl ether 25-40%) to give 1.47 g of ethyl 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate. 1.47 g (3.97 mmol) of ethyl 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate in 40 ml of diethyl ether are cooled to −15° C. and over 10 minutes 300 mg (7.9 mmol) of lithium aluminum hydride in solid form are added in portions. The mixture is stirred for 1 hour, during which it warms to 0° C., and is poured into saturated ammonium chloride solution. Saturated tartaric acid solution is added and the mixture is stirred for 30 minutes. The phases are separated and subjected to repeated extraction with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/ethyl acetate 0-50%) yields 0.38 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enal and 0.15 g of alcohol. 0.27 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pent-4-enal is dissolved in 14 ml of methanol and 0.3 ml of acetic acid, and 27 mg of palladium on carbon (10%) are added. The suspension is shaken for 2 hours under a hydrogen atmosphere under atmospheric pressure until the hydrogen uptake is 46 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 027 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal as a mixture of the diastereomers.

Provenance & Evidence