Binol → Ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate

Participants

Reaction Steps

1.56 g (5.7 mmol) of 1,1′-bi-2-naphthol are admixed with 5.7 ml (2.85 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred for 2 hours at room temperature. 9.5 g (57.2 mmol) of 2-fluoro-6-(1-methyleneethyl)anisole and 12.5 ml (95 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 18 hours. After cooling it is immediately purified by column chromatography on silica gel (hexane/ethyl acetate 0-5%) to give 8.9 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate. 8.9 g (26.5 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate are dissolved in 200 ml of methanol and 2 ml of acetic acid, and 890 mg of palladium on carbon (10%) are added. The suspension is shaken for 1.5 hours under a hydrogen atmosphere under atmospheric pressure until the hydrogen uptake is 560 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 8.6 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanoate. 8.6 g (25.4 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanoate in 350 ml of diethyl ether are cooled to −30° C. and over 15 minutes 1.7 g (44.7 mmol) of lithium aluminum hydride in solid form are added in portions. The mixture is stirred for 1.5 hours, in the course of which the temperature climbs to −15° C., followed by dropwise addition in succession of ethyl acetate and water and by a further hour of stirring until a readily filterable precipitate has formed. The suspension is filtered through Celite, the filter bed being thoroughly rinsed with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again 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/diisopropyl ether 0-15%) yields 3.1 g of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal

Provenance & Evidence