Toluene → (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanol

Participants

Reaction Steps

To a solution of 1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanone (46.8 g, 223.3 mmol) and 1.0 M KOtBu (4.47 mL, 4.47 mmol) in t-BuOH in IPA (136 mL) and toluene (34 mL) in a autoclave was added dichloro{(S)-(−)-2,2′-bis[di(3,5-xylyl)-phosphino-1,1′-binaphthyl}[(2S)-(+)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine (0.273 g, 0.22 mmol) (Strem Chemicals). The reaction mixture was degassed by three vacuum-filling with nitrogen cycles. Hydrogen was introduced into the autoclave at a pressure of 300 psi and then reduced to 20 psi by slowly releasing the stop valve. After this procedure was repeated three times, the autoclave was pressurized to 300 psi with hydrogen. The reaction mixture was vigorously stirred at ambient temperature for 4 days (pressure was recharged to 300 psi when the internal pressure dropped below 200 psi). The pressure was released and the solvent was removed under reduced pressure. Ethyl acetate (300 mL) and 10% citric acid solution (50 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3:1 DCM/ethyl acetate) to give (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanol (46.76 g, 99.0%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes: 10% (1:1 MeOH/EtOH) at 1.0 mL/min, 86.4% e.e. (S)-enantiomer). (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoro ethanol (97.8 g, 462 mmol, 76% e.e.) was dissolved in 4.5% ethyl acetate/hexane (v/v) (2170 mL) with heating to reflux. After complete dissolution, it was slowly cooled to ambient temperature overnight. The resulting solid was collected by filtration, washed with hexane and dried to give (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanol (62.5 g, 63.9%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes: 10% (1:1 MeOH/EtOH) at 1.0 mL/min, 98.8% e.e. (S)-enantiomer).

Provenance & Evidence