Ammonium Chloride → 1-Benzyl-3-(3,4-difluorophenyl)pyrrolidin-3-ol

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Reaction Steps

To a solution of 1-bromo-3,4-difluorobenzene (4 g, 20.7 mmol) in dry diethyl ether (25 mL), under nitrogen at −78° C. was added drop wise n-butyllithium (2.5 M in hexane, 8.3 mL, 20.7 mmol). The mixture was stirred at −78° C. for 1 h after which a solution of 1-benzylpyrrolidin-3-one (3.62 g, 20.7 mmol) in dry diethyl ether (15 mL) was added drop wise. The mixture was stirred at −78° C. for 15 min and at ambient temperature for 1 h after which aqueous saturated ammonium chloride solution (50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (Na2SO4), filtered and evaporated. Purification twice by flash chromatography on silica gel (isooctane/ethyl acetate, 4:1 to 1:1 and 3:2 isocratic) gave the title compound (2.32 g). MS m/z (relative intensity, 70 eV) 289 (M+, 4), 198 (23), 133 (29), 132 (23), 91 (bp). The enantiomers were separated by chiral HPLC (Kromasil 5-Cellucoat, heptane/2-propanol/diethyl amine, 99:1:0.1). Yield: enantiomer E1, 0.81 g, enantiomer E2 0.835 g.

Provenance & Evidence