p-Bromochlorobenzene → Tert-butyl 4-(4-chlorophenyl)-4-hydroxy-3-methylpiperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

A solution of 1-bromo-4-chlorobenzene (21.87 g, 114 mmol) in anhydrous THF (250 mL) was cooled to −78° C. and treated dropwise with n-butyllithium (43.5 mL, 109 mmol, 1.6 M in hexanes). The mixture was stirred at −78° C. for 45 minutes, during which time a precipitate was observed, then the slurry was treated dropwise with a solution of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (11.6 g, 54.4 mmol) in anhydrous THF (50 mL). The reaction was stirred at −78° C. for 2 hours, then allowed to slowly warm to −20° C. and quenched with saturated ammonium chloride. The layers were separated, and the organic phase was concentrated in vacuo. The aqueous phase was extracted once with ethyl acetate (300 mL), and the organic phase was combined with the residue from the original organic phase. The mixture was washed 3 times with water, and once with brine, then dried over sodium sulfate and concentrated in vacuo. The residue was digested in boiling hexanes (200 mL) for 1 hour, and then the mixture was cooled to room temperature. The solids were collected by filtration, rinsed with a small amount of hot hexanes, and dried under vacuum to yield tert-butyl 4-(4-chlorophenyl)-4-hydroxy-3-methylpiperidine-1-carboxylate (13.96 g, 42.8 mmol, 79% yield) as a powder. m/z=252.2 (M-tBuO)+.

Provenance & Evidence