Bromide ion → Tert-butyl 4-(3-benzyloxyphenyl)-4-hydroxypiperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

A suspension of magnesium metal (0.144 g, 6.0 mmol) in THF (10 mL) was rapidly stirred for 30 minutes under nitrogen then a solution of 3-benzyloxybromobenzene (1.58 g, 6.00 mmol) in THF (10 mL) added slowly via dropping funnel. Once approximately 1 mL of the bromide solution had been added a crystal of iodine was added to the reaction and the mixture gently heated until Grignard formation began. The remaining bromide solution was then added at a rate to maintain a reaction temperature range of 50-60° C. Once addition was complete the reaction was heated to gentle reflux for 1 hour then cooled in an ice bath. A solution of tert-Butyl 4-oxopiperidine-1-carboxylate (1.00 g, 5.02 mmol) in THF (10 mL) was the added to the reaction over a period of 30 minutes then the mixture was allowed to warm to room temperature with stirring over a 2 hour period. After this time the reaction was quenched by the addition of 25% ammonium chloride solution (50 mL) and the layers separated. The aqueous was extracted with ethyl acetate (2×10 mL) and the combined organics were washed with water (20 mL) and brine (20 mL) then dried over magnesium sulfate. Subsequent filtration, concentration and purification of the residue by column chromatography (SiO2, 0-25% ethyl acetate/heptanes) afforded a 61% yield of tert-butyl 4-(3-benzyloxyphenyl)-4-hydroxypiperidine-1-carboxylate as a viscous clear oil that became a white solid on standing.

Provenance & Evidence