Triphenylphosphine → 4-(2-Bromo-5-fluorophenoxy)piperidine

Participants

Reaction Conditions

Reaction Steps

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (50.6 g, 251 mmol) and di-tert-butyl azodicarboxylate (71.0 g, 308 mmol) in THF (350 mL) was added 2-bromo-5-fluorophenol (36 mL, 324 mmol). The mixture was cooled to −78° C. and a solution of triphenylphosphine (81.5 g, 311 mmol) in CH2Cl2 (130 mL) was added via a cannula. The reaction was then warmed to room temperature and stirred overnight. The solvents were removed under vacuum and the crude oil was dissolved in EtOH (200 mL). The solution was cooled to −78° C. and treated with 4 M HCl in 1,4-dioxane (450 mL). The reaction was warmed to room temperature and stirred 24 h. After this time, the solvents were removed under vacuum. The salts were neutralized with 1 N NaOH (750 mL) and extracted with a mixture of Et2O:hexanes (1:1) several times. The organic layers were combined and concentrated to dryness. The crude material was treated with heptane (1 L) and a white precipitate was filtered and discarded. The heptane layer was diluted with Et2O and treated with 4 M HCl in 1,4-dioxane (100 mL). The resulting precipitate was collected by filtration and washed three times with Et2O:hexanes (1:1). The salts were again neutralized with 1 N NaOH (500 mL) and extracted with a mixture of Et2O:hexanes (1:1) several times. The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated. The crude material was dissolved in heptane (2 L), washed four times with 1 N NaOH (250 mL), brine and dried (MgSO4). The organic layer was filtered and concentrated to dryness to afford the title product as a colorless oil.

Provenance & Evidence