1-Benzyl-4-piperidone → 1-Benzyl-4-(2-fluorobenzyl)piperidin-4-ol

Participants

Reaction Conditions

Reaction Steps

1-Benzyl-4-piperidone (10 g, 53 mmol) in diethyl ether (80 ml) was added dropwise to a cooled (-4° C.), stirred mixture of 2-fluorobenzyl magnesium bromide (prepared from magnesium and 2-fluorobenzyl bromide (9.56 ml, 80 mmol) in diethyl ether (65 ml)) under an atmosphere of nitrogen. The reaction mixture was stirred whilst warming to room temperature (30 minutes) then at room temperature for 20 minutes. The reaction mixture was quenched with 2M hydrochloric acid (100 ml). The aqueous was separated and washed with diethyl ether (100 ml). The aqueous was basified with 2M sodium hydroxide solution then exhaustively extracted with dichloromethane. The combined organics were dried (sodium sulphate) then evaporated to give crude 1-benzyl-4-(2-fluorobenzyl)-4-hydroxypiperidine as a gum (9.0 g). This crude product in methanol (100 ml) was treated with formic acid (6 ml), ammonium formate (9.5 g, 0.15 mol) and 10% palladium on carbon (900 mg). The mixture was stirred whilst heating at reflux for 4 hours, cooled, filtered then evaporated to afford 4-(2-fluorobenzyl)-4-hydroxypiperidine as a gum (3.4 g); m/z (ES) 210 (M+ +1). This amine (3.35 g, 16 mmol) in dichloromethane (75 ml) was treated with di-t-butyldicarbonate (3.5 g, 16 mmol) and stirred at ambient temperature for 18 hours, washed with aqueous 10% citric acid, dried (potassium carbonate), evaporated to give a gum which was purified by column chromatography on silica using ethyl acetate/n-hexane (1:1) to afford the title compound as a colourless, viscous gum (3.62 g, 73%). δH (360 MHz, CDCl3) 1.46 (9H, s, (CH3)3C), 1.48 (2H, d, J=13 Hz, 2×CH), 1.63 (2H, ddd, J1 =5, J2 =13, J3 =17 Hz, 2×CH), 2.82 (2H, d, J=1 Hz, CH2Ph), 3.11 (2H, ddd, J1 =3, J2 =J3 =13 Hz, 2×CH), 3.84 (2H, d, J=13 Hz, 2×CH), 7.02-7.27 (4H, m, C6H4); m/z (ES) 310 (M+ +1).

Provenance & Evidence