Hydrogen Peroxide → trans-Tert-butyl 4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate

Participants

Reaction Steps

To a suspension of NaBH4 (0.37 g, 9.8 mmol) in tetrahydrofuran (50 mL) was added BF3.OEt2 (1.3 mL, 10 mmol) at 0° C. The reaction mixture was warmed to rt for 1 h and then re-cooled to 0° C. Tert-butyl 4-(3-fluoro-4-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (1 g, 3.3 mmol) in tetrahydrofuran (10 mL) was then added. The resulting mixture was allowed to warm to rt over 2 h. It was then re-cooled to 0° C. and water (4 mL), ethanol (4 mL), 30% H2O2 (3 mL, 29.4 mmol) and a NaOH solution (4 mL, 3.25 mmol) were added sequentially and the final mixture was heated to 65° C. for 12 h. It was cooled to room temperature, and 50 mL water and 200 mL ethyl acetate were added. The layers were separated and the aqueous layer was twice extracted with 150 mL of ethyl acetate. The combined organic layers were washed with 1N HCl followed by brine. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to obtain 2 g of crude (±)-rel-(3S,4S)-tert-butyl 4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate as a brown gum. The crude compound was purified on a 40 g silica gel column eluting with 30% ethyl acetate in petroleum ether to obtain 450 mg of the pure product as a liquid. LCMS (Method P) RT 0.98 min, m/z 252 (M+H+−t-butyl), 270 (M+H+−t-butyl, —H2O); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 9H) 1.46-1.58 (m, 1H) 1.61-1.71 (m, 1H) 2.32-2.48 (m, 2H) 2.62-2.77 (m, 1H) 3.34-3.47 (m, 1H) 3.80 (s, 3H) 3.91-4.01 (m, 1H) 4.05-4.14 (m, 1H) 4.82 (s, 1H) 6.96-7.02 (m, 1H) 7.03-7.13 (m, 2H).

Provenance & Evidence