tert-butyl (2R,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl (2R,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate (4.50 g, 22.9 mmol) in DMSO (42 mL) was treated with NaH (0.60 g, 25.1 mmol) in portions, then allowed to stir for 15 min. Solid 4-cyano-2-fluoropyridine (3.83 g, 31.4 mmol) was then added and the reaction was stirred at RT overnight. The reaction was quenched by addition of saturated, aqueous NaHCO3, then diluted further with water. The mixture was extracted three times with EtOAc. The organics were washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography (0-25% ethyl acetate in hexanes), providing the titled compound as a colorless oil which quickly solidified to give white crystals. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=5.2 Hz, 1H), 7.05 (dd, J=5.18, 1.3 Hz, 1H), 6.96 (d, J=1.1 Hz, 1H), 5.16 (s, 1H), 4.51 (s, 1H), 4.34 (d, J=15.0 Hz, 1H), 3.05-3.08 (m, 2H), 2.07-2.20 (m, 1H), 1.89-1.95 (m, 2H), 1.35-1.38 (m, 2H), 1.30 (s, 9H), 1.19 (d, J=7.2 Hz, 3H) ppm. LRMS m/z (M+H) 318.4 found, 318.2 required. the reaction was stirred at RT overnight The reaction was quenched by addition of saturated, aqueous NaHCO3 diluted further with water The mixture was extracted three times with EtOAc The organics were washed with brine dried over MgSO4 filtered concentrated The crude material was purified by silica gel gradient chromatography (0-25% ethyl acetate in hexanes)