Sodium Hydroxide → tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

To a solution of 0.5 g (2.30 mmol) of N-Boc-3-fluoro-4-piperidinone 2 (J. Med. Chem. 1999, 42, 2087-2104) in 10 mL of dry THF was added dropwise 2.8 mL (2.76 mmol) of a 1M solution of Li-selectride in THF under N2-atmosphere at 0° C. The solution was stirred at 0° C. for 4 h, then 10 mL of NaOH 2M was added at 0° C. and the mixture was stirred overnight at rt. The reaction mixture was extracted with Et2O, dried over MgSO4, filtered and evaporated under reduced pressure. The crude mixture was subjected to flash silicagel chromatography (hex/EtOAc/Et3N 1:1:0.1) to yield 0.27 g (56%) of pure cis-1-Boc-3-fluoro-4-hydroxypiperidine 3 as a colorless oil which solidified upon standing at −20° C. (freezer). Mp 48° C. 1H NMR (300 MHz, CDCl3): δ 1.46 (9H, s, 3×CH3), 1.67-1.91 (2H, m, CH2), 2.40-2.65 (1H, m, OH), 2.92-3.35 (2H, m, CH2CHaHbN and CHaHbCHF), 3.55-3.94 (3H, m, CH2CHaHbN and CHOH and CHaHbCHF), 4.52 (1H, dm, J=48.4 Hz, CHF). 19F NMR (282 MHz, CDCl3): δ −201.9 and −203.1 (1F, 2×m). 13C NMR (75 MHz, CDCl3): δ 28.4 (3×), 29.2, 40.4, 44.8, 68.0 (d, J=17.3 Hz), 80.2, 88.6 (d, J=177.7 Hz), 155.1. IR (KBr): ν 3413, 1674, 1429, 1167 cm−1. GC-MS (EI): m/z (%): 219 (M+, 4), 164 (46), 146 (50), 57 (C4H9+, 100).

Provenance & Evidence