Benzylamine → 1,1-Dimethylethyl (3R,4S)-4-amino-3-fluoro-1-piperidinecarboxylate

Participants

Reaction Steps

A mixture of (+/−)-tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (0.33 g, 1.52 mmol), benzylamine (0.16 mL, 1.52 mmol) and sodium triacetoxyborohydride (0.382 g, 1.8 mmol) in dry 1,2-dichloroethane (6 mL) was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aq. K2CO3 solution (25 mL) and extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried over anhyd. Na2SO4 and concentrated under vacuum. The crude product obtained was purified by flash chromatography to give the cis isomer of the title compound (200 mg, 42.6%) as the major product and the trans isomer of the title compound (20 mg, 4.26%) as the minor product. Cis isomer: HPLC (condition D): retention time=10.20 min. LCMS (condition E): m/z 308.4 +ve with retention time=1.84 min. 1H-NMR (400 MHz, CDCl3) δ ppm: 7.32-7.37 (m, 4H), 7.24-7.29 (m, 2H), 4.69-4.82 (m, 1H), 4.32 (s, 1H), 4.11-4.16 (m, 1H), 3.88 (s 2H), 2.91-3.04 (dd, J=35.6 Hz, J=14 Hz, 1H), 2.66-2.80 (m, 2H), 1.78 (bs, 1H), 1.63-1.72 (m, 1H), 1.47 (s, 9H). 19F-NMR (400 MHz in CDCl3): δ ppm: −204.51 (1F). Trans isomer: HPLC (condition D): retention time=11.05 min. LCMS (condition E): m/z 308.4 +ve with retention time=1.99 min. 1H-NMR (400 MHz, CDCl3) δ ppm: 7.31-7.37 (m, 4H), 7.25-7.28 (m, 1H), 4.25-4.30 (m, 2H), 3.89-3.93 (d, J=13.6 Hz, 2H), 2.93 (bs, 1H), 2.80-2.89 (m, 2H), 1.96-2.01 (m, 1H), 1.48 (s, 9H), 1.37-1.40 (d, J=13 Hz, 1H). 19F-NMR (400 MHz in CDCl3): δ ppm: −189.58 (1F).

Provenance & Evidence