Bromide ion → (3R,6S)-3-amino-1-(cyclopropylmethyl)-6-phenylazepan-2-one

Participants

Reaction Steps

Phosphorus pentachloride (1.99 g, 9.57 mmol) was added to a solution of 1-(cyclopropylmethyl)-6-phenylazepan-2-one (2.33 g, 9.57 mmol) in dichloromethane (55 mL) at 0° C. After 1 h, iodine (0.024 g, 0.096 mmol) and a solution of bromine (0.49 mL, 9.57 mmol) in dichloromethane (5 mL) were added sequentially and the mixture was allowed to warm to ambient temperature. After 18 h, the reaction was quenched with aqueous sodium sulfite. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Sodium azide (5.60 g, 86.2 mmol) was added to a solution of the crude bromide in N,N-dimethylformamide (50 mL) and the mixture heated to 50° C. After 4 h, the reaction was allowed to cool to ambient temperature, concentrated, and diluted with water. The mixture was extracted with ethyl acetate, washed with water (3×) and saturated brine, dried over magnesium sulfate, filtered, and concentrated. 10% palladium on carbon (0.50 g) was added to a solution of the crude azide in ethanol (50 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 18 h, the mixture was filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/(10% ammonium hydroxide/methanol)] gave the racemic amine. The cis and trans enantiomers were both separated using a Chiralcel OD column eluting with 5% 2-propanol/90% (hexanes with 0.1% diethyl amine)/5% methanol to give the title compound (247 mg). MS 259 (M+1). 1H NMR (500 MHz, CDCl3) δ 7.34 (t, J=7.6 Hz, 2H), 7.26–7.23 (m, 1H), 7.17 (d, J=7.6 Hz, 2H), 3.86–3.81 (m, 2H), 3.62 (dd, J=13.9, 6.8 Hz, 1H), 3.32 (d, J=11.1 Hz, 1H), 3.08 (dd, J=13.9, 7.3 Hz, 1H), 2.79–2.74 (m, 1H), 2.14–2.12 (m, 1H), 2.02–1.97 (m, 2H), 1.77–1.67 (m, 1H), 1.03–0.99 (m, 1H), 0.55–0.49 (m, 2H), 0.28–0.25 (m, 2H).

Provenance & Evidence