Hydrochloric Acid → 3-Benzyl-3-azabicyclo(3.2.1)octan-8-one

Participants

Reaction Conditions

Reaction Steps

To a solution of benzylamine (21.85 ml, 200 mmol) in tert-butanol (48 ml) was added paraformaldehyde (12 g, 400 mmol), conc. HCl (18 ml, 220 mmol) and cyclopentanone (46 ml, 520 mmol) and the resulting mixture heated at 800° C. for 3 h. The mixture was cooled and diluted with water (200 ml) and extracted with EtOAc (3×200 ml); combined organic layers discarded and remaining aqueous layer evaporated. The residue dissolved in acetic acid (200 ml) and added over 1 h to a mixture of paraformaldehyde (12 g, 400 mmol) and cone. HCl (16.4 ml, 200 mmol) in acetic acid (200 ml) heated at 95° C. After complete addition mixture continued heating at 95° C. for 1 h then cooled to RT and evaporated. The residue was partitioned between EtOAc and sat. NaHCO3, the organic layer washed with sat. NaCl, dried over MgSO4, filtered and evaporated. The residue was purified by MPLC (Biotage Horizon: FLASH 65i) eluent: 100% Hexanes (450 ml), gradient rising from 100% Hexanes to 25% EtOAc in Hexanes (1500 ml), then 25% EtOAc in Hexanes (1000 ml), to afford the title compound 19 g (44%) as a clear oil. 1H NMR (CDCl3): 1.88 (m, 2H), 2.07 (m, 2H), 2.18 (s, 2H), 2.56 (d, J 10.0 Hz, 2H), 2.99 (m, 2H), 3.61 (d, J 2.0 Hz, 2H), 7.29 (m, 1H), 7.35 (m, 4H).

Provenance & Evidence