Acetic Acid → 7-Benzyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-one

Participants

Reaction Conditions

Reaction Steps

To a solution of tetrahydro-4H-pyran-4-one (6 g, 60 mmol) and powdered paraformaldehyde (4.50 g, 150 mmol) in isopropanol (150 mL) at 65° C. was added a solution of benzylamine (7.2 mL, 66 mmol) and acetic acid (3.77 mL, 66 mmol) in isopropanol (150 mL) dropwise over 1.5 h. The reaction mixture was stirred at 65° C. for 1.5 h. Upon cooling, the solvent was removed in vacuo. The residue was diluted with water (250 mL) and 1M hydrogen chloride solution (22.5 mL), and extracted with tert-butyl methyl ether (2×100 mL). The aqueous phase was basified to pH 13 with 1M aqueous sodium hydroxide solution and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (Biotage Isolera 4, SNAP 100 g), eluting with 0 to 100% ethyl acetate in heptanes, to afford the title compound 6 g, 37%) as a yellow oil. δH (500 MHz, DMSO-d6) 7.40-7.18 (m, 5H), 4.09 (d, J 10.9 Hz, 2H), 3.73 (dd, J 11.2, 2.8 Hz, 2H), 3.52 (s, 2H), 2.97 (dd, J 11.1, 2.9 Hz, 2H), 2.89 (dd, J 11.1, 6.8 Hz, 2H), 2.49-2.44 (m, 2H). Method E HPLC-MS: MH+ m/z 232, RT 4.10 minutes.

Provenance & Evidence