Methanol → 3-(4-Methoxy-benzyl)-8-(3-methoxy-phenyl)-3-aza-bicyclo[3.2.1]octane

Participants

Reaction Conditions

Reaction Steps

8-Chloro-3-(4-methoxy-benzyl)-8-(3-methoxy-phenyl)-3-aza-bicyclo[3.2.1]octane (2.46 g, 6.61 mmol) and t-butanol (9.48 mL, 99.1 mmol) in dioxane (25 mL) was heated to a gentle reflux with an oil bath (110° C.). Sodium (1.52 g, 66.1 mmol) was pre-washed sequentially with hexanes/ethanol/THF/hexanes then added portionwise to the above refluxing mixture over 20 min. The reaction mixture was heated overnight then cooled to room temperature. To this was added methanol (50 mL) to quench residual sodium. The solvent was removed in vacuo, and the product was partitioned between water (100 mL) and EtOAc (100 mL). The layers were separated and the product was further extracted with EtOAc (3×40 mL), washed with saturated aqueous NaCl solution (1×50 mL), dried over Na2SO4, filtered and concentrated to a light brown oil. Flash chromatography provided the title compound (780 mg, 35%). (TLC 20% EtOAc/hexanes Rf 0.60); 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J=8.7 Hz, 2H), 7.23 (t, J=7.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 6.88 (m, 1H), 6.84 (s, 1H), 6.74 (dd, J=7.9, 2.5 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.52 (s, 2H), 2.86 (dd, J=10.8, 3.7 Hz, 2H), 2.75 (s, 1H), 2.51 (br s, 2H), 2.28 (d, J=10.0 Hz, 2H), 1.79 (dd, J=12.7, 5.8 Hz, 2H), 1.63 (m, 2H); GCMS m/z 337 (M)+.

Provenance & Evidence