Acetovanillone → HCID 67245487, compound

Participants

Reaction Conditions

Reaction Steps

A mixture of acetovanillone (0.332 g, 2.0 mmol), N-phenyl-bis(trifluoromethane-sulfonimide) (710 mg, 2.0 mmol), potassium carbonate (830 mg, 6.0 mmol) and tetrahydrofuran (3.0 ml) was heated to 120° C. for 6 min in a microwave oven. 2-Methoxypyridine-3-boronic acid (611 mg, 4 mmol), tetrakis(triphenylphosphine)palladium (0) (115 mg, 100 μmol), N-methylpyrrolidinone (1 ml) were then added and the mixture heated in the microwave at 120° C. for 10 min. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated and washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and the solvent evaporated to give 1-[3-methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethanone in quantitative yield. Reductive amination with ammonium acetate (20 equivalents) in methanol (50 ml) containing sodium cyanoborohydride (1 equivalent) followed by aqueous work-up with saturated aqueous sodium bicarbonate and extraction into ethyl actetate gave, after solvent was evaporated 1-[3-methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethylamine. To 1-[3-methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethylamine was added 2-trifluoromethoxy-benzenesulfonyl chloride (1 equivalent) in dichloromethane, diisopropylethylamine (4 equivalents) and the mixture overnight. The racemic product was isolated by normal phase HPLC on silica gel eluting with heptane/ethyl acetate and the solvent evaporated to give a clear oily solid (72 mg). 1H NMR (400 MHz, CDCl3): δ 8.15 (d, 1H), 7.9 (d, 1H), 7.5 (m, 1H), 7.4 (m, 1H), 7.3-7.2 (m, 2H), 7.05 (d, 1H), 6.9 (m, 1H), 6.75-6.65 (m, 2H), 5.0 (d, 1H), 4.55 (m, 1H), 3.91 (s, 3H), 3.67 (s, 3H), 1.51 (d, 3H) ppm; MS (ESI) m/z: 483.3 [M+1]+. The racemate was resolved by chiral HPLC (CHIRALPAK-AS, eluting with 9:1 isohexane/ethanol) to give the title compound (11 mg) and its enantiomer (11) mg.

Provenance & Evidence