Hydrochloric Acid → Hexahydro-1H-quinolizin-2(6H)-one

Participants

Reaction Steps

To a solution of ethyl 2-pyridylacetate (9.2 mL, 60.5 mmol) in EtOH (100 mL) were added 6 N HCl (16 mL) and PtO2 (1 g). The reaction was stirred at room temperature under H2 until complete. The solvent was removed under reduced pressure, and the residue was diluted with 2 M NH4OH solution until slightly basic. The mixture was extracted with ether (3×50 mL). The combined organics were dried over Na2SO4, filtered and concentrated. The resulting yellow oil was diluted with EtOH (100 mL), and ethyl acrylate (14.5 mL, 133 mmol) and TEA (36 mL, 256 mmol) were added. The mixture was stirred at room temperature under argon for three days. The mixture was concentrated, and the resulting colorless oil was dried under vacuum. The oil was dissolved in THF (25 mL) and cooled to −78° C. LiHMDS (84 mL, 84 mmol) was added dropwise, and the mixture was stirred at −78° C. for 2 h. The reaction was quenched with H2O, diluted with ether, washed with sat. NaHCO3 solution and dried over Na2SO4. The organic solution was filtered and concentrated. The resulting oil was diluted with 6 M HCl (70 mL) and heated to reflux overnight. The mixture was cooled, neutralized with solid KHCO3 and extracted with ether. The combined organics were dried over Na2SO4. filtered and concentrated to give hexahydro-1H-quinolizin-2(6H)-one, which was carried forward without purification. The crude oil was dissolved in EtOH (15 mL), and 1-(3-bromophenyl)-1-methylhydrazine hydrochloride (2.1 g, 8.81 mmol) was added followed by concentrated HCl (15 mL). The reaction mixture was heated to reflux overnight. The mixture was concentrated, and the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give the title compound (1.02 g, 36%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J=2.0 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.10 (dd, J=8.5, 1.5 Hz, 1H), 4.56 (s, 2H), 4.03 (d, J=14.0 Hz, 1H), 3.62 (s, 3H), 3.41-3.35 (m, 1H), 3.20-3.16 (m, 1H), 2.92 (dd, J=16.0, 2.5 Hz, 1H), 2.64-2.53 (m, 2H), 2.40-2.37 (m, 1H), 2.03-2.00 (m, 1H), 1.85-1.67 (m, 2H), 1.52-1.45 (m, 1H); ESI MS m/z 319 [M+H]+.

Provenance & Evidence