Dimethyl Sulfoxide → HCID 69059725, compound

Participants

Reaction Conditions

Reaction Steps

Tetrahydrofuran (24 ml) was cooled to −60° C. with stirring and oxalyl chloride (1.15 ml, 13.2 mmol) was added. Dimethylsulfoxide (0.98 ml, 13.8 mmol) was then added dropwise. The mixture was stirred for 20 minutes, then a solution of 1-(2-chlorobenzoyl)-2-pyrrolidinemethanol (3.0 g, 12.5 mmol) in tetrahydrofuran (24 ml) was added dropwise over 15 minutes. After a further 15 minutes, the mixture was treated with triethylamine (7.0 ml, 50.1 mmol). The mixture was warmed briefly to 0° C. before re-cooling to −78° C. Ethylmagnesium bromide (3.0 M in diethyl ether; 16.7 ml, 50.1 mmol) was added dropwise to the vigorously stirred reaction mixture. The reaction was warmed to −40° C. for 1 h, re-cooled to −78° C. and then cautiously treated with ethanol (5 ml) followed by saturated ammonium chloride solution. The mixture was allowed to warm to room temperature, and then extracted with ethyl acetate (ca. 150 ml). The organic layer was dried (Na2SO4) and concentrated to afford crude (2S,αRS)-1-(2-chlorobenzoyl)-α-ethyl-2-pyrrolidinemethanol as a mixture of diastereoisomers. The crude product was dissolved in dimethylformamide (100 ml) under nitrogen. Sodium hydride (60% dispersion in mineral oil; 1.0 g, 25.0 mmol) was added, portionwise. The reaction was stirred at room temperature for 30 minutes and then heated to 120° C. for 5 h, after which the temperature was reduced to 80° C. for a further 16 h. The reaction was allowed to cool to room temperature and then quenched with methanol (10 ml) and stirred for 10 minutes. The solvents were removed under reduced pressure. The residue was taken up in water (50 ml) and extracted with dichloromethane (2×50 ml) to afford the product as a crude mixture of diastereoisomers (ratio approx. 30:70). Flash chromatography on silica (eluting with 0% to 80% ethyl acetate in heptane) afforded the title compound (80 mg) as a colourless oil; 1H NMR (400 MHz; CDCl3) δ 4.24 (1H, dt, J 10.5, 2.3 Hz, 11-H); EIMS: m/z=232 [M+H]+

Provenance & Evidence