Thionyl Chloride → (S)-2-(1,3-Dioxo-1,3-Dihydro-isoindol-2-yl)-propionyl chloride

Participants

Reaction Conditions

Reaction Steps

To a mixture of (S)-2-phthalimidopropionic acid (25.0 g) and chlorobenzene (25 mL), thionyl chloride (9.9 mL) was added and the resulting mixture was stirred at 85° C. (external temperature) for 12 hours. (S)-2-phthalimidopropionyl chloride was obtained by removing the solvent in vacuo. To a mixture of alminium chloride (16.7 g) and chlorobenzene (150 mL), anisole (18.6 mL) was added and this mixture was stirred at 60–65° C. (internal temperature). To this mixture, the solution of (S)-2-phthalimidopropionyl chloride, mentioned above, in chlorobenzene (30 mL) was added dropwise over 20 minutes, and the resulting mixture was stirred at 60–65° C. (internal temperature) for 12 hours. After the temperature of the reaction mixture was raised to 70–75° C. (internal temperature), aluminium chloride (45.6 g) was added to this mixture, and then stirred at same temperature for 3 hours. The mixture was cooled to 50° C. (internal temperature) and ethyl acetate (50 mL) was added dropwise. The resulting mixture was added to a mixture of water (250 g), ethanol (25 mL) and ethyl acetate (100 mL) at 30–45° C. (internal temperature), and stirred at same temperature for 30 minutes. Organic layer was separated from the reaction mixture, the organic layer was washed with brine, sodium bicarbonate solution, brine, 1 mol/L hydrochloric acid and brine, and dried over anhydrous sodium sulfate. After removing the solvent in vacuo, the resulting residue was recrystallized from toluene to obtain (S)-2-[2-(4-hydroxyphenyl)-1-methyl-2-oxoethyl]-isoindol-1,3-dione (18.1 g, 53.6% yield, optical purity 99.9% e.e.).

Provenance & Evidence