N,N,N',N'-Tetramethylphosphorodiamidic chloride → 5-Bromo-2-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-isoindol-1-one

Participants

Reaction Conditions

Reaction Steps

To a stirred solution of 4-bromo-2-(hydroxymethyl)-N-(2,2,2-trifluoroethyl)benzamide (3.37 g, 10.8 mmol) in anhydrous tetrahydrofuran (50 ml), N-methyl-2-pyrrolinone (20 mL), cooled to 5° C. under a nitrogen atmosphere was added a solution of 2M isopropyl magnesium chloride in anhydrous THF (25 ml) at such a rate to keep the temperature of the reaction mixture under 10° C. After complete addition, approximately 45 minutes, the reaction mixture was stirred at this temperature for an additional 60 minutes, and then at room temperature for 60 minutes. After that time, the reaction mixture was cooled down to 5° C. and a solution of bis(dimethylamino)phosphoryl chloride (1.85 g, 14.1 mmol) was added dropwise. No exotherm was observed and the reaction was heated at reflux for 72 hours once the addition was complete. After this time no starting material was observed by both TLC and LCMS and the reaction mixture was carefully quenched with water, and acidified with 1M aqueous hydrochloric acid. The aqueous was extracted with ethyl acetate (3×100 ml) and the organic layers were combined and dried over magnesium sulfate, filtered and concentrated under reduced pressure to leave a mobile oil which was purified by column chromatography eluting with 20% ethyl acetate/petroleum ether to afford the title compound as a white solid (2.81 g, 88% yield). 1H NMR (DMSO D6, 400 MHz) 4.36-4.43 (2H, m), 4.62 (2H, s), 7.68-7.74 (2H, m) and 7.93 (1H, s); MS (ES+) 296, (ES−) 292.

Provenance & Evidence