2-Chloroaniline → 4-(2-Chloroanilino)-2-fluorobenzonitrile

참여 물질

반응 조건

반응 단계

Palladium(II) acetate (0.561 g, 2.50 mmol) and rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.335 g, 3.75 mmol) was added to a stirred slurry of 2-chloroaniline (2.63 mL, 25.00 mmol), 4-bromo-2-fluorobenzonitrile (5 g, 25.00 mmol) and cesium carbonate (16.29 g, 50.00 mmol) in toluene (180 mL) at 23°Cunder nitrogen. The resulting slurry was stirred at 80 °C for 2 hours. The reaction was incomplete (both SM left) so the temperature was increased to 100°C and the reaction mixture was stirred for a further 2 hours. The reaction was incomplete and further Palladium(II) acetate (100mg), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (400mg) and cesium carbonate (3g) were added and the slurry was stirred at 100 °C for a further 3 hours. Only small amount of 2 SM left and more product being formed. So further Palladium(II) acetate (100mg), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (400mg) and cesium carbonate (3g) were added and the slurry was stirred at 100 °C for a further 6 hours. traces of SM left The reaction mixture was filtered through PTFE, diluted with DCM (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford product as a pale yellow solid. LCMS showed 97% pure and 3% aniline. It was resuspended in DCM and the precipitate was collected by filtration, washed with DCM (10 mL) and dried under vacuum to afford 4-(2-chlorophenylamino)-2-fluorobenzonitrile (5.15 g, 84 %) as a white solid. EN03289-99-01 (2.75 g, 11.15 mmol, 44.6 %) Filtrate repurified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-(2-chlorophenylamino)-2-fluorobenzonitrile (5.15 g, 84 %) as a pale yellow solid. (pic 2) EN03289-99-02 (0.760 g, 3.08 mmol, 12.32 %) Pic 1 from column gave compound not 100% pure. Therefore it was triturated with isohexane to give a solid which was collected by filtration and dried under vacuum to give 4-(2-chlorophenylamino)-2-fluorobenzonitrile (5.15 g, 84 %) as a pale yellow solid. EN03289-99-03 (1.64 g, 6.65 mmol, 26.6 %) mixed fractions not kept as small amount. 1H NMR (400 MHz, DMSO) d 6.63 - 6.77 (2H, m), 7.21 - 7.30 (1H, m), 7.39 (1H, m), 7.46 (1H, m), 7.54 - 7.69 (2H, m), 8.99 (1H, s). m/z (ES-), (M-H)- = 245-247; HPLC tR = 2.62 min (acid and basic)

출처 및 근거