反应详情

A reaction flask (500 mL) containing zinc chloride (6.98 g, 51.2 mmol) was dried by heating using a heat gun under vacuum. After cooling to room temperature, a solution of 3-chloro-5-fluorophenylmagnesium bromide (0.5 M in dry tetrahydrofuran, 100 mL, 50.0 mmol) was added to the reaction flask via a cannula, and the mixture was stirred until all zinc chloride solid was dissolved and the formation of a sluggish bright yellow solution (˜1 h). A warm bath (40° C) may be applied to complete this process. Anhydrous tetrahydrofuran (100 mL) was added, followed by tetrakis(triphenylphosphine)palladium (2.89 g, 2.50 mmol, 0.05 equiv.). After cooling to 0° C., 3-chloropropionyl chloride (5.05 mL, 52.5 mmol, 1.05 equiv.) was added dropwise and the mixture was stirred at 0° C. for 2 hours. The reaction mixture was acidified with an aqueous hydrochloric acid solution (3 N), then extracted with diethyl ether (2×250 mL). The combined ether extracts were washed with a saturated aqueous sodium bicarbonate solution, brine, dried (anhydrous sodium sulfate), and concentrated. The crude oil was purified by Isco CombiFlash Companion column chromatography (silica gel, 0-15% ethyl acetate/hexane) and the resulting white solid was recrystallized (minimal diethyl ether/hexane/−25° C.) to give pure 3-chloro-1-(3-chloro-5-fluorophenyl)propan-1-one as a white powder (5.54 g, 50%).

1. customwas dried
2. temperatureby heating
3. dissolutionwas dissolved
4. customthe formation of a sluggish bright yellow solution (˜1 h)
5. customA warm bath (40° C) may be applied
6. temperatureAfter cooling to 0° C.
7. extractionextracted with diethyl ether (2×250 mL)
8. washThe combined ether extracts were washed with a saturated aqueous sodium bicarbonate solution, brine
9. dry with materialdried (anhydrous sodium sulfate)
10. concentrationconcentrated
11. customThe crude oil was purified by Isco CombiFlash Companion column chromatography (silica gel, 0-15% ethyl acetate/hexane)
12. customthe resulting white solid was recrystallized (minimal diethyl ether/hexane/−25° C.)