1-Bromo-4-chloro-2-fluorobenzene → Ethyl(3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoate

Participants

Reaction Conditions

Reaction Steps

81.5 ml (81.5 mmol) of a 1 M solution of lithium hexamethyldisilazide in toluene were cooled to −20° C., and a solution of 10.0 g (50.3 mmol) of ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate in 50 ml of abs. toluene was added dropwise. The mixture was stirred for 10 min At −20° C., a solution, prepared beforehand, of 14.8 g (70.6 mmol) of 1-bromo-4-chloro-2-fluorobenzene, 366 mg (1.63 mmol) of palladium(II) acetate and 1.35 g (3.42 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl in 50 ml of abs. toluene was then added dropwise. After the addition had ended, cooling was removed and the resulting reaction mixture was initially stirred at RT for 1 h and then at 80° C. overnight. After cooling, the mixture was filtered through celite, the residue was washed repeatedly with toluene and the filtrate obtained was concentrated under reduced pressure. The residue gave, after chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 100:1→100:4), 4.26 g of the title compound (25.1% of theory).

Provenance & Evidence