Highly selective difluoromethylations of β-keto amides with TMSCF2Br under mild conditions

Without employing any transition metal and other additives, efficient methods for selective difluoromethylations of β-keto amides with TMSCF2Br reagent have been developed under mild conditions. This protocol allows a convenient access to various α-difluoromethyl β-keto amides with excellent yields (up to 93%) and high C/O regioselectivities (up to 99:1). The C/O selectivity of β-keto amides could be easily reversed and controlled by simply changing the base. This protocol can be easily scaled up and the C-difluoromethylation product could be reduced into CF2H contained amino-alcohol derivatives. Moreover, the first enantioselective electrophilic difluoromethylation of β-keto amides has been achieved by phase-transfer catalysis.