Abstract

Without employing any transition metal and other additives, efficient methods for selective difluoromethylations of β-keto amides with TMSCF₂Br reagent have been developed under alkaline and open-air 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 amino-alcohol derivatives. Moreover, the first enantioselective electrophilic difluoromethylation of β-keto amides has been achieved by phase-transfer catalysis.

Keywords: Difluoromethylation, β-Keto amides, C/O selectivity, Asymmetric synthesis

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Wang, Y.; Wang, S.; Zhang, C.; Zhao, T.; Hu, Y.; Zhang, M.; Chen, P.; Fu, Y.; Lv, J. Beilstein Arch. 2021, 202135. doi:10.3762/bxiv.2021.35.v1