Enantioselective Fluorination of β-Ketoamides Catalyzed by Ar-BINMOL-derived Salan-Copper Complex

A facile and powerful enantioselective construction of C-F containing molecules was successfully developed through asymmetric fluorination of beta-ketoamides catalyzed by Ar-BINMOL-derived salan-Cu-II system (Ar-BINMOL=1,1'-Binaphthalene-2-alpha-arylmethanol-2'-ol, Cu=copper). The present catalytic system exhibited excellent enantioselectivity and a broad substrate scope for indanone-derived beta-ketoamides under mild conditions (up to 99% ee and 99% yields). Notably, the biomimetic salan-copper complex was demonstrated for the first time to be a highly efficient catalyst in the fluorination of beta-ketoamides. Experimental results and mechanistic studies indicated that both excess amount of copper salt and electrophilic attack of cationic fluorine to activated methylene assisted by amide group on the beta-ketoamides were key factors for high yield and excellent enantioselectivity, respectively, in this enantioselective fluorination, which was controlled by the two-point binding between the salan-copper complex with cyclic beta-ketoamides and hydrogen-bonding activation of the electrophilic fluorinating reagent.