Cation versus Radical: Studies on the C/O Regioselectivity in Electrophilic Tri-, Di- and Monofluoromethylations of β-Ketoesters

Efficient synthesis of fluorinated organic compounds, which plays an important role in the research of biological and medicinal chemistry, and material science, is now becoming one of the most dynamic aspects of modern organic chemistry. Among several strategies for this purpose, late-stage fluoromethylation using easy-to-handle reagents under mild conditions is principally advantageous for the synthesis of complex molecules. Transferring a fluoromethyl group from the reagent to a target molecule is key for the reaction, and the reagents are classified according to their nucleophilic or electrophilic character. Over the past two decades, electrophilic tri-, diand monofluoromethylation have attracted considerable attention. During our research program for the development of direct fluoromethylation reactions and the synthesis of biologically attractive organofluorine compounds, we came across unique phenomena on C/O regioselectivity on the electrophilic triand monofluoromethylation reactions of b-ketoesters using fluorinated methylsulfoxinium salts 2a and 2b. Electrophilic trifluoromethylation of b-ketoesters 1 by 2a selectively occurs on the carbon centers of enolates, rather than on corresponding oxygen atoms, while monofluoromethylation by 2b takes place on the oxygen atoms completely regioselectively in the enolate alkylation. The curious results spurred us to investigate more closely the mechanistic aspect of the electrophilic fluoromethylation reactions of b-ketoesters. We herein disclose that different mechanisms are operating in the triand monofluoromethylation of b-ketoesters 1 from the view point of experimental results and computations. The C/O preference was found to be highly dependent on the number of fluorine atoms in the fluoromethyl group. Trifluoromethylation involves the formation of more cationic species represented by CF3 under the reaction conditions to provide complete C-alkylated products, while monofluoromethylation proceeds involving a radical-like species such as C FH2 to furnish completely O-alkylated products. Difluoromethylation of b-ketoesters 1 by difluoromethylsulfoxinium salts 2c was also investigated, and a mechanism joining the CF2H cation with the C F2H radical species is suggested (Scheme 1).