Enantioselective β-C-H Arylation of α-Fluoroalkyl Cyclopropane and Cyclobutane Carboxylic Acids.

Fluoroalkyl-substituted small-membered rings are highly valuable scaffolds in drug discovery; nevertheless, there exists no general method to prepare them enantioselectively. Herein, we report a highly enantioselective β-C-H arylation of simple and readily available α-fluoroalkyl cyclopropane and cyclobutane carboxylic acids via C-H activation. This transformation enabled by chiral monoprotected-N-amino sulfonamide (MPASA) ligand is compatible with a broad range of aryl iodides, affording an efficient route to diverse small-membered rings with all-carbon quaternary centers bearing fluoroalkyls, which have been difficult to access to date. The synthetic utility of the arylation product was demonstrated by converting the carboxylic acid into alcohol and amine, which may be used to prepare new analogues of bioactive compounds. Preliminary mechanistic studies were also conducted, giving initial insights into catalyst speciation and the stability of this reaction.