Ligand-Enabled Monoselective ß-C(sp3)-H Acyloxylation of Free Carboxylic Acids Using a Practical Oxidant.

The development of C-H activation reactions that use inexpensive and practical oxidants remains a significant challenge. Until our recent disclosure of the ß-lactonization of free aliphatic acids, the use of peroxides in C-H activation reactions directed by weakly coordinating native functional groups was unreported. Herein, we report C(sp3)-H ß-acetoxylation and γ-, δ-, and ε-lactonization reactions of free carboxylic acids enabled by a novel cyclopentane-based mono-N-protected ß-amino acid ligand. Notably, tert-butyl hydrogen peroxide is used as the sole oxidant for these reactions. This reaction has several key advantages over other C-H activation protocols: (1) exclusive monoselectivity was observed in the presence of two α-methyl groups; (2) aliphatic carboxylic acids containing α-hydrogens are compatible with this protocol; (3) lactonization of free acids, affording γ-, δ-, or ε-lactones, has been achieved for the first time.