Transient Directing Group Enabled Pd-Catalyzed γ‑C(sp3)–H Oxygenation of Alkyl Amines

We report a general protocol for γ-C­(sp3)–H acyloxylation and alkoxylation of free amines using 2-hydroxynicotinaldehyde as the transient directing group. In the presence of an electrophilic fluorinating bystanding oxidant and acetic acid, a wide range of aliphatic amines could be oxygenated selectively at the γ-methyl positions. A vast variety of aryl, heteroaryl, and aliphatic acids could also be successfully coupled under this C–O bond formation reaction to afford amine-containing esters. Switching the nucleophile from acids to alcohols enables alkoxylation of free amines. Importantly, natural products and drug molecules such as ibuprofen, isoxepac, fenbufen, and lithocholic acid are all compatible coupling partners. Notably, synthesis of these monoprotected amino alcohols from free amino alcohols using conventional selective protection are not always feasible.