Efficient alkyl ether synthesis via palladium-catalyzed, picolinamide-directed alkoxylation of unactivated C(sp ³)-H and C(sp ²)-H bonds at remote positions

We report the efficient synthesis of alkyl ethers by the functionalization of unactivated sp ³- and sp ²-hybridized C-H bonds. In the Pd(OAc) ₂-catalyzed, PhI(OAc) ₂-mediated reaction system, picolinamide-protected amine substrates undergo facile alkoxylation at the γ or δ positions with a range of alcohols, including t-BuOH, to give alkoxylated products. This method features a relatively broad substrate scope for amines and alcohols, inexpensive reagents, and convenient operating conditions. This method highlights the emerging value of unactivated C-H bonds, particularly the C(sp ³)-H bond of methyl groups, as functional groups in organic synthesis.