Silver-catalyzed site-selective C(sp(3))-H benzylation of ethers with N-triftosylhydrazones

A state-of-the-art tool in synthetic organic chemistry is a rhodium diazocarbene species, which despite its flexibility, is derived from expensive and highly reactive species. Here the authors present a methodology for C-H benzylation of ethers via an analogous silver carbene species, obtained from a more common metal and a more stable starting material. The insertion of carbenes into the alpha-C-H bonds of ethers represents one of the most powerful approaches to access polysubstituted alpha-branched ethers. However, intermolecular carbene insertions remain challenging, since current approaches are generally limited to the use of toxic and potentially explosive alpha-diazocarbonyl compounds. We now report a silver-catalyzed alpha-C-H benzylation of ethers using bench-stable N-triftosylhydrazones as safe and convenient carbene precursors. This approach is well suited for both inter- and intramolecular insertions to deliver medicinally relevant homobenzylic ethers and 5-8-membered oxacycles in good yields. The synthetic utility of this strategy is demonstrated by its easy scalability, broad scope with valuable functional groups, high regioselectivity, and late-stage functionalization of complex oxygen-containing molecules. The relative reactivities of different types of silver carbenes and C-H bonds were also investigated by experments and DFT calculations.