Understanding Cu(ii)-based systems for C(sp3)-H bond functionalization: insights into the synthesis of aza-heterocycles

Herein we report the synthesis of imidazo[1,5-a]pyridine heterocycles via a Cu(ii)-mediated functionalization of alpha '-C(sp(3))-H bonds of pyridinylaldimines and subsequent cyclization. This strategy exploits the inherent directing ability of heteroleptic aldimine and pyridine groups in the substrate yielding the C-H functionalization of alpha '-methylene groups in a regioselective fashion over distant methyl or methylene groups in beta or gamma positions. The observed correlation between the nature of the anionic ligands (halide vs. carboxylate) bonded to copper and the chemoselectivity of the C(sp(3))-H activation process points to a concerted metalation-deprotonation pathway prior to cyclization to furnish the corresponding imidazo[1,5-a]pyridine derivative. This copper-mediated C(sp(3))-H bond functionalization reaction works for a variety of substrates incorporating linear alkyl chains (from 3 to 12 carbon atoms), and good functional group tolerance (aryl, ether and ester groups). Cu-Catalyzed C(sp(2))-H cyanation on the imidazole ring can then take place selectively under oxidative conditions.