Regioselective Hydropyridylation of Heteroatom-Functionalized Internal Alkenes by Half-Sandwich Rare-Earth Catalysts

Catalytic C–H alkylation of pyridines with unactivated internal alkenes containing heteroatom functional groups is, in principle, an ideal means for the synthesis of functionalized alkylpyridines, which are important heterocyclic structural motifs in many pharmaceuticals, agrochemicals, and biologically active compounds. However, such a transformation has remained undeveloped to date, probably due to the lack of suitable catalysts. Here we report a rare-earth-catalyzed C–H alkylation of pyridines with unactivated internal alkenes that leverages a wide array of native heteroatom functional groups, including ethers, thioethers, and tertiary amines, to serve as an efficient promoter for the regioselective hydropyridylation and hydropyridylmethylation of internal alkenes. This protocol provides an atom-efficient and straightforward approach for the selective synthesis of a new family of C2-alkylated pyridines with diverse ether, thioether, and tertiary amine functional groups, featuring 100% atom efficiency, broad substrate scope, high yield, and excellent regioselectivity. Experimental and computational studies reveal that the coordination of the heteroatom (O, S, or N) in internal alkenes to the catalyst metal center is crucial for achieving the unprecedented activity and regioselectivity.