Scalable manganese-electrocatalytic three-component heteroarene azidoalkylation via a polarity-reversing radical cascade

Abstract

An electrochemical approach has been established for azidoalkylation of heteroarenes using unactivated alkenes and NaN₃via a polarity reversal radical cascade strategy, enabling the synthesis of diverse C6-azidoalkylated purine derivatives that possess significant yet unexplored medicinal relevance. This three-component Minisci-type reaction was promoted by the Mn^III/II redox couple and involved the in situ selective addition of an electrophilic N₃˙ to an alkene, generating a nucleophilic C-centered radical that rapidly coupled with a variety of heteroarenes to form the corresponding adducts. The present method is characterized by a wide substrate scope (90 examples, up to 92% yield), exceptional functional group tolerance, mild reaction conditions, high chemo- and regio-selectivities, facile derivatization of products, and easy scalability. This strategy is applicable to alkenes with various substitution patterns and electronic properties, enabling the efficient synthesis and late-stage derivatization of pharmacologically active molecules, which holds great value in medicinal chemistry. Mechanistic studies support a radical mechanism involving the generation of both azido and β-azido alkyl radicals.