Late‐Stage Alkylation of Heterocycles Using N‐(Acyloxy)phthalimides

Synthetic methods enabling late‐stage modification of heterocycles hold tremendous importance in the pharmaceutical and agrochemical industry and drug discovery. Accordingly, efficient, functional group tolerant and selective late‐stage alkylation of valuable molecular entities is of enormous significance and well‐acknowledged in medicinal chemistry. Radical alkylation of heteroarenes employing carboxylic acids as the alkyl radical precursor represents one of the most direct ways of C−H functionalizations of heterocycles. Recently, the field has undergone a revolutionary development especially with regard to the generation of alkyl radicals under much milder conditions. In this regard N‐(acyloxy)phthalimides (NHPI esters) have emerged as a suitable precursor of a diverse set of alkyl radicals allowing formal C−H alkylation of not only N‐heteroarenes but a diverse set of non‐aromatic heterocycles under visible light photocatalysis or electrochemical conditions. This review delineates all these discoveries and provides readers a comprehensive overview of this rapidly expanding field. The redox chemistry of N‐(acyloxy)phthalimides has been applied in the direct C‐H alkylation of several N‐heteroarenes and non‐aromatic heterocycles. The chemoselectivity and high functional group tolerance of these methods have allowed late‐stage alkylation of an array of bioactive molecules, pharmaceuticals, and natural products. This detailed review describes all these developments with representative examples and mechanistic insights.