Abstract
<title>Abstract</title> <p>Radical functionalization has transformed the synthesis of complex molecules, yet the direct formation of C–N bonds through intermolecular radical addition to heteroarenes remains largely unexplored. A major challenge is the intrinsically low reactivity of nitrogen-centered radicals towards heteroaromatic acceptors, which limits the development of radical amidation reactions analogous to the widely used Minisci alkylation. Here we report the direct radical amidation of heteroarenes through a metal-assisted activation strategy that lowers the energy of the accepting orbitals prior to radical addition. Using AgF₂, pyrazines undergo double amidation with amino acid-derived amidyl radicals to afford functionalized pyrimidopteridinetetraones in a single operation. Computational and experimental studies support an aza-Minisci-type mechanism in which coordination to AgF₂ progressively lowers the substrate LUMO, enabling efficient radical capture, while amidyl radicals are generated through dissociative proton-coupled electron transfer. The reaction proceeds under mild conditions, accommodates canonical and non-canonical α-amino acids, and preserves stereochemical integrity across a broad range of functional groups. Beyond providing the first net dehydrogenative radical amidation of heteroarenes, this work establishes metal-assisted LUMO lowering as a general strategy for promoting radical additions to otherwise unreactive heteroaromatic substrates.</p>