The Synthesis of Tertiary Alkylamines from Alkyl-Substituted Alkenes Using Amine Umpolung Strategy

Abstract

Radical-based aminomethyl functionalization of alkenes offers a powerful approach to synthesize tertiary alkylamines─key structural motifs in drug discovery─directly from alkenes, which are ideal and abundant feedstocks. However, due to polarity effects in radical reactions, existing strategies have been largely restricted to activated alkenes, such as electron-deficient alkenes or aryl-substituted alkenes. Here, we report a unified method that overcomes this limitation by employing α-ammoniomethyl radicals, electrophilic umpolung equivalents of α-aminomethyl radicals, to enable regioselective difunctionalization of unactivated alkenes, including a broad class of aliphatic substrates. Under visible-light photoredox catalysis, iodomethylammonium salts generate α-ammoniomethyl radicals that add efficiently to these unactivated alkenes, followed by iodine-atom transfer in a radical-chain mechanism. A streamlined one-pot sequence couples this difunctionalization with the demethylation of the ammonium moiety, affording highly substituted tertiary alkylamines with broad functional-group tolerance. The platform extends to homologative allylamine synthesis via in-situ allylammonium intermediates, enabling rapid access to extended amine scaffolds and bioisosteric analogues of pharmaceuticals. Furthermore, our reaction system using α-ammoniomethyl radicals enables diverse aminomethyl functionalization with various SOMOphiles─such as heteroarylation, alkynylation, azidation, and fluorination─greatly expanding the chemical space of tertiary amines. Collectively, this approach overcomes key limitations of prior radical difunctionalization methods and provides a modular, operationally simple route to complex amines from commodity alkenes, with broad implications for synthetic methodology and drug discovery.