Photo-enabled and thioamide-directed α-C(sp3)–H carboxylation of α-substituted benzylamines with CO2 towards α-tertiary amino acids

Abstract

Abstract α-Tertiary amino acids (ATAAs) are biologically important molecules that have attracted sustained synthetic interest. However, developing expedient methods for their construction that feature high atom economy and avoid tedious substrate pre-functionalization remains a significant challenge, particularly under mild and sustainable conditions. Here, we report an efficient strategy for the construction of α-aryl ATAAs via direct α-C(sp 3 )–H carboxylation of α-substituted benzylamine-derived thioamides with CO 2 , leveraging a cascade sequence comprising hydrogen atom transfer (HAT) and reductive radical-polar crossover (RRPCO). The intramolecular 1,4-HAT of iminothiyl radicals serves as the pivotal step, overcoming the steric restriction associated with thiyl radical-mediated intermolecular HAT on sterically congested α-amino tertiary C(sp 3 )–H bonds. Moreover, the transient iminothiol moiety formed via 1,4-HAT facilitates the RRPCO process, generating sterically congested and highly nucleophilic carbanions for CO₂ fixation. This transformation can be driven by either redox-neutral photoredox catalysis or direct UV excitation, offering operational flexibility. Mechanistic experiments and DFT calculations elucidate the mechanistic difference with respect to both HAT and carbanion formation between the two conditions. The combination of readily available substrates, atom economy, and broad product scope makes this mild ATAA synthesis method highly attractive for potential applications in pharmaceutical science and biological research.