Ligand-Relay Strategy Enabling Copper-Catalyzed C–C/C–O/C–N Cascade Trifunctionalization of Internal Alkynes and Propargylic Sites: Synthesis of Benzofuran-β-Lactams

Alkynes are versatile synthetic building blocks; however, trifunctionalizations involving both the alkyne and propargylic sites remain rare, primarily due to the challenge of achieving simultaneous π- and σ-activation within a single catalytic system. Herein, a ligand relay strategy has been applied to address this challenge in copper-catalyzed cascade coupling reactions involving the formation of C-C, C-O, and C-N bonds between internal alkynes and phenols in a single operation. This strategy involves an initial σ-activation mediated by a Cu/azodicarboxylate catalytic system to facilitate distal propargylic C-H activation. Subsequently, a nitrogen ligand exchange is employed to suppress the formation of propargylic hydrazide byproduct. Finally, a second ligand exchange with an <i>N</i>-heterocyclic carbene (NHC) induces π-activation of the alkyne moiety. DFT calculations demonstrate that the two ligands complementarily modulate the electronic properties of the copper center to facilitate their respective catalytic cycles, thereby accounting for the observed high chemoselectivity, excellent regioselectivity, and superior catalytic efficiency.