Harnessing Toluene Solvent as a Reactant: Regioselective Benzyl Radical Addition to Multi‐π 1,5‐Enynes in a Copper‐Catalyzed Cascade to Indenes

C─H activation of toluene generates a benzyl radical that undergoes C─C coupling, converting an abundant solvent into carbon building blocks. A major challenge, however, is to direct the highly reactive benzyl radical to add regioselectively to a multi-π system in a way that initiates a cascade leading to complex products. Here, we achieved this goal for the first time, to our knowledge, and demonstrated that polysubstituted indene derivatives can be efficiently obtained through a three-component cascade radical cyclization of 1,5-enynes with toluene solvent and benzoic acids in the presence of a copper catalyst and TBHP oxidant. Notably, the same indene products were also obtained when aldehydes were used in place of benzoic acids. Our combined experimental and computational investigations fully elucidated the reaction mechanism, showing that it proceeds through a Cu(I/II/III) redox cycle. This study further revealed that benzyl radicals are generated at the outset of the reaction but are highly reactive and prone to deactivation unless they undergo rapid and regioselective addition to the multi-π system. We show that these requirements are satisfied only when both terminal carbons of the alkene moiety in the 1,5-enyne bear strong electron-withdrawing substituents such as CN or CO₂Me.