Bifunctional 2-Aminopyridine-Catalyzed Aza-Friedel–Crafts/Oxa-6π Cascade: Synthesis of 2,2-Disubstituted Chromenes

In this study, we present an efficient organocatalytic one-pot strategy for the synthesis of 2-<i>gem</i>-dialkyl/aryl chromenes using a bifunctional 2-aminopyridine catalyst. The reaction employs inexpensive phenols and β,β-disubstituted enals and proceeds through an aza-Friedel-Crafts/oxa-6π electrocyclization cascade sequence. This operationally simple and scalable method exhibits a broad substrate scope and enables concise gram-scale syntheses of bioactive chromenes, including precocene I, confluentin, and α-daurichromenic acid, along with the formal synthesis of rhododaurichromanic acid A and (+) α-tocopherol. Detailed hybrid QM/MM MD and physicochemical studies provide mechanistic insight into the catalytic pathway.