Lewis Acid Catalyzed Cycloaddition of Bicyclobutanes with Ynamides for the Synthesis of Polysubstituted 2‐Amino‐bicyclo2.1.1hexenes

Abstract Synthesis of bicyclic scaffolds has gained significant attention in drug discovery due to their potential to mimic benzene bioisosteres. Here, we present a mild and scalable Sc(OTf) 3 ‐catalyzed 3+2 cycloaddition of bicyclo1.1.0butanes (BCBs) with ynamides, yielding a diverse array of polysubstituted 2‐amino‐bicyclo2.1.1hexenes in good to excellent yields. These products offer valuable starting materials for the construction of novel functionalized bicyclo1.1.0butanes. Preliminary mechanistic studies indicate that the reaction involves a nucleophilic addition of ynamides to bicyclo1.1.0butanes, followed by an intramolecular cyclization of in situ generated enolate and keteniminium ion. We expect that these findings will encourage utilization of complex bioisosteres and foster further investigation into BCB‐based cycloaddition chemistry.