Yb(OTf) 3 -Catalyzed [2π + 2σ] Cycloaddition of Bicyclo[1.1.0]butanes with Methylenimines for Modular Synthesis of 1,2,4-Trisubstituted 2-Aza-bicyclo[2.1.1]hexanes

Aromatic rings in drug candidates often exhibit poor developability. Three-dimensional bioisosteres like aza-bicyclo[2.1.1]hexanes (aza-BCHs) improve properties but face limited synthetic access to diverse substitutions. Herein, we report a Yb(OTf)₃-catalyzed [2π + 2σ] cycloaddition of methylenimines with bicyclobutanes (BCBs), featuring mild conditions, a broad substrate scope, and functional group tolerance. Compatibility with different substitution types of BCBs, amino acid-derived methylenimines, and complex bioactive molecule-derived imines was demonstrated, with gram-scale synthesis and downstream derivatization validating practical utility, expanding the toolbox for 3D heterocyclic scaffolds in drug discovery.