What question did this study set out to answer?

This research aims to develop a modular synthesis method for 1,2,4-trisubstituted 2-aza-bicyclo[2.1.1]hexanes.

February 16, 2026

Yb(OTf) 3 -Catalyzed 2π + 2σ Cycloaddition of Bicyclo1.1.0butanes with Methylenimines for Modular Synthesis of 1,2,4-Trisubstituted 2-Aza-bicyclo2.1.1hexanes

YCYi CaoXi'an University of Architecture and Technology HXHuanping XieNanyang Normal University XYXiaowen YuNanyang Normal University

Key Points

This research aims to develop a modular synthesis method for 1,2,4-trisubstituted 2-aza-bicyclo[2.1.1]hexanes.
Utilized Yb(OTf)3 as a catalyst in the cycloaddition of methylenimines with bicyclobutanes.
Conducted reactions under mild conditions.
Tested various BCBs and amino acid-derived methylenimines.
Validated gram-scale synthesis and downstream derivatization.
Demonstrated broad substrate scope and functional group tolerance.
Achieved practical utility with successful synthesis of complex bioactive molecule-derived imines.
Expanded options for synthesizing three-dimensional heterocyclic structures.

Abstract

Aromatic rings in drug candidates often exhibit poor developability. Three-dimensional bioisosteres like aza-bicyclo2.1.1hexanes (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.

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