Eu(OTf)3‐Catalyzed Formal Dipolar 4π+2σ Cycloaddition of Bicyclo‐1.1.0butanes with Nitrones: Access to Polysubstituted 2‐Oxa‐3‐azabicyclo3.1.1heptanes

Abstract Herein, we have synthesized multifunctionalized 2‐oxa‐3‐azabicyclo3.1.1heptanes, which are considered potential bioisosteres for meta ‐substituted arenes, through Eu(OTf) 3 ‐catalyzed formal dipolar 4π+2σ cycloaddition of bicyclo1.1.0butanes with nitrones. This methodology represents the initial instance of fabricating bicyclo3.1.1heptanes adorned with multiple heteroatoms. The protocol exhibits both mild reaction conditions and a good tolerance for various functional groups. Computational density functional theory calculations support that the reaction mechanism likely involves a nucleophilic addition of nitrones to bicyclo1.1.0butanes, succeeded by an intramolecular cyclization. The synthetic utility of this novel protocol has been demonstrated in the concise synthesis of the analogue of Rupatadine.