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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.
Zhang et al. (2024) studied this question.