Herein, we have synthesized multifunctionalized 2-oxa-3-azabicyclo[3.1.1]heptanes, which are considered potential bioisosteres for meta-substituted arenes, through Eu(OTf)3 -catalyzed formal dipolar [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes with nitrones. This methodology represents the initial instance of fabricating bicyclo[3.1.1]heptanes 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 bicyclo[1.1.0]butanes, succeeded by an intramolecular cyclization. The synthetic utility of this novel protocol has been demonstrated in the concise synthesis of the analogue of Rupatadine.
Keywords: Bicyclic Compounds; Bicyclo[1.1.0]butanes; Bioisosteres; Dipolar Cycloaddition; Strained Molecules.
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