Eu(OTf)3‐Catalyzed Formal Dipolar [4π+2σ] Cycloaddition of Bicyclo‐[1.1.0]butanes with Nitrones: Access to Polysubstituted 2‐Oxa‐3‐azabicyclo[3.1.1]heptanes

• Published in: Angewandte Chemie International Edition Vol. 63; no. 13; pp. e202318476 - n/a
• Main Authors: Zhang, Jian, Su, Jia‐Yi, Zheng, Hanliang, Li, Hao, Deng, Wei‐Ping
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 22.03.2024
• Subjects: Bicyclic Compounds; Bicyclo[1.1.0]butanes; Bioisosteres; Chemistry; Chemistry, Multidisciplinary; Dipolar Cycloaddition; Physical Sciences; Science & Technology; Strained Molecules; CHEMISTRY; Bicyclic Compounds; Bicyclo[1.1.0]butanes; Bioisosteres; Dipolar Cycloaddition; Strained Molecules; Strained molecules
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202318476

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. Rapid access of diverse polysubstituted 2‐oxa‐3‐azabicyclo[3.1.1]heptanes, which were not readily accessible by known methods, has been realized through Eu(OTf)3‐catalyzed formal dipolar [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes with easily accessible nitrones.