Electrophilic Activation of [1.1.1]Propellane for the Synthesis of Nitrogen‐Substituted Bicyclo[1.1.1]pentanes. (26th November 2021)

• Record Type: Journal Article
• Authors: Livesley, Sarah; Sterling, Alistair J.; Robertson, Craig M.; Goundry, William R. F.; Morris, James A.; Duarte, Fernanda; Aïssa, Christophe
• Is Part Of: Angewandte Chemie. Volume 134:Number 2(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-11-26
• Subjects: [1.1.1]propellane -- amination -- bicyclo[1.1.1]pentane -- bioisostere -- halogen bond; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202111291
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: Strategies commonly used for the synthesis of functionalised bicyclo[1.1.1]pentanes (BCP) rely on the reaction of [1.1.1]propellane with anionic or radical intermediates. In contrast, electrophilic activation has remained a considerable challenge due to the facile decomposition of BCP cations, which has severely limited the applications of this strategy. Herein, we report the electrophilic activation of [1.1.1]propellane in a halogen bond complex, which enables its reaction with electron‐neutral nucleophiles such as anilines and azoles to give nitrogen‐substituted BCPs that are prominent motifs in drug discovery. A detailed computational analysis indicates that the key halogen bonding interaction promotes nucleophilic attack without sacrificing cage stabilisation. Overall, our work rehabilitates electrophilic activation of [1.1.1]propellane as a valuable strategy for accessing functionalised BCPs. Abstract : The third way: the umpolung of nucleophilic [1.1.1]propellane into an electrophilic halogen bond complex enables the synthesis of nitrogen‐substituted bicyclo[1.1.1]pentanes (BCP) after attack of anilines and azoles. DFT calculations show that the halogen bond interaction helps avoiding the decomposition of the BCP cage. This approach opens a third avenue to access functionalised BCPs besides the better explored radical and anionic strategies.