Electrophilic Activation of [1.1.1]Propellane for the Synthesis of Nitrogen‐Substituted Bicyclo[1.1.1]pentanes

• Published in: Angewandte Chemie International Edition 2022-01, Vol.61 (2), p.e202111291-n/a
• Main Authors: Livesley, Sarah, Sterling, Alistair J., Robertson, Craig M., Goundry, William R. F., Morris, James A., Duarte, Fernanda, Aïssa, Christophe
• Format: Article
• Language: English
• Subjects: [1.1.1]propellane; amination; bicyclo[1.1.1]pentane; bioisostere; halogen bond
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202111291

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. 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.