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

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.

Automated summary

The study presents a method for electrophilic activation of [1.1.1]propellane in a halogen bond complex, allowing its reaction with electron-neutral nucleophiles to yield nitrogen-substituted BCPs. Computational analysis reveals that the halogen bonding interaction promotes nucleophilic attack without sacrificing cage stabilization. Overall, the work demonstrates the rehabilitation of electrophilic activation of [1.1.1]propellane as a valuable strategy for accessing functionalised BCPs.