Electrophilic Activation of Propellane for the Synthesis of Nitrogen‐Substituted Bicyclopentanes

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...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2022-01, Vol.61 (2)
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:
Aniline
Azoles
Cations
Computer applications
Heterocyclic compounds
Intermediates
Nitrogen
Nucleophiles
Pentanes
Substitutes
Synthesis
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Summary: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.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202111291