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

Autor: Livesley S; Department of Chemistry, University of Liverpool, Crown Street, Liverpool, L69 7ZD, UK., Sterling AJ; Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK., Robertson CM; Department of Chemistry, University of Liverpool, Crown Street, Liverpool, L69 7ZD, UK., Goundry WRF; Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Macclesfield, SK10 2NA, UK., Morris JA; Syngenta, International Research Centre, Bracknell, Berkshire, RG42 6EY, UK., Duarte F; Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK., Aïssa C; Department of Chemistry, University of Liverpool, Crown Street, Liverpool, L69 7ZD, UK.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2022 Jan 10; Vol. 61 (2), pp. e202111291. Date of Electronic Publication: 2021 Nov 26.
DOI: 10.1002/anie.202111291
Abstrakt: 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.
(© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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