[3+2]-Cycloaddition reactions of gem-difluorocyclopropenes with azomethine ylides – access to novel fluorinated scaffolds

Kian Donnelly, Amritpal Singh, Tell Tuttle, Marcus Baumann

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Abstract

The introduction of fluorinated moieties into drugs as well as the increase of their overall three-dimensionality have become key strategies amongst medicinal chemists to generate sets of compounds with favorable drug-like properties. However, the introduction of fluorinated cyclopropane ring systems which combines both strategies is not widely exploited to date. This paper reports synthetic strategies exploiting the reactivity of gem-difluorocyclopropenes in dipolar cycloaddition reactions with azomethine ylides to afford sets of new fluorine-containing 3-azabicyclo[3.1.0]hexanes. In addition, the unexpected formation of complex trifluorinated scaffolds arising from proline esters and gem-difluorocyclopropenes is highlighted along with computational studies to elucidate the underlying mechanism. This study presents new avenues towards pharmaceutically relevant fluorinated 3-azabicyclo[3.1.0]hexanes that are accessible via robust and short synthetic sequences.
Original languageEnglish
Article numbere202301861
Number of pages8
JournalChemistry - A European Journal
Volume29
Issue number54
Early online date18 Aug 2023
DOIs
Publication statusPublished - 26 Sept 2023

Keywords

  • Ar−H⋅⋅⋅F bonding
  • difluorocyclopropene
  • dipolar cycloaddition
  • fluorinated heterocycle
  • reaction mechanism

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