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

Donnelly, Kian and Singh, Amritpal and Tuttle, Tell and Baumann, Marcus (2023) [3+2]-Cycloaddition reactions of gem-difluorocyclopropenes with azomethine ylides – access to novel fluorinated scaffolds. Chemistry - A European Journal, 29 (54). e202301861. ISSN 0947-6539 (https://doi.org/10.1002/chem.202301861)

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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.

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