[3+2]‐Cycloaddition Reactions of gem‐Difluorocyclopropenes with Azomethine Ylides – Access to Novel Fluorinated Scaffolds

Abstract

AbstractThe 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.