Two-Step Synthesis of Trisubstituted Trifluoromethyl Cyclopropanes Using in situ Generated CF₃CHN₂

Graphical Abstract

An efficient approach to the multigram synthesis of trisubstituted trifluoromethyl cyclopropanes via [3+2] cycloaddition of electron-deficient alkenes and in situ generated CF₃CHN₂, followed by N₂ extrusion, is described. Albeit both steps of the key reaction sequence lack stereoselectivity, the target CF₃-substituted cyclopropanes – valuable building blocks for medicinal chemistry – can be obtained as pure diastereomers through the separation at further steps.

Abstract

A metal-free two-step approach for the synthesis of trisubstituted CF₃-cyclopropanes is reported. The method involves [3+2] cycloaddition of electron-poor alkenes and in situ generated 2,2,2-trifluorodiazoethane, followed by N₂ extrusion from intermediate pyrazolines. The protocol offers good yields of 39–90 %, is compatible with a range of functional groups, and enables multigram preparation on a scale of up to 30 grams. The method is limited by 1,1-disubstituted alkene partners, and both cycloaddition and N₂ extrusion steps are not stereoselective, resulting in ca. 1 : 1 mixtures of diastereomers. Nevertheless, the stereoisomeric mixtures can be separated at further steps by column chromatography or crystallization, thus allowing to produce diverse diastereopure (poly)functionalized CF₃-cyclopropane building blocks relevant to drug discovery.