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

Abstract

AbstractA 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.