Synthesis of monocyclic, spirocyclic and fused bicyclic building blocks (amines, acids, ketones) bearing gem-difluorocyclopropane moiety via difluorocyclopropanation of unsaturated protected substrates using CF3SiMe3 – NaI system is described. The appropriate protecting groups for the each function were found. Relative order of the substrate reactivity is established. The optimal conditions for the difluorocyclopropanation include refluxing of the starting materials in THF as the solvent is elaborated. Under these conditions, a remarkable decomposition of the Ruppert–Prakash reagent occurs to give a mixture of gaseous by-products (mainly CF2=CF2 and Me3SiF), which competes with the main reaction. While this side process is not a problem for the reactive substrates (possessing 1,1-disubstituted, tri- or tetrasubstituted double bonds), in the case of mono- and 1,2-disubstituted alkenes, it prevents the complete conversion, so that slow addition of CF3SiMe3 becomes necessary. The reactivity order of the substrates shows that the process is governed mainly by electronic and to lesser extent – by steric factors, which can be explained by partially non-synchronous transition state during addition of difluorocarbene (carbenoid) to the double bond. The method includes only two operationally simple steps, relies on the readily available and non-toxic starting materials, gives 48–85% overall yields of the target products, and has been used effectively on up to a 40 gram scale and, in our opinion, has potential for further scale-up. This makes secondary amines bearing a gem-difluorocyclopropane moiety readily available to the chemical community, first of all for the use as building blocks for medicinal chemistry programs.

Difluorocyclopropanation of functionalized alkenes using CF3SiMe3–NaI system

255th National Meeting (2018)

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