Difluorocarbenation of Olefin

About

Fluorination and organofluorination is essential to pharmaceuticals and agrochemicals since fluorine in organic molecules imparts unique properties such as increased lipophilicity, metabolic stability, and permeability of drugs and often results in enhanced biologic activity. An important subclass of organofluorine compounds are 1,1-difluorocyclopropanes, typically prepared by difluorocarbenation (1,1-difluorocyclopropanation) of olefins, showing an enhanced reactivity of cyclopropane rings, that gives rise to a variety of applications. Unfortunately, current difluorocarbenation methods suffer from distinct disadvantages (e.g. use of toxic heavy metals, high cost), and more commonly an inability to maintain low CF2 concentration results in need for reagent excess and the associated generation of toxic higher perfluoroalkenes upon CF2-recombination. There remains a critical need for novel, efficient, and cost effective difluorocarbenation methods. Almost every industry can benefit from an efficient cost effective method. Researchers at the University of Hawaii have developed a highly efficient process for the catalytic difluorocarbenation of olefin, resulting in 1,1-difluorocyclopropane. The Catalyst, a novel organobismuth complex, uses the readily available TMSCF3 as a stoichiometric difluorocarbene source. Ease of Catalyst recovery from the reaction mixture is an additional benefit of this method. Furthermore, the key difluorocarbene-generation step proceeds through a bismuth non-redox synchronous mechanism generating minute quantities of a highly reactive free CF2 in an endergonic pre-equilibrium. The reversible difluorocarbene generation is essential for achieving high selectivity and minimizing CF2-recombination side reactions. Thus overcoming the common atom economy disadvantages associated with many of the older difluorocarbenation methods. The university’s cyclable system is both robust and efficient at converting a wide range of alkene and alkyne substrates, including electron poor alkenes, into the corresponding 1,1-difluorocyclopropanes. The method has industrial advantages since it is very effective in regards to reagent (TMSCF3, only 1.2 equivalent is needed), which is safe and a relatively inexpensive source of CF2 with TMSF being the only byproduct. Additionally, bismuth-based reagents are an attractive alternative to heavy main group counterparts due to their benign and environmentally friendly (non-toxic) nature. Furthermore, the unique mechanism of this system prevents high consumption of the reagent (which can reach up to 7 equivalents) and formation of potentially dangerous (toxic, explosive perfluoroalkenes). Further details: Louis-Goff et al. https://chemrxiv.org/articles/preprint/The_Stabilizing_Effect_of_Pre-Equilibria_A_Trifluoromethyl_Complex_as_CF2_Reservoir_in_Catalytic_Olefin_Difluorocarbenation/13424117