Regioselective Di- and Tri-Fluoromethylative Difunctionalization of Olefinic Bonds Driven by Homolysis, Ionic and Single Electron Transfer Mechanisms

Abstract

The transition metal free and additive free difunctionalization of carbon-carbon olefinic bonds through di-and tri-fluoromethylation serve as a potent method for simultaneously introducing two functional groups across an olefinic bond, thus offering, highly functionalized molecules.[1] The incorporation of di- and tri-fluoromethyl groups into a molecule enhances its electronegativity, lipophilicity, and metabolic stability, thus having wide spread application in pharmaceuticals and agrochemicals.[2] While numerous groundbreaking studies have focused on simultaneous C-CF2H/CF3 and C-X (C/ heteroatom) bond formation, we have focused on relatively less explored di- and tri-fluoromethylative difunctionalization of olefinic bonds in a regioselective manner. In this context, our protocol describes the regioselective difunctionalization of unactivated alkenes through vicinal trifluoromethylative borylation, facilitated by the mutual activation of the Togni II and the bis(catecholato)diboron reagents in the absence of any catalyst and additives. [3] The process occurs under mild conditions and applies to various unsaturated systems, including cyclic alkenes, natural products, and drug derivatives in a regioselective manner. Mechanistic investigations indicate that the mutual interaction between diboron reagent and Togni II reagent leads to homolysis to generate CF3 and boryl radical species. Next, we attempted to explore whether generating hydro trifluoro methylated ketones from α, β-unsaturated ketones using catechol boron enolate can be achieved. The transformation developed is applicable to a series of α, β-unsaturated ketones, including chalcones, substrate-bearing heterocycles, and bioactive molecules. In addition to that, the derivatization of the ketone group in the final product has been showcased. [4] Mechanistic studies suggest the reaction undergoes via ionic and radical mechanisms. Hereafter, we moved on to a visible light driven difunctionalization of 1,1-diaryl styrenes through di- and tri-fluoromethylative benzylation reaction. In this protocol, the key step is formation of electron donor acceptor complex formation between pyridinium salt with sodium trifluoro(difluoro)methane sulfinate. [5] Furthermore, the radical trapping experiments suggest the reaction pathway undergoes via single electron transfer process. We are currently working on expanding the substrate scope and conducting a comprehensive study of the mechanistic process.