Studies On The Synthesis Of β-Difluoromethylated Alkyl Aryl Ketones

Due to their unique physical and chemical properties,difluoromethyl-containing compounds are now widely used in agriculture,medicine,and materials.Compared with the most common trifluoromethyl group,the introduction of the difluoromethyl group into a drug molecule can not only enhance the lipophilicity of the drug molecule,but also make the drug molecule metabolic stability and nucleophilic ability better.Therefore,how to introduce difluoromethyl groups has always been the focus of organic synthesis.In recent years,the most common method for introducing difluoromethyl groups into drug molecules is the difluoromethyl radical reaction.However,methods directly introducing difluoromethyl groups through radical pathways are so limited that the research for mild radical difluoromethylations with a wide range of substrates are favored by chemists.N-heterocyclic carbene is a catalyst with strongσ-donor and weakπ-acceptor properties,which can easily handle the single-electron transfer pathway in radical reactions.Therefore,we envisaged to use N-heterocyclic carbene catalysis to realize the single electron transfer pathway of difluoromethyl radicals which can be used to modify natural products.A novel N-heterocyclic carbene catalyst for formyl difluoromethyl bifunctionalization of styrene and its derivatives was proposed for the first time.Through the screening of catalysts,oxidants,temperatures and solvents,we screened out the optimal conditions,and explored different aldehyde and alkene substrates to prove the substrate adaptability of this method which can synthesize a series ofβ-Difluoromethyl alkyl aryl ketones in good yields.This method has a series of advantages such as mild conditions,availability of substrates and low cost of N-heterocyclic carbene catalyst.It is the first method obtained by coupling aldehyde,olefin and difluoromethylation reagent（NaSO₂CF₂H）β-Method for preparing difluoromethyl aryl ketone compounds.This method has been successfully applied to the modification of natural drug estrone,which provides a new idea for adding difluoromethyl groups to natural drug molecules.