Visible-light Photoredox Difluoromethylation Of Phenols And Thiophenols

The discovery of fluorine-containing new drugs is of great potential because more than 20%of the pharmaceuticals and agrochemicals on the market,including a couple of top-ten drugs,are organofluorines.Therefore,the fluorination of organic molecules has become an important strategy in drug development.Among the fluorinated molecules,difluoromethyl ethers are increasingly found in various fields.Especially,aryl difluoromethyl ethers are widely used as medicinally important compounds.The most popular strategy for the synthesis of difluoromethylated products is based on the reaction of nucleophilic reagents with difluorocarbene.However,some drawbacks of the difluorocarbene precursors limit their wide application such as use of the ozone-depleting compounds,difficult handling reagents as gas,commercially non-available chemicals and requirement of heating condition.Therefore,it is highly desirable to develop an efficient method with a broad substrate scope under relatively mild conditions by using an operationally simple and environmentally benign difluorocarbene precursor.Recently,the development of photoredox methods with visible light as a renewable energy source under mild condition provides a powerful reaction strategy.Photocatalytic organic reaction are generally achieved by single electron transfer process under visible light irradiation of the photocatalyst.Polypyridyl complexes of ruthenium and iridium are well-developed visible light photocatalysts.In this thesis,visible-light photoredox difluoromethylenation of phenols and thiophenols was investigated,and the corresponding results were obtained as follows:A simple,convenient and practical visible-light photoredox method for difluoromethylation of phenols and thiophenols has been developed.The protocol used commercially available,inexpensive and easy handling difluorobromoacetic acid as the difluoromethylating agent,[fac-Ir?ppy?₃]as the photocatalyst,visible light as the light source,Cs₂CO₃ as the base,N,N-dimethylforamide as the solvent,the reaction was performed well at room temperature in 6-12 h,and the diverse O-and S-difluoromethylated products were prepared in good yields.The mechanism investigations showed that the reaction underwent the formation of difluorocarbene via debromination and decarboxylation of difluorobromoacetic acid under visible-light photocatalysis,and the difluorocarbene was trapped with a variety of phenols and thiophenols to get the target products.The present method exhibited some advantages including simple and mild reaction conditions,inexpensive and readily available starting materials,wide substrate scope,good tolerance of functional groups.Therefore,the method should provide a novel strategy for the synthesis of difluoromethylated compounds.