Exploration Of New Strategies For Preparing Fluorine-Containing Organic Compounds By Free Radical Process

Fluorine is one of the most prominent elements in medicinal chemistry,crop protection and materials science.Trifluoromethyl and difluoromethyl have strong electron absorption,lipophilicity and stable C-F bond,and their introduction into organic compounds can significantly change the chemical and metabolic stability of the compounds.Currently,most of the reported preparation methods of trifluoromethyl compounds use TMSCF₃,CF₃SO₂Na,Togni reagent and other reagents as substrates,which require precious metal catalysts or have poor regional selectivity and other problems.Therefore,it is necessary to prepare trifluoromethyl compounds simply and efficiently.Current strategies for inserting difluoromethyl fragments into organic molecules mainly include direct fluoridation and fluorinated block methods.Direct fluorination often has some disadvantages such as harsh reaction condition and complex reaction.Fluorinated block method is one of the hot topics in organic fluorine chemistry because of its good selectivity and mild reaction conditions.Based on the above problems,the preparation of 2-（trifluoromethyl）pyrazolium[1,5-a]pyridine and its benzo-analogizes by radical cyclization and the preparation ofβ-difluoromethyl alkyl aryl ketone by NHC collaboration photocatalysis were systematically studied in this paper.Part I:Preparation of 2-（trifluoromethyl）pyrazole[1,5-a]pyridine and its benzo analogues by radical cyclization.The preparation of 2-（trifluoromethyl）pyrazolium[1,5-a]pyridine and its benzo analogues by a copper-catalyzed radical cyclization reaction has been studied.Four different ring systems were successfully constructed by optimizing catalyst,temperature and alkalinity.A series of 2-（trifluoromethyl）pyrazole[1,5-a]pyridine and its benzo analogues were synthesized with good yield by exploring the applicability of different substituents to this method.This methodology allows the synthesis of 4-or 6-substituted 2-（trifluoromethyl）pyrazole and[1,5-a]pyridine as a single product,which could not be feasibly prepared via known methods.PartⅡ:Preparation ofβ-difluoromethyl alkyl aryl ketone by NHC synergistic photocatalysis.Using aryl olefin as substrate,β-difluoroalkyl aryl ketone was successfully constructed by the bifunctional group of aryl fluoride and ethyl difluorobromoacetate electrophiles under the coordination of NHC photocatalysis.The optimum conditions of the synthesis were determined by screening NHC,photocatalyst,alkalinity and solvent.By exploring the applicability of different substituents to the method,a series ofβ-difluoroalkyl aryl ketones were synthesized with good yield.This method successfully realized the preparation ofβ-difluoroalkyl aryl ketone from aryl fluoride and ethyl difluorobromoacetate,which provided a new idea for the synthesis of difluoromethyl compounds.