Synthesis Of Phenylλ³-I-CF₃ And Studies On The Trifluoromethylation-Carbocyclizations Of Alkenes

The introduction of the trifluoromethyl group into organic molecules has become one of the most popular topics of organofluorine chemistry because the trifluoromethylated compounds usually exhibit significantly enhanced efficacy in physical,chemical,or biological properties.Thus the trifluoromethyl group is a privileged structure in pharmaceuticals,agrochemicals,and specialty materials.Consequently,trifluoromethylation is one of the most important study in the field of organic fluorine chemistry,among which one of the major challenges is the development and utilization of excellent CF₃ sources.However,the preparation and application of aryltrifluoromethylλ³-iodanes（ArICF₃X）,which were defined as fundamentally electrophilic trifluoromethylating reagents,is a never fully solved challenge in fluorine chemistry.Although the preparation and application of the similar electrophilic perfluoroalkylating reagents[ArICnF2n+1X（n>1）]could be successfully achieved,ArICF₃X,the simplest homologue of this series,could not be obtained for many years.In 2006,two types of CF3-hypervalent iodanes bearing rigid benziodoxolone cyclic backbones were successfully synthesized in Togni’s group,the skeleton structure of which increase both the stability and reactivity of the molecules,and has made great contributions to the research and development of electrophilic trifluoromethylation reagents.In recent years,our group has been engaged in the research of trifluoromethylation.After detecting the[PhICF₃]⁺species by the MS spectroscopic,we have successfully prepared stable PhICF₃Cl in air for the first time,which provide a groundbreaking basis for the synthesis and application of ArICF3X.Compared with neutral Togni reagents,it is the iodonium character of PhICF3Cl that endows it with an enhanced electrophilicity in the CF₃-transfer process.We believe that PhICF₃Cl would provide new opportunities for the methodology of trifluoromethylation.Based on the development and applications of electrophilic trifluoromethylating reagents,as well as recent research results of our group,our research focuses on the synthesis and application of PhICF₃Cl.We prepared a noncyclic CF₃-containingλ³-iodane via a direct ligand-exchange method for the first time.After investigating the reaction activity of PhICF₃Clintrifluoromethylation,wedescribedaconcise trifluoromethylation-carbocyclization of a range of both unactivated and activated alkenes under catalyst-free conditions subsequently.It is worth mentioning that the efficiency of this protocol was highlighted by the new bicyclization of dialkenes.A series of new methods for trifluoromethylation were established.The thesis is divided into five chapters:In Chapter 1,we mainly summarize the development and the applications of trifluoromethylation methodologies and corresponding reagents,and put forward the basis for this paper.In Chapter 2,we developed a direct route to synthesize PhICF₃Cl via a simple ligand-exchange method among PIFA,TMSCF₃,and Cl^-from saturated brine for the first time.The reactivity and the scope of application were examined preliminary in our group,the result shows that PhICF₃Cl was well used as a new CF₃ source in various trifluoromethylation reactions with commonly used nucleophiles under catalyst-free conditions.Compared with other electrophilic trifluoromethylation reagents,the easy availability and versatile usefulness of such low-cost PhICF₃Cl would provide new opportunities for continuing proliferation of CF₃-containing compounds in medicinal chemistry and biological chemistry.In Chapter 3,we have studied a concise trifluoromethylative cyclization of a range of activated alkenes.The use of readily prepared PhICF₃Cl as a powerful trifluoromethylation reagent enables a catalyst-free process for constructing trifluoro-methylated cycles of acryloanilides for the first time.Control experiments support the suggested ionic mechanism.Broad substrate scope,mild reaction conditions and easy operation make the method well-suited for wide applications in organic synthesis and drug design.In Chapter 4,we have studied a catalyst-free aryltrifluoromethylative cyclization of unactivated alkenes.Using PhICF₃Cl as a powerful trifluoromethylation reagent,a straightforward process of constructing a set of trifluoroethylated carbocycles or aza-heterocycles was successfully established.Control experiments support the suggested ionic mechanism as well.This method would be widely applied with the advantages of excellent selectivity,broad substrate scope,mild reaction conditions and easy operation.In Chapter 5,we have studied a catalyst-free aryltrifluoromethylative domino biscyclization of dialkene for the first time.By using PhICF₃Cl as the trifluoromethylation reagent,we managed to achieved this readily cis-trifluoromethylative domino biscyclization process of acrylic aniline styrenes.The trifluoromethylation reaction has been proved to occur with good selectivity.As the result of control experiments show,the suggested ionic mechanism is also suitable for this process.Significantly,the efficiency of this protocol was highlighted by the new biscyclization of dienes.With the good selectivity and the mild reaction conditions,this easily-oprated protoco would be widely used in organic cyclization and drug designs.In conclusion,we prepared a noncyclic CF₃-containingλ³-iodane via a direct ligand-exchangereactionofTMSCF₃forthefirsttime.Aconcise trifluoromethylation-carbocyclization of a range of both unactivated and activated alkenes under catalyst-free conditions was constructed after investigating the reaction activity of PhICF₃Cl in trifluoromethylation reactions.The efficiency of this protocol was well-proved by the new domino bicyclization of dialkenes.The synthesis of ArICF₃X type of trifluoromethylation reagent and the establish of series of new methods for trifluoromethylation-carbocyclization of alkenes based on PhICF₃Cl will greatly promote the development of trifluoromethylation chemistry and provide a new opportunity for new methodologies of trifluoromethylation.