The Exploration Of Fluoroalkylation Reactions Based On Non-covalent Interactions

Due to the characteristics of small atomic radius（0.071 nm）and large electronegativity（χ=3.98）of fluorine atom,introducing fluorine or fluorine-containing groups into organic molecules has a greater chance of making beneficial changes in the physical,chemical and biological properties of the parent molecules.As a result,fluorinated organic compounds have been widely used in materials science,biomedicine,pesticide and other fields.The development of efficient,green and selective synthetic methods to introduce fluorine atoms or fluorine-containing groups into organic molecules is a current research hotspot in organic fluorine chemistry.Non-covalent interactions are forces that are widely found in nature.Recently,it has been found that the non-covalent interactions（halogen bond or electron donor-acceptor complexes）between fluoroalkylation reagents and some electron donor compounds can induce active fluoroalkyl radicals under light,and then a variety of fluoroalkylation reactions can occur.This kind of reaction system has attracted our research interest,because it does not require additional transition metals or photocatalysts,reacts under mild conditions,and has excellent synthesis economy.In this dissertation,we focuse on the development of a new fluoroalkylation reaction based on non-covalent interactions.Chapter 1:Catalyst-Free and Visible Light Promoted Trifluoromethylation and Perfluoroalkylation of Uracils and Cytosines.Firstly,we developed a novel method for trifluoromethylation and perfluoroalkylation of uracils and cytosines.This method has been successfully applied to the synthesis of important drug intermediate 5-trifluoromethyluracil and antiviral drug trifluridine,and the fluoroalkylation of important heterocyclic quinolones compounds has been achieved.This reaction is distinguished by its mild reaction conditions,wide substrate scope,especially good applicability and without any photoredox catalyst.Mechanistic study indicates that the negatively ionized uracil and perfluoroalkyl iodide formed an electron donor-acceptor（EDA）complexes with photochemical activity,which induced the formation of fluoroalkyl radical under the irradiation of visible light,thus realized the transformation.It is worth mentioning that this is the first example of fluoroalkylation reaction initiated by non-covalent interactions between aromatic heterocyclic amines and fluoroalkyl iodides.Chapter 2:Organophosphine-Catalyzed Difluoroalkylation of Alkenes.Organophosphine is a class of very important electron donor compounds,especially plays an important role as ligand in transition metal-catalyzed reactions.However,their applications in radical chemistry have been rarely reported.In this section,using ICF₂CO₂Et as fluoroalkylation reagent,a cheap and readily available organic phosphine compound DPPM（diphenyl phosphine methane）as catalyst,we have realized the atom transfer radical addition（ATRA）reaction of olefin compounds catalyzed by organophosphine for the first time.In particular,a Heck-type difluoroalkylated product was furnished when styrenes performed the reaction.The significant advantages of this method are the high efficiency,excellent functional group tolerance,and synthetic simplicity.Mechanistic study indicates that the reaction might be initiated via non-covalent interactions between the phosphine catalyst and carbon-iodine bond.Chapter 3:Visible Light Induced Deaminative Difluoroalkylation of Aliphatic Amines via EDA Complexes.In this study,using cheap and easily available amines as starting materials,difluoroenoxysilanes as fluoroalkylation reagent,and Hantzsch ester as electron donor.We have developed a visible light induced deaminative difluoroalkylation of aliphatic amines via EDA Complexes.This protocol is characteriazed by its mild reaction conditions,broad substrate scope and high functional group tolerance,which converted a diverse array of amine-containing molecules to the alkyl-CF₂COPh products.Moreover,the resulting products can be easily transformed to a vast array of structurally novel fluorinated compounds.This strategy is the first example of cross-coupling reaction between alkyl radical and fluoroalkyl reagent initiated by EDA complexes.In addition,this synthesis strategy is one of the few direct difluoroalkylation reactions of C-sp³ that have been realized.