Methodological Study On The Transformation Of Halodifluoroalkyl Compounds

The halodifluoroalkyl compounds?halo=Br,I or Cl?are involved in many chemicalstudies,suchasethylchlorodifluoroacetate?sodium?,ethyl bromodifluoroacetate,ethyl iodide difluoroacetate,brominated difluoroamide derivatives,and bromodifluoromethane diethyl phosphate,chlorodifluoromethane?R22?ect.Recently,halodifluoroalkyl reagents are mainly used as difluoroalkyl reagents via the C-X?X=Cl,Br,I?single bond cleavageor as difluorocarbene sources via C-X bond and C-C bond double cleavage.However,other reactivities and roles of halodifluoroalkyl compounds have not been reported so far.In this dissertation,the halodifluoroalkyl reagents were disclosed as the C-1 synthons produced via the quadruple cleavage of C-X?X=F,Cl,Br,I?and C-C bonds and two C-F bonds.This dissertation mainly involves the following six aspects:One:The fluorine-containing drug molecules are firstly summarized.The application prospects of halodifluoroalkyl compounds in fluorine-containing pharmaceutical molecules and fluorine-containing materials are described.In addition,the research progress of halodifluoroalkyl reagents in recent years is also reviewed.Two:N-H and O-H difluoromethylation of N-heterocycles.This work involves double cleavage of the C-Br and C-C bonds of ethyl bromodifluoroacetate to produce difluorocarbene under transition-metal-free and basic condition merely,in which various nitrogen-containing heterocycles could capture the in situ generated difluorocarbene species and make N-H,O-H difluoromethylation go smoothly.In addition,this work has the potential to modify drug molecule and improve pesticide effect.Three:Halodifluoroacetates as formylation reagents with various amines via unprecedented quadruple cleavage.Carbon dioxide,carbon monoxide and formic acid are the most common and widely used C-1 source in current organic chemistry.We have disclosed that ethyl bromodifluoroacetate and sodium chlorodifluoroacetate could serve as C-1 sources via the unprecedented quadruple cleavages,which can carry out N-formylation possess with various amine compounds?fatty amines and aromatic amines?firstly.The work has the characteristics of mild condition,wide substrate range,good selectivity and high yields.In addition,this paper enriches and promotes the study and development of C-F bond cleavage.Four:Synthesis of?-aminoenones via cross-coupling of in situ generated isocyanides with ethyl bromodifluoroacetate and 1,3-dicarbonyl compounds.It is well known that isocyanide is a class of compounds that are chemically intriguing and carbene-like.However,it becomes a big hurdle on the development of isocyanide in modern synthetic chemistry due to its strong and unpleasant odor.This reaction represents the first example of utilization of readily available starting materials to generate isocyanides in situ and sequentially fully converted into various?-aminoenones with Co?acac?₂ and 1,3-dicarbonyl compounds.Five:Dual role of ethyl bromodifluoroacetate in the formation of fluorine-containing heteroaromatic compounds.An efficient one-pot cascade process via unprecedented quadruple cleavage of ethyl bromodifluoroacetate with primary amines to afford valuable fluorine-containing heterocycles is described,in which ethyl bromodifluoroacetate plays dual role as C-1 synthons and difluoroalkylating reagent for the first time.This reaction utilizes a cheap and readily available primary amine and ethyl bromodifluoroacetate to form active intermediates to afford useful6-difluoroacetatephenanthridinesand2-difluoroacetatebenzothiazoles compounds.This transformation has the merits of mild conditions,simple operation,and good functional groups tolerance.Six:Chlorodifluoromethane as novel C-1 synthons in the formations of N-containing compounds under mild conditions.Chlorofluoromethane is an industrial raw material with high storage capacity.Therefore,it is prevailing that researchers exploit new uses to chlorofluoromethane.And this process represents the first report that chlorodifluoromethane acts as a C-1 synthon to synthesize various nitrogen-containing compounds.In addition,chlorodifluoromethane could also serve a dual role as both C-1 source and difluorocarbene provider to lead to difluoromethyl-containing heteroatom compounds which could not be obtained by other C-1 sources.The current transformation features transition-metal-free,mild conditions and simple operation.