Iron-catalyzed CH Bond Fluorine Functionalization And Bromination Of Aromatic Rings

Carbon-hydrogen(C-H)bonds activation,known as the holy grail in organic chemistry,is a powerful tool in synthetic chemistry.However,the bond energy of inert C-H bond is relatively large,leading to be difficult to break.Particularly,the functionalization of aromatic C-H bonds has always been a hot and difficult topic.Among them,fluorinated and brominated aromatics are important structural units in synthetic chemistry and are widely found in many bioactive compounds and pharmaceutical materials.This paper consists of three parts:(1)the development of an iron-catalyzed oxidation to achieve direct ethoxycarbonyldifluoromethylation of aromatic C-H bonds;(2)the development of an iron-catalyzed oxidation for direct bromination of aromatic C-H bonds;(3)the development of an iron-catalyzed oxidation for direct perfluoroalkylation of aromatic C-H bonds.Our research results are summarized as follows:1.A new method of direct ethoxycarbonyldifluoromethylation of aromatic C-H bonds with good efficacy has been developed.N-acetanilide was used as the model substrate to optimize the catalyst,oxidant,solvent and temperature,respectively.The optimum conditions were obtained:Fe Cl₂ as the catalyst,H₂O₂ as the oxidant,DMSO as the solvent and the reaction temperature of 80?.Aromatic products of ethoxycarbonyldifluoromethylation were synthesized efficiently and selectively under these conditions.It is found that the method has wide range of substrate application and good functional group compatibility.Notably,this method can also be used to synthesize and modify drug molecules and complex molecules.Preliminary mechanism studies show that the reaction is involved in a free radical process.2.A new method of direct bromination of aromatic C-H bonds with high selectivity was developed.The catalyst,oxidant,solvent and temperature were optimized by using methyl 3,5-dimethoxybenzoate as the model substrate.The optimum conditions were obtained:Fe Cl₂as the catalyst,K₂S₂O₈ as the oxidant,CH₃CN and H₂O as the solvent and the reaction temperature of 80?.The substrate scope was investigated under the optimal reaction conditions.The method is safe,economical,efficient and has wide range of substrates.Moreover,bromination of drugs,materials and natural products was carried out and procceded well.This method solves the problems of unsafe and uneconomical brominated reagents,limited substrates and complicated steps in previous studies.Finally,we made a preliminary study on the reaction mechanism.3.A new method of direct perfluoroalkylation of aromatic compounds with good yield was developed.N-acetanilide was used as the model substrate to optimize the catalyst,oxidant,solvent and temperature respectively.The optimum conditions were obtained:Fe Cl₃ as the catalyst,H₂O₂ as the oxidant,DMSO as the solvent and the reaction temperature of 100?.The substrate scope was tested under the optimal conditions.The method has good compatibility of functional groups,can be used to obtain single-substituted or double-substituted perfluoroalkylation products,and also realize the perfluoroalkylation reaction at different positions of aryl ring,which addresses the issue of transition metal-catalyzed directing-group strategy.In addition,we preliminarily explored the mechanism of the reaction.