Visible Light-induced Synthesis Of α/β-aromatic Amide Substituted Aromatic Amines

The structure of aryl amines,aromatic carboxylic acids and aromatic carboxylic acid derivatives is an important part of many drug molecules and natural products,such as phenacetin,palbociclib,aspirin,lenalidomide,avenanthramide B,etc.Therefore,taking advantage of mild and effective methods to integrate these structures into one molecule through a simple aliphatic chain is important to the structural modification of existing drugs and the exploration and synthesis of new drugs.The use of methods of C-N bond coupling to synthesize aromatic amine compounds is an important branch in the field of modern synthetic chemistry and a crucial technical support for drugs synthesis.In the past ten years,from the advancement of transition metal catalysis to the introduction of light-induced methods,C-N bond coupling has been greatly developed in both the scope of application and the depth of theoretical research.Among them,the construction methods based on free radical mechanism have been extensively studied.Because of the distinct property of Hofmann-L?ffler-Freytag(HLF)-type 1,5-hydrogen atom transfer(1,5-HAT)reaction,the regioselective activation of remote inert C-H bonds could be finished and the corresponding C-center radical could be obtained.Thus,the HLF-type 1,5-HAT is often used in cyclization,remote functionalization,etc.In 2016,the new HLF-type substrates used by Cook’s group can be good sources of benzylic C-center radicals,and because of the benzamide core skeleton they contain,they can also be used as aromatic amide structure donors.Consequently,we innovatively use the C-center radicals provided by these type of substrates and the N-center radicals provided by primary and secondary aryl amines under visible light promoted conditions to construct C(sp~3)-N bond,and synthesize a series ofα-aromatic amide substituted aromatic amines.Based on the high reactivity of the N-αposition,the C-center radical adjacent to N can be easily obtained.Therefore,under the same reaction conditions,the use of tertiary aryl amines can smoothly construct C(sp~3)-C(sp~3)bond to synthesize a series ofβ-aromatic amide substituted aromatic amines.In addition,after the simple treatment of acid,the benzamide groups of the target products can be smoothly converted into the corresponding acid and lactam,which provides the possibility for further molecular modification.By successfully modifying the dehydroepiandrosterone-derived amine,this method has initially demonstrated its applicability in the field of drug synthesis.