Metal-Free And Radical-Mediated Heteroarylation Of C-H And C-C Bonds Of Aliphatic Alcohols

Compounds containing heterocycles account for about one-third of the total number of organic compounds,and are widely found in natural products,medicines,pesticides,dyes,and food additives.Therefore,the construction of heteroaryl groups into molecules,especially the heteroarylation of inert C-H and C-C bonds that are widely present in molecules,has very important research value.Most of the methods for radical-mediated heteroarylation of inert C-H and C-C bonds require the participation of transition metals or harsh reaction conditions.However,residual transition metals are not conducive to the development and later modification of drug molecules.In addition,most of the previous reactions were not able to perform gram-scale or larger scale experiments,which largely limited the practicality of this method.Therefore,the development of a more efficient,green,mild,and convenient synthetic method without using the transition metals to achieve the heteroarylation of inert C-H and C-C bonds has become one of the important scientific research problems to be solved urgently in the field of organic chemistry.First,remote inert C-H bond can be heteroarylated based on the radical-mediated intramolecular functional group migration strategy.Then,the heteroarylation of inert C-H and C-C bonds can be achieved via alcohol-directed Minisci-type reactions by flow chemistry.At the same time,this strategy is further upgraded and optimized,and a similar transformation is achieved using cheap and readily available iodobenzene as a catalyst,thus avoiding the use of stoichiometric hypervalent iodine reagents.1.The heteroarylation of inert C-H bond via intramolecular functional group remote migration strategyRegioselective grabbing of inert C-H hydrogen atoms using azido radical as hydrogen atom transfer species,and the generated alkyl radicals are captured by intramolecular heteroaryl groups and undergo intramolecular heteroaryl migration via a five-membered cyclic transition state,thereby realizing the heteroarylation of remote inert C-H bond,leading to a variety of heteroaryl-substituted aliphatic ketones.A library of heteroaryls such as benzofuryl,benzothiazolyl,benzothienyl,benzoxazolyl,thiazolyl,and oxazolyl are amenable to the migration approach.In addition,through simple transformation of the product,cyclic compounds and amide compounds can be easily obtained.The reaction is free of transition metals,good regioselectivity and broad functional group compatibility.2.Inert C-H and C-C heteroarylation of aliphatic alcohols by flow chemistryAliphatic alcohols react with hypervalent iodine reagent to directly generate alkoxy radical under blue light irradiation by flow chemistry device.The alkoxy radical undergo 1,5-HAT or β-C-C bond cleavage to generate alkyl radical,which can be captured by the heterocycle,thereby realizing the heteroarylation of inert C-H and C-C bonds.The reaction can be carried out on a gram scale by continuous-flow device,which reflects the practicability of the reaction.3.Iodobenzene-catalyzed Minisci reaction with aliphatic alcoholsIn this part,we use cheap and easily available,low-valence,catalytic amount of iodobenzene to replace the bis(trifluoroacetoxy)iodobenzene used in the second part,which is more expensive,high-valence,and more dosage.The aliphatic alcohols can also generate oxygen radicals react with m-CPBA under blue light,and then 1,5-HAT of long-chain alcohols and β-C-C scission of short-chain alcohols can occur,and the generated alkyl radicals are captured by heterocyclic compounds to offer various alkylated heteroaromatics.The cheap and readily available iodobenzene is employed as a catalyst in this reaction,which reduces the reaction cost to a certain extent and provides a new idea for the direct conversion of aliphatic alcohols into alkoxy radicals.