Chlorine Radical Induced The Reaction Study Of 8-Aminoquinoline Derivatives At C2 Position

Nitrogen heterocycles are important structural skeletons that widely exist in natural products,drug molecules,and biologically active molecules.In particular,8-aminoquinoline drugs exhibit significant characteristics,such as anti-Alzheimer’s disease and prominent antimalarial activity.8-aminoquinoline is not only an important drug skeleton structure,but also widely used as a bidentate ligand in organometallic catalytic reactions.Functionalization of inert C-H bonds by regioselective method has the advantages of less reaction steps and no pre-functionalization of precursors,which has been an efficient way to modify organic molecules;However,there are many reaction sites of 8-aminoquinoline,and the reaction selectivity is poor due to the mixture obtained during functionalization.Therefore,it is of great significance to develop efficient and convenient regioselective C-H activation methods for 8-aminoquinoline derivatives.In recent years,chlorine radical as a highly active radical,can extract hydrogen atom from C（sp³）-H to obtain active alkyl radical intermediates,which has received extensive attention.A variety of methods for producing chlorine free radicals mediated by metal photocatalysts have been reported.In fact,in the absence of metal and light irradiation,chlorine anion can also directly produce chlorine free radicals under oxidant conditions.Minisci reaction is defined as a reaction in which nucleophilic carbon radicals undergo radical addition to protonated electron deficient aromatic heterocycles to generate substituted heterocyclic compounds.This reaction is a valuable C-H functionalization process in pharmaceutical chemistry.Although this reaction is similar to the Friedel-Crafts reaction,the reaction activity and selectivity are just opposite,and the two reactions complement each other.Since the discovery of the Minisci reaction in 1968,the exploration of coupling various nucleophilic radicals with electron-deficient heterocycles has not been disconnected.The research work in this paper mainly includes three parts:In the first part,the photoless and metal-free position selective acylation of 8-aminoquinoline derivatives was realized using common primary alcohol as acyl source in the ⁿBu₄NCl/K₂S₂O₈ system.After optimizing the experimental conditions,the tolerance of substrate functional groups was tested.The results showed that the method had good tolerance to 8-aminoquinoline derivatives and various primary alcohols.After testing a series of nitrogen heterocycles,corresponding acylation products were also obtained.In the second part,we tested various substrates containing weak C-H bonds in the aforementioned system,and achieved position selective alkylation reactions of two 8-aminoquinoline derivatives using cyclic ether compounds and several special benzyl alcohol,further revealing the powerful role of chlorine radicals as hydrogen atom transfer reagents.In the third part,after studying the reaction mechanism and DFT calculations,we proposed that chlorine radicals participate in the activation of alcohol substrates as hydrogen atom transfer reagents,and proposed possible reaction mechanisms for acylation and alkylation.Compared with the traditional Minisci reaction,this scheme has the advantage of no light and no need to add additional protonic acid.The chlorine free radical,as hydrogen atom transfer reagent,can provide the required acidic environment by producing hydrogen chloride while activating the alcohol substrate.