Electrophilic Fluorine-containing Functionalization Of Nitrogen Heterocyclic Compounds And Electrochemical C-S Bond Construction

Nitrogen heterocyclic compounds are one of the most important structural components in medicines.On the other hand,the insertion of fluorine atoms or fluoroalkyl groups can significantly improve the pharmacological properties of drug molecules,such as lipophilicity and metabolic stability.The use of fluorine-containing groups to modify nitrogen heterocyclic compounds may achieve synergistic effects,thereby further improving the overall effect of drug molecules.Therefore,this thesis mainly uses sodium trifluoroethanesulfinate and fluoromethyl iodide as electrophiles to study the electrophilic fluorine-containing functionalization reaction with nitrogen heterocyclic compounds.In addition,the electrochemical coupling reaction of C-S bond is realized.Firstly,the electrophilic trifluoroethylthiolation reaction of sodium trifluoroethane-sulfinate with indole,pyrrole and thiophene was studied in the presence of reducing agent diethyl phosphite and Lewis acid trimethylchlorosilane.In terms of mechanism,sodium trifluoroethanesulfinate is reduced by diethyl phosphite to afford trifluoroethyl sulfoxide,which rearranged to form(2,2,2-trifluoroethyl)sulfanol.Under the action of trimethylchlorosilane,(2,2,2-trifluoroethyl)sulfanol produces trifluoroethylthio chloride with higher reactivity,which attacks electrophilically on indoles to give the final product.Meanwhile,the reaction of sodium trifluoroethanesulfinate and electron-rich aromatics was studied,and the corresponding products could be obtained with 38%-72%yields.Under the same reaction conditions,thiophenol compounds can also react electrophilically with sodium trifluoroethanesulfinate to obtain trifluoroethylthiolated products.The reaction operation is simple,the substrate range is wide,and the functional group tolerance is good.In addition,the trifluoroethylation reaction of sodium trifluoroethanesulfinate with aromatic compounds has been studied.Secondly,the synthetic method of monofluoromethoxymethylated nitrogen heterocyclic compound via using fluoromethyl iodide was developed for the first time.In the presence of base,fluoromethyl iodide undergoes an electrophilic substitution reaction with nitrogen heterocyclic compounds.Then the resulting monofluoromethylated intermediate is rapidly hydrolyzed and reacts electrophilically with fluoromethyl iodide to afford the fluoromethoxymethylated product.Indoles,carbazoles and 1H-indazoles can all be combined with fluoromethyl iodide to complete the conversion process,and products containing fluoromethoxymethyl can be obtained in 46%-84%yields.Finally,the C-S bond coupling reaction of arylazo sulfones and thiols under constant current was studied by using electrochemical synthesis technology.The reaction conditions are mild,and oxidants,catalysts,transition metals or base are avoided.And the range of reaction substrates is wide.Aryl mercaptans,heteroaryl mercaptans,alkyl mercaptans or selenophenols can react with arylazo sulfones to afford the corresponding sulfur(seleno)ether with 66%-91%yields.Among them,glucose derived thiol and L-cysteine can also obtain corresponding products with moderate yields,which provides the possibility for the application of this method in the field of drug synthesis.Radical capture and cycle voltammetric experiments proved that the reaction is a process involving free radical.By controlling the magnitude of the constant current,the sulfide or sulfoxide product can be selectively generated,which greatly increases the practicability of the reaction.In addition,under the same reaction conditions,arylboronates can also be obtained by reacting arylazo sulfones and B₂pin₂.