Research On The Establishment And Application Of Para-hydroxylation Method Of Aryl Alkyl Ethers

Background: p-Alkoxyphenol（p-Aop）is a kind of important structural unit that widely existing in active natural products and drug molecules,as well as important organic synthesis intermediate and pharmaceutical intermediate,and the study on synthesis of p-Aop is one of the research highlights in organic chemistry and drug synthesis.Due to similar chemical properties of several C-H bonds in aromatic rings,the traditional synthesis methods based on step-by-step synthesis strategy with aryl alkyl ether as the starting material often have a series of disadvantages,such as low region-selectivity,long synthesis route,low yield,and so on.Up to date,regioselective activation of C-H bonds to synthesize p-Aops in one step has not been developed although C-H hydroxylation has been widely used in organic synthesis.Therefore,it is of great significance to explore a new and facile method to synthesize p-Aops through C-H activation.Objective: p-Aops are functional groups that are widely found in natural products and pharmaceuticals.The existing synthesis methods require multi-step reactions,have no regioselectivity,and have low synthesis efficiency.This project intends to use transition metal ruthenium（II）as the catalyst and hypervalent iodine reagent（III）as the oxidant to realize the para-selective hydroxylation of aryl alkyl ethers,and to synthesize p-Aops in one step.The applicability and application value of this synthetic method in practical drug synthesis are also discussed,which provides a novel,simple and efficient synthetic method for the synthesis of p-AopsMethods: Two types of aryl alkyl ether substrates were synthesized from readily available commercial chemical products:（1）Synthesis of aryl alkyl ether substrates with different substituents in the ether bond;（2）Synthesis of aryl alkyl ethers with different substituents on the benzene ring substituted anisole.The para-selective hydroxylation of aryl alkyl ethers is achieved through experimental exploration,and the reaction conditions are optimized: screening transition metal catalysts,oxidants,ligands,additives,temperature,time and other factors to obtain the optimal conditions;（3）In the most The above two types of substrates were subjected to para-selective C-H hydroxylation under optimal conditions to test the substrate application scope of this method;（4）The reaction mechanism was proposed and verified;（5）The clinical freckle drug monobenzone and the local anesthetic pramoxine were prepared by this method,and repeated and enlarged experiments were carried out to verify the practical application value of the method.Results:（1）Through a large number of experimental explorations,the para-selective hydroxylation of aryl alkyl ethers was finally achieved,and the optimal conditions were obtained through a series of optimization experiments.（2）Under optimal conditions,p-Aops was synthesized by one-step selective para-hydroxylation,and a total of 30 target compounds were obtained.（3）The mechanism of the reaction was verified through the free radical inhibition experiment and capture experiment,and the intermediate product of the trifluoroacetoxy radical and the capture reagent was successfully captured,and a reasonable mechanism hypothesis was proposed.（4）Through the established method,two clinical drugs,monobenzone and pramoxine,were successfully prepared,and the reliability and applicability of the scheme were verified in the synthesis scale above the gram level.（5）The further application value of this methodology in the synthesis of natural products was explored: p-Aops was dearomatized into quinone monoacetals（QMAs）,and then 8 tetracyclic benzofurans were synthesized by derivatization.Conclusion:（1）Through the research on the para-selective hydroxylation of aryl alkyl ethers,a new method for para-hydroxylation of aryl alkyl ethers was successfully established.The method has a wide range of substrate adaptation,specific regioselectivity,mild reaction conditions,simple operation,high yield,and the reaction is a free radical process,and the mechanism is clear and reliable.（2）The scheme was synthesized and verified by taking the clinical drugs monobenzone and pramocaine as examples.Compared with the traditional methods for synthesizing such compounds,this scheme has the advantages of low catalyst loading rate,fewer steps and higher yield.the solvent can be recycled and a series of advantages,it has a strong potential application prospect for the synthesis of such important compounds.（3）In this scheme,p-Aops can also be dearomatized to obtain key intermediates QMAs,which can synthesize novel tetracyclic benzofuran natural products or pharmaceutical intermediates,providing a new and effective way for its efficient synthesis.