Investigation Into The Electrochemical C–H Bond Activation For Benzylic Functionalization

Benzyl compounds are widely present in drug molecules and are a class of organic compounds with significant research value.Therefore,developing more efficient synthetic methods for benzyl-substituted compounds has always been a hot topic in organic synthesis chemistry.In this paper,a series of benzylic functionalized products,including benzyl alcohols,benzyl esters,and benzyl ethers,were constructed by oxidizing the C(sp~3)–H bond at the benzyl position.Mechanistic studies confirmed that the generation of these products is closely related to the generation process of benzyl radicals and benzyl carbon cations.This paper mainly completes the following four parts of work:In Chapter 2,we achieved a direct hydroxylarylation of the C(sp~3)–H bond at the benzyl position via convergent paired electrolysis.This reaction represents the first report of constructing both C(sp~3)–C(sp~2)and C(sp~3)–O bonds simultaneously at the benzyl position of arylalkanes.With this method,we can directly synthesize diaryl alcohols containing bulky substituents with tertiary or quaternary carbon centers from arylalkanes.Compared to previous reported methods,our method uses milder reaction conditions,does not require the use of inert gases,and does not involve any external oxidants,reducing agents,additives,or photochemical(or electrochemical)catalysts.This reaction can be performed at room temperature and provides functional group transformation that cannot be achieved by other chemical means.Mechanism experiments were conducted,including a divided cell control experiment,isotope labeling experiments,radical trapping experiments,electron paramagnetic resonance experiments,reaction kinetics experiments,and cyclic voltammetry experiments,all of which support the proposed reaction mechanism.Finally,we demonstrated the practical application value of our method through scale-up experiments and modification experiments of drug derivatives.In Chapter 3,we achieved the first synthesis of bulky substituted diaryl alcohols starting from aromatic alkenes or alkynes.Through the divided cell control experiment,we have confirmed that the reaction proceeds through a paired electrolysis process.Isotope labeling experiments have demonstrated that the hydroxy group in the product is derived from water.Intermediate conversion experiments and electron paramagnetic resonance experiements have shown the presence of ketyl radicals in the reaction.Building on the work in Chapter 2,we have realized the first hydroxylarylation of benzylic carbons with three hybridized types(sp~3/sp~2/sp).In Chapter 4,we continued our study on the functionalization of benzyl positions through C(sp~3)–H activation.We conducted a three-component electrochemical reaction involving water and amides,which enabled benzyl esterification.This reaction is also the first report on the synthesis of benzyl esters using arylalkanes and amides.Through radical trapping experiments,radical precursor experiments,and electron paramagnetic resonance experiments,it was proved that there were benzyl radicals in the reaction.At the same time,intermediate conversion experiments excluded benzyl alcohol and aromatic aldehydes and ketones as possible reaction intermediates.Amide cleavage experiments combined with isotope labeling experiments confirmed the participation of water in the reaction,and water was involved in the formation of carbonyl oxygen in the product.Large-scale experiment and various transformations of the main product of this chapter,benzyl formate ester,further demonstrate the practical application value of the method developed in this chapter.In Chapter 5,we further explored the potential of functionalization of C(sp~3)–H bond at the benzylic position.By utilizing the electrochemical oxidation of the benzylic C(sp~3)–H bond,we attacked the benzylic carbocation generated by anodic oxidation with a series of alcohols,and achieved the synthesis of bulky benzylic ethers that are difficult to construct using conventional methods.Through mechanism studies,the key intermediate of the reaction was proven to be the benzylic radical and its further oxidation product,the benzylic carbon cation.We have synthesized a series of benzylic ethers with large steric hinderance using a simple reaction setup under very mild conditions,which is difficult to achieve by other methods...