Study On Electrochemical Synthesis Of 1,4-diphenylbutane,α-deuterated Amide,α-methyl Cinnamate And PMCB Removal Reaction

1,4-Diphenylbutanes,α-deuterated amides andα-methyl cinnamates are common chemical structures in the pharmaceutical field and exhibited many biological activities.1,4-Diphenylbutanes are an important structural feature of a variety of bioactive compounds,which include antifungal,antioxidant and cytotoxicity using for the treatment of rheumatoid arthritis,diabetes,and breast cancer.α-Deuterated amides can be used for the prevention and treatment of diabetes,Alzheimer’s disease and leukemia.α-Methyl cinnamates are prevalent in many natural products and can be used for the treatment of rheumatoid arthritis,breast cancer and tuberculosis.Protecting groups or linkers bind organic molecules to a support in drug delivery.Benzyl deprotection reaction is commonly used in the field of medicinal chemistry,which has great application potential in prodrug design and drug-controlled release and activation.It is found that the conventional methods have some drawbacks,such as complex synthesis steps,using precious metal catalysts or strong acids and bases,and limited substrates scope.Electrochemistry is a green,simple,safe,economical and practical synthesis method,which has many advantages compared with conventional methods:New compounds with novel structures can be synthesized directly by using electric energy;Electrons are used as redox reagents,avoiding the use of precious metal catalysts and strong acids and bases;The reaction process can be regulated by adjusting the electrode potential and controlling the current density,which can reduce the occurrence of side reactions and selectively synthesize or release drug molecules with diverse structures.Therefore,electrochemical methods can be used to construct novel compounds with structural diversity.This paper mainly focuses on the following four aspects:1.In the second chapter,the method of electrochemical-mediated reductive dimerization of electron-deficient styrenes to construct C-C bonds was introduced and applied to the synthesis of 1,4-diphenylbutane compounds.We first identified the optimal reaction conditions for the electroreductive linear dimerization of methyl 4-vinylbenzoate 2-1a,which involved constant-current electrolysis using graphite as anode and cathode in an undivided cell containing an electrolyte solution of tetrabutylammonium bromide in CH₃CN/DMF at room temperature,and the desired product was obtained with 60%yield by electrolysis at 10 m A for 3 hours.It is found that a variety of esters and functional groups substituents on the phenyl ring are well tolerated in the reaction system.It is found that large steric hindrance will reduce the reaction yield.To further evaluate the practicality of our electrochemical method,we found that not only the cross-coupling reaction of different olefins could be carried out,but also the gram-scale amplification reaction could be realized.26 1,4-Diphenylbutane compounds were synthesized with a yield of 32%to 78%by the newly developed electrochemical method.Control experiment indicated that the desired product was completely suppressed when radical scavenger 2,2,6,6-tetramethylpiperidine oxide（TEMPO）was added in the standard reaction conditions,and deuterium-labeling experiments showed that hydrogen atom came from the solvent acetonitrile.Based on the above research results,it is suggesting that a radical process should be involved in the electroreductive dimerization reaction.2.In the third chapter,the electrochemical-mediated exchange of hydrogen and deuterium inα-carbonyl of amide compounds was introduced and applied to the synthesis ofα-deuterated amide compounds.We first identified the optimal reaction conditions of 1-phenylpyrrolidine-2-one 3-1a,which involved constant-current electrolysis using graphite and stainless steel as anode and cathode,deuterated acetonitrile（CD₃CN）as deuterium source,TEMPO as mediator in an undivided cell containing an electrolyte solution of tetrabutylammonium bromide in DMF at room temperature,and the desired product was obtained with 94%yield and 99%deuterium incorporation by electrolysis at 5 m A for 1.5 hours.It is found that various chain amides and cyclic amides have good compatibility in the reaction.To further evaluate the practicality of our electrochemical method,we found that drugs or derivatives such as praziquantel,topiramate,zolpidem,ivabradine,aniracetam,oxaprozin,isosorbic acid,biphenylacetic acid,benzocaine,fenbufen and repaglic acid reacted well.24α-Deuterated amides were synthesized with 30%to 94%yield and 60%to99%deuteration incorporation by the newly developed electrochemical method.The preliminary mechanism study shows that the reaction is supposed to be carried out by carboanion mechanism.3.In the fourth chapter,the method of electrochemical-mediated C-O bond cleavage of Baylis-Hillman acetate was introduced and applied to the synthesis ofα-methyl cinnamates.We first identified the optimal reaction conditions of methyl 2-（acetoxy（phenyl）methyl）acrylate 4-1a,which involved constant-current electrolysis using graphite as anode and cathode and triethylamine（Et₃N）as additive in an undivided cell containing an electrolyte solution of tetrabutylammonium bromide in DCM/H₂O at room temperature,and the desired product was obtained with 80%yield by electrolysis at 10 m A for 1.5 hours.It is found that various functional groups and heterocyclic compounds on benzene ring are well tolerated in the reaction system.To further evaluate the practicality of our electrochemical method,we found that not only the products with strong fluorescence properties were synthesized,but also theα-methyl cinnamate of representative natural products,such as L-menthol,adamantanol and borneol,were successfully constructed.23α-Methyl cinnamates were synthesized with a yield of 50%to 87%by the newly developed electrochemical methods.Control experiment indicated that the desired product was completely suppressed when radical scavenger TEMPO was added in the standard reaction conditions,suggesting that a radical process should be involved in the reaction.4.In the fifth chapter,a broadly applicable method for the selective deprotection of p MCB group was reported for the first time,which provided an efficient protocol for the controlled release of small molecular compounds accurately under simulated physiological p H conditions.We first identified the optimal reaction conditions of p-toluic acid 4-（methoxycarbonyl）benzyl ester 5-1a,which involved constant-current electrolysis using graphite as anode and cathode and Et₃N as additive in an undivided cell containing an electrolyte solution of phosphate buffer（PBS）and acetonitrile at 37^oC,and the desired products methyl 4-methylbenzoate 5-2a and p-toluic acid 5-3 were obtained with 97%and 96%yield by electrolysis at 10 m A for 3.5 hours.It is found that all kinds of aromatic and aliphatic carboxylic acids,phosphoric acids and alcohols have high reactivity and selectivity.To further evaluate the practicality of our electrochemical method,we found that water-soluble esters derived from serine or diethylene glycol,which were frequently used as linker or anchoring group,were well tolerated in the reaction system.We also performed the deprotection of compound 5-40 at 1.0 m M concentration,high yield was obtained and the p H values almost remained unchanged in the range of 7.4-7.5 under the mild electrochemical conditions.At the same time,this method is also suitable for gram-scale amplification reaction.We selectively released 37 carboxylic acids（including drugs,natural products,fluorescent molecules,amino acids and peptides）,phosphoric acid and alcohol molecules with a yield of 41%to 100%through the newly developed electrochemical method.Control experiment indicated that the desired product was completely suppressed when radical scavenger TEMPO was added in the standard reaction conditions,and cyclic voltammetry（CV）experiment was carried out which showed that two obvious reduction peaks of substrate 5-1a was observed at-1.22 and-2.16 V,respectively.Based on the above research results,it is suggesting that a radical process should be involved in the electrochemical deprotection reaction.In conclusion,in view of the importance of 1,4-diphenylbutanes,α-deuterated amides,α-methyl cinnamates and benzyl deprotection reaction in the field of medicinal chemistry and the drawbacks of the already reported synthetic methods,we developed a mild,efficient,and universal electrochemical synthesis method.On the one hand,it realizes the diversified synthesis of three kinds of compounds,which is helpful to build a library of small molecular compounds with diverse structures and expand the"chemical space"of drug-like molecules;On the other hand,a broadly applicable method for the selective deprotection of p MCB group has been reported for the first time,which provides an efficient protocol for the controlled release of drug molecules under simulated physiological p H conditions by this method.Therefore,the electrochemical method developed in this paper provides a new idea for subsequent drug discovery and prodrug design,and has potential application value in the field of medicinal chemistry.