Study On Electrosynthesis Of Aryl Phosphines And Lactam Derivatives

Aryl phosphines and lactam derivatives are universal chemical structures in organic chemistry and medicinal chemistry,and could be widely applied to pharmaceutical,pesticide,and material science.For example,aryl phosphides can be used as inhibitors or agonists of a variety of protein kinases and receptors for the treatment of tumors,cardiovascular diseases,diabetes,etc.;lactam derivatives are found in numerous natural products and can be used as effective treatment drugs for various diseases such as hypertension,inflammation,anemia,etc..Phosphorylation of aryl halides is one of the commonly used methods for the synthesis of aryl phosphides,traditional methods have some drawbacks,such as the requirement of palladium catalysts,severe conditions,long reaction time,limited substrate scope,etc.;the selective monoreduction of readily available imides represents the most straightforward and efficient route to synthesize lactam derivatives,conventional methods generally rely on hydride reagents,metal reductants or transition-metal catalysts,which have disadvantages such as over-reduction,poor chemoselectivity,limited substrate scope,and the requirement of hydrogen pressure.Consequently,in order to solve the aforementioned-deficiencies,synthetic chemists are dedicated to find more concise and universal protocols to realize these two types of reactions.Electrochemical synthesis is a technology that has developed rapidly in recent years,compared with traditional methods,it possesses the following advantages:no need for redox agents;mild reaction conditions;reaction selectivity can be achieved by adjusting the voltage and current;the same electrolysis device can be used for different types of reactions,which is conducive to the realization of cascade reactions;overcome some difficulties in traditional synthesis.With the continuous development and improvement of electrosynthesis,some new technologies such as chiral electrodes,redox media,and"cation pools"have been applied and greatly improved the efficiency and application range of electrochemical reactions.In addition,the electrosynthesis instruments have also changed from early large-volume and complex devices to small household batteries,and then to devices that can realize standardized and modular synthesis(such as Electra Syn 2.0),which improves the operability of electrochemical synthesis and provides a new option for synthetic chemists.This paper is divided into three chapters:chapter one outlines the drug backgrounds and already existing synthesis methods of aryl phosphides and lactam derivatives,as well as the characteristics and development of organic electrochemical synthesis;chapter two introduces the method of nickel-catalyzed electrochemical cross-coupling of aryl halides and phosphine nucleophiles and applied it to the synthesis of aryl phosphides;chapter three introduces the method of selective monoreduction of cyclic imides under electrochemical conditions and applied it to the synthesis of lactam derivatives.The cross-coupling of aryl halides and phosphine nucleophiles is a common method for the synthesis of aryl phosphines.In chapter two,we explored the application of electrochemistry in this type of reaction.First,we identified the optimal reaction conditions for the electrochemical cross-coupling of1-bromo-4-(trifluoromethyl)-benzene with diethyl phosphite,by changing the dosage,system concentration,solvent,reaction time and electrode,the best conditions are obtained:under N₂protection,use cheaper and non-toxic carbon electrodes,electrolyzed at room temperature for 3 hours with a small current of 10 m A to obtain the desired product 2-3a with a yield of 90%.Next,the scope of the substrate was investigated,using diethyl phosphite as the phosphorus nucleophile,various functional groups on the bromobenzene ring were investigated,and the results showed that a variety of functional groups,including alkoxy(OMe),alkyl(Me and CF₃),halogen(F and Cl),cyano(CN),carbonyl(COMe),and ester(CO₂Et)substituents in the phenyl ring,were well tolerated in the reaction system;in addition,bicyclic/tricyclic aromatic substrates and aromatic heterocycles can be successfully converted into target products with medium to high yields.Further investigation of the substrate range showed that the system can be applied to1-chloro-4-(trifluoromethyl)-benzene with a yield of 42%;diisopropyl phosphite,ethyl phenylphosphonate and diphenyl phosphine oxide can also be used as phosphorus nucleophiles.As a result,nineteen aryl phosphides were obtained with a yield between 34%and 94%.Subsequently,in order to investigate the practicality of this method,we scaled up the template to 1 mmol and obtained the target product2-3a with 74%yield.Finally,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 cross-coupling reaction,and the anodic and cathodic processes are reconciled to synergistically generate reactive nickel species of different oxidation states in an undivided cell so that promote the generation of products.Selective monoreduction of imides represents the most direct and effective method for synthesizing lactams.In chapter three,we explored the application of electrochemical synthesis in this type of reaction.First,we carried out the conditional screening,choosing N-phenyl phthalimide as the template substrate,by changing amine,electrolyte,solvent,reaction current and time,we have obtained the optimal conditions:diisopropylamine as base,ethanol as solvent,the hydroxylactam product3-2a was obtained by electrolysis at 20 m A for 2 hours,and the lactam product 3-3a was obtained by electrolysis at 25 m A for 3 hours.Next,the scope of the substrate was investigated,the results show that high reactivity and selectivity were observed with N-aromatic and N-aliphatic substrates,and a range of reduction-sensitive N-alkyl functional groups,including alkenes,alkynes,epoxides,halides,esters,and ketones were all well compatible with our electrochemical conditions.Subsequently,in order to investigate the practicality of this method,we applied this method to thalidomide,and were able to obtain the corresponding hydroxylactam 3-2w,but could not get the further reduced lactam 3-3w;it is worth noting that by reacting at a constant current of20 m A for 24 hours or at a constant current of 30 m A for 30 hours,we scaled up the template to 6 mmol,and obtained hydroxylactam and lactam products with 87%and82%yield respectively,achieved the gram-level synthesis of the target product.As a result,twenty-three hydroxylactams were synthesized with a yield between 49%and95%,and twenty-one lactams were synthesized with a yield between 18%and 94%.Finally,in order to investigate the reaction mechanism,we did a series of experiments and the results were as follows:the reaction results of N,N-diisopropylethylamine,pyridine and 2,2,6,6-tetramethylpiperidine revealed that the use of amines which could generate?-aminoalkyl radicals is essential to promote the required reduction reaction;radical-trapping experiments indicated that the desired product was completely suppressed and the molecule that trapped by TEMPO was detected when radical scavenger TEMPO was added under the standard conditions,suggesting that a radical process should be involved in the electroreduction reaction;the results of deuterium-labeling experiments using C₂H₅OD and ^i-Pr₂ND showed that the proton comes from both the solvent ethanol and diisopropylamine,and there exists a fast proton exchange between them.In conclusion,by summarizing the pharmaceutical applications and the existing synthetic methods of aryl phosphides and lactam derivatives,in view of their importance in small drug molecules as well as natural products,and considering the drawbacks of the already reported synthetic methods.Encouraged by the advantages of electrosynthesis,we have developed new electrochemical synthesis methods of these two types of compounds and predicted their reaction mechanism.The methods introduced in this article do not need redox reagents,use simple undivided cell,cheaper and non-toxic carbon electrodes,completed in short time under mild conditions,with wide substrate range and fewer by-products,realize the cross-coupling of aryl halides and phosphines as well as the selective monoreduction of imides under electrochemical conditions,therefore offer alternatives to conventional methods and provide efficient tools for C-P bonds formation and C-O bonds cleavage and have potential application values in the field of drug synthesis.