Photoenolization/Nucleophilic Addition Synthesis Of 3-alkyl-3-hydroxyindole-2-one And Paired Electrolytic C(sp~3)-C(sp~3) Radical Cross Coupling To Construct Of New C-C Bond

Radicals,as highly reactive intermediates in synthetic chemistry,have been paid more and more attention over the past decades.When radicals were first recognized,they were rarely studied because of their unique electronic unsaturation,high energy,strong chemical activity,instability and uncontrollability during the reaction process.With an increasing number of more profound researches on radical chemistry reported,it is found that these intermediates can exhibit good selectivity under suitable reaction conditions.Besides,considering its high activity,radicals can undergo substitution reactions,addition reactions,elimination reactions,redox reactions,radical-radical couplings and other reactions with milder conditions.In addition to the high activity of free radicals,which is difficult to control,another dominant factor hindering the growth of radical chemistry is that radicals species are difficult to generate.Traditional methods for radical formation typically require harsh reaction conditions,such as high temperatures or ultraviolet light irradiation.Up to now,the situation of radicals is much better and has been transformed from chaotic to alive and efficient with the development of photocatalysis,electrocatalysis and transition metal catalysis.This thesis describes the photoenolization/nucleophilic addition synthesis of3-alkyl-3-hydroxyindole-2-one and paired electrolytic C(sp~3)-C(sp~3)radical cross coupling to construct new C-C bond.The first chapter summarizes the light-mediated organic chemical reactions,the organicreactionmediatedbyphotoenolationintermediate hydroxy-o-benzocarbaquinone,the electrosynthetic organic chemical reactions,free radical cross-coupling reactions,the foundation of our research and the significance of our subject.The most crucial characteristic of the photoenolization intermediate hydroxy-o-quinodimethanes must be their high activity and strong nucleophilicity.Besides,they can be combined with many electrophiles to synthesize various complex organic compounds which are hard accessiblethrough other methods.In terms of the special biological activity of 3-alkyl-3-hydroxyindole-2-one derivatives and their structural ubiquity in natural products and drug molecules,we studied the synthesis of3-alkyl-3-hydroxyindole-2-one derivatives via the reaction between photoalkenolization intermediate and isatin in the second chapter of this thesis.We attempt to construct3-alkyl-3-hydroxyindole-2-one in one step by making use of the strong nucleophilicity of the photoenolization intermediate and the electrophilic C3 of isatin.First,we chose2-methylbenzophenone and isatin as substrates for the model reaction,and the optimized reaction conditions were obtained through the screening of reaction solvent,feed ratio and light source.Then,the substrate scope was investigated under the optimized conditions,and we successfully realized the efficient synthesis of3-hydroxy-2-oxindole derivatives possessing excellent biological activity with the highest yield up to 98%.It is noteworthy that all of the products were reported for the first time.By screening a series of chiral small molecule catalysts,we found that a chiral urea-based small molecule catalyst realized the asymmetric synthesis of such compounds(ee up to 78%).The control experiment showed that the reaction might involve energy transfer between the photocatalyst and the model substrate.In order to further explore the reaction mechanism,deuterization experiment was carried out to explore the photochemical reactivity of substrate 2.2.The deuterization of ortho methyl group in 2-alkylbenzophenone was confirmed by ~1H NMR and HRMS,which further indicated that substrate 2.2 absorbed ultraviolet light and underwent the process of photoinduced enolization.Electrosynthesis is one of the most ideal methods to realize electron transfer under mild conditions.It employs cheap,clean and renewable electricity as the electron source to replace the traditional stoichiometric toxic and dangerous oxidants and reductants.Electrosynthesis is a mild,green and clean synthesis method because it is a traceless oxidation(anode)and reduction(cathode)agent,avoiding the side effects and by-products brought by external oxidant or reducing agent.In the third chapter,the methods of electrosynthesis of tertiary amine derivatives were studied.The reaction realizes radical cross-coupling process of C(sp~3)-C(sp~3)through the method of paired electrosynthesis.In order to verify the reaction mechanism,cyclic voltammetry experiments were first carried out.The experimental data showed that the medium DABCO was oxidized preferentially at the anode and the substrate imine was reduced preferentially at the cathode.Secondly,the radical inhibition experiment was carried out.When the free radical inhibitor was added,the reaction was completely inhibited,indicating that the reaction may involve free radical mechanism.Finally,the radical capture experiment was carried out,and the intermediate of nitrile methyl radical andα-amino radical was successfully captured by high resolution mass spectrometry(HRMS).Paired electrosynthesis can simultaneouslyorchestrate electrochemical anodic oxidation and cathodic reduction processes,and overcomes the problem of low current utilization.Since radicals feature high activity and short life span,the self-coupling reaction of radicals are difficult to avoid.As a result,it is extremely challenging to develop the cross-coupling strategy of paired electrosynthesis.After optimizing and adjusting various influencing factors in the reaction system,such as solvent,electrolyte,current,electrode,etc.,a cross-coupling strategy for paired electrosynthesis was successfully developed.This synthetic strategy is definitely a green and efficient way to introduce cyano groups and construct amines bearing tertiary carbons.