Electrochemically Oxidized Enantioselective Alkylation Of Indoles And Intramolecular Tandem Cyclization Involving Oxime Radicals

As a green and environmentally friendly synthetic method,organic electrochemical synthesis utilizes"green"electrons to replace traditional redox agents,which accords with the concept of green chemistry.In addition,compared to traditional synthetic methods,organic electrochemical synthesis has unique and flexible controllability.And it can control the chemo-selectivity and reaction rate by adjusting the potential or current.Therefore,organic electrochemical synthesis has made great progress in recent decades.However,in the field of asymmetric electrochemical synthesis,although there have been many attempts,most reported enantioselectivity is not high.The reason is that intermediates such as cationic radicals and anionic radicals produced by electrochemical redox are often difficult to control due to their high activity,which affects the yield and enantioselectivity of the target product.In addition,the interaction of the electrolyte and the instability of redox cause the chiral catalyst to be incompatible with the reaction conditions.Therefore,it is of great significance to develop organic electrochemical synthesis with high enantioselectivity.The C2 quaternary indole-3-one skeleton is widely present in natural products and pharmaceutical molecules.Therefore,the construction of C2 quaternary indole-3-one compounds has been a research hotspot for synthetic chemists.However,there are few successful examples of highly enantioselective synthesis of C2 quaternary indol-3-ones.Moreover,electrocatalytic synthesis of such compounds has not been reported.Therefore,we have developed a combination of electrochemical synthesis and organic catalysis to construct highly enantioselective C2 quaternary indole-3-one compounds.The chapter one is introduction.The first part briefly summarized the concept,development history,and advantages of organic electrochemical synthesis,and briefly introduced indirect electrochemical oxidation.The second part summarized the research progress of asymmetric organic electrochemical synthesis from three aspects:chiral catalysts（organic catalysts,metal catalysts and enzymes）,chiral media（chiral solvents,chiral electrolytes）and chiral electrodes.The third part briefly summarized the structure and properties of TEMPO,and summarized the application of TEMPO in organic synthesis.Finally,the basis and significance of the research of this thesis are expounded.In the second chapter of this thesis,the combination of electrochemistry and proline catalysis was used for asymmetric alkylation of indoles to construct chiral C2 quaternary carbon indol-3-one compounds.First,2-phenylindole and cyclohexanone were selected as substrates for the model reaction,and L-proline was selected as the organic catalyst.The reaction conditions were optimized under constant current（including mediums,solvents,electrolytes,substrate molar ratios,electrode materials,current and additives,etc.）.After obtaining the optimal conditions,the compatibility of the substrates was investigated,and 28 2,2-disubstituted indole-3-one compounds were obtained with moderate to good yields and excellent enantioselectivity,of which the enantioselectivity reached 99%ee and the diastereomer ratio was higher than 20:1.It is worth mentioning that when L-proline was replaced with D-proline,the enantiomeric product with the opposite configuration was obtained.Through a series of mechanism exploration experiments including free radical capture experiments,blank control experiments,cyclic voltammetry studies,isotope ¹⁸O labeling experiments and intermediate verification experiments,two possible reaction mechanisms were proposed.In the third chapter of this thesis,simple and easily availableγ,δ-unsaturated ketoxime and radical trapping agent TEMPO were used as substrates of the model reaction.Oxime radicals were generated under electrochemical conditions,which realized the synthesis of cyclic nitrone compounds through intramolecular tandem cyclization reaction.After preliminary condition screening（solvents,electrolytes,substrate molar ratios and temperatures,etc.）,the cyclic nitrone compound was obtained in 58%yield.In addition,through preliminary mechanism exploration,it was speculated that TEMPO not only serves as a substrate but also as a reaction medium in the reaction,and a possible mechanism was proposed accordingly.