Radical-based Tandem Reactions For Synthesis Of 3-bromomethyl-3,4-dihydroisocoumarin And Quinoline Heterocyclic Compounds

Radicals are important intermediates in organic synthesis.The reactions involving radical species have the advantages of mild reaction conditions,good functional group tolerance and high product yields,which have made radical reactions an indispensable tool for synthetic chemists.In this thesis,bromine radicals were generated by visible light catalysis,which underwent addition/cyclization reactions with olefins to synthesize 3-bromomethyl-3,4-dihydroisocoumarin compounds.Nitrogen radical cations were generated by copper catalysis,which promoted the oxidative tandem reaction of arylglycine esters with enamines to simultaneously synthesize quinolines and gem-diamine derivatives.This thesis developed two green,environmentally friendly,mild and efficient methods for the construction of heterocyclic compounds.Visible light,as an important part of sunlight,is a rich,green,clean and sustainable energy source.Visible-light-catalyzed reactions use visible light to provide energy,and generate radical intermediates through single electron transfer,energy transfer,or hydrogen atom transfer.Through a series of conversions,these radical intermediates can achieve the construction of the target products.Visible-light-catalyzed reactions can provide green,environmentally friendly,simple and efficient alternative methods for some harsh,complicated,highly toxic and dangerous reactions.The second chapter of this thesis concentrates on the synthesis of3-bromomethyl-3,4-dihydroisocoumarin compounds through addition/cyclization of2-allyl benzaldehydes with bromine radicals generated by visible light catalysis.3,4-Dihydroisocoumarin is the basic skeleton in many alkaloids and natural products.Many compounds containing 3,4-dihydroisocoumarin skeleton exhibit various biological activities,such as antibacterial,anticancer,antifungal,and antimalarial.2-allyl benzaldehyde and diethyl dibromomalonate were chosen as substrates for the model reaction.In order to find the best reaction conditions,the types and loading of photocatalysts,solvents,light sources,molar ratio of substrates,types and loading of additives were screened.With the optimized conditions in hand,substrate scope of the reaction was studied.A series of substituted 3-bromomethyl-3,4-dihydroisocoumarin compounds were obtained in moderate to good yields.A plausible mechanism involving energy transfer was proposed for this reaction based on control experiments,light on/off experiment,fluorescence quenching experiments,cyclic voltammetry and radical trap experiments.The work in this chapter provides a simple and mild method for the synthesis of 3-bromomethyl-3,4-dihydroisocoumarin compounds.Copper is an efficient redox agent,which can oxidize or reduce radical precursors through single electron transfer to generate active radical intermediates.Controlling these radical intermediates in further conversions can construct complex molecules.At present,copper-catalyzed reactions have successfully achieved the construction of C-C,C-N,C-O,C-S and C-P bonds.Compared with other transition metal catalysts,copper catalysts have the advantages of mild,low-cost,low toxicity and good tolerance.Therefore,copper catalysts can be used as a better alternative to some highly toxic,expensive and dangerous catalysts.In the third chapter of this thesis,nitrogen radical cations were generated by copper catalysis,which promoted the oxidative tandem reaction of arylglycine esters and enamines to achieve simultaneous synthesis of quinolines and gem-diamine derivatives.The quinoline framework is present in a quantity of biologically active natural products and synthetic drugs.Many compounds containing a quinoline backbone exhibit a variety of activities,including antibacterial,anticancer,anti-HIV,anti-inflammatory,and anti-tuberculosis.gem-diamine derivatives is an important scaffold present in a number of biologically active molecules,such as inhibitors of HIV-1 protease,antimicrobial agent and E.Coli inhibitor.Ethyl p-tolyl glycinate and N-(1-phenylvinyl)acetamide were chosen as substrates for the model reaction.Types and loading of catalysts,solvents,temperature,molar ratio of substrates were screened to find the optimized conditions.With the optimized conditions in hand,substrate scope of this reaction was studied.A series of substituted quinolines and gem-diamine derivatives were obtained in moderate to good yields.A plausible mechanism involving imine ion intermediates was proposed for this reaction based on control experiments.In this reaction,two fragments of one reactant each react with the same intermediate generated in situ by another reactant,simultaneously producing two valuable products,which is not only efficient,but also environmentally friendly.