Visible-Light Catalyzed Indole Alkylation Reactions

Visible light is considered as an ideal reaction condition as an environmentally friendly and renewable energy source in the green organic chemistry.However,the type of reactions catalyzed by visible light is limited,and photocatalytic asymmetric synthesis is a difficult and arduous challenge.This is due to that the important intermediates in the reaction pathway are free radicals(ions)which are highly active and have short lifetimes,so it is difficult to control the stereoselectivity of the visible light catalytic reaction.In recent years,double catalytic strategies which combined visible light catalysis and other catalysis have been used to extend the range of photocatalytic reactions and achieve photocatalytic asymmetric reactions.The fragments of indole are widely found in natural products and drug structures,and indole derivatives have a wide range of biological activities.Therefore,the structural modification of indoles,especially the asymmetric alkylation of indoles is of great significance in drug development,chemical engineering,and basic research.This thesis mainly focuses on visible light photocatalyzed alkylation of indoles,including the alkylation reaction of indoles with tertiary amines as a carbon source,the enzyme/visible light catalyzed asymmetric alkylation of indoles,and the amino acid/visible light catalyzed asymmetric alkylation of indoles.3-Alkyl indole is the basic structural skeleton of many natural products and drugs.The use of tertiary amines as a carbon source to achieve 3-position alkylation of indole is a novel method for efficiently synthesizing indole derivatives with medicinal value.In the second chapter of this thesis,we studied the alkylation of indoles with tertiary amines as a carbon source catalyzed by organic dye rose Benganl under visible light irradiation.Nineteen 3-arylmethyl indole derivatives were successfully synthesized with yields of up to 70% through the reaction between N,N-dialkylanilines and various substituted indoles,The reaction has wide applicability and good compatibility of functional groups.On the basis of control experiments,we proposed a possible reaction mechanism.This is the first report that photocatalytic oxidation of tertiary amines can be used to synthesize 3-arylmethyl indole derivatives,in which tertiary amines are used as carbon source to construct C-C bond.In the third chapter of this thesis,we studied the asymmetric alkylation of 2-phenylindole derivatives with ketones using wheat germ lipase as a chiral catalyst and ruthenium complexe as a photosensitizer.The oxindole derivatives with enantioselective quaternary carbon center were successfully constructed under irradiation of visible light.We first verified the compatibility of wheat germ lipase catalysis and visible light catalysis.We then systematically studied the influence of the type of enzymes,photosensitizers,solvents,enzyme amount,photosensitizer loading,water content,pH value,molar ratio of substrates,solvent volume,light source and temperature on the reaction.The reaction conditions were optimized and substrate adaptability was investigated under optimal reaction conditions.19 oxindole derivatives were successfully synthesized with yields of up to 70% and enantioselectivities of up to 85% ee.To understand the reaction mechanism,the experiments of control experiments,enzyme inhibition and inactivation were conducted.On the basis of these experiments,a possible mechanism was proposed.This work for the first time innovatively combined the non-natural catalytic activity of the enzyme with visible light catalysis,and successfully achieved asymmetric alkylation of 2-phenylindole derivatives.In view of the unsatisfactory yield and enantioselectivity of the asymmetric alkylation of 2-phenylindole derivatives with ketones in the previous chapter,in order to seek better results,we conducted the work presented in chapter 4.After extensive experimentation,we found that the dual catalytic system of L-proline/visible light can catalyze the asymmetric alkylation of indoles.Systematic condition screening was conducted to optimize the reaction conditions such as solvent,photosensitizer,photosensitizer loading,proline loading,and molar ratio of substrates.After optimizing the conditions,2,2-disubstituted indolin-3-ones were successfully obtained with yields of up to 80% and enantioselectivities of up to 99% ee.The research in this thesis provides novel green synthetic methods for the alkylation of indoles,which is a useful supplement to the existing methods.