Theoretical Study On C4 Functionalization Of 3-substituted Indoles Catalyzed By Transition Metals

Based on the experimental works of transition metal-catalyzed(Pd(?)or Rh(?))C4-functionalization(fluoroalkylation or alkenylation)of indole with various carbonyl directing groups at C3 site,we have proposed some possible catalytic mechanisms and performed detailed theoretical study on them.The main research contents include the exploration of the role of the acid additive in the reaction,the influence of different directing groups in substrates on the yield of the reaction and the correlation between the electronic effect of directing groups and 2,4-regioselectivity of indole.In the first chapter,firstly,we have briefly introduced the wide application of indoles and the development of their synthesis and functionalization.In the second chapter,we have introduced basic knowledge of quantum chemistry,including computational methods and basis set as well as the other analysis tools used in this dissertation.In chapter 3,based on the experimental report of palladium(Pd(?)catalyzed C4-fluoroalkylation of 3-acetylindole,the possible mechanism was proposed and performed via density functional theory to explain the role of additives(trifluoroacetic acid,TFA)and the control of the 2,4-regioselectivity in the functionalization of indole in the reaction process.The results suggest that the additive TFA is mainly used to form new palladium catalyst(such as Pd(TFA)₂).For this new catalyst Pd(TFA)₂,firstly,it could reduce the activation energy,which make the reaction easy to proceed.This feasibility is attributed to the strong electron withdrawing ability for ligand TFA.At the same time,this new catalyst could strengthen the difference of the nucleophilicity between C2 and C4 sites in 3-acetylindole substrate,which could make the regioselectivity easier to achieve.Therefore,this new type of catalyst based on additives not only makes the whole reaction easier to carry out,but also makes the 2,4-regioselectivity easier to realize,with dual roles.In chapter 4,based on the experimental report of the C4 fluoroalkylation of 3-substituted indoles catalyzed by palladium(Pd(?)),the influence of directing group on the yield of the reaction is attributed to the higher energy barrier of 3-formylindole in C-H activation process compared to 3-acetylindole substrate,which is consistent with the experimental observation.According to various analysis methods including Natural Population Analysis(NPA),transfer electron density(e),and activation strain model(ASM),we have found that the electron density of the reaction site in 3-formylindole substrate was small and the corresponding reactivity was relatively lower relative to 3-acetylindole.In chapter 5,based on the experimental work of the transition metal rhodium(Rh(?))catalyzed C4-alkenylation of 3-formylindole,the possible mechanism was proposed and performed density functional theory to explain 2,4-regioselectivity,which was attributed to the different nucleophilicity difference between C2 and C4 sites reduced by the electronic effect of the directing groups.Based on these results,we have further studied the correlation between the 2,4-regioselectivity of indole substrate and the electronic effects of a series of different directing groups(such as COCF₃,CHO,COMe,CONHMe,COOH),which are helpful for the study of the indole derivate.