Application Of Transition-Metal Catalysis In Indole Derivatization And Aza-indole Directed Synthesis

Indole is an important nitrogen-containing heterocyclic structure in organic chemistry,natural products and medicines.In the past few decades,transition-metal-catalyzed C-H bond activation has been widely used in the indole derivatization to construct C-C,C-N,C-O and C-X（X=F,Cl,Br,I）bonds.Among them,directed C-H bond activation using appropriate directing group（DG）is a reliable strategy to realize regioselective functionalization of indoles.This dissertation focuses on regioselective functionalization of indoles or aza-indole directed C-H bond activation via transition-metal catalysis,including indole amination and deuteration as well as aza-indole directed alkylation and alkenylation.These studies mainly include the following three parts.Part I.Rh-catalyzed synthesis of diverse indole derivatives.We present herein the Rh-catalyzed regioselective C–H amidation of N-methoxy-1H-indole-1-carboxamides by 1,4,2-dioxazol-5-ones.N-methoxy amide,the directing group（DG）of interest,undergoes four different transformations through DG-retained,-coupled,-eliminated,or-migrated processes under moderately varied reaction conditions.Solvents,additives and temperature play important roles in these selective transformations:A trace addition of water favors the functional group（FG）-assisted DG elimination;Extra addition of K₂S₂O₈ greatly enhances the formation of DG-coupled product;High temperature and proper FG together can shift the position of DG through intermolecular Friedel-Crafts-like acylation.The catalytic mechanisms underlying these reactions were further investigated through DFT calculations and experimental studies including the characterization of amido-inserted rhodacycle.An overall catalytic pathway was proposed to illustrate the reactions involved in the regioselective amidation of N-methoxy-1H-indole-1-carboxamide.Part II.Regioselective deuteration of indoles via transition-metal catalysis.We present herein the highly effective regioselective direct C–H deuteration of indole in D₂O using Cp*Co（CO）I₂,[Cp*Rh Cl₂]₂,or their combination as the catalyst.This transition-metal-catalyzed system made available mono（C2）-,di（C2/C7）-,tri（C2/C3/C7）-,and even C4-deuterated products from diverse indole substrates,equipped with the removable N1-directing group.The selective H/D exchanges on the rest sites of indoles were also realized by shifting the directing group.Furthermore,an example of this approach was demonstrated to acquire deuteromelatonin from the drug melatonin.Part III.Pd-catalyzed C（sp³）-H bond activation using 7-azaindole as the directing group.We present herein the Pd-catalyzedγ-C（sp³）-H selective alkylation and alkenylation with removable 7-azaindole as a directing group.Acid and base were found to be the decisive regulators for the selective alkylation and alkenylation on the same single substrate,respectively,under otherwise the same reaction conditions.Various acrylates were compatible for the formation of C（sp³）-C（sp³）and C（sp³）-C（sp²）bonds.The alkenylation protocol could be further extended to acrylates with natural product units andα,β-unsaturated ketones.The preliminary synthetic manipulation of the alkylation and alkenylation products demonstrates the potential of this strategy for structurally diverse aliphatic chain extension and functionalization.Mechanistic experimental studies showed that the acidic and basic catalytic transformations shared the same six-membered dimer palladacycle.In conclusion,a regioselective amination and deuteration of indole via transition-metal-catalysis was realized,andγ-C（sp³）-H selective alkylation and alkenylation using 7-azaindole as a directing group was achieved.These strategies expand the application of C-H bond activation in indole functionalization and azaindoles as directing groups,which may encourage researchers to develop more promising transition-metal-catalyzed synthetic methods.