Palladium-Catalyzed C-H Arylation For The Synthesis Of Indole Derivatives

Indole is one of the most common nitrogen-containing heterocycles in nature,and its framework widely exists in natural compounds and drug molecules.Arylindoles have important physiological functions and excellent pharmacological activities such as antitumor,antiviral,antibacterial and antidepressant.Therefore,it is important to develop an efficient and novel method for the synthesis of aryl indole derivatives.In this thesis,the direct arylation of indole was investigated for the structural modification of indole through carbon-hydrogen bond functionalization.In this paper,arylindoles were synthesized from N-(p-toluenesulfonyl)indole by the Pdcatalyzed C-H arylation of indoles using iodobenzenes as the aryl reagents.The paper investigated the effect of ligands on the reaction and obtained the optimized conditions:palladium acetate as the catalyst(10 mol%),triphenylphosphine as the ligand(1.0 eq),sodium carbonate(2.0 eq)as the base,silver carbonate(2.0 eq)as the additive,and 1,4-dioxane as the solvent under 1 atm nitrogen atmosphere at 120 ℃ for 24 h,the corresponding products can be obtained in 93% yield.Based on the above result,the paper synthesized 27 arylindole derivatives by changing the structure of iodobenzene substrates,and further investigated the scope and limitations of the reaction.The experimental results showed that:(1)the reaction has good functional group tolerance,and the yields of the obtained products range from 22% to 93%;(2)when iodobenzene substrates are attached with different substituent groups,the electrondonating groups exhibit higher yields than the electron-wanting groups;(3)the reaction has excellent regioselectivity when 2-substituted iodobenzene substrates were used,only 2-aryl indole products can be formed.This thesis describes the possible pathways of Pd-catalyzed C-H arylation of indole to generate arylindoles.Firstly,palladium acetate coordinates with the direct group(sulfonamide)in the substrate to activate the 2-position C-H bond of indole,achieving the formation of aryl C-Pd bond under the action of base.The intermediate undergoes oxidative addition with aryl iodide to form a Pd(Ⅳ)intermediate.Then,silver carbonate promotes the departure of iodine anion from the Pd(Ⅳ)intermediate to form an active cationic intermediate,followed by reductive elimination to provide the target 2-aryl-1-p-toluenesulfonyl-1H-indole and palladium acetate.At this time,Pd(Ⅳ)was reduced to Pd(Ⅱ)to complete the catalytic cycle.Palladium acetate and 2-aryl-1-ptoluenesulfonyl-1H-indole continue to participate in the next cycle.In the next cycle,the 2-aryl-1-p-toluenesulfonyl-1H-indole product forms a C-Pd bond at the position 7 of indole,similar to the arylation process at the position 2 of indole.The 2,7-diaryl-1-p-toluenesulfonyl-1H-indole product and palladium acetate are generated through oxidation addition and reduction elimination steps.The palladium-catalyzed C-H activation of indole to generate aryl indole derivatives reported in this paper has the advantages of high efficiency,simplicity and high atomic economy,which opens up a new method for the synthesis of aryl indole derivatives.