Palladium-Catalyzed C-H Arylation Of Pyrimidine Indoles

Indoles are one of the most important heterocyclic compounds that widely exist in nature and medicine,food,spices,dyes,pesticides,and materials.Due to their unique biological and pharmacological activities,they play an important role in the field of new drug discovery and development.The characteristics of indoles with low toxicity and high biocompatibility make them have good binding ability with many receptors.They are a dominant framework for drug development.Scientists have conducted extensive and in-depth research on them.Through structural modification and optimization,many marketed drugs have been developed,such as antiviral,antibacterial and antifungal,anticancer,anti-inflammatory,antimalarial,antidepressant,and COX-2 inhibitors.Due to important value and broad application,in recent years,synthetic methods based on the transition metal-catalyzed cross-coupling reaction for the modification of indole skeleton through C-H bond functionalization to efficiently form C-C bond,have received widespread attention.In this paper,N-methyl-3-(2-morpholine pyrimidin-4-yl)indole and iodobenzene were selected as the starting substrates to synthesize 2-aryl indoles through palladium acetate catalyzed C-H activation at the 2-position of indole.A synthetic method with high atomic economy,high efficiency,and wide substrate application was developed for the structural modification of indole.Firstly,the effect of various factors such as catalyst,ligand,additive,and base on the reaction have been examined.After screening and optimizing the conditions,the standard conditions for the template reaction were obtained: under nitrogen conditions,palladium acetate(30 mol%)as the catalyst,triphenylphosphine as the ligand,silver carbonate as the additive,sodium carbonate as the base,and 1,4-dioxane as the solvent,the yield of the reaction reached 91% at 120 ℃ for 24 hours.On this basis,this paper synthesized 25 diverse indoles by changing the substituent groups,and investigated the scope and limitations of this reaction.The experimental results show that:(1)The reaction has a good generality with the yield of indole products ranging from 7% to 91%;(2)The scope of aryl iodides in the reaction is greatly affected by steric hindrance.Meta and para-substituted iodobenzenes are well tolerated,while ortho-substituted iodoarenes cannot undergo such reactions.For meta or parasubstituted aryl iodides,the reaction can happen smoothly regardless of whether the substituent is an electron-donating group(such as alkyl)or an electron-withdrawing group(such as halogen,nitro,cyano,etc.),and the yield is in the range of 34% to 90%;(3)When the amine moiety linked to the pyrimidine ring in the structure of the N-methyl-3-(2-morpholine pyrimidin-4-yl)indole substrate changes,the reactive activity of substrate decreases,and the yield of obtained indole products is between 7% and 51%;(4)The C-H bond arylation of indole derivatives at the 2-position has been realized in the high atomic economy and step economy manner,thus adding a novel tool through Pd-catalyzed C-H bond functionalization to construct indole-containing compounds.