Copper-Catalyzed Synthesis Of Indole Derivatives

The indole subunit represents one of the most abundant and important heterocycles in nature,found in neurotransmitters such as serotonin and complex alkaloids such as the clinically used chemotherapeutic agent vinblastine.In particular,indole scaffolds are generally utilized as"privileged structures" for drug discovery and development,pharmaceuticals and agrochemicals,and advanced organic functional materials.Numerous substituted indoles display a wide range of biological and therapeutical activities,therefore,a variety of powerful methods have been well established for the construction of indole scaffold over the last hundred years.The development of new,more efficient and atom economical methods is still highly desirable.Among the various transition-metal catalysis,copper-mediated Ullmann-type C-heteroatom and C-C cross-coupling reactions have emerged as one of the most powerful routes for the synthesis of indoles and received increased attention in the synthesis of structurally diverse heterocycles due to their atom-and step-economy attractiveness.Merging fundamentally different copper catalysis into one operation is no doubt very challenging,however,such sequential one-pot process would provide a straightforward and ideal method for the synthesis of heterocycles.Herein we report a one-pot synthesis of multisubstituted indoles through a sequential Cu-catalyzed intermolecular Ullmann-type C-N formation and intramolecular cross-dehydrogenative coupling.Iodobenzene and ethyl(Z)-3-amino-3-phenylacrylate were selected as the coupling partners for a copper-catalyzed synthesis of indole.Extensive experiments were conducted in the presence of different ligands for the copper catalyst,bases,solvents,and reaction time.In general,Johnphos(35 mol%)for CuI(10 mol%)was found to be the best catalyst system with KHCO3 as the base in DMSO at 130 ℃ for 48 h,providing the desired product in 88%yield.With the optimized reaction conditions in hand,the scope and generality of the present process were then explored.Twenty-five different indoles were synthesized and characterized.(1)Aryl halides smoothly underwent the cyclization to afford the desired products.The yield for the aryl halide substrates follows the order aryl iodide>aryl bromide>aryl chloride.(2)For the para-and orrtho-substituted aryl iodides,both electron-donating and-withdrawing groups were tolerant under the reaction conditions and afforded the corresponding indole derivatives in good to excellent yields(60-90%).(3)When meta-substituted aryl iodides were used,regioselectivity issues surfaced in the cross-dehydrogenative coupling process,and a mixture of two regioisomers was obtained(from 1:1 to 1:1.7).(4)A great variety of ethyl(Z)-3-amino-3-arylacrylate can be smoothly converted into the corresponding indole products in good to high yields(65-81%)and the electronic nature of the aromatic motifs does not seem to affect the efficiency of this transformation.To gain insight into the mechanism of the reaction,some designed control experiments were conducted.On the basis of the results,a plausible catalytic cycle for the synthesis of indoles was proposed.The initial step involved Ullmann-type C-N coupling process,affording N-arylated intermediate,which was then transformed into indole product through Cu(I)-catalyzed cross-dehydrogenative coupling.The method for the synthesis of indoles has the advantages of simple operation,cheap catalyst,practicality and high efficiency.It is a new entry to the metal-catalyzed synthesis of nitrogen-containing heterocyclic compounds.The result presented here could be of considerable interest of the valuable synthetic building blocks for medicinal science.