Br(?)nsted Acid-catalyzed C6 Functionalization Of Indoles

Indoles are crucial and prevalent structural units in natural products,pharmaceuticals and materials.Therefore,the synthesis of functionalized indoles has attracted considerable attention and has been developed.The C-H functionalization of indoles is efficient and straightforward strategy for synthesizing indole derivatives.Due to the inherent activity of the pyrrole ring,the C-H functionalization usually occur at the C2 and C3 positions of indoles.On the contrary,the C-H functionalization at the low active C4-C7 positions of the fused benzene ring is challenging.Owing to the C6 position is an electrically neutral site and far away from the usual guide sites,the C6 functionalization of indoles could be regarded as an extremely challenging task.In this dissertation,the synthesis of indole derivatives by C6 functionalization of indoles and electrophiles has been studied using the Br?nsted acids as catalysts.(1)A facile method for the synthesis of pyrrolo[2,3-j]phenanthridines from indoleanilines and aldehydes in the presence of p-toluenesulfonic acid catalyst and benzoquinone oxidant has been established,and with up to 96% yield.A series of aromatic and aliphatic aldehydes were suitable.This reaction could be conducted on gram scale without loss of reactivity.(2)Fluoro-substituted chiral phosphoric acid-catalyzed the direct regio-and enantio-selective C6 functionalization of 2,3-disubstituted indoles with azadienes has been developed,optically active hetero-triarylmethanes could be prepared with broad substrate scope,up to 98% ee and99% yield.Mechanistic studies revealed that N-alkylation of indoles with azadienes could be reversible,and enantioselective C6 functionalization could be enabled.In addition,the gram scale reaction could proceed smoothly without loss of yield and enantioselectivity.(3)Using Br?nsted acid as catalyst,2,3-dichloro-5,6-dicyano-4-benzoquinone as oxidant,the direct C6 oxidation coupling of 2,3-disubstituted indoles with 2,2-diarylacetonitriles has been realized,giving the indole derivatives bearing cyano-substituted all-carbon quaternary centers with up to 96% yield.Control experiments suggested that this process involves C-H oxidation of 2,2-diarylacetonitriles to in situ generate δ,δ-disubstituted p-quinone methide intermediates.The synthetic utility was demonstrated by the divergent transformation of cyano-substituted products to valuable compounds including aldehyde,primary amine and amide.In conclusion,the Br?nsted acid-catalyzed direct C6 functionalization of indoles was successfully developed,providing straightforward route for the synthesis of 6-substituted indole derivatives and further enriching the C6 functionalization reactions of readily available indoles.