Synthesis Of Isoquinoline And Indole Compounds By Tandem Reaction

Diversity-oriented synthesis (DOS) is a breakthrough in the thought of chemical synthesis, which is overlapped and penetrated by chemical biology, combinatorial chemistry and medicinal chemistry. Among the strategies utilized in diversity-oriented synthesis, tandem reaction is highly characterized by simple operation, outstanding resource utilization and atom economy; which can greatly reduce the operation procedures as well as build up the structural diversity of compounds. Meanwhile, it is well-known that the isoquinoline and indole skeletons are found in many natural products and pharmaceuticals that exhibit remarkable biological activities. This thesis is mainly focused on the tandem reactions for the generation of isoquinoline and indole derivatives.The dissertation is divided into five parts.Chapter one introduces the development of diversity oriented synthesis briefly.In chapter two, tandem reactions of N'-(2-alkynyl-benzylidene)hydrazides with dimethyl acetylenedicarboxylate (DMAD) or terminal alkynes are described. The unexpected isoquinoline-based azomethine ylides were obtained when the reaction of N'-(2-alkynylbenzylidene)hydrazide with DMAD was catalyzed by AgOTf or in the presence of bromine, while the fused 1,2-dihydroisoquinolines were afforded when iodine was employed in the above tandem reactions. Additionally, N'-(2-alkynylbenzylidene)hydrazide reacted with terminal alkynes catalyzed by AgOTf or in the presence of electrophile leading to H-pyrazolo[5,1-a]isoquinoline in good yields. The halide-containing products could be further elaborated by palladium-catalyzed cross-coupling reactions.In chapter three, a three-component reaction of N'-(2-alkynylbenzylidene)-hydrazide,?,?-unsaturated aldehyde, and MeOH co-catalydzed by AgOTf and N-heterocyclic carbene (NHC) is presented, which produces 2-amino-1,2-dihydroiso-quinolines with high efficiency. Subsequently, based on the above results, a multicomponent reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, alcohol, and a,?-unsaturated aldehyde or ketone catalyzed by AgOTf or in the presence of an electrophile is discovered. Preliminary biological assays showed that some of these compounds display promising activities as CDC25B inhibitor, TC-PTP inhibitor, and PTP1B inhibitor.In chapter four, an efficient tandem reaction of 2-alkynylbenzaldoximes with isocyanides co-catalyzed by AgOTf and Bi(OTf)3 is illustrated, which affords the unexpected N-(isoquinolin-1-yl)formamide in good to excellent yields. The iodo-or bromo-containing products can be obtained as well by variation of the reaction conditions, which may undergo further elaboration via known palladium chemistry.The last chapter describes a Copper(?)-catalyzed three-component reaction of 2-ethynylaniline, sulfonyl azide, and nitroolefin. The reaction generates functionalized indoles in good yields and proceeds smoothly under mild conditions. Furthermore, some hits as HCT-116 inhibitor are found from the preliminary biological screening.