Using The Cascade Reaction To Build Different Quinoline And Indole Compounds

In the last decade, diversity-oriented synthesis (DOS) has been widely used to efficiently generate diverse small molecules. It 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 employed in diversity-oriented synthesis, tandem reactions are very attractive processes that push the limits of synthetic efficiency by using more than two reactants to create novel products with an optimal number of new bonds and functionalities. These reactions are ideally suited for the construction of natural product-like libraries prone to display biological activity.Meanwhile, it is well-known that the isoquinoline and isoindole skeletons are found in many natural products and pharmaceuticals that exhibit remarkable biological activities. Due to their great importance as substructures in a broad range of natural products as well as synthetic intermediates in total synthesis of natural alkaloids, significant effort continues to be given to the development of new methods for their construction.The thesis is mainly focused on the diversity-oriented synthesis (DOS)-based tandem reactions for the generation of diverse natural product-liked small molecule compounds such as isoquinoline and isoindole derivatives as well as "privileged structure" chemical libraries used for new drug and pesticide pilot study.In Chapter1, the development of diversity-oriented synthesis (DOS) and its application for construction of natural product-like libraries are introduced.In Chapter2, tandem reactions which generate the isoquinoline derivatives are described. Three-component reactions of2-alkynylbenzaldehydes, amines, and indoles catalyzed by AgOTf under mild conditions afford the1-(1H-indol-3-yl)-1,2-dihydroisoquinolines in good yields. The combination of AgOTf and Dy(OTf)3shows high efficiency as a catalyst in the tandem reactions of N’-(2-alkynylbenzylidene)hydrazides with indoles, which generate the unexpected1-(indol-3-yl)-2-aminoisoquinolinium triflates in good yields. Cu(OTf)2or Pd(OAc)2-catalyzed reactions of N’-(2-alkynylbenzylidene)hydrazides with diethyl phosphite, offering an unprecedented and straightforward route for the synthesis of isoquinolin-1-ylphosphonate or2-amino-1,2-dihydroisoquinolin-1-ylphosphonate. Three-component reactions of2-alkynylbenzaldehyde, sulfonohydrazide, with dimethyl cyclopropane-1,1-dicarboxy late co-catalyzed by AgOTf and Ni(C104)2·6H20afford2,3,4,11b-tetrahydro-1H-pyridazino[6,1-α]isoquinolines in moderate to good yields. CuX2-mediated cyclization of2-alkynylbenzaldehyde O-methyl oximes in DMA gave rise to4-chloroisoquinolines in good yield, which underwent the Pd-catalyzed cross-coupling reactions of arylboronic acids subsequently to afford the functionalized isoquinolines. Subsequent biological assays discover that some of isoquinoline compounds exhibit promising biological activities for inhibition of HCT-116and PTP1B.In Chapter3, tandem reactions based on N-(2-alkynylbenzylidene)hydrazide which generate the H-pyrazolo[5,1-a]isoquinolines are described. A AgOTf-catalyzed tandem reaction of N’-(2-alkynylbenzylidene)hydrazide with silyl enolate is described, which generates the unexpected H-pyrazolo[5,1-a]isoquinolines in good to excellent yields. We introduce an amino group in the scaffold for its elaboration with an expectation for finding better hits in the assays. A three-component reaction of2-alkynylbenzaldehyde, sulfonohydrazide, and nitrile catalyzed by AgOTf under mild conditions is reported, which generates pyrazolo[5,1-a]isoquinolin-2-amines in good to excellent yields. A novel and efficient route for the generation of H-pyrazolo[5,1-a]isoquinolines via AgOTf-catalyzed one-pot tandem reaction of2-alkynylbenzaldehyde, sulfonohydrazide, and ketone or aldehyde is described. For generation of the diverse H-pyrazolo[5,1-a]isoquinoline library, we explore a multi-component reaction of2-alkynylbenzaldehyde, sulfonohydrazide, electrophile (bromine or iodine), and ketone or aldehyde under mild conditions proceeds smoothly to afford the functionalized H-pyrazolo[5,1-a]isoquinolines in good yields. Subsequent biological assays discover that some of H-pyrazolo[5,1-a]isoquinoline compounds exhibit promising biological activities for inhibition of CDC25B, TC-PTP, and PTP1B.In Chapter4, diverse2H-isoindol-1-ylphosphonates as potential HCT-116inhibitors are easily generated via FeCl3and PdCl2co-catalyzed three-component reaction of2-alkynylbenzaldehyde, amine, and phosphite. The focused small library is constructed as well based on parallel diversity-oriented synthesis.