Construction Of Several Small Molecule Composites By Diversity - Oriented Synthesis Strategy

Diversity-oriented synthesis (DOS) plays an important role in drug discovery, which is overlapped and penetrated by pharmaceutical chemistry, biological chemistry and combinatorial chemistry. The main goal of diversity-oriented synthesis is to generate diverse small molecules efficiently for High-Throughput Screening (HTS) in drug discovery process. For the atom economy and high efficiency, tandem reaction is one of the strategies employed in diversity-oriented synthesis to generate small molecules with structural diversity and complexity. This thesis mainly focuses on the tandem reactions for the generation of some privileged skeletons (isoquinolines, indenes, benzofurans and sulfonamides) which exhibit remarkable biological activities.Firstly, a dual-activation system that combined metal catalysis (AgOTf) and organocatalyst (PPh3) has been successfully employed in the three-component reaction of2-alkynylbenzaldehydes, amines, and α,β-unsaturated carbonyl compounds. This reaction proceeded smoothly under mild conditions, leading to the functionalized1,2-dihydroisoquinolines in moderate to good yields. Next, a silver triflate-catalyzed three-component reaction of2-alkynylbenzaldehydes, sulfonohydrazide, and α,β-unsaturated carbonyl compounds to generate H-pyrazolo[5,1-α]isoquinolines was reported. In the meantime, a three-component reaction of2-alkynylbenzaldoximes, α,β-unsaturated carbonyl compounds with electrophilic reagents was described, which generated the unexpected isoquinoline derivatives in good to excellent yields. Moreover, a tandem reaction of2-alkynylbenzaldoximes and carbodiimides catalyzed by AgOTf or involved with electrophilic reagents to generate1-aminoisoquinolines was developed.Secondly, a palladium catalyzed tandem reaction of2-alkenylphenylacetylenes in the presence of CuCl2or CuBr2generated1-methyleneindenes, which could be further elaborated via palladium-catalyzed cross-coupling reactions. The1-methyleneindenes could be also synthesized via a palladium-catalyzed tandem reaction of1-(2,2-dibromovinyl)-2-alkynylbenzenes with arylboronic acids. This reaction proceeded under mild conditions with high efficiency and excellent selectivity. The palladium-catalyzed reaction of1-(2,2-dibromovinyl)-2-alkenylbenzenes with arylboronic acids was explored as well, which generated the functionalized1-methyleneindenes in good yields. In this transformation, the tandem Suzuki-Miyaura coupling and Heck reaction were involved in the process. Meanwhile, a palladium-catalyzed carbonylative reaction of1-(2,2-dibromovinyl)-2-alkenylbenzenes, carbon monoxide, with phenols or alcohols was reported, which afforded1-methylene-1H-indene-2-carboxylates in moderate to good yields. This cascade process, which included carbonylation and Heck reaction, proceeded smoothly with good functional group tolerance and high selectivity.Subsequently, the synthesis of2-(perfluoroaryl)-benzofurans via a copper(Ⅰ)-catalyzed tandem reaction of2-(2,2-dibromovinyl)-phenols with perfluoroarenes was investigated. During the reaction process, a copper-catalyzed intramolecular C-O bond formation and a C-H activation were involved. In the meantime, the generation of4-(perfluoroaryl)pyrrolo[1,2-a]quinolines via a palladium-catalyzed tandem reaction of1-(2-(2,2-dibromovinyl)phenyl)-1H-pyrroles with perfluoroarenes was explored. The intra-and inter-molecular C-H activation was the key step.Finally, we developed an efficient route to aryl N-aminosulfonamides via a palladium-catalyzed three-component coupling of arylboronic acids, sulfur dioxide and hydrazines in the presence of a balloon of dioxygen. DABCO·(SO2)2was used as the source of sulfur dioxide. These compounds could be easily produced as well via a palladiumcatalyzed coupling of aryl halides, potassium metabisulfite, and hydrazines. Potassium metabisulfite was an excellent equivalent of sulfur dioxide in the palladium-catalyzed aminosulfonylation.