Diversity-Oriented Syntheses Of Heterocyclic Compounds Via Multicomponent Reactions And Microwave-Assisted Organic Chemistry

Diversity-oriented synthesis of small organic molecules is a rapidly developing interdisciplinary field in recent years, which aims to synthesize libraries of compounds with structural complexity and diversity for use in a systematic exploration in biology. Diversity-oriented synthesis offers a powerful means to access structurally complex and diverse small molecules by considering three distinct diversity elements: building blocks, stereochemistry, and skeletons. Multicomponent reactions along with combinatorial chemistry techniques can efficiently provide products with structural diversity needed for discovery of new lead compounds and for lead optimization. Therefore, multicomponent reactions are the most enabling synthetic tools in diversity-oriented synthesis. This thesis research focuses on microwave-assisted multicomponent reactions and their application in efficient synthesis of selected hetefocyclic skeletons.After a brief review in Chapter 1 on the basic aspects of diversity-oriented synthesis of small molecules, microwave-assisted organic synthesis, and multicomponent reactions, our study on microwave-assisted aza-Diels-Alder reaction is presented in Chapter 2. Starting from 2-aminophenols, a rapid acid-catalyzed synthesis of highly functionalized furano- and pyrano-quinolines has been established under controlled microwave heating at 60℃for 15 min. The diastereoselectivity is 35:75-16:84 in favor of the trans products. However, the yields are moderate (39-59%) probably due to the intrinsic lower reactivity of 2-aminophenols in the aza-Diels-Alder reaction.Chapter 3 describes the results on establishment of one-pot microwave-assisted Ugi-4CR and intramolecular O-alkylation process for synthesis of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines, which feature a 6/6-fused bicyclic ring system. Comparison between the microwave-assisted and the room temperature syntheses has been made, revealing that the microwave-assisted protocol can significantly shorten the reaction times from 31-49 h to 35 min while maintaining similar or slightly lower yields (56-90%) for the desired products.Chapter 4 is a continuation of the above mentioned work and it deals with one-pot microwave-assisted Ugi-4CR and intramolecular O-arylation process for synthesis of dibenz[b,f][1,4]oxazepin-11(10H)-ones possessing a 6/7/6-fused tricyclic ring system. The synthesis takes a total of 30 min for each compound and the yields are in the range of 81-97%. Furthermore, a Pd-catalyzed intramolecular amidation has been successfully performed to furnish the conjugates of dibenz[b,f][1,4]oxazepin-11(10H)-ones with a 2-oxindole subunit linked through a C-N single bond.Overall, by using 2-aminophenols as the common amine component, two one-pot Ugi-4CR and intramolecular O-alkylation / O-arylation processes have been successfully established with controlled microwave heating. According to the structures of the selected aldehyde and acid components, the 6/6-fused bicyclic and 6/7/6-fused tricyclic ring systems can be obtained. The reaction times for both synthetic processes are remarkably short (<35 min) and the product yields are good to excellent. Moreover, additional ring formation has been demonstrated by using the Pd-catalyzed intramolecular N-arylation of secondary amides, leading to the first synthesis of a novel class of heterocyclic conjugates tethered through a C-N single bond. The thesis research provides efficient synthetic methods for the described heterocyclic scaffolds and encourages further studies on microwave-assisted multicomponent reactions and post structural modifications.