Microwave-assisted Selective Annulation Cascades For Synthesis Of Diverse Heterocyclic Scaffolds

Diversity-oriented organic synthesis (DOS) aims at creation of a maximum number of molecules possessing distinct molecular shape diversity for addressing questions in chemical biology and related fields. It has been well accepted that Ugi four-component reaction (U-4CR) is one of the powerful tools to access structural complexity with wide applicability. Moreover, the linear dipeptide-like U-4CR products are transferable into various cyclic scaffolds via post-Ugi transformations, providing an efficient and attractive strategy for attaining molecular shape diversity. This thesis research focuses on exploration of post-Ugi annulations under controlled microwave heating. The results on construction of novel heterocyclic skeletons from the same types of intermediates via highly selective annulation cascades are described.Chapter 1 briefly introduces microwave-assisted organic synthesis, multicomponent reactions, and progress in post-Ugi transformations described in the literature. The prior results from our labs on the post-Ugi annulations starting 2-aminophenols are described, followed by the planned study in this thesis research.Described in Chapter 2 are the results on establishment of microwave-assisted selective annulation cascades for assembling three distinct novel heterocyclic skeletons from the common precursors. Starting from 2-aminophenols, a series of linear precursors were prepared via U-4CR and subsequent phenolic O-2-bromobenzylation. Under microwave heating with carefully optimized reaction conditions (temperature, time, and catalyst) and the nature of substrate structure, three different heterocycles were synthesized in high selectivity and moderate to good yields. The accomplished results include:(a) a cascade annulation via intramolecular direct arylation (IMDAR), Intramolecular Michael addition (IMMA), and intramolecular amidation (IMAD) to form a spirocyclic scaffold; (b) a cascade annulation via IMDAR and intramolecular Heck reaction (IMHR) to afford an isoquinolinone skeleton; and (c) a cascade annulation via double IMDAR and IMMA to furnish an indolizidinone core. Brief studies on the substrate scope and reaction mechanisms were performed.The experimental section including the synthetic procedures and full characterization data for all new compounds, cited references, and copies of original NMR spectra and X-ray crystal structures of the novel heterocycles are found at the end of the thesis.