In three years at Yale Prof. Hartwig's group has developed a class of transition metal-catalyzed reactions that is fundamentally distinct from other metal-mediated processes. This proposal presents studies to extend the scope of this catalytic chemistry and to apply it to current synthetic problems. The reactions they have developed are palladium.catalyzed aminations of aryl halides. These reactions produce N-alkyl and N-aryl anilines by intermolecular amination or nitrogen-containing heterocycles from intramolecular amination in high yields and with high turnover numbers. Their published work has provided a thorough mechanistic understanding of palladium-catalyzed aminations. As a result of these studies, they have recently produced new reaction procedures, amide reagents, and palladium catalysts that significantly improve upon published methods. The research described in this proposal stems from these recent synthetic advances and includes the following specific aims. The general strategy for their proposed research is to develop the scope and essential mechanistic features of our recently developed systems for aryl halide amination including reactions with primary amines, heteroaromatics, aryl halides and aryl sulfonates. Concurrently, they will seek metal complexes that will catalyze the formation of aryl ethers from aryl halides and alkoxides. These methodological studies constitute the majority of this proposed work. Once the scope of these synthetic methods are developed to the stage of understanding the general strengths and limitations of the published and newly developed methods, however, they will use these reactions to construct isosteric analogs of isodityrosine-containing materials, to adapt these methods for their use in solid-phase reactions, and to evaluate their use in producing solid-supported libraries, including those of isodityrosine natural product analogs.
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