Several efficient, transition metal-catalyzed routes to amines and ethers are presented in this proposal. Many amines and ethers are biologically active, and most of the best-selling drugs contain this type of functionality. During the past funding period, we uncovered several transition metal-catalyzed routes to amines and ethers. We developed palladium-catalyzed C-N and C-O coupling of aryl halides and we recently uncovered new metal-catalyzed hydroaminations. The amination of aryl halides and accompanying mechanistic information has already affected dramatically how drug discovery and process groups prepare arylamines. Our hydroaminations should influence the way they prepare alkylamines. In the next funding period, we will gain an understanding of how our new, most active catalysts work and we will determine the extent to which these catalysts improve the scope of C-N bond formation. In addition, we will seek an understanding of the mechanism of related C-O bond forming cross-couplings that use recently discovered catalysts. We will also outline rules that govern the scope and rates for palladium- catalyzed aromatic aminations with medicinally important heterocyclic substrates. In addition to aromatic C-N and C-O bond-forming processes, we will investigate our new hydroaminations of dienes and vinylarenes. Diene hydroaminations produce allylic amines, which are common synthetic intermediates. Vinylarene hydroaminations produce phenethylamines, which are part of drugs such as Sertraline. We will define the scope of these new processes, will investigate enantioselective hydroaminations and will obtain a detailed understanding of how the reactions occur. This information should enable us to design efficient hydroamination catalysts with broad substrate scope and to use mild reaction conditions for highly enantioselective hydroaminations.
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