Nitrogen-containing motifs are ubiquitous in biologically active molecules. Thus, the development of new methods for the selective incorporation of nitrogen into organic structures is essential for the synthesis of medicinally important compounds. One efficient strategy for the formation of carbon-nitrogen bonds is hydroamination, the addition of an amine across a double bond. If this transformation could be directed to occur with high levels of regio- and stereoselectivity, the hydroamination of olefins would be an atom-economical method for synthesizing a wide range of nitrogen-containing molecules. The goal of this research proposal is to develop the first substrate-directed hydroamination of olefins into a synthetically useful transformation. This objective will be achieved through the use of cationic transition metal complexes that are able to exploit the coordinating ability of common polar functional groups to direct the addition of an amine across an unsaturated carbon-carbon bond. Several catalyst systems based upon late transition metals will be studied for their ability to mediate this transformation. The catalyst structures studied i this proposal will include ruthenium complexes containing a tethered ?,?-bidentate ligand framework, rhodium complexes of bidentate, bisphosphine ligands, and chelate-stabilized, ?2-olefin palladium complexes. Mechanistic studies to help identify the factors that govern the reactivity and selectivity of each catalyst system will also be conducted. These studies will include a complete characterization of the organometallic catalysts and their corresponding olefin complexes, both in solution and in the solid-state. Experiments to characterize how the amine, the olefin, and the directing group interact with the metal will be carried out. The relativ binding affinities of these components will also be determined. In addition, experiments to determine the stereochemical course of hydroamination will be conducted. Finally, these new catalysts will be employed to synthesize amine-analogues of medicinally important compounds. Because carbon-heteroatom bonds are ubiquitous in biologically relevant structures, substrate-directed hydroamination can be a powerful strategy for accessing a wide range of structurally diverse pharmaceutical derivatives with high atom economy. The selectivity and predictability of this approach will enable more efficient routes to biologically and pharmaceutically relevant structures in the drug development process.
The development of new synthetic tools for the incorporation of nitrogen into organic molecules is essential for the synthesis of medicinally important compounds. This proposal describes the design and discovery of new transition metal catalysts for the substrate-directed hydroamination of olefins. The selectivity and predictability of this approach will enable more efficient routes for accessing biologically and pharmaceutically relevant structures in the drug development process.