Nickel-Catalyzed Alkyne Hydroamination for Efficient Amine Synthesis

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PROJECT SUMMARY Amines are ubiquitous subunits of biologically active compounds. Transition metal-catalyzed hydroamination enables atom-efficient synthesis of amines using readily available chemical feedstocks. Many classes of metal catalysts and ligands have been developed to facilitate hydroamination of alkynes, generating enamine and imine products that are valuable building blocks for nitrogen-containing molecules. In spite of these advances, catalytic alkyne hydroamination faces several major challenges including the high costs of catalysts that are largely based on precious metals, the common requirement of high reaction temperatures, as well as the long-standing hurdle of regiochemistry control. Overcoming these challenges would widen practical applications of catalytic alkyne hydroamination in biomedical research and drug synthesis. The long-term goal of our proposed research is to develop earth-abundant transition metal- based catalysts to promote selective and efficient synthesis of amines and other nitrogen- containing compounds. The overall objective of this research is to advance the reaction scope and catalyst efficiency for nickel-catalyzed alkyne hydroamination processes. Our research strategy emphasizes on in-depth reaction mechanism understanding by experimental and computational methods, which will guide our efforts on hydroamination catalyst optimization and development of mechanistically relevant aminative tandem transformations. Our proposed studies are based on the central hypothesis that N-heterocyclic carbene (NHC)-ligated nickel complexes possess unique reactivity of N-H bond activation and C-N bond formation at low energy barriers, which unlocks a broad scope of alkyne hydroamination and relevant catalytic processes under mild and neutral conditions. Feasibility of this research is demonstrated by our published and unpublished results on Ni/NHC-catalyzed alkyne hydroamination with various N-H nucleophiles including biomedically important heteroaryl-amines, as well as reactivity evaluation of structurally characterized novel Ni- NHC complexes with amide-type ligands. Guided by strong preliminary data, we propose to pursue the following two Specific Aims: (1) To advance the scope and functional group compatibility of Ni/NHC-catalyzed alkyne hydroamination. (2) To define the mechanism of Ni/NHC-catalyzed alkyne hydroamination. Our proposed research is innovative because it aims to exploit unique bond-transformation reactivity of Ni/NHC complexes for alkyne hydroamination. Results from these proposed studies are significant because they will provide new and efficient catalytic methods for transformations of simple building blocks to synthesize nitrogen-containing small molecules of biomedical relevance.