The conversion of C-H bonds into new functional groups represents a powerful strategy for the synthesis and elaboration of organic molecules. Over the past 20 years, there has been tremendous progress in the development and application of C-H functionalization reactions in organic synthesis. However, despite this progress, selective C-H functionalization can only be achieved in the context of a relatively limited set of organic substrates and C-H sites. One class of substrates that has historically proven challenging for selective C-H functionalization is aliphatic amines. This proposal seeks to address this unmet need through the development of a series of predictable and selective C-H functionalization reactions of aliphatic amines, with a particular focus on saturated nitrogen heterocycles. The proposed efforts will deliver a suite of complementary synthetic methods for the oxidation of C(sp3)-H bonds at sites remote to the amine nitrogen. In each Specific Aim, a different type of metal catalyst will be employed, and a fundamentally different strategy will be used to control site selectivity. As such, the proposed methods will provide a variety of new synthetic disconnections for the construction and derivatization of aliphatic amine-based cores. The overall objective of Aim 1 is to develop Pd-catalyzed ligand-directed reactions for the transannular C-H functionalization of cyclic amines. The overall objective of Aim 2 is to develop metal-oxo/peroxo-catalyzed C(sp3)-H oxidation reactions of amines that proceed with high selectivity for sites remote to nitrogen. Finally, the overall objective of Aim 3 is to employ Pt- catalysis to achieve the sterically selective C-H oxidation of aliphatic amine substrates.

Public Health Relevance

The proposed work will develop new chemical reactions that directly convert carbon-hydrogen bonds in aliphatic amine substrates into more valuable functional groups. Aliphatic amines are extremely common in bioactive molecules (e.g., FDA approved pharmaceuticals, drug candidates, imaging agents, biological probes). Thus, the proposed reactions have the potential for major impact by providing more efficient and environmentally benign routes to therapeutic agents for the diagnosis and treatment of human disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Yang, Jiong
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University of Michigan Ann Arbor
Schools of Arts and Sciences
Ann Arbor
United States
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Malapit, Christian A; Bour, James R; Brigham, Conor E et al. (2018) Base-free nickel-catalysed decarbonylative Suzuki-Miyaura coupling of acid fluorides. Nature 563:100-104
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