This proposal describes the development of general and selective Pd-catalyzed methods for the ligand-directed conversion of unactivated arene and alkane carbon-hydrogen bonds into new functional groups.
Aims 1 and 2 focus on exploring new methods for C-H bond fluorination and trifluoromethylation, utilizing readily available and inexpensive fluoride and trifluoromethyl starting materials. A key objective is to identify novel (and potentially broadly applicable) reactivity modes for the Pd-catalyzed introduction of fluorinated groups into organic molecules.
Aim 3 seeks to develop methods that use readily available dioxygen as the terminal oxidant for converting C-H bonds into diverse functional groups.
Aim 4 focuses on developing widely applicable asymmetric catalytic C-H functionalization reactions. All of these aims will be tackled by taking advantage of the Sanford group's expertise in new reaction development/optimization, in detailed mechanistic investigations, and in the synthesis/characterization of reactive organopalladium intermediates. The reactions developed herein will find application in the synthesis/diversification of pharmaceutical candidates, natural products, positron emission tomography (PET) imaging agents, and biological probes.

Public Health Relevance

The proposed work focuses on developing novel chemical reactions that use metal catalysts to convert readily available carbon-hydrogen bonds into more valuable functional groups in a single step. These reactions will result in faster and more environmentally benign routes to therapeutic agents for the 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 B Study Section (SBCB)
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Lees, Robert G
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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; Ichiishi, Naoko; Sanford, Melanie S (2017) Pd-Catalyzed Decarbonylative Cross-Couplings of Aroyl Chlorides. Org Lett 19:4142-4145
Lee, Melissa; Sanford, Melanie S (2017) Remote C(sp3)-H Oxygenation of Protonated Aliphatic Amines with Potassium Persulfate. Org Lett 19:572-575
Mbofana, Curren T; Chong, Eugene; Lawniczak, James et al. (2016) Iron-Catalyzed Oxyfunctionalization of Aliphatic Amines at Remote Benzylic C-H Sites. Org Lett 18:4258-61
Topczewski, Joseph J; Cabrera, Pablo J; Saper, Noam I et al. (2016) Palladium-catalysed transannular C-H functionalization of alicyclic amines. Nature 531:220-224
Mossine, Andrew V; Brooks, Allen F; Makaravage, Katarina J et al. (2015) Synthesis of [18F]Arenes via the Copper-Mediated [18F]Fluorination of Boronic Acids. Org Lett 17:5780-3
Lee, Melissa; Sanford, Melanie S (2015) Platinum-Catalyzed, Terminal-Selective C(sp(3))-H Oxidation of Aliphatic Amines. J Am Chem Soc 137:12796-9
Topczewski, Joseph J; Sanford, Melanie S (2015) Carbon-Hydrogen (C-H) Bond Activation at Pd(IV): A Frontier in C-H Functionalization Catalysis. Chem Sci 6:70-76
Allen, Laura J; Cabrera, Pablo J; Lee, Melissa et al. (2014) N-Acyloxyphthalimides as nitrogen radical precursors in the visible light photocatalyzed room temperature C-H amination of arenes and heteroarenes. J Am Chem Soc 136:5607-10
Brooks, Allen F; Topczewski, Joseph J; Ichiishi, Naoko et al. (2014) Late-stage [(18)F]Fluorination: New Solutions to Old Problems. Chem Sci 5:4545-4553
Ichiishi, Naoko; Brooks, Allen F; Topczewski, Joseph J et al. (2014) Copper-catalyzed [18F]fluorination of (mesityl)(aryl)iodonium salts. Org Lett 16:3224-7

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