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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM073836-08
Application #
8299468
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2005-08-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
8
Fiscal Year
2012
Total Cost
$273,615
Indirect Cost
$78,615
Name
University of Michigan Ann Arbor
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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
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
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
Neufeldt, Sharon R; Sanford, Melanie S (2013) Asymmetric chiral ligand-directed alkene dioxygenation. Org Lett 15:46-9
Seigerman, Cydney K; Micyus, Tiffiny M; Neufeldt, Sharon R et al. (2013) Palladium-Catalyzed C-H Arylation Using Aryltrifluoroborates in Conjunction with a Mn(III) Oxidant under Mild Conditions. Tetrahedron 69:5580-5587
Ichiishi, Naoko; Canty, Allan J; Yates, Brian F et al. (2013) Cu-catalyzed fluorination of diaryliodonium salts with KF. Org Lett 15:5134-7
Neufeldt, Sharon R; Seigerman, Cydney K; Sanford, Melanie S (2013) Mild palladium-catalyzed C-H alkylation using potassium alkyltrifluoroborates in combination with MnF3. Org Lett 15:2302-5
Hickman, Amanda J; Sanford, Melanie S (2012) High-valent organometallic copper and palladium in catalysis. Nature 484:177-85
Stowers, Kara J; Fortner, Kevin C; Sanford, Melanie S (2011) Aerobic Pd-catalyzed sp3 C-H olefination: a route to both N-heterocyclic scaffolds and alkenes. J Am Chem Soc 133:6541-4
Satterfield, Andrew D; Kubota, Asako; Sanford, Melanie S (2011) Palladium-catalyzed 1,1-aryloxygenation of terminal olefins. Org Lett 13:1076-9

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