The research outlined in this proposal targets a new class of """"""""C-H functionalization"""""""" reactions, involving Pd-catalyzed dehydrogenation of aliphatic carbon-carbon single bonds to form aromatic, heteroaromatic and alkene products. These reactions should have widespread utility in the synthesis of pharmaceuticals and biologically active molecules. This novel reactivity will build upon recent advances in aerobic oxidation catalysis to enable molecular oxygen to serve as the stoichiometric oxidant/hydrogen acceptor, forming of water as the sole byproduct of the reaction. Empirical studies directed toward the development of new Pd catalysts and investigation of their synthetic applications will be complemented by systematic mechanistic studies to establish the fundamental principles that contribute to successful reactivity. Four different classes of reactions are targeted: (1) dehydrogenation of cyclohexanones and cyclohexenones to prepare a variety of substituted phenol derivatives, (2) dehydrogenation of ketones and other carbonyl compounds to prepare versatile 1,2-unsaturated carbonyl compounds, (3) dehydrogenation of cyclohexenes to prepare a variety of substituted arenes, and (4) dehydrogenation of 6-membered nitrogen heterocycles to prepare quinoline and pyridine derivatives. Substrates for these reactions can be obtained from readily available starting materials via a number of versatile synthetic routes, including Diels-Alder cycloadditions, Robinson annulations, and simple condensation and addition reactions. Key steps in these dehydrogenation reactions include PdII-mediated activation of a C-H bond, often from a relatively activated site (e.g., adjacent to a carbonyl group or in an allylic position), to form a PdII- alkyl intermediate, followed by 2-hydride elimination to produce the unsaturated product and a PdII-hydride intermediate. Oxidation of the PdII-H species by molecular oxygen regenerates the active PdII catalyst. The identification of new ligands for the Pd catalysts will play an important role in this work because the ligands are critical to modulate the reactivity of PdII in the reactions involving the organic substrate and to stabilize the reduced forms of Pd (Pd0 and PdII-H) in the catalyst reoxidation process. Overall, the development of efficient new catalysts for aerobic dehydrogenation of C-C bonds, together with the ease of synthetic access to diverse organic substrates for these reactions, will provide environmentally benign routes to selectively substituted aromatic and heteroaromatic compounds that rival or surpass the utility of some of the most powerful synthetic transformations in organic chemistry, such as metal-catalyzed cross-coupling reactions.

Public Health Relevance

The development of efficient methods for the synthesis of organic molecules is critical for the discovery, development and commercial production of pharmaceuticals and therapeutic agents. The research outlined in this proposal will lead to new catalytic methods for the preparation of such biologically active molecules.

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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Lees, Robert G
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University of Wisconsin Madison
Schools of Arts and Sciences
United States
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Nutting, Jordan E; Rafiee, Mohammad; Stahl, Shannon S (2018) Tetramethylpiperidine N-Oxyl (TEMPO), Phthalimide N-Oxyl (PINO), and Related N-Oxyl Species: Electrochemical Properties and Their Use in Electrocatalytic Reactions. Chem Rev 118:4834-4885
Wang, Fei; Rafiee, Mohammad; Stahl, Shannon S (2018) Electrochemical Functional-Group-Tolerant Shono-type Oxidation of Cyclic Carbamates Enabled by Aminoxyl Mediators. Angew Chem Int Ed Engl 57:6686-6690
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Lennox, Alastair J J; Goes, Shannon L; Webster, Matthew P et al. (2018) Electrochemical Aminoxyl-Mediated ?-Cyanation of Secondary Piperidines for Pharmaceutical Building Block Diversification. J Am Chem Soc 140:11227-11231
Jaworski, Jonathan N; McCann, Scott D; Guzei, Ilia A et al. (2017) Detection of Palladium(I) in Aerobic Oxidation Catalysis. Angew Chem Int Ed Engl 56:3605-3610
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Zultanski, Susan L; Zhao, Jingyi; Stahl, Shannon S (2016) Practical Synthesis of Amides via Copper/ABNO-Catalyzed Aerobic Oxidative Coupling of Alcohols and Amines. J Am Chem Soc 138:6416-9
Huynh, Mioy T; Anson, Colin W; Cavell, Andrew C et al. (2016) Quinone 1 e- and 2 e-/2 H+ Reduction Potentials: Identification and Analysis of Deviations from Systematic Scaling Relationships. J Am Chem Soc 138:15903-15910
Iosub, Andrei V; Stahl, Shannon S (2016) Palladium-Catalyzed Aerobic Dehydrogenation of Cyclic Hydrocarbons for the Synthesis of Substituted Aromatics and Other Unsaturated Products. ACS Catal 6:8201-8213
Wendlandt, Alison E; Stahl, Shannon S (2015) Quinone-Catalyzed Selective Oxidation of Organic Molecules. Angew Chem Int Ed Engl 54:14638-58

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