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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM100143-03
Application #
8607575
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2012-04-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
$249,065
Indirect Cost
$78,065
Name
University of Wisconsin Madison
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Iosub, Andrei V; Stahl, Shannon S (2015) Palladium-catalyzed aerobic oxidative dehydrogenation of cyclohexenes to substituted arene derivatives. J Am Chem Soc 137:3454-7
Osterberg, Paul M; Niemeier, Jeffry K; Welch, Christopher J et al. (2015) Experimental Limiting Oxygen Concentrations for Nine Organic Solvents at Temperatures and Pressures Relevant to Aerobic Oxidations in the Pharmaceutical Industry. Org Process Res Dev 19:1537-1543
Rafiee, Mohammad; Miles, Kelsey C; Stahl, Shannon S (2015) Electrocatalytic Alcohol Oxidation with TEMPO and Bicyclic Nitroxyl Derivatives: Driving Force Trumps Steric Effects. J Am Chem Soc 137:14751-7
Wendlandt, Alison E; Stahl, Shannon S (2015) Quinone-Catalyzed Selective Oxidation of Organic Molecules. Angew Chem Int Ed Engl 54:14638-58
Wendlandt, Alison E; Stahl, Shannon S (2014) Modular o-quinone catalyst system for dehydrogenation of tetrahydroquinolines under ambient conditions. J Am Chem Soc 136:11910-3
Wendlandt, Alison E; Stahl, Shannon S (2014) Bioinspired aerobic oxidation of secondary amines and nitrogen heterocycles with a bifunctional quinone catalyst. J Am Chem Soc 136:506-12
Mannel, David S; Stahl, Shannon S; Root, Thatcher W (2014) Continuous Flow Aerobic Alcohol Oxidation Reactions Using a Heterogeneous Ru(OH) x /Al2O3 Catalyst. Org Process Res Dev 18:1503-1508
Diao, Tianning; Pun, Doris; Stahl, Shannon S (2013) Aerobic dehydrogenation of cyclohexanone to cyclohexenone catalyzed by Pd(DMSO)2(TFA)2: evidence for ligand-controlled chemoselectivity. J Am Chem Soc 135:8205-12
Hong, Wan Pyo; Iosub, Andrei V; Stahl, Shannon S (2013) Pd-catalyzed Semmler-Wolff reactions for the conversion of substituted cyclohexenone oximes to primary anilines. J Am Chem Soc 135:13664-7
Kim, Jinho; Stahl, Shannon S (2013) Cu/Nitroxyl Catalyzed Aerobic Oxidation of Primary Amines into Nitriles at Room Temperature. ACS Catal 3:1652-1656

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