Heterocycles are ubiquitous in pharmaceutical compounds, natural products, and other bioactive compounds. For this reason, new methods for their preparation are sought after by researchers. A notable catalytic reaction for the preparation of heterocycles is palladium-catalyzed carbonylation. This reaction uses carbon monoxide as a C1 source for the heterocycle. Many palladium-catalyzed carbonylation reactions have (pseudo)halide functionality built into the substrate to improve the regioselectivity of the reaction. However, this halide functionality is often installed into the substrate using waste-generating and time-consuming manipulations. An attractive alternative to this so-called classical carbonylation reaction is the palladium-catalyzed aerobic oxidative C-H carbonylation reaction. Under these conditions, a (pseudo)halide in the substrate is replaced with a C-H bond, and an oxidant is used to attain catalytic turnover. Directed aerobic oxidative C-H carbonylation is attractive because the only byproduct of the reaction is water, O2 can be used as the terminal oxidant, and heterocycle products can be synthesized with excellent regiocontrol. However, many published directed oxidative carbonylation reactions use stoichiometric amounts of cooxidants such as copper(II), silver(I), and 1,4-benzoquinone (BQ) to achieve efficient catalytic turnover, and high loadings of palladium (10 mol%) are typical. These conditions prevent oxidative C-H carbonylation reactions from being applied on an industrial process scale. Ideally, the loading of cooxidants could be reduced to a cocatalytic level, and the loading of palladium could be reduced to the single digits or less mol%. The chemistry proposed herein constitutes a detailed study of the reaction mechanism of a published oxidative C-H carbonylation reaction using innovative techniques such as operando high-pressure NMR spectroscopy and operando X-ray absorption spectroscopy (XAS). The development of high-pressure NMR spectroscopic instrumentation will also be a portion of this project. Additionally, a published reaction that prescribes two equivalents of BQ for aerobic oxidative carbonylation to afford bioactive 3,4-dihydro-?-carbolin-1-ones is targeted for further development by lowering the palladium loading as well as the BQ loading to a cocatalytic level. The substrate scope for this reaction is also targeted for expansion including bioactive targets. Moreover, a new reaction is proposed: The palladium-catalyzed aerobic oxidative C-H carbonylation of 2-ester substituted E-ethenylanilines to 4-quinolone-3-carboxylate esters, which are privileged scaffolds in FDA-approved antibiotics like ciprofloxacin and levofloxacin (a.k.a. Levaquin(r)). The proposed substrate scope of this reaction includes bioactive targets such as approved antibiotics.
Medications constitute a significant component of citizens' healthcare needs; prescription drugs are used to help prevent, treat, and cure diseases. Though many different drugs are approved by the FDA, closer inspection on a molecular level reveals that a small number of common motifs underlie the cores of these drugs; the development of new and improved methods to construct these motifs more cheaply and efficiently, while generating fewer waste byproducts, is needed. The research proposed herein involves the mechanistic study of an existing reaction that produces a motif found in antioxidants, the improvement of a reaction for the synthesis of a motif found in biologically active compounds, and the design of a new reaction that generates a product with a motif commonly found in FDA-approved antibiotics.
| Tereniak, Stephen J; Stahl, Shannon S (2017) Mechanistic Basis for Efficient, Site-Selective, Aerobic Catalytic Turnover in Pd-Catalyzed C-H Imidoylation of Heterocycle-Containing Molecules. J Am Chem Soc 139:14533-14541 |
