Heterocycles and C-N bonds are ubiquitous structural features in biologically active molecules and pharmaceutical drugs. For example, these motifs are found in the two most prominent pharmaceutical compounds from recent years, Lipitor(r), which contains a pyrrole N-heterocyclic core, and Plavix(r), which contains a benzylic C-N bond. Most methods to access heterocycles and C-N bonds involve functional group interconversions. Consequently, the direct formation of these structures through the functionalization of C-H bonds is of significant current interest. Such C-H oxidation methods have the potential of reducing the number of steps required to access the desired structural motifs and of reducing waste. Oxidative C-N bond forming reactions are known; however, their substrate scope is limited, and examples that use O2 as the sole stoichiometric oxidant are still rare. Recently, several examples of copper-catalyzed oxidative C-N bond forming reactions have been published. However, these methodologies are not amenable to large-scale applications and have limited substrate scope because they either proceed through highly reactive copper-nitrene intermediates or they use harsh, shock sensitive peroxide oxidants. This research proposal describes copper-catalyzed C-N bond forming reactions that use O2 as the terminal oxidant. The proposed methodology could overcome the major limitations of copper-catalyzed C-H oxidative functionalization because O2 is a mild and inexpensive oxidant. The chemistry described herein will be initiated with an emphasis on intramolecular C-N bond formations, providing efficient access to N-heterocycles, and intermolecular reactions will also be explored. The proposed methods have the potential to access a wide array of N-heterocycles, such as oxazolidones, pyrrolidones, and pyrroles. The aerobic chemistry will be achieved by developing copper catalyst systems that employ phenoxyl and nitroxyl co-catalysts. Specialized bifunctional ligands for the copper catalysts will be developed with phenoxyl or nitroxyl co-catalysts tethered to the ligand. These ligands are expected to increase the selectivity of the phenoxyl and nitroxyl mediated reactions.
Pharmaceutical drugs are produced on large multi-ton scales and are an integral part of today's system of healthcare, as they help to prevent, treat, and cure diseases. Given our society's large and continuing demand for pharmaceutical drugs, significant efforts are being dedicated to developing efficient, environmentally friendly methods of methods to access these molecules. This proposal describes new synthetic methods that will facilitate the efficient construction of pharmaceutical molecules without generating toxic waste byproducts.
| Rafiee, Mohammad; Wang, Fei; Hruszkewycz, Damian P et al. (2018) N-Hydroxyphthalimide-Mediated Electrochemical Iodination of Methylarenes and Comparison to Electron-Transfer-Initiated C-H Functionalization. J Am Chem Soc 140:22-25 |
