New Synthetic Methodology Enabled by Base-Promoted Halogen and Electron Transfer Processes

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Project Summary There remains a critical need to develop synthetic methodology that increases the efficiency and diversity of access to chemicals desired in medicinal research. In particular, fundamentally new transformations that employ abundantly available starting materials can greatly facilitate the discovery and manufacture of new drugs. The long-term goal of this research program is to use strong bases as catalysts and promoters for new reactions that address major limitations in organic synthesis. The overall objective for this application is to use inexpensive Brønsted and Lewis bases to achieve new functionalization methods of aryl halides, heteroarenes and trifluoromethylarenes. This proposal is built on the hypothesis that strong bases can unlock previously unknown or underutilized mechanistic processes of common organic functional groups. Specifically, the research plan will exploit base-catalyzed aryl halide isomerizations and intermolecular halogen transfers, as well as single electron transfer processes from base-activated organosilicates. Based on extensive preliminary results, a series of novel arene functionalization reactions are described that are primarily targeted at improving heteroarene derivatization. The monoselective coupling of organosilanes to trifluoromethylarenes is also presented as a practical and broadly useful approach to difluorobenzylic compounds. The impact of these methods is demonstrated through single-step access to compounds that were either previously inaccessible or required tedious multistep operations, their use for late stage diversification of drug-like structures and dramatically improved routes to specific drug candidates. Upon completion of the proposed work, chemists will have at their disposal a set of powerful reactions that increase the efficiency, practicality and scope of access to molecules widely desired in the pharmaceutical industry.