Catalytic C-H Activation and Boronic Acid Synthesis

Michigan State University, East Lansing MI

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Abstract

DESCRIPTION: Applicant's Description) Alkyl and arylboronic acids play important rolesin medicinal chemistry. There are presently commercialized sensing applications based on boronic acids and boron compounds have interesting activities for protease inhibition and for treating gliboplastoma via boron neutron capture therapy (BNCT). Boron compounds make a wide range of transformations accessible under mild conditions. Thus they are well suited to combinatorial methods that are central to drug discovery. In this regard, the metal catalyzed cross-coupling reactions of alkyl or arylboronic acids with alkyl or aryl halides have been broadly applied. Presently, the combinatorial space that is accessible to cross-coupling reactions is limited by the availability of boronic acids. If the range of boronic acids could be expanded to rival the diversity of alkyl and aryl halides that are commercially available, the number of compounds that is accessible through carbon-carbon coupling could be increased by twenty-five fold. Large-scale applications of boronic acid couplings for pharmaceutical synthesis are currently being developed. The most economical route to boronic acids requires aryl chlorides as synthons. Given the environmental concerns associated with chlorinated aromatics, fundamentally new chemistry that eliminates the requirement for chlorinated aromatic precursors would alleviate waste disposal problems. This proposal targets the application of recent catalytic chemistry to the synthesis of boronic esters from aromatic hydrocarbons and boranes. In particular, the metal-catalyzed C-H activation eliminates the need for chlorinated aromatic hydrocarbons in aryl boronic acid synthesis. In addition, the only by-product of the reaction is hydrogen gas, which is cleanly and easily converted to water. Importantly, the proposed methodology requires thermal activation; thus, the cryogenic conditions that are required for traditional metallation reactions are avoided. The breadth of functional group tolerance will be examined, and approaches to controlling selectivity are proposed. Since large scale applications will ultimately require more robust catalysts, strategies for improving catalyst stability are also presented.