New Base-Promoted Oxidative and Reductive Coupling Reactions

Colorado State University, Fort Collins CO

Investigators

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Abstract

Project Summary There is a critical need to develop synthetic methods that improve access to chemicals required for the discovery and production of new medicines. The long-term goal of this research program is to invent generalizable base-promoted reactions that address major limitations in organic synthesis. In contrast to widely used traditional base-promoted reactions that combine a pronucleophile with an electrophile, this proposal introduces general strategies for oxidative and reductive coupling reactions that combine two nucleophiles or two electrophiles, respectively. These protocols unlock a wide array of new base-promoted reactions that employ common functional groups to provide previously difficult-to-access products. Specifically, haloarenes are used as a new type of oxidant to transfer halogens to transiently formed carbanion species that enable oxidative coupling processes of mildly acidic C–H bonds. This process greatly streamlines the synthesis of ether and amine-containing arenes, alkenes and alkanes. Additionally, base-activation of disilanes generates silyl anions that transform electrophiles into nucleophilic species for C–C bond-forming reactions. This approach is used for the monoselective substitution of trifluoromethylaryl C–F bonds to access new difluoroalkyl chemical space and for the combination of alternative electrophile classes to form complex Csp2-Csp3 and Csp3-Csp3 carbon backbones. The methods in this proposal rely on base-activation strategies and thus have distinct scope, selectivity and utility over alternative means of reaction promotion such as the use of transition metals, electrochemistry or photochemistry. These impacts are demonstrated through single-step access to compounds that were either previously inaccessible or required tedious multistep syntheses and through shortened and modular routes to specific drug substructures. The reactions can also be used on complex drug-like structures to modify and diversify bioactive molecules. Upon completion of this work, chemists will have at their disposal a set of powerful reactions that increase the efficiency, practicality and range of access to molecules desired in the pharmaceutical industry.