Supplement: Improving Small Molecule Synthesis by Controlling Reactions between Transition Metals and Carbon-Heteroatom Electrophiles

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PROJECT SUMMARY Multiply-substituted heteroarenes are ubiquitous in small molecule drugs. Transition metal- catalyzed cross-coupling reactions are a common strategy used to elaborate these motifs during the synthesis of small molecules for biomedical research. However, controlling site selectivity of cross-coupling is critical if multiple substituents need to be installed, and a key goal of this project is to address this challenge. Cross-coupling reactions of dihalogenated heteroarenes tend to obey well-established selectivity preferences, and methods to invert selectivity are scarce or non- existent. For example, palladium-catalyzed cross-couplings of 2,4-dihalopyrimidines always lead to cleavage of the C4–halide bond. Preparation of the complementary products that would result from C2–halide cleavage is not possible through cross-coupling methods, and instead requires more circuitous synthetic strategies. However, a strategy for C2-selective cross-coupling of 2,4- dihalopyrimidines was recently discovered involving unconventional reaction conditions. The proposed supplement will allow the purchase of a ReactIR for monitoring reaction kinetics in order to understand the mechanism behind the unique selectivity of this reaction and facilitate expansion of this C2-selective manifold to diverse classes of cross-couplings. The ReactIR will also enable elucidation of kinetics for other reactions studied under this award.