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

项目摘要 多取代的杂芳烃在小分子药物中普遍存在。过渡金属- 催化的交叉偶联反应是在制备这些基序的过程中使用的常用策略。 用于生物医学研究的小分子的合成。然而，控制位点选择性 如果需要安装多个取代基，则交叉偶联是至关重要的，并且该项目的一个关键目标是 就是应对这一挑战。二卤代杂芳烃的交叉偶联反应倾向于服从 公认的选择性偏好，以及逆转选择性的方法很少或没有， 存在的例如，钯催化的2，4-二卤代嘧啶的交叉偶联总是导致 C4-卤键的断裂。准备补充产品， 通过交叉偶联方法从C2-卤化物裂解是不可能的，而是需要 更迂回的合成策略然而，用于2，4-二甲基甲酰胺的C2-选择性交叉偶联的策略是不可行的。 最近发现了涉及非常规反应条件的二卤代嘧啶。的 拟议的补充将允许购买ReactIR用于监测反应动力学， 了解这种反应独特的选择性背后的机制， 这种C2-选择性歧管的扩展到不同类别的交叉耦合。ReactIR将 也能阐明本奖项下研究的其他反应的动力学。

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.