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

补充：通过控制过渡金属和碳杂原子亲电子试剂之间的反应来改进小分子合成

基本信息

批准号：
10797227
负责人：
Sharon Neufeldt
金额：
$ 8.83万
依托单位：
MONTANA STATE UNIVERSITY - BOZEMAN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-06-30
项目状态：
未结题

项目摘要

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.

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。