Catalytic Carbon-Carbon Bond Forming Reactions

说明（由申请人提供）：烯醇化物是最常见的碳亲核试剂，但这些亲核试剂与芳基或乙烯基亲电试剂的反应在没有催化剂的情况下不会发生。在过去的资助期间，我们发现并开发了含有空间位阻烷基膦的钯配合物，其催化几种类型的烯醇化物与芳基卤化物的高收率和高周转数的偶联。我们建议使用作为发射台为未来的研究最近的初步数据，新类别的烯醇化物耦合和新类别的孤立的钯配合物。这些研究将联合收割机的合成方法的发展与定量机理实验相结合，以创建一个概念框架，允许人们选择合适的催化剂和预测反应范围。虽然酮、酯、丙二酸酯和氰基酯的芳基化现在可以用几种类型的芳基卤化物有效地进行，但其他常见的羰基化合物和腈的反应还不够有效，不能广泛用于合成。拟议的研究将解决目前的这些局限性。我们将开发直接从天然氨基酸形成季氨基酸的方法，使用机械数据来改善酰胺和腈的α-芳基化，合成光学活性，富电子膦的对映选择性偶联，并开发中性介质中烯醇化物的α-芳基化条件。中性介质将容许更宽范围的官能团，增加单芳基化的选择性，并产生在可烯醇化立体中心控制对映选择性的潜力。机理研究将描述反应中间体的化学和整个催化循环的动力学行为。我们将研究第一个三配位的芳基钯卤化物配合物的形成和反应，这是在烯醇化物以及其他亲核试剂偶联的真正中间体。我们将研究的反应化学的芳基钯配合物的官能化的烷基基团，以揭示，第一次，还原消除的烷基基团的电子效应，并将确定如何最近开发的，高活性的催化剂与芳基氯和甲苯磺酸酯反应。最近的数据表明，催化剂的高活性部分是通过在与芳基氯或甲苯磺酸酯反应之前将化学计量碱、卤化物副产物或亲核试剂配位到钯（0）上而产生的。催化反应和单周转实验，将测试这一建议在有效的催化系统。

DESCRIPTION (provided by applicant): Enolates are among the most common carbon nucleophiles, but reactions of these nucleophiles with aryl or vinyl electrophiles do not occur in the absence of catalyst. During the past grant period, we discovered and developed palladium complexes containing sterically hindered alkylphosphines that catalyze the coupling of several types of enolates with aryl halides in high yields with high turnover numbers. We propose to use as a launching pad for future studies recent preliminary data on new classes of enolate couplings and new classes of isolated palladium complexes. These studies will combine the development of synthetic methods with quantitative mechanistic experiments to create a conceptual framework that allows one to choose appropriate catalysts and predict reaction scope. Although arylations of ketones, esters, malonates and cyanoesters now occur efficiently with several types of aryl halides, the reactions of other common carbonyl compounds and nitriles are not yet efficient enough for widespread use in syntheses. Proposed studies will address these current limitations. We will develop methods to form quaternary amino acids directly from natural amino acids, use mechanistic data to improve amide and nitrile alpha-arylations, synthesize optically active, electron-rich phosphines for enantioselective couplings, and develop conditions for alpha-arylation of enolates in neutral media. Neutral media will tolerate a wider range of functional groups, increase selectivity for monoarylation, and create the potential to control enantioselectivity at enolizable stereocenters. Mechanistic studies will delineate the chemistry of reaction intermediates and the kinetic behavior of the overall catalytic cycle. We will study the formation and reactions of the first three-coordinate arylpalladium halide complexes, which are true intermediates in the coupling of enolates as well as other nucleophiles. We will study the reaction chemistry of arylpalladium complexes of functionalized alkyl groups to uncover, for the first time, the effect of alkyl group electronics on reductive elimination and will determine how the recently developed, highly active catalysts react with aryl chlorides and tosylates. Recent data suggests that the high activity of the catalyst is created, in part, by coordination of stoichiometric base, halide byproduct, or nucleophile to palladium(0) prior to reaction with aryl chloride or tosylate. Experiments on catalytic reactions and single turnovers are presented that will test this proposal in efficient catalytic systems.