Catalytic Carbon-Carbon Bond Forming Reactions

描述（由申请人提供）：烯醇酸酯是最常见的碳亲核试剂之一，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位阻烷基膦的钯配合物，催化几种类型的烯醇化酯与芳卤化合物的高收率和高周转率偶联。我们建议利用最近关于新型烯醇偶联和新型分离钯配合物的初步数据作为进一步研究的跳板。这些研究将把合成方法的发展与定量机理实验结合起来，建立一个概念框架，使人们能够选择合适的催化剂并预测反应范围。虽然酮、酯、丙二酸酯和氰酸酯的芳基化反应现在可以有效地与几种芳基卤化物进行，但其他常见羰基化合物和腈的反应还不够有效，无法在合成中广泛使用。拟议的研究将解决这些目前的限制。我们将开发从天然氨基酸直接形成季胺基氨基酸的方法，利用机理数据改进酰胺和腈的α -芳基化，合成光学活性的富电子膦进行对映选择性偶联，并开发中性介质中烯醇化α -芳基化的条件。中性介质可以容忍更大范围的官能团，增加单芳基化的选择性，并有可能控制可烯化立体中心的对映体选择性。机理研究将描述反应中间体的化学性质和整个催化循环的动力学行为。我们将研究第一个三坐标芳基卤化钯配合物的形成和反应，它是烯醇酸酯和其他亲核试剂偶联的真正中间体。我们将研究功能化烷基芳基钯配合物的反应化学，首次揭示烷基电子对还原消除的影响，并将确定最近开发的高活性催化剂如何与芳酰氯和甲苯酸盐反应。最近的数据表明，催化剂的高活性部分是由化学计量碱、卤化物副产物或亲核试剂与钯(0)在与芳酰氯或甲磺酸盐反应之前的配位产生的。催化反应和单次翻转实验将在高效催化系统中验证这一建议。

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.