Catalytic Carbon-Carbon Bond Forming Reactions

说明(申请人提供)：烯醇类化合物是最常见的碳亲核剂之一，但在没有催化剂的情况下，这些亲核剂与芳基或乙烯基亲电剂不会发生反应。在过去的资助期间，我们发现和开发了含有空间位阻的烷基膦的钯配合物，这些配合物催化几种类型的烯醇酸盐与芳基卤化物的偶联，产量高，周转次数高。我们建议用来作为未来研究的发射台，最近关于新类型的烯醇偶合和新的孤立钯配合物的初步数据。这些研究将把合成方法的发展与定量的机理实验相结合，以创建一个概念框架，使人们能够选择合适的催化剂并预测反应范围。虽然现在酮、酯、丙二酸酯和氰酸酯的芳基化反应在几种类型的芳基卤化物中发生得很有效，但其他常见的羰基化合物和腈的反应还不够有效，不足以在合成中广泛使用。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生成季胺类氨基酸的方法，利用机理数据改进酰胺和丁腈的α-芳基化反应，合成光学活性、富含电子的膦对映体选择性偶联，并为烯醇酸酯在中性介质中的α-芳基化反应创造条件。中性介质将容忍更广泛的官能团，提高单芳化的选择性，并创造在可烯化的立体中心控制对映体选择性的可能性。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芳基钯卤化物络合物的形成和反应，这些络合物是烯醇酸盐和其他亲核试剂偶联的真正中间体。我们将研究官能化烷基的芳基钯配合物的反应化学，以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基氯化物和甲苯磺酸盐反应。最近的数据表明，催化剂的高活性部分是由于化学计量比碱、卤化物副产物或亲核剂在与芳基氯或甲苯磺酸盐反应之前与钯(0)配位而产生的。介绍了催化反应和单次转化率的实验，这些实验将在有效的催化系统中检验这一建议。

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.