RATIONAL DESIGN OF CATALYSTS FOR C-C BOND FORMATION

C-C 键形成催化剂的合理设计

• 批准号: 6519916
• 负责人: John F Hartwig
• 金额: $ 32.34万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6519916
• 关键词: alkyl group; catalyst; chemical kinetics; chemical synthesis; covalent bond; ligands; phosphines

My group recently discovered a new class of C-C bond-forming reaction: the direct alpha-arylation of ketones catalyzed by palladium complexes. We have now extended this reaction to include the alpha-arylation of carboxylic acid derivatives such as amides and malonates, while finding remarkable catalysts that provide alpha-arylation of ketones at room temperature using aryl bromides and at only 70 C using aryl chlorides. Under NIH support my group would 1) study new alkylphosphine ligands for the catalytic process based on our hypothesis that sterically hindered, chelating alkyl phosphines accelerate reaction rates, 2) expand the scope of this new process to other types of carbonyl compounds, alkyl cyanides, and nitroalkanes and 3) develop a detailed, quantitative mechanistic understanding of the reactions comprising the catalytic cycle. More specifically, we will prepare alkylphosphine ligands containing large and small substituents at phosphorus and with backbones that provide large and small bite angles. These ligands will be used to further improve yields, rates, and substrate scope, while uncovering the features of our current ligands that provide such fast rates. These ligands will also be used in studies toward extending the scope of electrophiles to vinyl and heteroaromatic halides and sulfonates, and to nucleophilic partners such as the anions of alpha-diketones, alpha-siloxy ketones, alpha, beta-unsaturated ketones, beta-dicarbonyl compounds, esters, nitriles, nitroalkanes, and azlactones. A detailed mechanistic description of the catalytic chemistry based on firm quantitative data is an important goal of the proposed research. In general, we will conduct a careful study to determine how ligands steric and electronic properties affect each step of the catalytic cycle, including oxidative addition of aryl halide that is likely to be the rate determining step of the reaction, formation of an arylpalladium enolate complex from the resulting arylpalladium halide complex, and C-C bond-forming reductive elimination that is the crucial coupling step in the catalytic cycle. We have conducted the first direct observation of this type of reductive elimination. Beta-Hydrogen elimination from the palladium enolate complexes, which competes with reductive elimination, will be investigated to determine how this process can be prevented. Finally, we will begin a detailed mechanistic study of the initial asymmetric version of the ketone arylation process in conjunction with Buchwald's synthetic effort as a means for our two groups to create improved enantioselective catalysts.

我的团队最近发现了一类新的C-C键形成反应：钯配合物催化的酮的直接α -芳基化。我们现在已经扩展了这一反应，包括羧酸衍生物如酰胺和丙二酸酯的α -芳基化，同时发现了在室温下使用芳基溴和仅在70℃下使用芳基氯化物进行酮的α -芳基化的显著催化剂。在美国国立卫生研究院的支持下，我的小组将1)研究新的烷基磷化氢配体用于催化过程，基于我们的假设，即空间阻碍，螯合烷基磷化氢加速反应速率，2)将这一新过程的范围扩展到其他类型的羰基化合物，烷基氰化物和硝基烷烃，3)对包括催化循环的反应进行详细的，定量的机制理解。更具体地说，我们将制备在磷上含有大取代基和小取代基的烷基膦配体，并具有提供大和小咬角的骨架。这些配体将用于进一步提高产率、速率和底物范围，同时揭示我们目前提供如此快速速率的配体的特征。这些配体还将用于将亲电试剂的范围扩展到乙烯基和杂芳香卤化物和磺酸盐，以及亲核伙伴，如-二酮、-硅氧基酮、-不饱和酮、-二羰基化合物、酯类、腈、硝基烷和氮化内酯的阴离子。基于可靠的定量数据对催化化学进行详细的机理描述是本研究的重要目标。总的来说，我们将进行仔细的研究，以确定配体的空间和电子性质如何影响催化循环的每个步骤，包括芳基卤化物的氧化加成，这可能是反应的速率决定步骤，由芳基卤化钯络合物形成芳基钯烯酸酯络合物，以及催化循环中至关重要的耦合步骤C-C键形成还原消除。我们首次对这种还原性消除进行了直接观察。钯烯酸酯配合物的β -氢消除与还原消除竞争，将被研究以确定如何防止这一过程。最后，我们将结合Buchwald的合成努力，开始对酮芳基化过程的初始不对称版本进行详细的机制研究，作为我们两个团队创造改进的对映选择性催化剂的手段。