RATIONAL DESIGN OF CATALYSTS FOR C-C BOND FORMATION

我的团队最近发现了一类新的C-C键形成反应：由钯配合物催化的酮的直接α-芳基化反应。我们现在已经将这一反应扩展到包括酰胺和丙二酸酯等羧酸衍生物的α-芳基化反应，同时发现了出色的催化剂，可以在室温下使用芳基溴化物对酮进行α-芳基化反应，而在仅70℃下使用芳基氯化物提供酮的α-芳基化反应。在NIH的支持下，我的小组将1)基于我们的假设，即空间受阻的、螯合的烷基膦加速反应速度，研究用于催化过程的新的烷基膦配体；2)将这一新过程的范围扩大到其他类型的羰基化合物、烷基氰化物和硝基烷烃；3)对组成催化循环的反应进行详细的、定量的机理理解。更具体地说，我们将制备在磷上含有大小取代基的烷基膦配体，并具有提供大小咬合角的主链。这些配体将被用来进一步提高产量、速率和底物范围，同时揭示我们目前提供如此快速率的配体的特征。这些配体还将用于将亲电的范围扩大到乙烯基卤化物和杂芳族卤化物和磺酸盐的研究，以及亲核伙伴的研究，如α-二酮、α-硅氧基酮、α，β-不饱和酮、β-二羰基化合物、酯、腈、硝基烷和氮内酮的阴离子。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一个重要目标。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一步，包括可能是反应速度决定步骤的芳基卤化物的氧化加成，从生成的芳基钯卤化物络合物形成芳基钯烯醇络合物，以及C-C键形成还原消除，这是催化循环中关键的耦合步骤。我们首次直接观察到了这种类型的还原消除。将对与还原消除竞争的钯烯醇络合物中的β-氢消除进行研究，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理研究，作为我们两个小组创造改进的对映选择性催化剂的一种手段。

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.