Oxidative carbon-carbon bond formation: a synergy of enamine and Pd(II) catalysis

描述(由申请人提供)：有机化学品的选择性氧化是当今化学和制药行业面临的最关键的挑战之一。在过去的10年里，许多组织努力将已知的和新的氧化过程与世界上含量最丰富的氧化剂--分子氧结合起来。这一领域的一个具有挑战性的研究领域是钯(11)介导的碳亲核试剂与未活化的烯烃的氧化偶联。在有氧氧化研究的同时，有机催化，特别是亚胺/亚胺催化，已经引起了合成界的极大关注，并被证明在非常温和的条件下催化高水平对映体控制的反应是非常有效的。建议的研究涉及这两个概念的协同作用：成功地将烯胺催化与Pd(11)化学相结合，在有氧条件下催化相对较弱的a-羰基亲核试剂与未活化的烯烃的氧化偶联。这一建议的最终目标是探索反应的机理，并使其在胺和钯中都具有催化作用，同时能够诱导高水平的对映选择性。所提议的反应通过仲胺与含有烯烃系留羰基的分子缩合生成烯胺来进行。钯(11)源亲电活化被束缚的烯烃导致碳-碳键的形成。由此产生的亚胺离子的水解伴随着钯的对氢化物的消除而得到氧化偶联产物。新生成的Pd(0)可以被O2重新氧化为Pd(11)，Pd(11)可以重新进入催化循环。手性、富含对映体的仲胺的使用有望实现高度的对映体控制。具有钯配体双重作用的手性仲胺也将被研究其在不对称反应中的潜力。设计高效和良性的氧化化学转化对于环境可持续的全球经济的发展至关重要，因此对于所有生物的健康至关重要。在这个应用中，我们提出了一种强大而温和的化学反应的设计，它使用分子氧作为唯一的氧化剂，并产生水作为唯一的副产品。

DESCRIPTION (provided by applicant): Selective oxidation of organic chemicals is one of the most critical challenges facing the chemical and pharmaceutical industries today. Over the past 10 years, many groups have endeavored to couple known and novel oxidation processes to the world's most abundant oxidant, molecular oxygen. One challenging area of research in this field is the palladium(ll) mediated oxidative coupling of carbon nucleophiles with unactivated olefins. Concurrent with aerobic oxidation research, organocatalysis, particularly iminium/enamine catalysis, has garnered significant attention from the synthetic community and has proven to be extremely effective at catalyzing reactions with high levels of enantiocontrol under very mild conditions. The proposed study involves a synergy of these two concepts: to successfully merge enamine catalysis with Pd(ll) chemistry to catalyze the oxidative coupling of relatively weak a-carbonyl nucleophiles with unactivated olefins under aerobic conditions. The ultimate goal of this proposal entails probing the mechanism of the reaction and rendering it catalytic in both amine and palladium while being capable of inducing high levels of enantioselectivity. The proposed reaction proceeds via condensation of a secondary amine with a molecule containing an alkene tethered carbonyl to generate an enamine. Electrophilic activation of the tethered alkene by a palladium(ll) source leads to carbon-carbon bond formation. Hydrolysis of the resulting iminium ion with concomitant p-hydride elimination of the palladium affords the oxidatively coupled product. The newly generated Pd(0) can be reoxidized by O2 to Pd(ll) which can re-enter the catalytic cycle. It is expected that use of chiral, enantioenriched secondary amines will enable high enantiocontrol. Chiral secondary amines that have the dual role of palladium ligand will also be investigated for their potential in asymmetric reactions. The design of efficient and benign oxidative chemical transformations is critical for the development of an environmentally sustainable worldwide economy, and therefore, the health of all living things. In this application, we propose the design of a powerful yet mild chemical reaction that uses molecular oxygen as the sole oxidant and generates water as the only byproduct.