A Cooperative Approach to C-N Bond Formation

胺在包括农用化学品、食品、纺织、塑料和制药在内的一系列工业领域得到了广泛的应用，在前200种畅销药品中约占20%，在候选药物中占80%以上。2016年全球胺市场估计为144亿美元，预计到2025年将增加到293亿美元，因为随着世界人口的增加，对胺产品的需求大幅增加。传统上，胺的合成供应是通过基于Hofmann烷基化、羰基还原胺化、酰胺还原和添加到活化亚胺衍生物的过程来提供的。近年来，在催化氢胺化、C-H胺化和生物催化等领域取得的重要进展极大地扩展了化学家可用的胺合成方法的合成工具箱。尽管如此，对含有新胺的结构的持续需求意味着直接将现成的化学物质转化为复合胺的新的催化工艺的发明已经成为日益重要的合成挑战。在这个项目中，我们将开发一种基于含硼路易斯酸配体的低价铁配合物的过渡金属FLP，能够参与金属-配体的协同作用。鉴于胺的重要性，这种合作方法将被用于C-N键的形成反应，通过N-H活化合成胺。本建议中概述的方法为两条重要的胺支架合成路线提供了一种概念上截然不同的方法：1)氢胺化--通常在Lewis酸性金属存在下通过pi-键活化发生的反应；以及2)N-芳基/烷基化--经典的通过羰基还原胺化或金属催化的交叉偶联实现。目前正在探索利用富含稀土的元素实现N-H键直接官能化的温和催化方法，发明稳健和可持续的程序来实现这种转化将构成胺合成的一步变化。

Amines have found widespread applications in a range of industrial sectors including agrochemicals, food, textiles, plastics, and pharmaceuticals, where they make up approximately 20% of the top 200 best-selling pharmaceuticals and over 80% of drug candidates. The global market for amines in 2016 was estimated at $14.4bn USD and is projected to increase to $29.3bn USD by 2025 as demand for amine products significantly increases with the increase in world population. Traditionally, the synthetic supply of amines has been delivered by processes based on Hofmann alkylation, carbonyl-reductive amination, amide reduction and additions to activated imine derivatives. Recently, important advances in fields such as catalytic hydroamination, C-H amination and biocatalysis have significantly expanded the synthetic toolbox of amine-synthesis methods available to chemists. Despite this, the ongoing need for novel amines containing structures means the invention of new catalytic processes which directly convert readily available chemicals into complex amines has become an increasingly essential synthetic challenge. In this project, we will develop a transition metal FLP based on low-valent iron complexes bearing boron-based Lewis acid ligands, capable of participating in metal-ligand cooperativity. Given the importance of amines, this cooperative approach will be exploited in C-N bond formation reactions towards amine synthesis via N-H activation. The approaches outlined in this proposal offer a conceptually-distinct approach to two important synthetic routes towards amine scaffolds: 1) hydroamination - a reaction which typically occurs in the presence of Lewis acidic metals via pi-bond activation; and 2) N-aryl/alkylation - classically achieved via carbonyl reductive amination or metal-catalyzed cross coupling. Mild, catalytic approaches using earth-abundant elements towards the direct functionalization of N-H bonds are currently under explored, and the invention of robust and sustainable procedures to effect such transformations will constitute a step-change in the synthesis of amines.