A Cooperative Approach to C-N Bond Formation

胺在一系列工业部门中得到了广泛的应用，包括农用化学品、食品、纺织品、塑料和制药，它们占前200种最畅销药物的约20%，占候选药物的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，对胺产品的需求显着增加。传统上，胺的合成供应已经通过基于霍夫曼烷基化、羰基还原胺化、酰胺还原和添加到活化的亚胺衍生物的方法来提供。近年来，催化氢胺化、C-H胺化和生物催化等领域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，对新型含胺结构的持续需求意味着直接将容易获得的化学品转化为复杂胺的新催化方法的发明已经成为越来越重要的合成挑战。在本计画中，我们将发展一种以低价铁配合物为基础，并以硼为基础的刘易斯酸配位体，能够参与金属-配位体协同作用的过渡金属FLP。考虑到胺的重要性，这种协同方法将在C-N键形成反应中被利用，通过N-H活化进行胺合成。本提案中概述的方法为两种重要的胺骨架合成路线提供了概念上不同的方法：1）加氢胺化--一种通常在刘易斯酸性金属存在下通过π键活化发生的反应;和2）N-芳基/烷基化--典型地通过羰基还原胺化或金属催化的交叉偶联实现。目前正在探索使用地球上丰富的元素直接官能化N-H键的温和催化方法，并且实现这种转化的稳健和可持续的程序的发明将构成胺合成的逐步变化。

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.