Nickel-Catalyzed Alkyne Hydroamination for Efficient Amine Synthesis

项目总结 胺是生物活性化合物中普遍存在的亚单位。过渡金属催化 氢胺化能够利用现成的化学物质，以原子效率合成胺 原料。已经开发了许多类别的金属催化剂和配体来促进 炔烃的氢胺化反应，生成对建筑有价值的烯胺和亚胺产品 用于含氮分子的阻挡块。尽管有这些进展，催化炔 氢胺化反应面临几个主要挑战，包括催化剂的高昂成本，这些催化剂在很大程度上 基于贵金属，高反应温度的常见要求，以及 区域化学控制的长期障碍。克服这些挑战将扩大实践范围 催化炔氢胺化在生物医学研究和药物合成中的应用。 我们提出的研究的长期目标是开发富含地球的过渡金属- 以催化剂为基础，促进胺和其他氮气的选择性和高效合成 含有化合物的。本研究的总体目标是推进反应范围和 镍催化的烯烃氢胺化反应的催化剂效率。我们的研究策略 强调通过实验和计算深入了解反应机理 方法，将指导我们在氢胺化催化剂的优化和开发方面的努力。 力学上相关的氨基串联变换。我们建议的研究是基于 N-杂环卡宾(NHC)连接的镍配合物具有唯一性的中心假设 在低能垒下N-H键的活化和C-N键的形成的反应性，这解锁了 温和和中性条件下广泛的炔氢胺化反应及其催化过程 条件。我们已发表和未发表的结果证明了这项研究的可行性。 Ni/NHC催化的多种N-H亲核试剂催化的烯烃氢胺化反应 重要的杂芳胺，以及结构表征的新型镍-胺的反应性评价 具有酰胺类配体的NHC络合物。 以强劲的初步数据为指导，我们建议追求以下两个具体目标： (1)提高Ni/NHC催化的炔烃的范围和官能团的相容性 氢胺化反应。(2)明确了Ni/NHC催化的烯烃氢胺化反应机理。 我们提出的研究具有创新性，因为它旨在探索独特的键转换。 Ni/NHC络合物对炔氢胺化反应的活性。这些拟议研究的结果 具有重要意义，因为它们将提供新的高效催化方法来转化 合成与生物医学相关的含氮小分子的简单构件。

PROJECT SUMMARY Amines are ubiquitous subunits of biologically active compounds. Transition metal-catalyzed hydroamination enables atom-efficient synthesis of amines using readily available chemical feedstocks. Many classes of metal catalysts and ligands have been developed to facilitate hydroamination of alkynes, generating enamine and imine products that are valuable building blocks for nitrogen-containing molecules. In spite of these advances, catalytic alkyne hydroamination faces several major challenges including the high costs of catalysts that are largely based on precious metals, the common requirement of high reaction temperatures, as well as the long-standing hurdle of regiochemistry control. Overcoming these challenges would widen practical applications of catalytic alkyne hydroamination in biomedical research and drug synthesis. The long-term goal of our proposed research is to develop earth-abundant transition metal- based catalysts to promote selective and efficient synthesis of amines and other nitrogen- containing compounds. The overall objective of this research is to advance the reaction scope and catalyst efficiency for nickel-catalyzed alkyne hydroamination processes. Our research strategy emphasizes on in-depth reaction mechanism understanding by experimental and computational methods, which will guide our efforts on hydroamination catalyst optimization and development of mechanistically relevant aminative tandem transformations. Our proposed studies are based on the central hypothesis that N-heterocyclic carbene (NHC)-ligated nickel complexes possess unique reactivity of N-H bond activation and C-N bond formation at low energy barriers, which unlocks a broad scope of alkyne hydroamination and relevant catalytic processes under mild and neutral conditions. Feasibility of this research is demonstrated by our published and unpublished results on Ni/NHC-catalyzed alkyne hydroamination with various N-H nucleophiles including biomedically important heteroaryl-amines, as well as reactivity evaluation of structurally characterized novel Ni- NHC complexes with amide-type ligands. Guided by strong preliminary data, we propose to pursue the following two Specific Aims: (1) To advance the scope and functional group compatibility of Ni/NHC-catalyzed alkyne hydroamination. (2) To define the mechanism of Ni/NHC-catalyzed alkyne hydroamination. Our proposed research is innovative because it aims to exploit unique bond-transformation reactivity of Ni/NHC complexes for alkyne hydroamination. Results from these proposed studies are significant because they will provide new and efficient catalytic methods for transformations of simple building blocks to synthesize nitrogen-containing small molecules of biomedical relevance.