Nickel-Catalyzed Alkyne Hydroamination for Efficient Amine Synthesis

镍催化炔氢胺化用于高效胺合成

• 批准号: 10292302
• 负责人: Pinjing Zhao
• 金额: $ 41.48万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292302
• 关键词: Acids; Alkenes; Alkynes; Amides; Amines; Aminopyridines; Biological; Biomedical Research; Characteristics; Chemicals; Complex; Computing Methodologies; Data; Development; Evaluation; Face; Goals; Hydrogen Bonding; Imines; Investigation; Kinetics; Lanthanoid Series Elements; Lead; Ligands; Mediating; Medical; Metals; Methods; Natural Product Drug; Nickel; Nitrogen; Organometallic Chemistry; Pathway interactions; Planet Earth; Process; Publishing; Reaction; Reagent; Reporting; Research; Role; Science; Structure; System; Temperature; Testing; Transition Elements; Work; base; carbene; catalyst; cost; design; drug development; drug synthesis; feasibility research; functional group; innovation; method development; novel; pi bond; practical application; research and development; small molecule

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.

项目概要 胺是生物活性化合物中普遍存在的亚基。过渡金属催化 加氢胺化能够使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以促进 炔烃的加氢胺化，生成有价值的建筑用烯胺和亚胺产品 含氮分子的块。尽管取得了这些进展，催化炔烃 加氢胺化面临着几个重大挑战，包括催化剂的高成本 基于贵金属，高反应温度的共同要求，以及 区域化学控制的长期障碍。克服这些挑战将扩大实际应用范围 催化炔氢氨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地球上丰富的过渡金属- 基于催化剂促进胺和其他氮的选择性和高效合成 含有化合物。本研究的总体目标是提高反应范围和 镍催化炔氢胺化过程的催化剂效率。我们的研究策略 强调通过实验和计算深入理解反应机理 方法，这将指导我们在加氢胺化催化剂的优化和开发方面的努力 机械相关的主动串联转变。我们提出的研究基于 中心假设是N-杂环卡宾（NHC）连接的镍配合物具有独特的 在低能垒下 N-H 键活化和 C-N 键形成的反应性，这解锁了 温和和中性条件下的广泛的炔氢胺化和相关催化过程 状况。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 催化的炔氢胺化与各种 N-H 亲核试剂（包括生物医学） 重要的杂芳基胺，以及结构特征新颖的 Ni- 的反应性评估 NHC 与酰胺型配体形成复合物。 在强有力的初步数据的指导下，我们建议实现以下两个具体目标： (1) 提高Ni/NHC催化炔烃的适用范围和官能团相容性 加氢氨化。 (2)明确Ni/NHC催化的炔氢胺化反应机理。 我们提出的研究具有创新性，因为它旨在利用独特的键转化 Ni/NHC 配合物对炔氢胺化的反应活性。这些拟议研究的结果 意义重大，因为它们将为转化提供新的、有效的催化方法 用于合成具有生物医学相关性的含氮小分子的简单构建模块。