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.

项目摘要 胺是生物活性化合物的普遍存在的亚基。过渡金属催化 加氢胺化使得能够使用容易获得化学品 原料。已经开发了许多种类的金属催化剂和配体以促进 炔的氢化胺化，产生有价值的结构的烯胺和亚胺产物 用于含氮分子的块。尽管有这些进展，催化炔 加氢胺化面临几个主要挑战，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的 催化炔氢化胺化在生物医学研究和药物合成中的应用。 我们研究的长期目标是开发地球上丰富的过渡金属- 的催化剂，以促进胺和其它氮- 含有化合物。本研究的总体目标是提高反应范围， 用于镍催化的炔加氢胺化方法的催化剂效率。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，这将指导我们的努力，加氢胺化催化剂的优化和开发， 机械相关的胺化串联转化。我们提出的研究是基于 中心假设，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， 在温和和中性条件下的宽范围的炔加氢胺化及相关催化过程 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催化的炔与各种N-H亲核试剂的氢胺化反应，包括生物医学上的 重要的杂芳基胺，以及结构特征的新的Ni- 具有酰胺型配体的NHC络合物。 在强有力的初步数据的指导下，我们建议追求以下两个具体目标： (1)提高Ni/NHC催化炔的范围和官能团相容性 氢化胺化。(2)探讨Ni/NHC催化炔氢胺化反应的机理。 我们提出的研究是创新的，因为它旨在利用独特的键转换 Ni/NHC络合物对炔加氢胺化的反应性。这些拟议研究的结果 是重要的，因为它们将提供新的和有效的催化方法， 合成生物医学相关的含氮小分子的简单构建块。