Photoredox-Enabled Applications of Primary Amines as Alkylating Reagents

伯胺作为烷基化试剂的光氧化还原应用

• 批准号: 9978569
• 负责人: Jacob Geri
• 金额: $ 6.17万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978569
• 关键词: Affinity; Agrochemicals; Alcohols; Alkenes; Alkynes; Amines; Amino Acids; Ammonia; Ammonium; Architecture; Azides; Binding; Biological; Carbon; Carbon Dioxide; Carboxylic Acids; Catalysis; Cations; Chemicals; Chemistry; Complement; Complex; Copper; Coupling; Crown Ethers; Development; Diazomethane; Electron Transport; Electrons; Esters; Ethers; Gases; Goals; Hydrogen; Hydrogen Bonding; Lead; Methodology; Molecular; Natural Products; Nature; Organic Chemistry; Organic Synthesis; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Process; Reaction; Reagent; Research; Structure; System; Time; Transition Elements; Variant; Vertebral column; Work; base; c new; catalyst; chemical reaction; cost; drug discovery; drug efficacy; functional group; improved; side effect; skeletal; small molecule; tertiary amine

PROJECT SUMMARY/ABSTRACT Synthetic organic chemistry is essential for the preparation of complex small molecules used as drugs and agrochemicals, and advances in this field are driven by the discovery of new types of bond-forming chemical reactions. Research in reaction development allows wider pools of starting materials to be used for the construction of complex molecular architectures, and new fragment-coupling reactions which use widely available, bench stable, and biologically prevalent organic functional groups as reactive handles are highly impactful. Catalytic reactions that use such “native” functional groups, such as alcohols, carboxylic acids, and amines, can be immediately and widely deployed in medicinal chemistry settings for both small-scale drug discovery and in large-scale process development settings because of their greater opportunities for molecular diversification and the lower cost of the associated starting materials. In the proposed research, a new reactivity manifold for amines will be developed that will enable their use as electrophilic alkylating reagents in C-C bond forming reactions with ammonia as the sole byproduct. This contrasts with their traditional reactivity profile, which is limited to their use as nucleophiles in C-N bond forming reactions. A dual-catalysis approach is proposed which will use a strongly reducing photoredox catalyst to transfer a single electron to an alkylammonium cation to form an unstable, neutral ammonium radical. Typically, such hypervalent radicals decompose through loss of hydrogen atoms through N-H bond homolysis to generate hydrogen gas after self- annihilation. However, it is proposed that multiple hydrogen bonding interactions between an alkylammonium cation and a crown ether-type organocatalyst can be exploited to stabilize ammonia as a leaving group and bias the reaction pathway towards C-N bond homolysis, releasing a synthetically useful alkyl radical and ammonia. The alkyl radical thus generated will then be captured by organic and inorganic radicalphiles in C-C bond forming reactions proceeding through conjugate addition, radical aromatic substitution, and transition- metal cocatalyzed cross-coupling pathways. The intermediacy of a free alkyl radical makes this methodology highly modular, and it is anticipated that a wide variety of photoredox C-C coupling methodologies can be developed which will merge reductive C-N activation with oxidative C-CO2-, C-OH, and C-H activation.

项目摘要/摘要 合成有机化学是制备用作药物和药物的复杂小分子的关键 农用化学品，以及这一领域的进展是由新型成键化学品的发现推动的 反应。反应开发方面的研究允许更广泛的起始材料池用于 构建复杂的分子结构和应用广泛的新型片段偶联反应 有效的、稳定的和生物上普遍存在的有机官能团，作为反应性手柄是高度 很有影响力。使用这种“天然”官能团的催化反应，如醇、羧酸和 胺，可以立即和广泛地部署在药物化学环境中，用于两种小规模药物 发现并在大规模过程开发环境中，因为他们有更大的分子机会 多样化和相关起始材料的较低成本。在拟议的研究中，一项新的 将开发胺的反应歧管，使其能够用作亲电的烷基化试剂 以氨为唯一副产物的C-C键形成反应。这与他们传统的反应能力形成了鲜明对比。 仅限于它们在C-N键形成反应中作为亲核剂的用途。一种双重催化方法是 建议使用强还原光氧化还原催化剂将单电子转移到 烷基铵阳离子形成一种不稳定的中性氨基。通常，这样的超价自由基 通过N-H键均解损失氢原子分解生成氢气 歼灭。然而，有人认为烷基铵之间的多重氢键相互作用 阳离子和冠醚型有机催化剂可以用来稳定作为离开基团的氨和 使反应路径偏向C-N键均解，释放一种合成有用的烷基自由基和 氨水。这样产生的烷基随后将被C-C中的有机和无机亲基捕获 键形成反应通过共轭加成、自由基芳烃取代和过渡- 金属共催化的交叉偶联途径。游离烷基团的中间性使得这种方法 高度模块化，预计各种各样的光氧化还原C-C耦合方法可以 开发了一种将还原C-N活化与氧化C-CO2-、C-OH和C-H活化相结合的方法。