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.

项目概要/摘要 有机合成化学对于制备用作药物和药物的复杂小分子至关重要。 新型成键化学品的发现推动了农用化学品的发展 反应开发研究允许使用更广泛的起始材料。 复杂分子结构的构建以及广泛使用的新片段偶联反应 可用的、工作台稳定的、生物学上普遍存在的有机官能团作为反应性手柄是高度 使用此类“天然”官能团（例如醇、羧酸和）的催化反应。 胺，可以立即广泛应用于小规模药物的药物化学环境中 发现和大规模工艺开发环境中，因为它们有更多的分子机会 在拟议的研究中，一种新的方法是实现多样化和降低相关原材料的成本。 将开发胺的反应流形，使其能够用作亲电烷基化试剂 C-C 键形成反应以氨为唯一副产物，这与它们的传统反应性形成鲜明对比。 概况，其仅限于在 C-N 键形成反应中用作亲核试剂，双催化方法是。 提出将使用强还原性光氧化还原催化剂将单个电子转移到 烷基铵阳离子形成不稳定的中性铵基，通常是高价基团。 通过N-H键均裂失去氢原子而分解，自分解后产生氢气 然而，有人提出烷基铵之间存在多个氢键相互作用。 阳离子和冠醚型有机催化剂可用于稳定氨作为离去基团和 使反应途径偏向C-N键均裂，释放出合成上有用的烷基自由基并 由此产生的烷基自由基将被C-C中的有机和无机自由基亲和物捕获。 通过共轭加成、自由基芳族取代和过渡反应进行成键反应 金属共催化交叉偶联途径自由基烷基的中介作用使得该方法成为可能。 高度模块化，预计可以采用多种光氧化还原 C-C 耦合方法 开发了将还原性 C-N 活化与氧化性 C-CO2-、C-OH 和 C-H 活化相结合的技术。