Late stage C-H functionalization and C-C/N coupling enabled by new strategies for electrochemically-controlled radical formation

电化学控制自由基形成的新策略实现了后期C-H功能化和C-C/N耦合

• 批准号: 10388445
• 负责人: Christo Sevov
• 金额: $ 8.78万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388445
• 关键词: Alkylation; Amination; Amines; Award; Carboxylic Acids; Catalysis; Chlorides; Complement; Complex; Coupling; Decarboxylation; Electrochemistry; Electrolyses; Electron Transport; Epoxy Compounds; Ethers; Event; Goals; Hydrogen Bonding; Intercept; Ligands; Mediating; Metals; Methodology; Modification; Natural Products; Organic Synthesis; Organometallic Chemistry; Oxidants; Oxides; Parents; Pharmacologic Substance; Physiologic pulse; Preparation; Reaction; Reagent; Research; Research Proposals; Side; Site; System; Techniques; Therapeutic Agents; Work; base; catalyst; cost; next generation; novel therapeutics; oxidation; programs

Project Summary The proposed research seeks to develop metal-catalyzed C–C and C–N bond-forming methodologies that streamline organic synthesis by leveraging the unique control that electrochemistry provides over electron trans- fer events. In particular, this work will develop synthetic methodologies based on dual-catalyst systems. One catalyst is electrochemically activated to mediate the formation of alkyl radicals, while a second catalyst selec- tively activates the complementary substrate to effect coupling with the electrogenerated radicals. The long-term goal of this program is to establish electrochemistry as a standard synthetic strategy in a way that complements the successful integration of photoredox catalysis into organic synthesis: another dual-catalyst system that relies on one catalyst to promote electron transfer and a second to mediate bond-forming reactions. The proposed research relies on the merger of multiple scientific fields to develop next-generation methodologies in organic synthesis. The Sevov team has a unique combination of expertise in synthetic methodology, mecha- nistic organometallic chemistry, and homogeneous electrochemistry that will lead to new synthetic strategies that impact both the rate of discovery and large-scale synthesis of new therapeutic agents. These strategies and the targeted transformations of the proposal are summarized below: Goal 1. to develop C–C and C–N coupling reactions with alkyl electrophiles: Electrochemically-driven cross-coupling will be developed using a dual-catalyst system that allows each substrate to be activated by a distinct catalyst. Dedicated electrocatalysts will be developed that mediate formation of alkyl radicals from alkyl halides or ethers/epoxides. The radical intermediates will be intercepted and functionalized by co-catalysts that exclusively (i) activate aryl chlorides and ethers to form alkyl arenes, (ii) mediate C–N coupling from high-valent complexes to form amines, or (iii) utilize chiral nonracemic ligands to enable enantioselective C–C/N coupling. Goal 2. to develop C(sp3)–H bond alkylation/arylation and amination: Aliphatic C–H bond activation will be accomplished via directed H-atom abstraction (HAA) from a tethered aryl radical. Aryl radicals will be generated by electroreduction of Ni(II)aryl intermediates to form low-valent organonickel(I) complexes that are susceptible to Ni–C bond homolysis. Radical relay by HAA from the aryl directing group to the alkyl side-chain provides access to an activated aliphatic site for C–X coupling. Goal 3. to develop decarboxylative functionalization of carboxylic acids: The first of two complementary approaches will investigate pulsed-electrolysis techniques to enable decarboxylation at potentials that are mild and compatible with catalysts for selective C-C/N/X of the resulting alkyl radicals. A second approach will utilize electrocatalysts that are photoactive upon oxidation at mild potentials. Photoexcitation of the oxidized species will transiently generate a high energy oxidant that can effect oxidative decarboxylation to form alkyl radicals.

项目概要 拟议的研究旨在开发金属催化的 C-C 和 C-N 键形成方法， 通过利用电化学对电子反式提供的独特控制来简化有机合成 fer 事件。特别是，这项工作将开发基于双催化剂系统的合成方法。一 催化剂被电化学激活以介导烷基自由基的形成，而第二种催化剂则选择 主动激活互补底物以实现与电产生的自由基的偶联。 该计划的长期目标是以某种方式将电化学建立为标准合成策略 补充了光氧化还原催化在有机合成中的成功整合：另一种双催化剂 该系统依靠一种催化剂来促进电子转移，另一种催化剂来介导成键反应。 拟议的研究依赖于多个科学领域的合并来开发下一代方法 在有机合成中。 Sevov 团队在合成方法学、机械学等方面拥有独特的专业知识组合。 本质有机金属化学和均相电化学将带来新的合成策略 这会影响新治疗药物的发现速度和大规模合成。这些策略和 该提案的目标改造概述如下： 目标 1. 开发与烷基亲电子试剂的 C-C 和 C-N 偶联反应：电化学驱动 交叉偶联将使用双催化剂系统进行开发，该系统允许每个底物被 独特的催化剂。将开发专用电催化剂来介导从烷基形成烷基自由基 卤化物或醚/环氧化物。自由基中间体将被助催化剂拦截并官能化， 仅 (i) 活化芳基氯和醚形成烷基芳烃，(ii) 介导高价键的 C-N 偶联 配合物形成胺，或 (iii) 利用手性非外消旋配体实现对映选择性 C-C/N 偶联。 目标 2. 开发 C(sp3)–H 键烷基化/芳基化和胺化：脂肪族 C–H 键活化 通过从束缚的芳基中直接提取氢原子（HAA）来完成。会产生芳基自由基 通过电还原 Ni(II) 芳基中间体形成易受影响的低价有机镍 (I) 配合物 Ni-C 键均裂。 HAA 从芳基导向基团到烷基侧链的自由基中继提供了 访问活化的脂肪族位点进行 C-X 偶联。 目标 3. 开发羧酸的脱羧功能化：两个互补的第一个 方法将研究脉冲电解技术，以在温和的电位下实现脱羧 并与所得烷基的选择性 C-C/N/X 催化剂相容。第二种方法将利用 在温和电位下氧化时具有光活性的电催化剂。氧化物质的光激发 将瞬时产生高能氧化剂，可实现氧化脱羧形成烷基自由基。