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: 10028826
• 负责人: Christo Sevov
• 金额: $ 32.93万
• 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/10028826
• 关键词: Alkylation; Amination; Amines; 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; 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.

项目摘要 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变速器提供的独特控制，通过利用有机合成 事件。特别是，这项工作将基于双催化剂系统开发合成方法。一 催化剂在电化学上被激活以介导烷基自由基的形成，而第二催化剂选择 - Timely激活完整的底物，以与电矿自由基耦合。 该计划的长期目标是以某种方式建立电化学作为标准合成策略 这完成了将光毒素催化成功整合到有机合成中的：另一种双催化剂 依靠一种催化剂来促进电子转移的系统，第二个系统介导形成键的反应。 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团队在合成方法论方面具有独特的专业知识，Mecha- 有机化学和均质的电化学，将导致新的合成策略 这会影响新治疗剂的发现率和大规模合成。这些策略和 该提案的目标转换如下： 目标1。与烷基电物质开发C – C和C-N偶联反应：电化学驱动 交叉耦合将使用双催化剂系统开发，该系统允许每个底物通过 独特的催化剂。将开发专用的电催化剂，该烷基从烷基介导的烷基自由基形成 卤化物或醚/环氧化物。自由基中间体将被共同催化剂拦截和功能化 仅（i）激活芳基氯化物和醚形成烷基芳烃，（ii）介导高价值的C – N偶联 形成胺的复合物，或（iii）利用手性非流行配体来实现对映选择性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键激活将为 通过束缚芳基自由基的定向H原子抽象（HAA）完成。将产生芳基自由基 通过ni（ii）芳基中间体的电化，形成了易感的低价孔（I）配合物 到Ni – C键同型。 HAA从芳基指导组到烷基侧链的激进继电器提供 访问激活的脂肪族位点进行C – X耦合。 目标3。开发羧酸的脱羧官能化：两个完整的羧酸 方法将研究脉冲 - 电解技术以在中间的电势下实现脱羧 并与所得烷基自由基的选择性C-C/N/X催化剂兼容。第二种方法将使用 在轻度电势下氧化时具有光活性的电催化剂。氧化物种的光激发 将瞬时产生高能氧化剂，该氧化剂可以影响氧化脱羧以形成烷基自由基。