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: 10453666
• 负责人: Christo Sevov
• 金额: $ 36.55万
• 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/10453666
• 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， 通过利用电化学提供的对电子反式的独特控制， 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 催化剂被电化学活化以介导烷基自由基的形成，而第二催化剂选择性地被电化学活化， 有效地激活互补基底以实现与电生自由基的耦合。 该计划的长期目标是建立电化学作为一种标准的合成策略， 补充了光氧化还原催化与有机合成的成功整合：另一种双催化剂 依靠一种催化剂促进电子转移和第二种催化剂介导成键反应的系统。 拟议的研究依赖于多个科学领域的合并，以开发下一代方法 在有机合成中。Sevov团队在合成方法学、机械方面拥有独特的专业知识组合 nistic有机金属化学，均相电化学，将导致新的合成策略 这影响了新治疗药物的发现率和大规模合成。这些战略和 该提案的有针对性的转变概述如下： 目标1.开发与烷基亲电试剂的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来开发，该系统允许每个底物被 独特的催化剂。将开发专用的电催化剂，其介导由烷基形成烷基自由基。 卤化物或醚/环氧化物。自由基中间体将被共催化剂拦截和官能化， 仅（i）活化芳基氯化物和醚以形成烷基芳烃，（ii）从高价 络合物以形成胺，或（iii）利用手性非外消旋配体以实现对映选择性C-C/N偶联。 目标2.开发C（sp3）-H键烷基化/芳基化和胺化：将脂肪族C-H键活化 通过从束缚的芳基中直接提取H原子（HAA）来完成。会产生芳基自由基 通过电还原Ni（II）芳基中间体以形成低价有机镍（I）络合物， Ni-C键均裂。通过HAA从芳基导向基团到烷基侧链的自由基中继提供了 接近用于C-X偶联的活化脂族位点。 目标3.开发羧酸的脱羧官能化：两个互补的第一个 方法将研究脉冲电解技术，使脱羧电位是温和的， 并且与用于所得烷基的选择性C-C/N/X的催化剂相容。第二种方法将利用 电催化剂在温和电位下氧化时是光活性的。氧化物种的光激发 将瞬时产生高能氧化剂，其可实现氧化脱羧以形成烷基自由基。