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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

基本信息

批准号：
10663182
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
项目类别：
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

项目摘要

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。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Persistent organonickel complexes as general platforms for Csp2-Csp3 coupling reactions.

DOI：
10.1038/s41557-024-01528-7
发表时间：
2024-04
期刊：
Nature chemistry
影响因子：
21.8
作者：
Long P. Dinh;Hunter F Starbuck;Taylor B. Hamby;Matthew J. LaLama;C. Q. He;D. Kalyani;C. Sevov
通讯作者：
Long P. Dinh;Hunter F Starbuck;Taylor B. Hamby;Matthew J. LaLama;C. Q. He;D. Kalyani;C. Sevov

Mediator-Enabled Electrocatalysis with Ligandless Copper for Anaerobic Chan-Lam Coupling Reactions.