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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， 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团队拥有独特的合成方法学，机械， 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。

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.