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:
  • 金额:
    $ 36.55万
  • 依托单位:
  • 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:
  • 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.
Synergistic Catalyst-Mediator Pairings for Electroreductive Cross-Electrophile Coupling Reactions.
  • DOI:
    10.1021/acscatal.1c05144
  • 发表时间:
    2022-01
  • 期刊:
  • 影响因子:
    12.9
  • 作者:
    Jordan L S Zackasee;Samir Al Zubaydi;Blaise L Truesdell;C. Sevov
  • 通讯作者:
    Jordan L S Zackasee;Samir Al Zubaydi;Blaise L Truesdell;C. Sevov
Controlling Ni redox states by dynamic ligand exchange for electroreductive Csp3-Csp2 coupling.
  • DOI:
    10.1126/science.abo0039
  • 发表时间:
    2022-04-22
  • 期刊:
  • 影响因子:
    56.9
  • 作者:
    Hamby, Taylor B.;LaLama, Matthew J.;Sevov, Christo S.
  • 通讯作者:
    Sevov, Christo S.
Catalyst-controlled functionalization of carboxylic acids by electrooxidation of self-assembled carboxyl monolayers.
  • DOI:
    10.1038/s41467-022-28992-4
  • 发表时间:
    2022-03-14
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Hintz HA;Sevov CS
  • 通讯作者:
    Sevov CS
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Christo Sevov其他文献

Christo Sevov的其他文献

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{{ truncateString('Christo Sevov', 18)}}的其他基金

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
  • 财政年份:
    2020
  • 资助金额:
    $ 36.55万
  • 项目类别:
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:
    10222733
  • 财政年份:
    2020
  • 资助金额:
    $ 36.55万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 36.55万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 36.55万
  • 项目类别:

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DNA 中化学不稳定烷基化损伤的研究
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