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
- 来源:
- 关键词:AccelerationAlkylationAminationAminesCarboxylic AcidsCatalysisChloridesComplementComplexCouplingDecarboxylationDedicationsElectrochemistryElectrolysesElectron TransportEpoxy CompoundsEthersEventGoalsHydrogen BondingInterceptLigandsMediatingMetalsMethodologyModificationNatural ProductsOrganic SynthesisOrganometallic ChemistryOxidantsPharmacologic SubstancePhysiologic pulsePredispositionPreparationReactionReagentResearchResearch ProposalsSiteSystemTechniquesTherapeutic AgentsWorkcatalystcostnext generationnovel therapeuticsoxidationprograms
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
这项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传递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
催化剂是电化学活化的,以介导烷基自由基的形成,而第二种催化剂选择-
有效地激活互补底物以实现与电生自由基的偶联。
该计划的长期目标是在某种程度上将电化学确立为标准的合成策略
这是对光氧化还原催化与有机合成成功结合的补充:另一种双催化剂
一种依靠一种催化剂促进电子转移,另一种催化剂促进成键反应的体系。
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。塞沃夫团队在合成方法论、机械--
自然有机金属化学和均相电化学将导致新的合成策略
这既影响了新治疗剂的发现速度,也影响了新治疗剂的大规模合成。这些战略和
该提案的目标转型摘要如下:
目标1.发展与烷基亲电体的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,该系统允许每个衬底通过
独特的催化剂。将开发专用的电催化剂,以促进烷基生成烷基
卤化物或醚/环氧化物。自由基中间体将被辅助催化剂截取和功能化,
唯一的(I)活化芳基氯化物和醚形成烷基芳烃,(Ii)从高价碳-氮偶联。
或(Iii)利用手性非外消旋配体实现对映体选择性的C-C/N偶联。
目标2.发展C(SP3)-H键烷基化/芳基化和胺化:脂肪族C-H键的活化
通过直接从系留芳基上提取氢原子(HAA)完成。将生成芳基自由基
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)络合物
对Ni-C键的均解。通过HAA从芳基定向基团到烷基侧链的自由基继电提供
进入C-X偶联的活化脂肪族部位。
目标3.发展羧酸的脱羧基功能化:两个互补中的第一个
将研究脉冲电解技术,使其能够在温和的电位下进行脱羧化
并与生成的烷基的选择性C-C/N/X催化剂兼容。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。氧化物种的光激发
会瞬间产生一种高能氧化剂,可以影响氧化脱羧基形成烷基自由基。
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.
- DOI:10.1021/jacs.1c02103
- 发表时间:2021-04-28
- 期刊:
- 影响因子:15
- 作者:Walker BR;Manabe S;Brusoe AT;Sevov CS
- 通讯作者:Sevov CS
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
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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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