Umpolung Amine Synthesis: Photocatalytic Generation of Nucleophilic Alpha-Amino Radicals

Umpolung 胺合成：光催化生成亲核 α-氨基自由基

• 批准号: 2112433
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2112433
• 关键词: Umpolung; Amine; Synthesis; Photocatalytic; Generation

Amines are ubiquitous motifs in organic chemistry, with applications extending into pharmaceuticals, agrochemicals, natural products and fine chemical research. For this reason, amine formation has been at the forefront of synthetic method development for decades, and has remained a key focal point in the establishment of contemporary methods. A significant proportion of these methods rely on the reductive chemistry of imines to afford complex amine architectures, with much well-established chemistry relying on the addition of various nucleophilic species to the electrophilic imine. For example, Grignard reagents are commonly added to imines to afford alpha-branched amines, and reductive amination (the addition of hydride) is a common technique to obtain simpler amines. This commonplace use of imines is largely due to the ease with which they may be synthesised from the corresponding anilines or alkyl amines and aldehydes or ketones. However, these techniques are inherently limited to the addition of nucleophilic species, and thus, many modern methods seek to use imines in an umpolung (reverse polarity) fashion.One such method, which has come to be of significant interest to the Dixon group in the past few years, is the generation of inherently-nucleophilic alpha-amino radical species. Such species have been shown to engage in radical-radical couplings, as well as in Giese-type additions to unsaturated olefins.The single electron reduction of imines to form alpha-amino radicals was first reported in a samarium-iodide-induced aza-pinacol coupling reported by Imamoto in 1990, and subsequent work proceeded to validate the alpha-amino radical as a viable reactive intermediate. However, the development of a catalytic method of single electron imine reduction was to come with the advancement of reductive photocatalytic methods. In this sense, the use of visible-light-activated photocatalysts allows for a controlled enhancement of the reactivity of imines, allowing them to participate in reactions that would otherwise be infeasible. Reports by the Dixon group, as well as Chen, demonstrated the feasibility of the reductive coupling of alpha-amino radical species with electrophiles in 2017, and it is upon this work that this project is based.Falling within the EPSRC Synthetic Organic Chemistry research area, the proposed project looks to develop methods of preparing amine-based architectures with increased structural complexity, by means of a photocatalytic approach. In the preliminary work undertaken, this has involved trapping alpha-amino radical species with intramolecular Michael acceptors, affording carbocyclic amine products. The project looks to expand this work to form structures that are of interest to pharmaceutical, agrochemical, and natural product chemistry alike.

胺是有机化学中普遍存在的基序，其应用延伸到药物、农用化学品、天然产物和精细化学研究中。因此，胺的形成几十年来一直处于合成方法发展的最前沿，并且仍然是建立当代方法的关键焦点。这些方法中的很大一部分依赖于亚胺的还原化学来提供复杂的胺结构，其中许多成熟的化学依赖于将各种亲核物质添加到亲电亚胺中。例如，格氏试剂通常被添加到亚胺中以提供α-支链胺，并且还原胺化（氢化物的添加）是获得更简单的胺的常用技术。亚胺的这种普遍使用主要是由于它们可以容易地由相应的苯胺或烷基胺和醛或酮合成。然而，这些技术本质上局限于亲核物质的加成，因此，许多现代方法寻求以反极性（umpolung）（反极性）方式使用亚胺。这类物种已被证明参与自由基-自由基偶联反应，以及对不饱和烯烃的Giese型加成反应。亚胺的单电子还原形成α-氨基自由基最早是在1990年由Imamoto报道的钐-碘诱导的氮杂-频哪醇偶联反应中报道的，随后的工作继续验证α-氨基自由基作为一种可行的反应中间体。然而，单电子亚胺还原的催化方法的发展是随着还原光催化方法的进步而出现的。在这个意义上，可见光活化的光催化剂的使用允许亚胺的反应性的受控增强，允许它们参与否则将不可行的反应。2017年，狄克逊团队和陈光诚团队的报告证明了α-氨基自由基与亲电试剂还原偶联的可行性，该项目正是基于这一工作而开展的。该项目属于EPSRC合成有机化学研究领域，旨在通过光催化方法开发制备结构复杂性增加的胺基结构的方法。在进行的初步工作中，这涉及用分子内迈克尔受体捕获α-氨基自由基物种，提供碳环胺产物。该项目旨在扩大这项工作，以形成对制药，农业化学和天然产物化学感兴趣的结构。