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

胺是有机化学中普遍存在的主题，广泛应用于制药、农用化学品、天然产物和精细化学研究。由于这个原因，几十年来，胺的形成一直处于合成方法发展的前沿，并一直是建立当代方法的关键焦点。这些方法中有很大一部分依赖于亚胺的还原化学来提供复杂的胺结构，而许多成熟的化学依赖于在亲电亚胺中添加各种亲核物种。例如，格氏试剂通常被添加到亚胺中以获得α-支化胺，而还原胺化(氢化物的添加)是获得更简单的胺的常见技术。亚胺的这种常见用途在很大程度上是因为它们可以很容易地从相应的苯胺或烷基胺和醛或酮中合成。然而，这些技术本质上仅限于亲核物种的添加，因此，许多现代方法寻求以反极性的方式使用亚胺。其中一种方法是生成固有的亲核α-氨基物种，这在过去几年引起了Dixon小组的极大兴趣。这些物种已经被证明参与了自由基-自由基偶联以及不饱和烯烃的Giese类型的加成。Imamoto在1990年首次报道了亚胺的单电子还原形成α-氨基的偶联反应，随后的工作证实了α-氨基是一种可行的反应中间体。然而，单电子亚胺还原催化方法的发展是伴随着还原光催化方法的发展而来的。从这个意义上说，使用可见光激活的光催化剂可以控制地增强亚胺的反应活性，使它们能够参与原本不可能进行的反应。Dixon小组和Chen的报告在2017年证明了α-氨基物种与亲电分子还原偶联的可行性，该项目正是基于这一工作。该项目落在EPSRC合成有机化学研究领域内，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，这涉及到用分子内迈克尔受体捕获α-氨基物种，提供碳环胺产品。该项目希望扩大这项工作，以形成对制药、农用化学品和天然产品化学都感兴趣的结构。

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.