Iron-Catalysed Reductive Cross-Coupling

在亲核试剂和亲电试剂之间形成C-C键的传统交叉偶联方法是现代有机合成的主要方法。然而，当使用更强的亲核试剂（例如，熊田偶联中的格氏试剂）时，这些方法在官能团耐受性方面可能具有挑战性，限制了它们的合成效用。解决这一挑战的一种方法是还原交叉偶联，即两种不同的亲电试剂在金属催化剂（镍是最常见的）和末端还原剂的存在下偶联。相比之下，尽管铁催化在成本、毒性和可持续性方面具有优势，并且可能与镍还原交叉偶联产生新的/互补反应，但与铁的还原性交叉偶联仍然非常罕见。铁催化的还原偶联是合成化学的一个新兴领域，但与镍等金属相比，它仍然不发达。为了克服这一挑战，该项目利用Neidig小组开发的物理-无机方法来定义关键的铁种类和反应途径，从而使两种亲电试剂的选择性交叉偶联成为必要，以便开发更有效的铁基方法。反过来，这一基本见解将用于开发铁催化还原偶联的有利方法。本项目主要有三个目标：1)鉴定活性铁种类及糖酰氯和烯酰卤化物与简单铁盐还原交偶联的机理；2)确定了铁催化卤代烷对烯烃的还原交偶联反应机理，包括Xantphos在实现高收率中的作用；3)铁催化芳基亲电试剂还原交偶联体系的建立。方法：机制研究将集中在Koh和同事最近报道的糖基氯与不饱和亲电试剂（如烯基卤化物）的还原性交叉偶联的最新例子上。虽然这种方法广泛适用于在Mn作为末端还原剂的情况下，仅使用fe2作为催化剂合成多种c -糖苷，但导致亲电活化的原位形成的铁物种和交叉亲电偶联的机制仍未明确。进一步的机理研究将集中在与铁的还原性交叉偶联上，也可能将有机卤化物和烯烃偶联形成新的C-C键，例如Fu和同事报道的烷基亲电试剂和烯烃与铁的还原性交叉偶联。最后，该项目将利用对催化剂结构和机制的基本见解，开发新的定制配体和更广泛底物的还原交叉偶联方法，包括通过两个芳基亲电试剂的还原偶联形成芳基-芳基键。该项目属于EPSRC催化研究领域。>85%的化学产品都是通过至少一个催化步骤产生的（被EPSRC认可为“关键使能技术”），因此向可持续的地球丰富金属催化过渡是维持和确保英国未来在该领域优势的关键。

Traditional cross-coupling methods involving C-C bond formation between a nucleophile and electrophile are a staple of modern organic synthesis. However, these methods can be challenging in terms of functional group tolerance when stronger nucleophiles (ex. Grignard reagents in Kumada couplings) are employed, limiting their synthetic utility. One approach to this challenge is reductive cross-couplings, where two different electrophiles are coupled in the presence of a metal catalyst (nickel is the most common) and a terminal reductant. By contrast, reductive cross-couplings with iron remain extremely rare despite the benefits of iron catalysis in terms of cost, toxicity and sustainability and the potential for novel/complementary reactivities to nickel reductive cross-couplings. Iron-catalysed reductive couplings are an emerging area of synthetic chemistry, yet remain poorly developed compared to metals such as nickel. To overcome this challenge, this project with utilise the physical-inorganic methodology developed by the Neidig group to define the key iron species and reaction pathways that enable the selective cross-coupling of two electrophiles is essential in order to develop more effective iron-based methods. In turn, this foundational insight will be utilised to develop advantaged methods for iron-catalysed reductive couplings. The three objectives comprising this project are the following: 1) Identification of active iron species and mechanism of reductive cross-coupling of glycosyl chlorides and alkenyl halides with simple iron salts; 2) Definition of the mechanism of iron-catalysed reductive cross-coupling of alkyl halides para olefins, including the role of Xantphos in achieving high product yields; 3) Development of an iron-catalysed system for reductive cross-coupling of aryl electrophiles. Approach: Mechanistic studies will focus on the state-of-the-art example of reductive cross-coupling of glycosyl chlorides with unsaturated electrophiles (ex. alkenyl halides) recently reported by Koh and co-workers. While this method is broadly useful for the synthesis of a broad array of C-glycosides using only FeBr2 as a catalyst in the presence of Mn as a terminal reductant, the in situ formed iron species that lead to electrophile activation and the mechanism of cross-electrophile coupling remain undefined. Further mechanistic studies will focus on reductive cross-couplings with iron are also possible that couple an organohalide and an olefin to form a new C-C bond, exemplified by the reductive cross-coupling of alkyl electrophiles and olefins with iron-Xantphos reported by Fu and co-workers. Lastly, this project will leverage the fundamental insight into catalyst structure and mechanism to develop new bespoke ligands and methods for reductive cross-couplings of a broader range of substrates, including aryl-aryl bond formation via reductive couplings of two aryl electrophiles. This project falls within the EPSRC Catalysis research area. >85% of all chemical products are generated through at least one catalysed step (recognised by EPSRC as a "key enabling technology"), thus the transition to sustainable Earth-abundant metal catalysis is key to maintaining and ensuring the future of the UK's strength in this area.