Iron-Catalysed Reductive Cross-Coupling

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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.