Mechanism driven, divergent iron-catalysed C-H functionalisation Luke Britton a , Gary S. Nichol a , Andrew P. Dominey b and Stephen P. Thomas* a a University of Edinburgh, UK, b GSK Medicines Research Centre, UK
Direct C–H functionalisation reactions offer a sustainable method for molecular construction and diversification, 1,2 however, these reactions remain dominated by the use of precious metal catalysts. Due to their high abundance, inexpensiveness, and low toxicities, Earth-abundant metal alternatives have gained significant interest. 3 This poster will present our mechanistic studies on the iron-catalysed C-H functionalisation of carboarenes, heteroarenes, and alkenes. We have isolated and characterised (solution- and solid state) the key iron-aryl, and for the first time, iron-alkenyl C-H metallation products. These species have been shown to be on-cycle and enabled divergent C-H functionalisation to be achieved for C-H borylation, 4,5 or hydrogen isotope exchange (HIE) reactions. 6 Alongside this, a novel activation method was revealed whereby the catalytically active iron dihydride was generated in the absence of a hydride source. 6 Using pinacolborane (HBpin), we were able to catalyse the C-H borylation reaction of carboarenes and heteroarenes with the largest functional group tolerance of any Earth-abundant metal catalysed C-H borylation reaction (including amines, alcohols, silanes, phosphonates, esters, and amides). Reactivity was demonstrated across 50 examples and orthogonal selectivity was observed to precious metal catalysed C-H borylation. Further fundamental studies gave insight into observed side reactivity. 4,5 Chemo- and regioselective HIE reactions were enabled by simply swapping HBpin for CD 3 OD. HIE exchange reactions of heteroarenes and, for the first time, alkenes, gave up to 97% “D” incorporation across 38 examples including complex natural products and pharmaceuticals (including caffeine, cimetidine, ketoconazole, and quinine). 6 Most significantly, mechanistic investigations led to the first and only example of an iron-alkenyl complex isolated and characterised in the solid-state. Additionally, we have identified a new mechanism for the formation of the catalytically active iron-dihydride using alcohols as the hydride source. The broad reactivity, mechanistic understanding, and operational simplicity of these catalytic protocols provides a platform for the wider adoption of sustainable, Earth-abundant metal catalysts. References 1. Seregin, I. V.; Gevorgyan, V., Direct transition metal-catalyzed functionalization of heteroaromatic compounds. Chem. Soc. Rev. 2007, 36 , 1173-1193. 2. Díaz-Requejo, M. M.; Pérez, P. J., Coinage Metal Catalyzed C−H Bond Functionalization of Hydrocarbons. Chem. Rev. 2008, 108 , 3379-3394. 3. Egorova, K. S.; Ananikov, V. P., Which Metals are Green for Catalysis? Comparison of the Toxicities of Ni, Cu, Fe, Pd, Pt, Rh, and Au Salts. Angew. Chem. Int. Ed. 2016, 55 , 12150-12162. 4. Britton, L .; Docherty, J. H.; Dominey, A. P.; Thomas, S. P., Iron-Catalysed C(sp 2 )-H Borylation Enabled by Carboxylate Activation. Molecules 2020, 25 , 905. 5. Britton, L .; Docherty, J. H.; Nichol, G. S.; Dominey, A. P.; Thomas, S. P., Iron-catalysed C(sp 2 )-H Borylation with Expanded Functional Group Tolerance. Chin. J. Chem . 2022 . 6. Britton, L .; Docherty, J. H.; Sklyaruk, J.; Cooney, J.; Nichol, G. S.; Dominey, A. P.; Thomas, S. P., Iron-catalysed Alkene and Heteroarene H/D Exchange by Reversible Protonation of Iron-hydride Intermediates. Chem. Sci. 2022, 13 , 10291-10298.
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© The Author(s), 2022
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