Iron-catalysed H/D exchange enabled by reversible protonation of iron-hydride intermediates Luke Britton 1 , Jamie H. Docherty 1 , Jan Sklyaruk 1 , Jessica Cooney 1 , Gary S. Nichol 1 , Andrew P. Dominey 2 , Stephen P. Thomas 1 1 University of Edinburgh, UK, 2 GSK Medicines Research Centre, Stevenage, UK Metal-catalysed C-H functionalisation, often referred to as C-H activation, has emerged as a powerful synthetic method for the direct derivatisation of typically inert C-H bonds. 1 While the application of C-H functionalisation strategies has expanded, these methods generally rely on precious metal catalysis. Earth-abundant metal, 2 and even non-metal, 3 catalysts have emerged as potential alternatives, however their use and development remains limited. We have developed an iron-catalysed C(sp 2 )-H H/D exchange reaction of heteroarenes and, for the first time, alkenes. 4 We have used an operationally simple in situ catalyst activation method to forego the need for air- and moisture-sensitive reagents/catalysts and used CD 3 OD as the deuterium source. 5,6 Mechanistic studies revealed an in situ generated iron hydride, a new route to the formation of this iron hydride, and solid-state characterisation of iron-aryl and the first iron-alkenyl C-H metallation product. Up to 97% “D” incorporation across 38 examples including complex natural products and pharmaceuticals was achieved. The reactivity and practicality of this iron- catalysed system provides a promising advance in the broader use and adoption of sustainable Earth-abundant metal catalysts.
References 1. Yamaguchi, J.; Yamaguchi, A. D.; Itami, K., C-H Bond Functionalization: Emerging Synthetic Tools for Natural Products and Pharmaceuticals. Angew. Chem. Int. Ed. 2012, 51, 8960-9009. 2. Gandeepan, P.; Muller, T.; Zell, D.; Cera, G.; Warratz, S.; Ackermann, L., 3d Transition Metals for C-H Activation. Chem. Rev. 2019, 119, 2192-2452. 3. Légaré, M.-A.; Courtemanche, M.-A.; Rochette, É.; Fontaine, F.-G., Metal-free catalytic C-H bond activation and borylation of heteroarenes. Science 2015, 349, 513-516. 4. 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. 5. 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. 6. Britton, L.; Skrodzki, M.; Nichol, G. S.; Dominey, A. P.; Pawluć, P.; Docherty, J. H.; Thomas, S. P., Manganese-Catalyzed C(sp 2 )–H Borylation of Furan and Thiophene Derivatives. ACS Catal. 2021, 11, 6857-6864
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