Modular photocatalytic synthesis of α-trialkyl α-tertiary amines Milo Smith * , J. Henry Blackwell, Georgia R. Harris*, Matthew J. Gaunt 1 University of Cambridge, UK, *These authors contributed equally Alkylamines are valuable motifs that feature in over 40% of pharmaceutical agents and have profound influence over biological activity. 1 The development of new catalytic methods for the facile preparation of complex amines is therefore an important goal in contemporary organic chemistry. 2 α-Trialkyl-α-tertiary amines (α-trialkyl- ATAs) 3,4 – amines with an α-carbon bearing three C–C bonds to aliphatic substituents – represent a subclass of amine that remains particularly challenging to synthesise, despite having proven application in a therapeutic context; examples of α-trialkyl-ATA-containing therapeutic agents include fingolimod (multiple sclerosis),Elayta (Alzheimer’s disease),CCT128930 (AKT inhibitor),and virantmycin (antiviral). In this work, 5 we developed a modular photocatalytic method for the synthesis of α-trialkyl-ATAs from three commercially available feedstock components: benzylic primary amines, dialkyl ketones and olefin acceptors. This operationally straightforward process exploits the well-established union of primary amines and ketones to form ketimines, which undergo single-electron reduction under our conditions to form a reactive α-amino radical. 6,7 Radical addition to the alkene followed by 1,5-hydrogen atom transfer from the benzylic C–H of the amine scaffold gives a benzylic α-amino radical, which is oxidised by the photocatalyst to deliver the product α-trialkyl-ATA and close the catalytic cycle. This redox-relay mechanism circumvents the need for an exogenous reductant and results in a particularly simple reaction system. Using this methodology it was possible to prepare over 50 new α-trialkyl- ATAs, with excellent functional group tolerance across all three components. These included heterocycles such as tetrahydronaphthyridines, 8 which are valuable but underexplored motifs in medicinal chemistry, as well as a single-step synthesis of Novartis’ multibillion dollar multiple sclerosis drug fingolimod from commercially available starting materials. References 1. Roughley, S. D.; Jordan, A. M. The Medicinal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates. J. Med. Chem. 2011 , 54 , 3451–3479. 2. Trowbridge, A.; Walton, S. M.; Gaunt, M. J. New Strategies for the Transition-Metal Catalyzed Synthesis of Aliphatic Amines. Chem. Rev. 2020 , 120 , 2613–2692. 3. Clayden, J.; Donnard, M.; Lefranc, J.; Tetlow, D. J. Quaternary Centres Bearing Nitrogen (α-Tertiary Amines) as Products of Molecular Rearrangements. Chem. Commun. 2011 , 47 , 4624–4639. 4. Hager, A.; Vrielink, N.; Hager, D.; Lefranc, J.; Trauner, D. Synthetic Approaches towards Alkaloids Bearing α-Tertiary Amines. Nat. Prod. Rep. 2016 , 33 , 491−522. 5. Blackwell, J. H.; Harris, G. R.; Smith, M. A.; Gaunt, M. J. Modular Photocatalytic Synthesis of α-Trialkyl-α-Tertiary Amines. J. Am. Chem. Soc. 2021 , 143 , 15946–15959. 6. Trowbridge, A.; Reich, D.; Gaunt, M. J. Multicomponent Synthesis of Tertiary Alkylamines by Photocatalytic Olefin- Hydroaminoalkylation. Nature 2018 , 561 , 522–527. 7. Leitch, J. A.; Rossolini, T.; Rogova, T.; Maitland, J. A. P.; Dixon, D. J. α-Amino Radicals via Photocatalytic Single-Electron Reduction of Imine Derivatives. ACS Catal. 2020 , 10 , 2009–2025. 8. Fairhurst, R. A.; Knoepfel, T.; Buscmann, N. et al. Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4. J. Med. Chem. 2020 , 63 , 12542−12573.
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