Alkylamines are valuable motifs that feature in over 40% of pharmaceutical agents and have profound influence over biological activity. The development of new catalytic methods for the facile preparation of complex amines is therefore an important goal in contemporary organic chemistry. α-Trialkyl-α-tertiary amines (α-trialkyl-ATAs) – 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, 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. 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, 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.

Modular photocatalytic synthesis of α-trialkyl-α-tertiary amines

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