Internal Homologation of Amines

Tertiary amines are one of the most common motifs in bioactive molecules and their homologation has been employed in the discovery of a range of different therapeutics. However, each homologue tested in drug optimisation trials requires a de novo synthesis, greatly slowing down the process of drug discovery. Consequently, a reaction for the internal homologation of complex, bioactive, tertiary amines is of great synthetic value. Based on previous work exploring the cross-coupling of ammonium salts through cleavage of an activated C-N bond, we imagined a reaction in which a quaternary ammonium salt was substituted with a group capable of undergoing transmetallation, thus forming the homologue of the starting amine upon cross-coupling. We developed a set of optimised conditions for the homologation of tertiary benzylamines first through alkylation to form a betaine intermediate with an appended trifluoroborate substituent on a quaternary benzylammonium centre, then reaction with a palladium catalyst and base to furnish the tertiary, phenethylamine product. Our work has shown that both the alkylation and homologation steps are quite robust and able to modify a range of bioactive molecules, demonstrating the great synthetic power of the reaction. We hope that our results in this work will pave the way for the homologation of anilines and the stereospecific homologation of tertiary amines in the future, further expanding the tools available to medicinal chemists in drug discovery.