The nucleophilicity, polarity and basicity of aliphatic tertiary amines allows for the facile modulation of the solubility and hydrogen-bonding properties of drug candidates, which are essential parameters in achieving high potency and bioavailability. Therefore, it is of no surprise to see that this unique functionality is encountered in 26% of all pharmaceuticals and agrochemicals. Despite this, the modification of these privileged motifs via C(sp3)–H activation has remained elusive due to the difficulties in adjusting their binding properties via exogenous directing groups, and their easiness to undergo oxidation by electron-deficient metal centres. Here, we present a novel C(sp3)–H activation strategy which is capable of selective γ-arylate a broad range of tertiary amines with commercially available (hetero)aryl boronic acids. Computational studies elucidated that the commonly used family of amino acid ligands prevented substrate decomposition by β–H elimination pathways. Furthermore, the inherent chirality of these low-cost ligands enabled the development of a series of desymmetrisation transformations. This enantioselective cyclopalladation occurs through a distinct model where, rather than exploiting ligand-substrate steric interactions, stereoinduction is achieved by the ligand rigidity, which restricts the amine conformations available for C–H cleavage.

Palladium-catalysed C–H activation of aliphatic tertiary amines

ACS Fall 2020 Virtual Meeting

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