Dual ligand approach increases functional group tolerance in the Pd-catalysed C-H arylation of N -heterocyclic pharmaceuticals.

The excellent functional group tolerance of the Suzuki-Miyaura cross-coupling reactions has been decisive for their success in the pharmaceutical industry. Highly diversified (hetero)aromatic scaffolds can be effectively coupled in the final step(s) of a convergent synthetic route. In contrast, electrophilic Pd catalysts for non-directed C-H activation are particularly sensitive to inhibition by coordinating groups in pharmaceutical precursors. While C-H arylation enables the direct conversion of (hetero)aromatics without preinstalled functional or directing groups, its functional group tolerance should be increased to be viable in late-stage cross-couplings. In this work, we report on a dual ligand approach that combines a strongly coordinating phosphine ligand with a chelating 2-hydroxypyridine for the highly robust C-H coupling of bicyclic N -heteroaromatics with aryl bromide scaffolds. The catalyst speciation was studied via in situ XAS measurements, confirming the coordination of both ligands under the reaction conditions. The C-H activation catalyst was shown to be tolerant to a wide range of pharmaceutically relevant scaffolds, including examples of late-stage functionalization of known drug molecules.