Data-Rich Experimentation Enables Palladium-Catalyzed Couplings of Piperidines and Five-Membered (Hetero)aromatic Electrophiles

To circumvent a current limitation in palladium-catalyzed C–N cross-coupling methodology, high-throughput experimentation was used to identify a catalyst capable of fusing piperidine-based nucleophiles with five-membered (hetero)aromatic bromides. A decomposition pathway for the standard electrophile was found, and a base screen was used to identify conditions that suppress this undesired transformation. Building on this, systematic optimization using a Design of Experiments approach delivered mild reaction conditions that were then subsequently applied to a variety of coupling partners.