Palladium-Catalyzed α-Arylation of Methyl Ketones Enables Modular Synthesis of 2,4,5-Trisubstituted Imidazoles

A three-step synthesis of 2,4,5-trisubstituted imidazoles involving Pd-catalyzed a-arylation of aromatic methyl ketones, here represented by 4-acetyl pyridine, with 2-bromo-6-alkoxynaphtalenes, followed by in situ oxidation with selenium dioxide, featuring only two chromatographic purifications, provides the corresponding 1,2-diketones which underwent a Debus-Radziszewski condensation to furnish 2,4,5-trisubstitued imidazoles in moderate to good overall yields (30 examples). The methodology is particularly appropriate for the late-stage introduction of the substituent at C-2 in the imidazole ring and nicely complements previously described methods where the substituent at C-5 was incorporated at the end of the synthetic route.