Pyridine to Pyridazine Skeletal Editing via CN-to-NN Atom-Pair Swap

Skeletal editing has emerged as a powerful strategy for the late-stage diversification of drug molecules. Recently, transmutation of widely available pyridine motifs into less explored pyridazines via C-to-N single-atom swaps has garnered attention. Here, we report a CN-to-NN atom-pair swap to transmute pyridopyrimidones, dienamines that are generated by temporary dearomatization of pyridines, into pyridazines in a one- or two-pot dearomatization-4 + 2-retro-4 + 2-cycloaddition-aromatization sequence with 4-phenyl-1,2,4-triazoline-3,5-dione as the N═N dienophile. Crucially, this transformation only works with pyridopyrimidones and not with the previously established oxazinopyridine-based temporary dearomatization strategy; for the latter, the driving force for the retro-4 + 2 cycloaddition is insufficient, since the formation of the target product itself does not facilitate a gain in arene resonance energy. Pyridopyrimidones provide such a driving force through the formation of an aromatic pyrimidone byproduct. The synthetic utility of the method is demonstrated through late-stage skeletal editing of complex molecules and a 7-mmol large-scale reaction.