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.