Bridging the pyridine-pyridazine synthesis gap by skeletal editing
Mikus Puriņš, Hikaru Nakahara, Mark D. Levin
Abstract
Pairs of heterocycles differing by a single constitutive ring atom can exhibit stark differences in the retrosynthetic disconnections available for their preparation. Such a synthesis gap is exemplified by pyridine and pyridazine. Pyridine (a six-membered C 5 N ring) has risen to prominence in discovery chemistry, its ease of assembly spurring further synthetic development. Despite a host of favorable properties, pyridazine (an analogous C 4 N 2 ring) has comparatively lagged behind—a discrepancy attributable to its often-challenging preparation, which arises from an electronically dissonant heteroatom arrangement. In this work, we achieve a single-atom skeletal edit that produces pyridazines from pyridines by direct carbon-to-nitrogen atom replacement: Azide introduction at the ortho position enables a photoinitiated rearrangement of N -amino-2-azidopyridinium cations. This transformation links the two heterocycles such that the richness of pyridine retrosynthesis becomes available to pyridazines.