Bridging the pyridine-pyridazine synthesis gap by skeletal editing

Area of Science:

• Organic Chemistry
• Heterocyclic Chemistry
• Synthetic Methodology

Background:

• Pyridine (C5N) is widely used in discovery chemistry due to its accessible synthesis.
• Pyridazine (C4N2), an analogous heterocycle, lags behind in synthetic development due to preparation challenges.
• The electronic arrangement in pyridazines often complicates their synthetic routes.

Purpose of the Study:

• To bridge the synthesis gap between pyridine and pyridazine.
• To develop a novel method for pyridazine preparation from pyridine.
• To enable the application of pyridine's synthetic richness to pyridazine chemistry.

Main Methods:

• A single-atom skeletal edit involving carbon-to-nitrogen atom replacement.
• Introduction of an azide group at the ortho position of pyridine.
• Photoinitiated rearrangement of N-amino-2-azidopyridinium cations.

Main Results:

• Successful conversion of pyridine derivatives to pyridazine derivatives.
• Demonstration of a direct C-to-N atom replacement strategy.
• Establishment of a new synthetic pathway linking pyridine and pyridazine retrosynthesis.

Conclusions:

• The developed method facilitates pyridazine synthesis by leveraging pyridine's established chemistry.
• This single-atom transformation opens new avenues for pyridazine discovery and application.
• The approach overcomes previous limitations in preparing pyridazine heterocycles.