Pyridine-to-Pyridazine Skeletal Editing

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Nitrogen-containing heterocycles are crucial in pharmaceuticals.
• Pyridazines, with two adjacent ring nitrogens, are underexplored due to limited synthetic accessibility.
• Pyridines are common pharmaceutical scaffolds, but their conversion to pyridazines is challenging.

Purpose of the Study:

• To develop a novel skeletal editing strategy for converting pyridines into pyridazines.
• To provide a simple, scalable, and broadly applicable method for accessing pyridazine scaffolds.
• To expand heterocyclic chemical space for drug discovery and late-stage diversification.

Main Methods:

• A two-step sequence involving N-amine assembly followed by m-chloroperoxybenzoic acid (mCPBA)-mediated ring remodeling.
• The process facilitates carbon-to-nitrogen substitution, converting pyridine rings into pyridazines.
• The reaction proceeds via a 1,2-diazatriene intermediate.

Main Results:

• The method successfully converts pyridines to pyridazines while preserving aromaticity.
• The process is operationally simple, runs at ambient temperature in air, and requires no specialized conditions or preinstalled groups.
• Broad functional-group tolerance was observed, including with complex, drug-derived molecules.

Conclusions:

• This skeletal editing strategy provides rapid and scalable access to pyridazines.
• The developed method significantly expands the availability of pyridazine scaffolds for medicinal chemistry.
• The platform enables late-stage diversification, facilitating drug discovery efforts.