2-Aminopyridines are common structural motifs found throughout medicinal chemistry and drug discovery. In addition to being featured in bioactive small molecules, this versatile class of compounds has found widespread use as intermediates for heterocycle synthesis and structure diversification. Despite their ubiquitous nature, the limitations of synthesizing 2-aminopyridines using classical methods have been well documented. These methods typically require harsh reaction conditions and frequently provide low yields of the desired products, often as mixtures of regioisomers. More recently, it has been demonstrated that pyridine N-oxides can serve as effective starting materials for synthesizing N-substituted 2-aminopyridines, taking advantage of a redox-neutral transformation. Our efforts expand upon this strategy and we present a practical, two-step protocol featuring mild reaction conditions using inexpensive and widely available reagents to provide unsubstituted 2-aminopyridine products with excellent regioselectivities and functional group tolerance. Isotopic labeling confirms the origin of the nitrogen atom of the newly installed amino function, and this method has been applied to a diverse set of pyridine and heterocyclic substrates.

Mild, general and regioselective synthesis of 2-aminopyridines from pyridine N-oxides via 2-pyridylpyridinium salts

255th National Meeting (2018)

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