Moving nitrogen within pyridine opens a new path for molecular editing

Researchers have devised a novel approach to convert pyridine compounds into their positional isomers by relocating the nitrogen atom within the pyridine ring itself. Unlike traditional methods that focus on moving individual substituents around the molecule, this new strategy moves the nitrogen atom itself, preserving the existing substituents attached to the carbon atoms.

Pyridine, a fundamental structural motif in many pharmaceutical compounds, exhibits varying properties depending on the position of the nitrogen atom relative to the substituents. By altering the nitrogen's position, medicinal chemists can modify properties such as solubility, metabolic stability, and interactions with biological targets, enabling them to investigate structure-activity relationships more effectively.

Traditionally, obtaining these positional isomers required separate starting materials and unique synthetic routes, with attempts to move substituents directly proving challenging due to diverse functional group requirements. The innovative approach, led by Hong Sungwoo of the Institute for Basic Science (IBS) and the Korea Advanced Institute of Science and Technology (KAIST), involves selectively removing the original nitrogen atom from the stable pyridine ring and inserting a new nitrogen atom at a different position, thus rearranging the positional relationship of the substituents.

This process, achieved through a series of nitrogen insertion and deletion steps, generates an expanded nitrogen-containing intermediate, followed by the removal of the original nitrogen as nitrogen gas (N₂), providing a thermodynamic driving force for the transformation. The researchers utilized isotope-labeling experiments to confirm that the nitrogen in the final pyridine originated from an external reagent, while the carbon atoms retained their original positions.

The reaction's success across various substituent types and functional groups, including those common in medicinal chemistry, highlights its versatility. Additionally, solvent selection can influence the formation of specific positional isomers, offering another means to access different molecular structures from the same starting material.

Demonstrating the method's applicability, the researchers successfully applied it to structurally complex molecules and marketed pyridine-containing drugs, including Vismodegib, Abiraterone acetate, and Etoricoxib. This nitrogen transposition strategy allows for the alteration of the atomic framework of the pyridine ring while leaving the substituents unchanged, offering a more general and flexible approach to positional isomerization.

By treating the nitrogen position within a pyridine ring as a variable that can be modified later, chemists can explore new structural possibilities and directly compare the effects of different substitution patterns on physicochemical properties and biological activity, enhancing drug discovery efforts.