Diverse “Scaffold-Hopping” from 4-Arylpyrimidines

Keywords

skeletal editing - scaffold-hopping - pyrimidines - pyridines - vinamidinium salts

Significance

A series of skeletal-editing strategies for nitrogen heterocycles have been reported that expedite structure–activity relationship (SAR) studies through obviating the need to engage in lengthy syntheses to access desired molecules related to a lead template. This “scaffold-hopping” can be achieved through addition of a nucleophile, ring-opening and ring-closing (ANRORC) reactions. This approach distinguishes itself through its versatility and efficiency, with the current report describing the editing of a 4-arylpyrimidine to form a diverse range of other nitrogen heteroaromatics through the intermediacy of four-atom (N–C–C–C) synthons.

Comment

Initial reaction development experiments using 4-phenylpyrimidine as the model substrate focused on identification of a suitable activating reagent combination to trigger the opening of the heterocyclic ring to generate a four-atom synthon that could engage in ring-closing reactions with suitable coupling reagents to yield pyrroles and pyridines respectively. Further experiments allowed isolation of a vinamidinium salt, which could then be exploited as either a three- or four-atom synthon for the formation of a range of functionalized nitrogen-based heterocycles.

Publication History

Article published online:
30 October 2025