Scaffold Hopping of Pyrimidines into 2-Acylpyrroles

Abstract A practical skeletal-editing strategy was developed for the conversion of 4-substituted pyrimidines into 2-acyl-5-arylpyrroles. The transformation directly converts a six-membered, electron-deficient pyrimidine into a five-membered azole while simultaneously installing an acyl group. The reaction sequence involves pyrimidine activation, ring-opening, fragmentation, and ring reconstruction. Central to this strategy is the controlled generation of pyrimidine-derived vinamidinium salts as open-chain A4 synthons, which are then intercepted by α-bromoketones as functionalized annulation reagents. The developed scaffold-hopping method can be applied for late-stage modification of pyrimidine-containing bioactive or pharmaceutical molecules.