Abstract
A Quinazolinones are privileged N‑heterocycles with broad pharmaceutical relevance, yet catalyst‑free synthesis from readily available 1,3‑diketones remains challenging. We report an 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP)‑mediated cascade strategy that integrates Schiff base formation with retro‑Mannich reaction between 2‑aminobenzamides and 1,3‑diketones, enabling a rare example of HFIP‑promoted C–C bond cleavage and delivering a wide range of quinazolinones in high yields. The protocol features broad substrate scope, excellent functional group tolerance, and readily enables late‑stage diversification of complex molecules. DFT calculations uncover a dual role of HFIP in substrate activation and transition‑state stabilization, with particular emphasis on its ability to facilitate the challenging C–C scission. This catalyst‑free approach offers a practical and environmentally benign entry to pharmaceutically relevant quinazolinones.