Chromone derivatives are widely found in natural products and biologically active molecules, and serve as important building blocks in organic synthesis. Although significant progress has been made in the synthesis of chromone-based molecular frameworks, exploring new synthetic methods for chromone derivatives using a building-block chemistry strategy remains of great importance. The ortho-hydroxyaryl enaminones cyclization cascade has become the preferred method for constructing chromones (especially C3 substituted chromones), offering efficient and selective access to these valuable scaffolds. Hexafluoroisopropanol (HFIP) has emerged as a versatile solvent and promoter in organic synthesis, owing to its unique combination of high ionization ability, low nucleophilicity, and strong hydrogen bond donor capacity. The strategic incorporation of morpholine and other cyclic amine motifs into heterocyclic frameworks significantly enhances bioactive compounds' drug-like properties, accelerating the discovery of novel therapeutic candidates. In light of this, we developed a streamlined three-component tandem cyclization of ortho-hydroxyaryl enaminones, morpholine, and aryl glyoxals in HFIP, enabling efficient synthesis of C3-functionalized chromones. This metal-free protocol leverages HFIP's dual role as solvent/promoter at room temperature, offering operational simplicity, broad substrate scope, and excellent functional group tolerance with commercially available starting materials. The results demonstrated that the target C3-functionalized chromone derivatives containing cyclic amine were obtained with moderate to excellent yields. The optimized reaction conditions of one pot synthesis of chromone derivatives are as follows: into a dry 10 mL reaction flask were sequentially added a magnetic stir bar, morpholine 2 (0.9 mmol), phenylglyoxal monohydrate 3 (0.45 mmol), and 1.5 mL of HFIP. The mixture was stirred at room temperature for 30 min. Subsequently, enaminone 1 (0.45 mmol) was evenly added portion wise in five equal portions (with 20-min intervals between additions). The reaction was stirred at room temperature for 12 h. The reaction progress was monitored by thin layer chromatography (TLC). After completion, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 4.

Key words: ortho-hydroxyaryl enaminones, chromone, hexafluoroisopropanol, one-pot, morpholine