Three-Component Reaction of 3-Formyl-6-Methylchromone, Primary Amines, and Secondary Phosphine Oxides: A Synthetic and Mechanistic Study

A fast, mild, and efficient catalyst-free approach has been developed for the synthesis of chromonyl-substituted alpha-aminophosphine oxides by the three-component reaction of 3-formyl-6-methylchromone, primary amines, and secondary phosphine oxides at ambient temperature. Carrying out the reaction with aliphatic amines or aminoalcohols at a higher temperature (80 degrees C), phosphinoyl-functionalized 3-aminomethylene chromanones were formed instead of the corresponding chromonyl-substituted alpha-aminophosphine oxides. No reaction occurred when 3-formyl-6-methylchromone and secondary phosphine oxides were reacted with aromatic amines in the absence of any catalyst. Applying a basic catalyst, the formation of the phosphinoyl-functionalized 3-aminomethylene chromanones was observed; however, the reaction was not complete. Detailed experimental and quantum chemical studies were performed to study the transformation. Moreover, the in vitro cytotoxicity of phosphinoyl-functionalized 3-aminomethylene chromanones was also investigated in three different cell lines, such as human lung adenocarcinoma (A549), mouse fibroblast (NIH/3T3), and human promyelocytic leukemia (HL60) cells. Several derivatives showed modest activity against the human promyelocytic leukemia (HL60) cell line.

Automated summary

A catalyst-free approach was developed for the synthesis of chromonyl-substituted alpha-aminophosphine oxides. The reaction was carried out at ambient temperature using 3-formyl-6-methylchromone, primary amines, and secondary phosphine oxides. When aliphatic amines or aminoalcohols were used at a higher temperature, phosphinoyl-functionalized 3-aminomethylene chromanones were formed instead. The cytotoxicity of the synthesized compounds was investigated in different cell lines.