Total Synthesis of Small Molecule Natural Product: 7‑Hydroxy-6-methoxyquinolin-2(1H)‑one, Its Variants, and...

7-Hydroxy-6-methoxyquinolin-2-(1H)-one (HMQ) is one of the active components of the natural product, Spondias pinnata, reported to have very high antioxidant and anti-inflammatory activities. Low bioavailability and scalability limit its bioapplications. Herein, a simple and elegant synthetic route has been developed to form HMQ and its variants. Anilines were coupled with cinnamoyl chloride/3,4,5-trimethoxycinnamoyl chloride to form cinnamanilides. They were then cycloeliminated in the presence of TfOH at RT-110 °C, to form quinolin-2-(1H)-ones in 62-97% yield. In addition to spectroscopic characterization, the structures of the natural product and its regioisomer were unambiguously established by a single-crystal XRD study. The developed protocol can be adopted for the gram-scale synthesis of HMQ. Furthermore, a series of HMQ variants were synthesized, offering SAR evaluation for bioactivity studies. The scope of the process is demonstrated with the synthesis of 21 quinolin-2-yl esters from the corresponding quinolin-2-(1H)-ones.