Total Synthesis of Small Molecule Natural Product: 7-Hydroxy-6-methoxyquinolin-2(1 <i>H</i> )-one, Its Variants, and Quinolin-2-yl Esters

7-Hydroxy-6-methoxyquinolin-2-(1<i>H</i>)-one (HMQ) is one of the active components of the natural product, <i>Spondias pinnata</i>, 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-(1<i>H</i>)-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-(1<i>H</i>)-ones.