Synthesis of quinolinyl lactones

The combination of pharmacophoric moieties of different bioactive substances can produce a new hybrid molecule with improved biological efficacy and affinity, a modified selectivity profile, and different and/or dual modes of action, and may reduce undesired side effects1. The combination of lactone and quinoline rings provides quinolinyl lactones, which are azo-analogues of arylnaphtalene lignan lactones. Despite the biological and synthetic importance of these compounds, there are few publications reporting efficient syntheses for obtained these azo-derivatives 2,3. Therefore, the objective of this work was to synthesize, more efficiently, quinolinyl lactones through a domino reaction initiated by the MW-assisted reaction between tetronic acid (1) and 3,4-dimethoxy aniline (2) in acetonitrile. After the formation of the intermediate 4-azo-butenolide (3)4, trifluoracetic acid and the aromatic aldehyde (4) were added at reactive vessel (Scheme 1). Derivatives 6a-e were obtained in yield ranging from 80 to 90% (Scheme 1) in a total reaction time of 1 hour. When only TFA was used, the reaction occurred slowly with yields lower than 40% and formation of several byproducts. Other acids were also evaluated, but the results were not satisfactory. The use of the CH3CN/TFA mixture (2: 1) decreased the reaction time and favored the oxidation process of the intermediate 5. The advantage of this synthetic route over that described in the literature3 is that it is not necessary use a strong oxidizing agent; moreover this route provide the desired product more quickly and efficiently.