Synthesis of 2,5,8(1H)-Quinolinetrione Derivatives through Vilsmeier-Haack Formylatioin of 2,5-Dimethoxyanilides

8hstrau-The preparation of 2 J,8(1H)-quinolinetrione derivatives bearing both electron-withdrawing and electron-releasing groups at C3 is described. The reaction sequence employed involves Vilsmeier-Haack cyclization of 2 5-dimethoxyanilides into 3-substituted 5,8-dimethoxy-2-chloroquinolines, followed by hydrolysis to the corresponding 2(1H)-quinolinones and oxidative demethylation with cerium ammonium nitrate.Diazaquinomycin A' is a smcturally novel Streptomyces metabolite with good activity as a thymidilate synthase inhibitor that departs from previous lead compounds in this field.2We have shown3 that the hetero Diels-Alder reaction between I-azadienes4 and derivatives of the 2,5,8(1H)-quinolineuione ("carbostyrilquinone") system provides ready access to diazaquinomycin analogues, many of which show excellent in vitro antiturnour activity3b (Scheme 1).Diazaquinomycin A Scheme 1 'H, 63 MHz for 13c) and Varian VXR-300 (300 MHz for 'H, 75 MHz for 13c) spectrometers; CDC13,