An efficient synthesis of quinoline-2,5,8(1H)-triones bearing alkyl groups at C 3 and/or C 4 is described. The reaction sequence employed involves Knorr cyclization of 2,5-dimethoxyanilides into 5,8-dimethoxyquinoline systems, followed by oxidative demethylation with cerium ammonium nitrate. The starting 2,5-dimethoxyanilides were prepared by chemoselective acylation of 2,5dimethoxyaniline with a series of b-oxo thioesters obtained by regioselective alkylation of S-tert-butyl acetothioacetate (1) at C 2 and/or C 4 . The introduction of electrophiles other than alkyl groups at C 2 on 1 was also studied.Quinoline-2,5,8(1H)-triones have been employed by our group 1 as precursors to antitumor 1,8-diazaanthracene-2,9,10-triones, designed as analogs of the natural thymidilate synthase inhibitor diazaquinomycin A. 2 The methods currently available for the preparation of these quinones are restricted to 3-substituted 3 or to 4-methyl derivatives, 4 and this limits the range of structural variations that can be introduced in the 1,8-diazaanthracene system. We envisaged that the acid-promoted cyclization of b-oxo anilides (i.e., the Knorr quinoline synthesis 5 ) might serve as the key step of a more general route. However, and in spite of the long tradition of this reaction, there are very few examples of its application to the preparation of 3,4-disubstituted quinoline systems, 6 probably because of difficulties in the synthesis of the anilide precursors.