Concise Preparation of 1,8-Diazaanthracene-2,7,9,10-Tetraones. Two Alternative Syntheses of the Natural Antifolate Diazaquinomycin A

Treatment of compounds bearing one or two 1-dimethylamino-1,4-dihydropyridine moieties with the urea-hydrogen peroxide complex (UHP) led to their efficient aromatization. Double N-oxidation of 1,8-diazaanthraquinones thus obtained is the first example of a double N-oxidation of a diaza heterocycle by UHP in trifluoroacetic acid. Treatment of the crude double N-oxides with tosyl chloride in acetonitrile–water afforded 1,8-diazaanthracene-2,7,9,10-tetraones (including diazaquinomycin A) in 25–40% overall yields. An alternative synthesis of diazaquinomycin A was also devised, whose key steps are the hetero Diels–Alder reaction between 2-methyl-2-hexenal dimethylhydrazone and 3-methyl-4-propyl-2H-quinoline-2,5,8-trione and the oxidative functionalization of the 1,8-diazaanthracene-2,9,10-trione derivative thus obtained.