DIELS-ALDER REACTION OF PYRANO[3,4-b]INDOLONES WITH AN ELECTRON-DEFICIENT PYRIDAZINONE: A NEW PATHWAY TO CARBAZOLE-FUSED PYRIDAZINES

Thermally induced [4+2] cycloaddition reactions of 5-ethanesulfonyl2-methylpyridazin-3(2H)-one (2) with pyrano[3,4-b]indol-3(9H)-ones (1, 4) affords isomeric pyridazino[4,5-b]carbazolones (3a,b, 5a,b), the product ratio depending on the substitution pattern of the diene. Two carbazolocarbazoles (6, 7) were obtained as side products. The antineoplastic activity of ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) has stimulated considerable interest in the field of b-fused carbazoles and has led to the synthesis of a large number of derivatives of the natural lead compound, some of them with superior antitumor properties. Among those congeners, also some aza-analogous ellipticines like 6,11-dimethyl-5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinoline (9-azaellipticine), the drug candidate pazelliptine, or a series of 1,4-dialkoxypyridazino[4,5-b]carbazoles have been described. Whereas the latter 3-azaellipticines had been found to be almost inactive, several new representatives of this ring system were prepared in our laboratory recently and some of them turned out to be remarkably active in an in-vitro assay. In this context, the examination of alternative pathways to this tetracyclic ring system became an object of interest. In particular, a cycloaddition reaction between a synthon with a preformed pyridazine ring and another component representing the remaining part of the tetracyclic system was considered a promising strategy. As an indole-derived diene, an appropriately substituted pyrano[3,4-b]indol-3(9H)-one should be a useful building block, as such compounds had already been employed for the construction of condensed or substituted carbazoles previously, e.g. by Plieninger, Moody, and Pindur. As the dienophile, we chose the electron-deficient 5-ethanesulfonyl-2-methylpyridazin-3(2H)-one, which – as well as one example of a nitro-substituted pyridazinone – had been shown to react with simple butadiene derivatives in a Diels-Alder fashion to afford (tetrahydro-)phthalazinones, due to its low LUMO energy. When the dimethyl-substituted pyranoindolone (1) was heated with the pyridazinone (2) in bromobenzene to 156°C (conditions which are suitable e.g. for the reaction of 1 with dimethyl acetylenedicarboxylate), no conversion was observed. However, employment of a higher-boiling solvent (1,2,4trichlorobenzene) turned out to effect the cycloaddition reaction at a temperature of 190°C. An excess of 1 was used (with gradual addition), and careful exclusion of air oxygen was found to be crucial. Column chromatography of the reaction mixture afforded the two isomeric cycloaddition products (3a and 3b) in a ratio of 1:3 (43% combined yield; Scheme 1) as well as two side products (see Scheme 2). Obviously, compounds (3a,b) are formed by spontaneous elimination of carbon dioxide and ethanesulfinic acid from the initially formed, highly strained cycloadducts. Structural assignment for 3a,b is based on NOE difference spectroscopy, using the resonances of the two C-methyl groups, H-10, and/or the pyridazine proton as irradiation points (see Experimental).