Fused pyrazino[2,3-b]indolizine and indolizino[2,3-b]quinoxaline derivatives; synthesis, structures, and properties

The synthesis of six new compounds incorporating either a pyrazino[2,3-b]indolizine or indolizino[2,3-b]quinoxaline core are reported in good yield (58–87%). The intermediates for the key cyclization reaction for one set of compounds (5a–c), with a sterically demanding 3,5-dimethylpyrazole group in the 5-position of the core, were found to be mono-substituted. These intermediates could be isolated and cyclized by heating under acid-catalyzed conditions. To further demonstrate the versatility of the chemistry, compounds 6a–c were synthesized in 58–68% yields. Compounds 5a–c are non-planar in solution and the solid-state, while 6a–c have close to planar conformations, pointing to weak hydrogen bonds between the acidic C–Hs and the adjacent azine nitrogen atoms. The cytotoxicity of the six newly synthesized and three previously prepared compounds was assessed against a human glioblastoma multiforme cell line.