Dienophilicity of imidazole in inverse electron demand Diels–Alder reactions: cycloadditions with 1,2,4,5-tetrazines and the structure of zarzissine

Abstract

The inverse electron demand cycloadditions of 2-substituted imidazoles with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate produced imidazo[4,5- d]pyridazines in good yields. This chemistry was applied to the synthesis of 2-amino-1 H-imidazo[4,5- d]pyridazine ( 1), the structure reported for zarzissine, a cytotoxic marine alkaloid. Differences in the 1H- and 13C NMR spectra of 1 with those reported for zarzissine necessitated a structural revision, and zarzissine was then considered to be the corresponding 2-amino-1 H-imidazo[4,5- b]pyrazine ( 2), which was subsequently synthesized from the parent heterocycle.