Nucleophilic substitution studies on nitroimidazoles, and applications to the synthesis of biologically active compounds

The rationalization of the synthesis of substituted analogs of megazol, a biologically active 5‐nitroimidazole at position 4 of the imidazole ring, had led to the study of intermediate steps. The methylation by diazomethane of 2,4‐(5)dihalogeno‐5‐(4)nitroimidazole is regioselective leading to 2,4‐dihalogeno‐1‐methyl‐5‐nitroimidazole 2. On this compound 2, hard nucleophiles such as cyanide, methoxide or hydride anions react only with the halogen at the 2 position; whereas soft nucleophiles such as amine, thiol or trifluoromethyl anion from an organocopper species react only with the halogen at postion 4 in the intermediate 3b or compound 4b.