Synthesis and antimalarial effects of N,N ‐dialkyl‐6‐(substituted phenyl)‐1,2,4,5‐tetrazin‐3‐amines

The synthesis of a series of N,N ‐dialkyl‐6‐(substituted phenyl)‐1,2,4,5‐tetrazin‐3‐amines (IV) by two routes is described. The first route (Scheme I) involved the oxidative cyclization of formazans (II) to 3‐bromo‐6‐(substituted phenyl)‐1,2,4,5‐tetrazines (III), followed by treatment with amines. The second (Scheme II) utilized the treatment of 3‐(methylthio)‐6‐(substituted phenyl)‐1,2,4,5‐tetrazines (VII) with amines to provide the desired products. The intermediate 3‐(methylthio)‐6‐(substituted phenyl)‐1,2,4,5‐tetrazines (VII) were obtained by thiobenzoylation of hydrazinecarbohydrazonothioic acid methyl ester with [[(substituted phenyl)thioxomethyl]thio]‐acetic acids (V) to afford the 1,2‐dihydro‐3‐(methylthio)‐6‐(substituted phenyl)‐1,2,4,5‐tetrazines (VI). Oxidation with bromine in acetic acid provided the desired intermediates. The target 6‐(substituted phenyl)‐1,2,4,5‐tetrazin‐3‐amines (IV) displayed modest antimalarial activity.