Synthesis of 6‐(arylthio)‐ and 6‐[(arylmethyl)thio] ‐1,2,4,5‐tetrazin‐3‐amines and n‐phenyl‐ and n‐(phenylmethyl)‐1,2,4,5‐tetrazine‐3,6‐diamines as potential antimalarial agents

Alkylation of tetrahydro‐1,2,4,5‐tetrazine‐3,6‐dithione with iodomethane and 1,2‐dichloro‐4‐(chloromethyl)benzene, respectively (Scheme 1, 4) followed by oxidation afforded 3,6‐bis(methylthio)‐ and 3,6‐bis[[(3,4‐dichlorophenyl)methyl]thio]‐1,2,4,5‐tetrazines (6, 15). The reaction of 15 with amines provided the 6‐[(arylmethyl)thio]‐1,2,4,5‐tetrazin‐3‐amines (16) while sequential displacement of both methylthio groups in 6 afforded the tetrazine‐diamines 8 and 10. Hydrolysis of N,N‐dimethyl‐6‐(methylthio)‐1,2,4,5‐tetrazin‐3‐amine (11) with potassium hydroxide afforded the tetrazin‐3‐ol (12) which was chlorinated and then treated with 4‐chlorobenzenethiol to provide 13. The target 6‐substituted‐1,2,4,5‐tetrazin‐3‐amines displayed negligible antimalarial activity.