Nucleophilic substitution with amines: dihydro-1,2,4,5-tetrazines are more useful precursors than 1,2,4,5-tetrazines

A one step synthesis of (di)alkylamino-substituted 1,2,4,5-tetrazines direct from 3,6-disubstituted- 1, 2-dihydro-1, 2,4,5-tetrazine precursors is described. A comparative study revealed that the described method not only avoids the up-to-now required oxidation step but also lower reaction times and/or temperatures compared to usual protocols. The efficiency of the reaction was highlighted by a practical synthesis of 3,6-bis(methylamino)-1,2,4,5-tetrazine using aqueous methylamine. Other primary and secondary amines were also found to give disubstitution products when reacted with 3,6-bis(methylsulfanyl)-1,2,4,5-dihydrotetrazine. (c) 2008 Elsevier Ltd. All rights reserved.