Synthesis of 3-Alkyl-6-Methyl-1,2,4,5-Tetrazines via a Sonogashira-Type Cross-Coupling Reaction

1,2,4,5-Tetrazines have become extremely useful tools in chemical biology. However, the synthesis of some challenging substrates such as 3,6-dialkyl-1,2,4,5-tetrazines is still a limitation for the widespread use of this class of compounds. Herein we describe an efficient route to these compounds based on the Sonogashira coupling of 3-bromo-6-methyl-1,2,4,5-tetrazine with terminal alkynes. The preparation of the starting reagent has been also optimized. The alkynyl products have been used as intermediates for the synthesis of dialkyl-tetrazines through a sequence of hydrogenation and re-oxidation with unprecedented yields. The synthetic applicability of this new approach is showcased through the preparation of several unnatural amino acids bearing alkynyl- and alkyl-1,2,4,5-tetrazine fragments.