Synthesis of 3-alkyl-6-methyl-1,2,4,5-tetrazines via a Sonogashira-type cross-coupling reaction
Enric Ros1, Amparo Prades, Dominique Forson
1Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain. antoni.riera@irbbarcelona.org lluis.ribas@irbbarcelona.org.
Abstract:
1,2,4,5-Tetrazines have become extremely useful tools in chemical biology. However, the synthesis of some challenging substrates such as asymmetrically disubstituted alkyltetrazines 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 and 3-bromo-6-phenyl-1,2,4,5-tetrazine with terminal alkynes. The preparation of the starting reagents has also been 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.
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