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

preprint
submitted on 07.07.2020 and posted on 09.07.2020 by Dominique Forson, Xavier Verdaguer, Lluís Ribas de Pouplana, Antoni Riera, Enric Ros, Amparo Prades, Jacqueline Smyth
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.

History

Email Address of Submitting Author

enric.ros@irbbarcelona.org

Institution

Institute for Research in Biomedicine (IRB) Barcelona

Country

Spain

ORCID For Submitting Author

0000-0001-6269-3058

Declaration of Conflict of Interest

There are no conflicts on interest

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