Synthesis of 3-alkyl-6-methyl-1, 2, 4, 5-tetrazines via a Sonogashira-type cross-coupling reaction. Issue 75 (19th August 2020)

• Record Type: Journal Article
• Authors: Ros, Enric; Prades, Amparo; Forson, Dominique; Smyth, Jacqueline; Verdaguer, Xavier; Pouplana, Lluís Ribas de; Riera, Antoni
• Is Part Of: Chemical communications. Volume 56:Issue 75(2020)
• Page Start: 11086
• Page End: 11089
• Publication Date: 2020-08-19
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1039/d0cc03482g
• Languages: English
• ISSNs: 1359-7345

Abstract

Abstract : A new methodology involving Sonogashira cross-coupling was applied to the synthesis of new amino acids bearing a 6-methyltetrazin-3-yl fragment. 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.