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Updated: Mar 11, 2026

A Direct, Early Stage Guanidinylation Protocol for the Synthesis of Complex Aminoguanidine-containing Natural Products
Published on: September 9, 2016
Concise Xanthine Synthesis through a Double-Amidination Reaction of a 6-Chlorouracil with Amidines using Base-Metal
Bénédicte Morel1, Philippe Franck1, Johan Bidange1
1Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, 2020, Antwerp, Belgium.
Abstract:
A new and concise route towards xanthines through a double-amidination reaction is described; consecutive intermolecular C-Cl and intramolecular oxidative C-H amidination. N-uracil amidines are obtained through SN AE on a 6-chlorouracil with amidines. Direct Cu-catalyzed oxidative C-H amidination on these N-uracil amidines yields polysubstituted xanthines. Sustainable oxidants, tBu2 O2 or O2 , can be used in this oxidase-type reaction. The protocol allows for the introduction of N1, N3, N7, and C8 substituents during the xanthine-scaffold construction, thus avoiding post-functionalization steps. Both 6-chlorouracils and amidines are readily available commercially or through synthesis.
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