Concise Xanthine Synthesis through a Double-Amidination Reaction of a 6-Chlorouracil with Amidines using Base-Metal Catalysis

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 S_N 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.

Keywords: amidination; base metal; cross-dehydrogenative reaction; oxidative C−H amination; xanthines.