Synthesis of 6-aryl-2′-deoxyuridine nucleosides via a Liebeskind cross-coupling methodology

Hitherto, the synthesis of 6-substituted 2′-deoxyuridine nucleoside analogues via Pd-catalyzed Suzuki cross-coupling reaction was hampered by the instability of the TIPDS-protected precursor 6-iodo-2′-deoxyuridine 1 in alkaline media due to cleavage of the glycosidic bond. Herein, the successful application of the Liebeskind reaction under base-free conditions is reported. This method comprises of the stoichiometric use of copper thiophene carboxylate (CuTC) as co-reagent at slightly elevated temperatures. Fluoride-mediated desilylation and Yoshikawa-phosphorylation afforded the nucleotide analogues 4b–c, 4e, and 4i.