A mild and efficient methodology for the synthesis of 5-halogeno uracil nucleosides that occurs via a 5-halogeno-6-azido-5,6-dihydro intermediate

Abstract

A mild and efficient methodology for the synthesis of 5-halogeno (iodo, bromo, or chloro) uracil nucleosides has been developed. 5-Halo-2′-deoxyuridines 4a–c (84–95%), 5-halouridines 7a–c (45–95%), and 5-haloarabinouridines 8a–c (65–95%) were synthesized in good to excellent yields by the reaction of 2′-deoxyuridine (2), uridine (5), and arabinouridine (6), respectively, with iodine monochloride, or N-bromo (or chloro)succinimide, and sodium azide at 25–45 °C. These C-5 halogenation reactions proceed via a 5-halo-6-azido-5,6-dihydro intermediate (3), from which HN3 is eliminated, to yield the 5-halogeno uracil nucleoside. The 5-halo-6-azido-5,6-dihydro intermediate products (10a, 10b) could be isolated from the reaction of 3′,5′-di-O-acetyl-2′-deoxyuridine (9) with iodine monochloride or N-bromosuccinimide and sodium azide at 0 °C. The isolation of 10a, 10b indicates that the C-5 halogenation reaction proceeds via a 5-halo-6-azido-5,6-dihydro intermediate.