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

A mild and efficient methodology for the synthesis of 5-halogeno (iodo , bromo, or chloro) uracil nucleosides has been developed. 5-Halo-2'-d eoxyuridines 4a-c (84-95%), 5-halouridines 7a-c (45-95%), and 5-haloar abinouridines 8a-c (65-95%) were synthesized in good to excellent yiel ds by the reaction of 2'-deoxyuridine (2), uridine (5), and arabinouri dine (6), respectively, with iodine monochloride, or N-bromo (or chlor o)succinimide, and sodium azide at 25-45 degrees C. These C-5 halogena tion reactions proceed via a 5-halo-6-azido-5,6-dihydro intermediate ( 3), from which HN, is eliminated, to yield the 5-halogeno uracil nucle oside. 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'-deoxyurid ine (9) with iodine monochloride or N-bromosuccinimide and sodium azid e at 0 degrees C. The isolation of 10a, 10b indicates that the C-5 hal ogenation reaction proceeds via a 5-halo-6-azido-5,6-dihydro intermedi ate.