BENZI~AZOLE R~ONUCLEOS~~S: OBSERVATION OF AN UNRXP~CTED N~RATXON WHEN PERFORMING NON-AQ~OUS D~ZOT~ZATIONS WITH t-BUTYL NITRITE1

Mild, non-acidic cordons used in the n~-~u~us ~~~~ of a 2-~o~n~~~e nu&uside with t-butyi nitrite gave an unexpected ~~~~~~-2~e nuckoside which was not formed when primary a&y1 nitrites were used. The isolated compounds were evaluated for activity against herpesviruses and for cytotoxicity against human foreskin fibroblast cells. Benzimidazoles have demonstrated widespread biological activity ranging from antifkia12 to antiviral. Since the initial qort~ of activity for halogenated benzimidazole ribonucleosi&s against certain RNA viruses, considerable interest has been generated among analogs of 5,tidichloro-l-(BPriboFuranosyl)b~le ORB). Recenuly, we have found that polyhalogenated benzimida&e ribonucleosides are potent and selective inhibitors of human cytomegalovirus (HCMV) replication. In an effort to establish a structure-activity relationship in this specific area, we have been preparing and ev~ua~g new ~~~~le ~~n~l~sides. It was during the preparation of these compounds that we encountered an interesting observation pertaining to non-aqueous diazotization. Non-aqueous diazotization employs the known ability of alkyl nitrites to produce a@ radicals from arylamine& the ensuing aryl radical can then abstract an atom from a suitable donor such as the solvent. Although an early use of non-~ueous diazotization using THG as the solvent involved tbe astir of 2’,3’,5’-tri-Q-acetykuienosine to furnish 2’,3’,5’-ti-Q-acetylnebularines, more recent applications have involved the synthesis of various halogenated nucleosides 6. The deamination-halogenation of purine nucleosides with alkyl nitrites in halogenated solvents has been reported to occur at the dposition7 and the 2-position@ to provide various halogenated purine n~le~ides. Although the synthesis of several 2-h~ogenat~ ~n~~~le nucleosides has been reported,t@-t* the non-aqueous diazotization of benzimidanole nuckosides to afford the cozening 2”h~ogenat~ nucl~sides has not. We now wish to report on the unexpected results from a nonaqueous diazotization of a ~-~~o-5,~disu~timt~ benximidazole riboside when using a tertiary a&y1 nitrite and the antiviral evakation of the isolated compounds. Treatment of 2-~no-S,6-dichloro-l-(2,3,~-~-Q-~e~~-~-~~~f~syI)~n~~let~ (1) with IO equiv of r-butyl nitrite in CH212 under anhydrous conditions for 24 h at 110 OC gave (after solvent removal via a Kugehhr apparatus and column chromatography) a bright-yellow product A mass spectrum (lZAB+) of the product iden~~ a molecular ion at t&z 506 instead of the expected n&z 571 for 5,6-dichl~2-iodo-1-(23J-ai~acetyl-~-D-~~f~~osyl)~nzi~~ole (3). The structure of this unexpected product (m/z 506) was subsequently elucidated fmm spectral dataI as foilows: The lE% NMR (CDCl3) sperm of the product revealed an ex~h~g~ble proton at 6 10.05 (one proton, RO ex~h~g~ble) and only one peak {one proton) in the aromatic region at 6 7.56. The 1% NM.R spectrum revealed the presence of a urea-like carbon at S 152.70. These data indicated that changes or substitutions had occurred on both the benzo and imidazo moieties of the benzimidazole