Facile syntheses of C-6 azidopurine ribonucleosides and 2′-deoxyribonucleosides have been developed. For silyl and acetyl protected as well as unprotected nucleosides, access to the azido derivatives could be readily attained via displacement of BtO − from the O 6 -(benzotriazol-1-yl) inosine nucleosides by azide anion. Use of diphenylphosphoryl azide/DBU as a simple route to the acetyl-protected azido nucleosides was also evaluated, but this proved to be inferior. Since these azido nucleosides can exist in an azide•tetrazole equilibrium, the effect of solvent polarity on this equilibrium was investigated. Subsequently, a detailed analysis of Cu-mediated azide-alkyne ("click") ligation was undertaken. Biphasic CH 2 Cl 2 /H 2 O medium proved to be best for the ligation reactions, suppressing the undesired azide reduction that was competing. Interestingly, although the tetrazolyl isomer predominates (ca 80%) in CD 2 Cl 2 and in CD 2 Cl 2 /D 2 O, the Cu-catalyzed click reactions proceed smoothly with the silyl-protected ribo and 2′-deoxyribonucleosides, leading to the C-6 triazolyl products in good to excellent yields. Thus, depletion of azido form from the reaction mixture shifts the azide•tetrazole equilibrium, eventually resulting in complete consumption of azide and tetrazole. In several cases, major and minor azide-alkyne ligation products were observed and characterization data are provided for both. In order to confirm the regiochemistry leading to the major isomer, one product was crystallized and evaluated by X-ray crystallography. The Cucatalyzed azide-alkyne ligation is clearly efficient and significantly superior to thermal reactions, which were slow. Biological evaluation showed low cytotoxicities for the agents, suggesting their usefulness as biological probes.* To whom correspondence should be addressed. Tel.: (212) 650-7835; fax: (212) 650-6107. lakshman@sci.ccny.cuny.edu. Supporting Information Available: General experimental details, materials and methods for antiproliferative tests and the results, ORTEP of 4b, copies of 1 H and 13 C NMR spectra of 2c, 2d, 3a-f, 4a-g, 4f′, 5a-g, 5a′, 5c′-f′, 6a-6g and 7a-7g. This information is available free of charge via the Internet at

C(sp3)–N bond-forming reactions between benzotriazole and 5,6-dimethylbenzotriazole with N-methylpyrrolidinone, tetrahydrofuran, tetrahydropyran, diethyl ether, 1,4-dioxane, and isochroman have been conducted using RuCl3•3H2O/t-BuOOH in 1,2-dichloroethane. In all cases, N1 and N2 alkylation products were obtained, and these are readily separated by chromatography. One of these products, 1-(isochroman-1-yl)-5,6-dimethyl-1H-benzotriazole, was examined by X-ray crystallography. It is the first such compound to be analyzed by this method, and notably, the benzotriazolyl moiety is quasi-axially disposed, consistent with the anomeric effect. This has plausible consequences, not observed previously. In contrast to other hemiaminal ether-forming reactions, which proceed via radicals, this Ru-catalyzed process is not suppressed in the presence of a radical inhibitor. Therefore, an oxoruthenium-species-mediated rapid formation of an oxocarbenium intermediate is believed to occur. In the radical-trapping experiment, previously unknown products containing both the benzotriazole and the TEMPO unit have been identified. In these products, it is likely that the benzotriazole is introduced via a Ru-catalyzed C–N bond formation, whereas C–O bond-formation with TEMPO occurs via a radical reaction. We show that reactions of THF with TEMPO are influenced by ambient light. A competitive reaction of THF and THF-d8 with benzotriazole indicated that C–H bond cleavage occurs ca. 5 times faster than C–D cleavage. This is comparable to other metal-mediated radical reactions of THF, but lower than that observed for a reaction catalyzed by n-Bu4N+I−. Detailed mechanistic experiments and comparisons are described. The catalytic system was also evaluated for reactions of benzimidazole, imidazole, 1,2,4-triazole, and 1,2,3-triazole with THF, and successful reactions were achieved in each case. In the course of our studies, we discovered an unexpected but significant isomerization of some of the benzotriazolyl hemiaminal ethers. This is plausibly attributable to the pseudoaxial orientation of the heterocycle in the products and the stability of oxocarbenium ions, both of which can contribute to C–N bond cleavage and reformation. Predominantly, the N2-isomers rearrange to the N1-isomers even upon storage at low temperature! This previously unknown phenomenon has also been studied and described.

Easily synthesized aldoximes have been converted to the corresponding nitriles under very mild conditions by a simple reaction with 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and DBU in CH 2 Cl 2 , THF or DMF. As an alternative reagent that