The Journal of Organic Chemistry ARTICLE Scheme 4. Preparation and Coupling of Protected D-Riboses 17 Scheme 5. Coupling of 1-O-Acetyl-2,3,5-tri-O-benzoyl-α-D- ribofuranose with NI-TES by the Vorbru€ggen Method β-nucleoside β-15 was also needed, CH3CN was replaced by 1,2- C2H4Cl2, hoping to increase the amount of the β-anomer. When NI-TMS and the mixture of α- and β-14 were coupled in 1,2- C2H4Cl2 with 0.5 equiv of TfOTMS as a catalyst for 4 h at rt, the yield for β-15 was 13% and that for α-15 16%. The yield of β-15 increased to 31%, when the coupling was modiﬁed (NI-TES, 50 C, 1.2 equiv of TfOTES, 2 h). The low and irreproducible yields in this halogenated solvent were attributed to the unsa- tisfactory solubility of NI-TES. Although the β-nucleoside was formed preferentially, the method was not suitable for the preparation of relevant amounts of β-7. The preferred formation of the α-anomer is attributed to the neighboring group eﬀect by the 2-acetoxy group, which is β-orientated.22 However, the formation of the β-anomer results very likely from the inter- mediacy of a nitronate ester as suggested by others.19 Preparation of 2-Nitroimidazole Nucleosides Derived from D-Ribose. To broaden the scope of the method, we studied the reaction of NI-TES with D-ribose and D-galactose derivatives catalyzed by silyl triflates as well. First, D-ribose was silylated and acetylated in a one-pot reaction in the same way as D-arabinose, except that the acetylation was performed at 50 C, to give a mixture (54:46) of α- and β-triacetate 17 which could be separated by flash chromatography (Scheme 4). Each anomer was reacted with NI-TES in CH3CN catalyzed by 1 equiv of TfOTES. When the reaction mixture was allowed to warm from 20 to 8 C within 2 h, triacetate β-17 furnished a 72% yield of β-nucleoside β- 18 and a trace of the α-nucleoside as detected by TLC. Similarly, α-triacetate yielded 87% of the β- and a trace of the α-nucleoside (20 C to rt within 2 h). As the two anomers reacted similarly, their separation was not worthwhile. In the latter case, the influence of the temperature on the outcome was studied. Below 20 C, coupling did not take place; between 10 and 5 C at a reaction time of 4 h, a mixture of nucleosides resulted (β-18:α-18 = 2:1, combined yield 60%). No nucleoside was formed in 1,2-C2H4Cl2 under a variety of conditions. An alternative for the preparation of azomycin nucleosides derived from D-ribose is the coupling of commercially available acetate 19 (Scheme 5). It was found that TfOTMS was a better catalyst than TfOTES with this sub- strate. When the Vorbr€uggen coupling was effected in CH3CN Scheme 6. Coupling of 1,2,3,4,6-Penta-O-acetyl-β-D-galacto- pyranose with NI-TES by the Vorbru€ggen Method ( 20 to 10 C, 1.2 equiv of TfOTMS), a 72% yield of nucleo- side β-20 resulted. However, when the same reaction was per- formed for 30 min at rt, a separable mixture (α-20, 42%; β-20, 31%) of nucleosides was obtained. These results underlined the necessity to control the reaction temperature carefully and use CH3CN as the solvent of choice for a good yield. For comparison, Prisbe et al. found that NI and 19 gave a 61% yield of α-20, when treated with 2 equiv of SnCl4 and Hg(CN)2 in CH3CN at 60 C.19 To obtain β-20 in 68% yield, acetate 19 had to be first converted to the corresponding bromide by bubbling HBr through a solution of it and then reacting it analogously to before with 2 equiv of Hg(CN)2 without SnCl4. The predominant formation of the β-anomer here is again attributed to the neighboring group effect (2-acyloxy group is α) and the α-anomer to the possible involve- ment of a nitronate ester. Preparation of 2-Nitroimidazole Nucleoside Derived from D-Galactose. At last, commercially available β-D-galactopyranose pentaacetate was converted to the 2-nitroimidazole nucleoside β-22 in high yield (92%) in CH3CN under very mild conditions, when the reaction mixture was stirred for 1 h at 0 C and 1 h at rt (Scheme 6). For comparison, the coupling of acetobromo-α-D- galactose with 2-nitroimidazole catalyzed by 2.5 equiv of Hg- (CN)2 for 23 h at 40 C in a large volume of CH3CN yielded 88% of the desired β-nucleoside.21 Conversion of 2-Nitroimidazole Nucleosides Derived from α- and β-D-Arabinose and D-Ribose to (Putative) Pre- cursors for Tracers To Image Hypoxia. The precursor α-7 for the preparation of α-[18F]FAZA can be accessed easily from silylated nucleoside α-15. It was deblocked with HF generated in situ from KF/benzoic acid27 in refluxing CH3CN in 90% yield and tosylated to give precursor α-728 in 94% yield, first prepared by Wiebe et al. (Scheme 7). This sequence comprises only four steps and is the shortest synthesis of precursor α-7, starting from D-arabinose. The synthesis of β-7 was ﬁrst accomplished also by Wiebe et al., starting from 1-β-(D-ribofuranosyl)-2-nitroimidazole 8161 dx.doi.org/10.1021/jo200727k |J. Org. Chem. 2011, 76, 8159–8167