The Journal of Organic Chemistry Scheme 1. Synthesis of α-[18F]FAZA 2-nitroimidazole β-D-galactosides 6 were used to image tumor hypoxia in mice.17 As the uptake of α-[18F]FAZA is diﬀusion controlled and its renal clearance is rapid, it is still attractive to prepare other 2-nitroimidazole nucleosides and evaluate them as precursors for tracers to image hypoxia. To improve the tumor/ background ratio of tracers, their active transport by cellular transport systems such as nucleoside transporters could be exploited. Emami et al. have established a yeast system for testing the transport of ﬂuoroazomycin nucleosides by four nucleoside transporters, which might help to ﬁnd better tracers than α-[18F]FAZA.18 Tracer 5 most favored at present for imaging hypoxia is prepared from precursor α-7 by a substitution reaction (SN2) with cyclotron-generated 18F in combination with Kryptoﬁx 2.2.2, followed by base-catalyzed removal of acetyl groups and HPLC puriﬁcation (Scheme 1). The 2-nitroimidazole nucleosides underlying tracers 4, 5, and 6 are formed by a K€onigs Knorr reaction of 2-nitroimidazole or in some cases its trimethylsilylated species in acetonitrile at 50 60 C with a benzoyl- or an acetyl-protected D-1-bromofuranose or D-1-bromo- pyranose derivatives of D-arabinose or D-galactose, respec- tively. Normally, excess Hg(CN)2 (2.2 equiv), sometimes in combination with SnCl4, was used as a catalyst.19 21 This method was used by Schneider et al. to prepare a number of 2-nitroimidazole nucleosides, two of which were converted to radioiodinated tracers. When we started this project to prepare known and new precursors for tracers to image hypoxia, we decided to search for an alternative to the K€onigs Knorr procedure not involving metal salts, especially toxic Hg(CN)2. Ideally, the method should use easily accessible starting materials with an adequately silylated hydroxyl group at C-5 and acetyl groups for the other hydroxyls of furanoses derived from D- arabinose and D-ribose. The 2-nitroimidazole nucleosides then formed would yield products which could be deprotected and tosylated at C-5 to give the desired precursors. Additionally, the desilylated products could be transformed to the ﬂuorides and deblocked to give the cold ﬂuoro standards. ’ RESULTS AND DISCUSSION Preparation of Triethylsilylated 2-Nitroimidazole and 2-Nitroimidazole Nucleosides Derived from D-Arabinose. We envisaged to test the Vorbr€uggen method for the coupling first.22 It is based on the coupling of trimethylsilylated hetero- cyclic bases with protected sugar derivatives with an acetoxy or methoxy group at C-1 in CH3CN, CH2Cl2, or 1,2-C2H4Cl2, catalyzed by trimethylsilyl triflate. Surprisingly, it has never been used for the synthesis of azomycin nucleosides. The solubility of 2-nitroimidazole is very low in all common solvents, especially at rt or below, and even trimethylsilylation with hexamethyldisila- zane/(NH4)2SO4 in pyridine had only a marginal effect on its solubility. Therefore, we decided to use triethylsilylation to increase the solubility further, which proved to be critical for our success. ARTICLE Scheme 2. Synthesis of Hexaethyldisilazane and Its Use for the Triethylsilylation of 2-Nitroimidazole Scheme 3. Preparation of D-Arabinofuranose Derivative 14 and Its Coupling with NI-TES by the Vorbru€ggen Method We accessed hexaethyldisilazane, a known23 but diﬃcult to prepare reagent, easily from (triethylsilyl)amine24 and chloro- triethylsilane in the presence of a catalytic amount of triethylsilyl triﬂate (TfOTES) in dry toluene in 79% yield (Scheme 2). Initially, we reﬂuxed a mixture of 2-nitroimidazole (NI) and 4 6 equiv of hexaethyldisilazane and a catalytic amount of (NH4)2SO4 in pyridine until the reaction mixture was homo- geneous. However, later we found that 2 equiv was suﬃcient for silylation within 30 min and that the catalyst could be omitted. Removal of volatile components left NI-TES (2-nitro- 1-(triethylsilyl)imidazole) as a crystalline product, which was used directly. Surprisingly, (triethylsilyl)amine did not silylate NI in reﬂuxing pyridine. In the ﬁrst place, we wanted to couple NI-TES with a suitable D-arabinofuranose derivative containing a silyl-proteced C-5 hydroxyl group. Thus, a mixture of D-arabinose and tert-butyldi- phenylsilyl chloride (TBDPSCl) in pyridine was allowed to warm in the cooling bath from 20 C to rt for 18 h. Stirring was continued for 6 h after the addition of acetic anhydride. Aqueous workup and ﬂash chromatography furnished a mixture of anomeric acetates (α:β = 60:40) in an admixture with impurities as a syrup in 71% yield (Scheme 3). The predominat- ing α-anomer crystallized and was fully characterized. Recently, Chatterjee et al. isolated the 5-O-TBDPS-protected D-arabinose and then acetylated it in an overall yield of 46%.25 The coupling experiments were performed with the anomeric mixture 14. Under optimized conditions, a mixture of NI-TES and 14 in CH3CN was cooled to 20 C, and 1 equiv of a 1 M solution of TfOTES in 1,2-C2H4Cl2 was added dropwise. Stirring was continued while the reaction mixture was allowed to warm to 8 C within 3 h. Extractive workup and ﬂash chromatography furnished the α-nucleoside26 α-15 in 72% yield beside some starting material and a trace of the β-anomer detected by TLC, which was not isolated (Scheme 3). Anticipating later results, α-15 was converted in two steps into precursor α-7. As the 8160 dx.doi.org/10.1021/jo200727k |J. Org. Chem. 2011, 76, 8159–8167