Pyrimidine Acyclo-C-Nucleosides by Ring Transformations of 2-Formyl-L-arabinal

The protected 2-formyl-L-arabinal 2 reacted with thiourea and cyanamide in the presence of sodium hydride to afford via ring transformations the 5-[1R,2S-1,2-bis(benzyloxy)-3-hydroxypropyl]-1,2-dihydropyrimidines 3 and 4, respectively. Similarly, treatment of 2 with 3-amino-2H-1,2,4-triazole yielded 6-[1R,2S-1,2-bis(benzyloxy)-3-hydroxypropyl][1,2,4]-triazolo[1,5-a]pyrimidine (5).


Results and Discussion
Thiourea was reacted with 2-formyl-L-arabinal 2 in the presence of sodium hydride in tetrahydrofuran to afford through the sequential combination of addition-elimination and ring closure reaction the required pyrimidine C-nucleoside analogue 3 in 38% yield as a pale yellow syrup (Scheme 1). Compound 3 was characterized by 1 H-and 13 C-NMR as well as IR and mass spectroscopy. In the 1 H-NMR spectrum, H-4 and H-6 exhibit only one signal at δ = 8.50, which is due to the tautomerization involving the proton on the N atoms. In the 13 C-NMR spectrum C-4 and C-6 appeared also as one signal at δ = 157.0. For C-2 a chemical shift of δ = 170.7 was found. The IR spectrum showed a typical absorption for the associated OH group at 3418 cm -1 . Furthermore, the mass spectrum confirmed the presence of the thiourea structural element by giving a [M+H] + peak at 383.

Scheme 1.
In order to prepare the corresponding 5-[1R,2S-1,2-bis(benzyloxy)-3-hydroxy-propyl]-1,2-dihydropyrimidin-2-one (4), formylarabinal 2 was treated under reflux with an excess of cyanamide in tetrahydrofuran for 30 hours in the presence of sodium hydride. As first step in this reaction we assume a nucleophilic attack of the cyanamide amino group at formyl carbon followed by hydrolysis of the nitrile to give the carboxamide group. Ring transformation to 4 then occurred through carboxamide attack at C-1.
The carbonyl resonance was found at δ = 162.8 in the 13 C-NMR spectrum, while H-4 and H-6 appeared as a common singlet at δ = 8.25 in 1 H-NMR spectrum. In the same way C-4 and C-6 gave a signal at δ = 158.1 in the 13 C-NMR spectrum. Furthermore, the IR spectrum showed typical absorption for the associated NH group of the pyrimidinone.
Next  The 1 H-NMR spectrum displayed two doublets for H-5 and H-7, each having a coupling constant of 2.2 Hz due to coupling over four bonds (W type). In order to distinguish between the alternative structures 5 and 6 a NOESY spectrum was recorded. The absence of cross peaks between H-3 and H-5 protons, as expected for structure 6, confirmed structure 5. On the other hand, a correlation between H-7 and H-1´ was found.
Four conceivable pathways can be formulated for this reaction. The first nucleophilic attack of 3amino-1,2,4-triazole may occur with the ring NH and NH 2 groups, respectively, at C-1 of the 2formyl-L-arabinal resulting in cleavage of the pyranose ring. After that recyclization is possible by reaction of the NH 2 or ring NH group with the formyl function to yield [1,2,4]triazolo[1,5-a]pyrimidine 5. On the other hand, the first nucleophilic attack of ring NH and NH 2 groups, respectively, could take place at the carbonyl group of 2-formyl-L-arabinal 2 followed by ring transformation including now the NH 2 and ring NH groups. Finally, all these reaction pathways result in the formation of the same [1,2,4]triazolo[1,5-a]pyrimidine 5.

Acknowledgments
We thank the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie for financial support.

General
Solvents were distilled and if necessary, dried using standard procedures. TLC was carried out on silica gel 60 GF 254 (Merck) with detection by UV light (λ = 254 nm) and/or by charring with 10% sulfuric acid in methanol. Silica gel 60 (70-230 mesh) (Merck) was used for column chromatography. Melting points were determined by using a Boetius melting point apparatus and are corrected. Specific rotations were determined with a Gyromat HP (Dr. Kernchen). IR spectra were recorded with a Nicolet 205 FT-IR spectrometer. 1 H-NMR spectra (250.13 MHz and 300.13 MHz, respectively) and 13 C-NMR spectra (62.9 MHz and 75.5 MHz, respectively) were recorded on Bruker instruments AC 250 and ARX 300, with CDCl 3 as solvent. The calibration of spectra was carried out on the solvent signals (δ( 1 H) = 7.25; δ( 13 C) = 77.0). The 1 H-and 13 C-NMR signals were assigned by DEPT and twodimensional 1 H, 1 H COSY and 13 C, 1 H correlation spectra (HETCOR). The mass spectra were recorded on an AMD 402/3 spectrometer (AMD Intectra GmbH). Elemental analyses were performed on a CHNS automatic elemental analyser Flash EA 1112 (ThermoQuest).