An Efficient Route to Pyrimidine Nucleoside Analogues by [4 + 2] Cycloaddition Reaction

Abstract

We report here an efficient synthesis for pyrimidine nucleoside analogues by [4 + 2] cycloaddition reaction. These compounds were obtained by convergent chemistry from glycosyl isothiocyanates 3a-f (pyranoses, furanoses, and dissaccharides) and diazadienium salt 5. In fact, diazapentadienium iodide 5 prepared from vinylthioamide 4 is an efficient intermediate in heterocyclic synthesis and reacts with isothiocyanates 3a-f affording beta-D-uracil analogues 7a-f in good yields and with total regiocontrol. All compounds were fully characterized by IR, HRMS, and 13C and 1H NMR (COSY and HMQC).

Straightforward Pyrimidine Ring Construction: A Versatile Tool for the Synthesis of Nucleobase and Nucleoside Analogues

“…Pyrimidines 3-9: Isothiocyanate or isocyanate (2.2 mmol) was added to a solution of diazadienium iodide 2 [18] (272 mg, 1.0 mmol) in dichloromethane (10 mL). After 15 min, triethylamine (300 µL, 2.2 mmol) was added and the reaction mixture was stirred at room temperature over a period of 4-18 h (18 h for 3, 5, 8 and 9; 6 h for 4 and 6; 4 h for 7).…”

“…The organic mixture was then washed twice with water, dried with magnesium sulfate and concentrated under vacuum. Pyrimidines 10 and 11: Isocyanate (1.2 mmol) was added to a solution of diazadienium iodide 2 [18] (272 mg, 1.0 mmol) in dichloromethane (10 mL). After 15 min, triethylamine (200 µL, 1.4 mmol) www.eurjoc.orgwas added and the reaction mixture was stirred at room temperature for 18 h. Then, the organic mixture was washed twice with water, dried with magnesium sulfate and concentrated under vacuum.…”

“…The residue was purified by chromatography on silica gel (dichloromethane/petroleum ether/triethylamine, 40:57:3) or was washed with diethyl ether (39). [18] (244 mg, 0.5 mmol) in methanol (15 mL) was stirred at 0°C for 3 h. Then, dichloromethane (50 mL) was added to the reaction mixture and the mixture was concentrated under reduced pressure without heating. The resulting solid was washed with diethyl ether.…”

“…The resulting solid was washed with diethyl ether. [18] (301 mg, 0.5 mmol), first dissolved in dichloromethane (5 mL), and potassium carbonate (3.5 mg, 0.025 mmol) in methanol (15 mL) was stirred at 0°C for 7 h. Then, dichloromethane (50 mL) was added to the reaction mixture and the mixture was concentrated under reduced pressure without heating. …”

“…We recently reported [18] that the [4+2] cyclocondensation reaction between glycosyl isothiocyanates and diazadienium iodide 2 is very efficient in terms of chemical yield and diastereo-and regioselectivity for the synthesis of nucleosides 44a-f. These compounds were synthesised in a range of 72 to 84 % yield from preconstructed β-glycosyl isothiocyanates 43a-f (Scheme 6).…”