Pyridine-Free and Solvent-Free Acetylation of Nucleosides Promoted by Molecular Sieves

Abstract

A practical method for the acetylation of purine and ­pyrimidine nucleosides employing a combination of acetic an­hydride and potassium-exchanged molecular sieves is described. Besides the high yields obtained for the acylated nucleosides, the procedure is simple, inexpensive and environmentally benign, avoiding the use of pyridine or co-solvents as additives.

green chemistry - acylation - heterogeneous catalysis - molecular sieves - nucleosides

References and Notes

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Preparation of Potassium-Exchanged Molecular Sieves.
A suspension of the appropriate molecular sieves (1.0 g) and 1 M KCl (10 mL) was stirred at r.t. for 15-18 h, followed by vacuum filtration and air-drying, obtaining a clear amorphous solid that can be stored for months without any special precautions.
General Procedure for the Synthesis of Acetylated Nucleosides 1-10.
Nucleoside (1.0 mmol), catalyst (0.6 g) and Ac₂O (8-10 mmol) were stirred at 90-100 °C for the time indicated in Table [2] . The final mixture was cooled to r.t., filtered, the catalyst was rinsed with CH₂Cl₂, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted in EtOAc and washed with sat. NaHCO₃ and H₂O. Then the aqueous phases were back-extracted with CH₂Cl₂ and the combined organic extracts were dried over Na₂SO₄, filtered and concentrated to give a solid residue that was purified by recrystallization with CH₂Cl₂.
Selected Data.
2′,3′,5′-O-Triacetylxanthosine (4): white solid; mp 135-137 °C. IR (KBr): ν_max = 3475, 3193, 1749, 1700, 1232 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.04 (s, 3 H, CH₃), 2.10 (s, 6 H, CH₃), 4.22-4.38 (m, 3 H, H-4′ and H-5′), 5.39 (m, 1 H, H-3′), 5.66 (t, J = 5.5 Hz, 1 H, H-2′), 6.04 (d, J = 5.5 Hz, 1 H, H-1′), 7.86 (s, 1 H, H-8), 10.33 (s, 1 H, D₂O exchange). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 25.64 (CH₃), 25.78 (CH₃), 25.96 (CH₃), 68.40 (CH₂), 75.16 (CH), 77.69 (CH), 84.80 (CH), 89.98 (CH), 120.72 (C), 139.40 (CH), 150.20 (C), 158.83 (C), 163.88 (C), 174.74 (C=O), 174.89 (C=O), 175.54 (C=O). Anal. Calcd for C₁₆H₁₈N₄O₉·2H₂O (%): C, 43.05; H, 4.97; N, 12.55. Found: C, 43.28; H, 4.57; N, 12.74.
2′,3′-O-Isopropylidene-2-N-5′-O-diacetylguanosine (9b): white solid; mp 124-125 °C. IR (KBr): ν_max = 3454, 3202, 3178, 1738, 1708, 1683, 1250 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.32 (s, 3 H, CH₃), 1.52 (s, 3 H, CH₃), 1.97 (s, 3 H, CH₃), 2.20 (s, 3 H, CH₃), 4.08 (dd, J = 7.0, 12.0 Hz, 1 H, H-5′), 4.19 (dd, J = 4.5, 12.0 Hz, 1 H, H-5′), 4.30 (m, 1 H, H-4′), 5.18 (dd, J = 3.5, 6.5 Hz, 1 H, H-3′), 5.30 (dd, J = 2.0, 6.5 Hz, 1 H, H-2′), 6.11 (d, J = 2.0 Hz, 1 H, H-1′), 8.16 (s, 1 H, H-8), 11.54 (s, 1 H, D₂O exchange), 12.07 (s, 1 H, D₂O exchange). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 21.19 (CH₃), 24.61 (CH₃), 26.04 (CH₃), 27.69 (CH₃), 64.54 (CH₂), 81.47 (CH), 84.29 (CH), 84.92 (CH), 89.24 (CH), 114.15 (C), 121.33 (C), 139.19 (CH), 148.56 (C), 148.64 (C), 155.46 (C), 170.76 (C=O), 174.23 (C=O). Anal. Calcd for C₁₇H₂₁N₅O₇·H₂O (%): C, 48.00; H, 5.45; N, 16.46. Found: C, 47.92; H, 5.80; N, 16.41.
General Procedure for the Microwave-Assisted Synthesis of Acetylated Nucleosides.
Microwave reactions were performed in 10 mL sealed tubes in a commercially available monomode reactor (CEM Discover) with IR temperature monitoring and non-invasive pressure transducer. In a typical procedure, nucleoside (1.0 mmol), Ac₂O (8-10 mmol) and the catalyst (0.6 g) were placed in a 10 mL glass tube. The vessel was then sealed with a septum, placed into the microwave cavity and irradiated with stirring under the conditions presented in Table [3] . After allowing the mixture to cool to r.t., the reaction vessel was opened and the contents were treated as above to give pure acetylated products after recrystallization.

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