Highly Efficient AgNO₃-Catalyzed Preparation of Substituted Furano­pyrimidine Nucleosides

Abstract

An efficient method for the synthesis of substituted ­furanopyrimidine nucleosides is described. Upon treatment with catalytic AgNO₃, 5-alkynyl uracil derivatives were almost quanti­tatively converted into their corresponding bicyclic nucleoside ­analogues.

Key words

AgNO₃ - cyclization - furanopyrimidines

References

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14

Typical Procedure for Sonogashira Cross-Coupling. Under dry nitrogen, the iodo derivatives (0.026 mmol) were dissolved in DMF (0.5 mL), then alkyne (0.079 mmol), Et₃N (0.079 mmol), CuI (0.005 mmol), PdCl_{2 (}PPh₃)₂ (0.003 mmol) were added. The reaction was stirred at r.t. until complete conversion was reached. After evaporation of volatiles the crude residue was purified by flash chromatography.

15

5-(1-decynyl)-1-[( E )-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-propenyl]-2,4 (1 H ,3 H )-pyrimidinedione ( 12b): ¹H NMR (CDCl₃): δ = 0.86 (t, 3 H, J = 6.9 Hz), 1.15-1.48 (m, 16 H), 1.50-1.63 (m, 1 H), 2.36 (t, 2 H, J = 6.9 Hz), 3.58 (dd, 1 H, J = 8.0 Hz), 4.10 (dd, 1 H, J = 6.3 Hz, J = 8.0 Hz), 4.22-4.41 (m, 2 H), 4.48-4.61 (m, 1 H), 5.72 (dd, 1 H, J = 6.0 Hz, J = 15.4 Hz), 5.83 (dt, 1 H, J = 5.7 Hz, J = 15.4 Hz), 7.31 (s, 1 H), 9.17 (s, 1 H). ¹³C NMR (CDCl₃): δ 14.2 (CH₃), 19.7 (CH₂), 22.7 (CH₂), 25.8 (CH₃), 26.7 (CH₃), 28.6 (CH₂), 29.1 (CH₂), 29.2 (CH₂), 29.3 (CH₂), 31.9 (CH₂), 49.3 (CH₂), 69.3 (CH₂), 70.8, 75.9 (CH), 95.9, 101.3, 109.8, 126.6 (CH), 133.4 (CH), 145.4 (CH), 149.8, 162.2. HRMS (ESI): m/z calcd for C₂₂H₃₂N₂O₄Na: 411.2260 [M + Na]⁺. Found: 411.2259.

16

General Procedure for Alkyne Cyclization Reactions: Under dry nitrogen, the alkyne derivatives (0.047 mmol) were dissolved in acetone (1 mL), then AgNO₃ (0.009 mmol) was added. The reaction was stirred at r.t. until complete conversion was reached. After evaporation of volatiles, the crude residue was dissolved in EtOAc, washed 3 times with H₂O, dried over MgSO₄, filtered and concentred in vacuo. The cyclized compound was pure enough (purity determined by proton-decoupled ¹³C NMR) to be subjected to the next reaction without further purification.

17

3-[( E )-3-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2-propenyl]-6-(4-pentylphenyl)furo[2,3- d ]pyrimidin-2-(3 H )-one ( 15a): ¹H NMR (CDCl₃): δ = 0.90 (t, 3 H, J = 6.7 Hz), 1.21-1.41 (m, 4 H), 1.38 (s, 3 H), 1.42 (s, 3 H), 1.55-1.71 (m, 2 H), 2.64 (t, 2 H, J = 7.3 Hz), 3.61 (dd, 1 H, J = 8.0 Hz), 4.11 (dd, 1 H, J = 6.1 Hz, J = 8.0 Hz), 4.50-4.76 (m, 3 H), 5.77 (dd, 1 H, J = 7.0 Hz, J = 15.5 Hz), 6.01 (dt, 1 H, J = 6.0 Hz, J = 15.5 Hz), 6.64 (s, 1 H), 7.25 (d, 2 H, J = 8.1 Hz), 7.66 (d, 2 H, J = 8.1 Hz), 7.89 (s, 1 H). ¹³C NMR (CDCl₃): δ = 14.1 (CH₃), 22.6 (CH₂), 25.9 (CH₃), 26.7 (CH₃), 31.0 (CH₂), 31.5 (CH₂), 35.9 (CH₂), 52.4 (CH₂), 69.3 (CH₂), 76.1 (CH), 96.4 (CH), 108.9, 109.8, 125.1 (CH × 2), 125.7, 127.5 (CH), 129.2 (CH × 2), 133.4 (CH), 138.9 (CH), 145.4, 155.2, 156.4, 171.9. HRMS (ESI): m/z calcd for C₂₅H₃₀N₂O₄Na: 445.5186 [M + Na]⁺. Found: 445.5182.

18

General Procedure for Deprotection of Acetalic Derivatives: The protected derivative (acetal, 0.22 mmol) was stirred at r.t. for 3 h in a mixture of TFA-H₂O (10 mL/5 mL). After evaporation of volatiles the crude residue was purified by flash chromatography.

19

General Procedure for Deacetylation: Acetylated nucleoside analogue (1 mmol) was dissolved in pyridine (10 mL) and EtOH (5 mL). The reaction mixture was cooled to -10 °C and 5 mL of 1 M NaOH aq solution was added. The resulting solution was stirred at this temperature until completion (typically 1-4 h, followed by TLC). The reaction mixture was neutralized with Dowex (H⁺ form) then filtered through a fritted glass funnel. Solvents were evaporated in vacuo and the oily residue was submitted to a flash column chromatography using an appropriate eluent (typically hexanes-EtOAc 25:75, EtOAc, and MeOH-EtOAc 1%) to furnish the desired nucleosides.

20

1-[( E )-4,5-dihydroxy-2-pentenyl]-5-[2-(4-pentyl-phenyl)ethynyl]-2,4 (1 H ,3 H )-pyrimidinedione ( 6a): ¹H NMR (DMSO-d ₆): δ = 0.73-0.91 (m, 3 H), 1.18-1.37 (m, 4 H), 1.49-1.68 (m, 2 H), 2.57 (t, 2 H, J = 7.5 Hz), 3.22-3.33 (m, 2 H), 3.91-4.03 (m, 1 H), 4.25-4.39 (m, 2 H), 4.51-4.61 (m, OH), 4.86 (d, OH, J = 4.5 Hz), 5.69-5.85 (m, 2 H), 7.22 (d, 2 H, J = 8.0 Hz), 7.36 (d, 2 H, J = 8.0 Hz), 8.10 (s, 1 H) 11.64 (s, NH). ¹³C NMR (DMSO-d ₆): δ = 13.9 (CH₃), 21.9 (CH₂), 30.3 (CH₂), 30.8 (CH₂), 34.9 (CH₂), 48.9 (CH₂), 65.7 (CH₂), 71.4 (CH), 81.6, 92.0, 97.7, 119.6, 123.7 (CH), 128.7 (CH × 2), 131.0 (CH × 2), 135.8 (CH), 143.2, 148.3 (CH), 149.8, 161.9. HRMS (ESI): m/z calcd for C₂₂H₂₆N₂O₄Na: 405.1790 [M + Na]⁺. Found: 405.1791.