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Synlett 2004(13): 2406-2408  
DOI: 10.1055/s-2004-831330
LETTER
© Georg Thieme Verlag Stuttgart · New York

Highly Efficient AgNO3-Catalyzed Preparation of Substituted Furano­pyrimidine Nucleosides

Vincent Aucagne, Franck Amblard, Luigi A. Agrofoglio*
ICOA UMR CNRS 6005, BP 6759, 45067 Orleans Cedex 2, France
Fax: +33(2)38510728; e-Mail: luigi.agrofoglio@univ-orleans.fr;
Further Information

Publication History

Received 19 June 2004
Publication Date:
31 August 2004 (online)

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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

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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), PdCl2 (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.