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.

AgNO₃ - cyclization - furanopyrimidines

References

<A NAME="RD16304ST-1">1</A> Agrofoglio LA. Gillaizeau S. Saito Y. Chem. Rev.  2003,  103:  1875 ; and references cited therein

<A NAME="RD16304ST-2A">2a</A> McGuigan C. Yarnold CJ. Jones G. Velasquez S. Barucki H. Brancale A. Andrei G. Snoeck R. De Clercq E. Balzarini J. J. Med. Chem.  1999,  42:  4479 

<A NAME="RD16304ST-2B">2b</A> McGuigan C. Barucki H. Blewett S. Carangio A. Erischen JT. Andrei G. Snoeck R. De Clercq E. Balzarini J. J. Med. Chem.  2000,  43:  4993 

<A NAME="RD16304ST-2C">2c</A> Srinivasan S. McGuigan C. Andrei G. Snoeck R. De Clercq E. Balzarini J. Bioorg. Med. Chem. Lett.  2001,  11:  391 

<A NAME="RD16304ST-2D">2d</A> McGuigan C. Brancale A. Barucki H. Srinivasan S. Jones G. Pathirana R. Blewett S. Alvarez R. Yarnold CJ. Carangio A. Velazquez S. Andrei G. Snoeck R. De Clercq E. Drugs Future  2000,  25:  1151 

<A NAME="RD16304ST-2E">2e</A> Carangio A. McGuigan C. Andrei G. Snoeck R. De Clercq E. Balzarini J. Antivir. Chem. Chemother.  2001,  12:  187 

<A NAME="RD16304ST-3">3</A> Mansour TS. Evans CA. Charron M. Korba BE. Bioorg. Med. Chem. Lett.  1997,  7:  303 

<A NAME="RD16304ST-4A">4a</A> Robins MJ. Barr PJ. J. Org. Chem.  1983,  48:  1854 

<A NAME="RD16304ST-4B">4b</A> Robins MJ. Barr PJ. Tetrahedron Lett.  1981,  22:  421 

<A NAME="RD16304ST-5">5</A> Castro CE. Gaughan EJ. Owsley DC. J. Org. Chem.  1966,  31:  4071 

<A NAME="RD16304ST-6">6</A> Bleackley RC. Jones AS. Walker RT. Tetrahedron  1976,  32:  2795 

<A NAME="RD16304ST-7">7</A> Aucagne V. Berteina-Raboin S. Guenot P. Agrofoglio LA. J. Comb. Chem.  2004,  in press 

For electrophilic cyclization using NIS or NBS, see:

<A NAME="RD16304ST-8A">8a</A> Rao MS. Esho N. Sergeant C. Dembinski R. J. Org. Chem.  2003,  68:  6788 

<A NAME="RD16304ST-8B">8b</A> Arcadi A. Cacchi S. Di Giuseppe S. Babrizi G. Marinelli F. Org. Lett.  2002,  4:  2409 

<A NAME="RD16304ST-9">9</A> Jong T.-T. Leu S.-J. J. Chem. Soc., Perkin Trans. 1  1990,  423 

<A NAME="RD16304ST-10">10</A> Marshall JA. Wang XJ. J. Org. Chem.  1990,  55:  2995 

<A NAME="RD16304ST-11">11</A> Robins MJ. Barr PJ. J. Org. Chem.  1983,  48:  1854 

<A NAME="RD16304ST-12">12</A> Kelly JL. Kelsey JE. Hull WR. Krochmal MP. Schaeffer HJ. J. Med. Chem.  1981,  24:  753 

<A NAME="RD16304ST-13">13</A> Amblard F. Nolan SP. Gillaizeau I. Agrofoglio LA. Tetrahedron Lett.  2003,  44:  9177 

<A NAME="RD16304ST-14">14</A>

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.

<A NAME="RD16304ST-15">15</A>

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.

<A NAME="RD16304ST-16">16</A>

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.

<A NAME="RD16304ST-17">17</A>

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.

<A NAME="RD16304ST-18">18</A>

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.

<A NAME="RD16304ST-19">19</A>

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.

<A NAME="RD16304ST-20">20</A>

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.