Synthesis of 8-Heteroaryl-2′-deoxyguanosine Derivatives

Gerard Hobley; Vladimir Gubala; María Del C Rivera-Sánchez; José M. Rivera

doi:10.1055/s-2007-1077795

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Synlett 2008(10): 1510-1514
DOI: 10.1055/s-2007-1077795

LETTER

Synthesis of 8-Heteroaryl-2′-deoxyguanosine Derivatives

Gerard Hobley, Vladimir Gubala, María Del C. Rivera-Sánchez, José M. Rivera*
Department of Chemistry, College of Natural Sciences, University of Puerto Rico, Río Piedras Campus, San Juan 00931, Puerto Rico
Fax: +1(787)7568242; e-Mail: jmrivortz@mac.com;

Further Information

Publication History

Received 14 December 2007
Publication Date:
19 May 2008 (online)

Abstract
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Abstract

We describe the synthesis of 8-heteroaromatic-2′-deoxyguanosine analogues using Suzuki-Miyaura or Stille conditions. Unprotected and protected 8-bromo-2′-deoxyguanosine was coupled with commercially available heteroarylboronic acids or the trialkyltin derivatives of 2-pyridylbromides either with or without microwave irradiation in good yields.

Key words

Stille reaction - nucleosides - nucleobases - palladium - coupling

References and Notes

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1

Current address: Dublin City University, Biomedical Diagnostics Institute, Glasnevin, Dublin 9, Ireland.

16

Suzuki couplings were performed according to the procedures outlined in ref. 8 and 10.
Analytical Data Compound 2a: yield 79% (391 mg, 1.14 mmol); mp 225 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 10.89 (br s, 1 H), 8.85 (d, J = 2 Hz, 1 H), 8.71 (dd, J = 5, 1 Hz, 1 H), 8.09 (dt, J = 8, 2 Hz, 1 H), 7.59 (dd, J = 8, 5 Hz, 1 H), 6.50 (s, 2 H), 6.06 (t, J = 7 Hz, 1 H), 5.19 (d, J = 5 Hz, 1 H), 4.96 (t, J = 6 Hz, 1 H), 4.33 (br m, 1 H), 3.80 (m, 1 H), 3.64 (m, 1 H), 3.53 (m, 1 H), 3.17 (m, 1 H), 2.08 (ddd, J = 13, 6, 2 Hz, 1 H). ¹³C NMR (80 MHz, DMSO-d ₆): δ = 174.1, 173.6, 153.7, 151.1, 149.6, 118.8, 115.9, 83.3, 79.8, 72.1, 61.1, 31.9, 31.2, 27.1, 16.5. IR (neat): 3206, 1677, 1631, 1560, 1244 cm^-1. Anal. Calcd for C₁₅H₁₆N₆O₄: C, 52.32; H, 4.68; N, 24.41. Found: C, 51.65; H, 4.73; N, 24.16.
Compound 2b: white solid, yield 88% (164 mg, 304 µmol); mp 203 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 10.87 (s, 1 H), 8.05 (m, 1 H), 7.97 (m, 1 H), 7.94 (s, 1 H), 7.46 (m, 2 H), 6.59 (s, 2 H), 6.45 (t, J = 7 Hz, 1 H), 5.24 (d, J = 5 Hz, 1 H), 5.04 (t, J = 6 Hz, 1 H), 4.46 (m, 1 H), 3.88 (q, J = 9, 5 Hz, 1 H), 3.72 (m, 1 H), 3.62 (m, 1 H), 3.27 (m, 1 H), 2.15 (m, 1 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 157.1, 153.7, 152.8, 141.9, 132.6, 129.3, 128.8, 128.6, 117.8, 88.5, 85.2, 71.8, 62.7, 37.1. IR (neat): 2928, 1679, 1631, 1101, 940
cm^-1.
Compound 2c: grey solid, yield 81% (179.4 mg, 468.0 µmol). ¹H NMR (500 MHz, DMSO-d ₆): δ = 10.89 (br s, 1 H), 7.79 (br d, J = 7 Hz, 1 H), 7.70 (br d, J = 8 Hz, 1 H), 7.46 (br s, 1 H), 7.43 (br t, J = 8 Hz, 1 H), 7.36 (br t, J = 7 Hz, 1 H), 6.57 (br s, 2 H), 6.50 (t, 1 H), 5.25 (br s, 1 H), 4.97 (br s, 1 H), 4.45 (br s, 1 H), 3.85 (br s, 1 H), 3.68 (m, 1 H), 3.54 (m, 1 H), 3.23 (quin, J = 7 Hz, 1 H), 2.17 (br ddd, J = 7 Hz, 1 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 157.1, 154.8, 154.0, 152.6, 146.5, 137.9, 128.2, 126.2, 124.2, 122.4, 118.3, 11.9, 108.5, 88.4, 84.9, 71.6, 62.5, 37.7. IR (KBr): 3144, 2949, 1678, 1566, 750 cm^-1.

18

General Procedure for a Microwave-Assisted Suzuki Coupling Using the Synthesis of Compound 2d as an Example
Palladium(II) acetate (2.10 mg, 9.30 µmol), TPPTS (13.0 mg, 23.1 µmol), Na₂CO₃ (69.5 mg, 656 µmol) and 8-BrdG (125 mg, 345 µmol) were placed in a microwave reaction vessel. To this was added H₂O-MeCN-DMF (2:1:1). The corresponding boronic acid (0.5 equiv of 1d) was added and the mixture irradiated with microwaves at 100 W, 120 °C with constant cooling for 5 min. The addition of the boronic acid and microwave irradiation was repeated until TLC revealed that the starting material was consumed. The reaction mixture was then poured into H₂O (25 mL) and pH was adjusted to 6-7 (0.1 M HCl). The precipitate formed was stirred at 0 °C for another 30 min, filtered, and dried in vacuo to give compound 2d as a solid.
Analytical Data
Compound 2d: yield 77% (88.2 mg, 265 µmol). ¹H NMR (500 MHz, DMSO-d ₆): δ = 10.81 (s, 1 H), 7.75 (d, J = 6 Hz, 1 H), 7.50 (d, J = 4 Hz, 1 H), 7.22 (dd, J = 5, 4 Hz, 1 H), 6.47 (s, 2 H), 6.27 (t, J = 8 Hz, 1 H), 5.20 (d, J = 5 Hz, 1 H), 4.96 (t, J = 5 Hz, 1 H), 4.39 (d, J = 3 Hz, 1 H), 3.83 (t, J = 3 Hz, 1 H), 3.64 (m, 1 H), 3.54 (m, 1 H), 3.33 (m, 1 H), 2.09 (m, 1 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 156.9, 153.8, 153.0, 141.4, 140.1, 139.8, 132.9, 126.0, 125.3, 125.0, 122.7, 117.8, 88.3, 84.6, 71.2, 62.1, 31.1. IR (neat): 1687, 1612, 1437, 999 cm^-1.
Compound 2e: yield 82% (98.8 mg, 283 µmol). ¹H NMR (500 MHz, DMSO-d ₆): δ = 11.11 (s, 1 H), 7.92 (s, 1 H), 6.96 (d, J = 4 Hz, 1 H), 6.70 (dd, J = 3, 2 Hz, 1 H), 6.56 (s, 2 H), 6.38 (t, J = 7 Hz, 1 H), 5.21 (d, J = 4 Hz, 1 H), 5.10 (br s, 1 H), 4.40 (br s, 1 H), 3.81 (t, J = 3 Hz, 1 H), 3.64 (m, 1 H), 3.51 (m, 1 H), 3.18 (m, 1 H), 2.10 (m, 1 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 152.4, 145.0, 144.9, 138.2, 120.4, 118.2, 116.8, 112.6, 111.5, 88.6, 85.3, 71.9, 62.9, 37.8. IR (neat): 1688, 1619, 1527, 1446, 1379, 951 cm^-1.
Compound 2f: grey solid, yield 94% (45 mg, 135 µmol). ¹H NMR (500 MHz, DMSO-d ₆): δ = 10.76 (br s, 1 H), 8.17 (s, 1 H), 7.86 (t, J = 1 Hz, 1 H), 6.87 (br d, J = 1 Hz, 1 H), 6.43 (br s, 2 H), 6.17 (t, 1 H), 5.22 (d, 1 H), 5.00 (t, 1 H), 4.40 (br dt, J = 3 Hz, 1 H), 3.81 (m, 1 H), 3.64 (m, 1 H), 3.55 (m, 1 H), 3.22 (q, J = 7 Hz, 1 H), 2.09 (ddd, J = 7, 3 Hz, 1 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 157.3, 153.6, 152.6, 144.6, 143.3, 140.9, 117.6, 117.0, 111.6, 88.4, 84.7, 71.4, 62.5, 37.2. IR (KBr): 3341, 3143, 2919, 1678, 1568, 877 cm^-1.

19

Esterifications were performed according to the procedures outlined in ref. 8.
Analytical Data
Compound 3a: yield 89% (63.0 mg, 129 µmol); mp 126 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 11.0 (br s, 1 H), 8.88 (d, J = 2 Hz, 1 H), 8.74 (dd, J = 5, 1 Hz, 1 H), 8.10 (d, J = 8 Hz, 1 H), 7.68 (dd, J = 5, 8 Hz, 1 H), 6.61 (s, 2 H), 6.13 (t, J = 7 Hz, 1 H), 5.50 (q, J = 3 Hz, 1 H), 4.45 (dd, J = 11, 5 Hz, 1 H), 4.30 (dd, J = 11, 7 Hz, 1 H), 4.20 (m, 1 H), 3.57 (q, J = 7 Hz, 1 H), 2.57 (m, 2 H), 2.44 (q, J = 5 Hz, 1 H), 1.12 (d, J = 2 Hz, 1 H) 1.10 (s, 6 H), 1.08 (s, 3 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 176.0, 175.7, 156.7, 153.3, 152.1, 150.2, 139.3, 144.2, 136.5, 126.3, 123.6, 117.4, 84.72, 81.8, 74.7, 63.5, 34.0, 33.1, 33.0, 18.71, 18.68, 18.60, 18.59. IR (neat): 1727, 1689, 1627, 1150 cm^-1. Anal. Calcd for C₂₃H₂₈N₆O₆: C, 57.02; H, 5.82; N, 17.35. Found: C, 54.86; H, 5.99; N, 15.51.
Compound 3b: yield 91% (128 mg, 237 µmol); mp 201 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 10.83 (s, 1 H), 8.01 (m, 1 H), 7.93 (m, 2 H), 7.42 (m, 2 H), 6.54 (s, 2 H), 6.41 (t, J = 7 Hz, 1 H), 5.00 (t, J = 6 Hz, 1 H), 4.42 (m, 1 H), 3.68 (m, 1 H), 3.57 (m, 1 H), 3.23 (m, 1 H), 2.53 (m, 2 H), 2.09 (m, 1 H), 1.10 (m, 6 H), 1.05 (m, 6 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 206.9, 175.8, 175.6, 156.9, 153.7, 153.0, 141.4, 140.1, 139.8, 132.9, 126.0, 125.3, 125.0, 122.7, 117.8, 88.3, 84.6, 71.2, 62.1, 37.2, 31.1, 18.5, 18.4. IR (neat): 1734, 1683, 1635, 1597, 1190, 1156 cm^-1. Anal. Calcd for C₂₆H₂₉N₅O₆S: C, 57.87; H, 5.42; N, 12.96. Found: C, 58.03; H, 5.67; N, 12.59.
Compound 3c: yellow solid, yield 65% (133.8 mg, 256 µmol). ¹H NMR (500 MHz, DMSO-d ₆): δ = 11.04 (br s, 1 H), 7.78 (d, J = 7 Hz, 1 H), 7.69 (d, J = 8 Hz, 1 H), 7.44 (br s, 1 H), 7.43 (br t, J = 8 Hz, 1 H), 7.36 (t, J = 7 Hz, 1 H), 6.66 (br s, 2 H), 6.65 (m, 1 H), 5.56 (br d, 1 H), 4.45 (br d, 1 H), 4.28 (br d, 1 H), 4.24 (m, 1 H), 3.58 (br quin, 1 H), 2.61 (br quin, J = 7 Hz, 1 H), 2.50 (m, 1 H), 2.47 (m, 1 H), 1.14 (d, J = 7 Hz, 1 H), 1.05 (d, 1 H). ¹³C NMR (125 MHz, DMSO-d ₆):
δ = 176.8, 176.5, 157.8, 155.0, 154.5, 152.8, 146.6, 138.1, 128.3, 126.42, 124.41, 122.6, 118.5, 112.0, 108.5, 85.3, 82.5, 75.3, 64.3, 35.2, 33.9, 33.8, 19.3, 19.3. IR (KBr): 3308, 3138, 2973, 2935, 2877, 1737, 1687, 1570, 1258, 751 cm^-1.
Compound 3d: yield 89% (113 mg, 231 µmol); mp 134 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 10.85 (s, 1 H), 7.76 (d, J = 5 Hz, 1 H), 7.48 (d, J = 5 Hz, 1 H), 7.10 (dd, J = 5, 4 Hz, 1 H), 6.53 (s, 2 H), 6.32 (t, J = 7 Hz, 1 H), 5.50 (m, 1 H), 4.32 (m, 1 H), 4.30 (m, 1 H), 4.20 (m, 1 H), 3.64 (m, 1 H), 2.57 (m, 2 H), 2.43 (m, 1 H), 1.11 (m, 6 H), 1.05 (m, 6 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 176.6, 176.4, 157.1, 153.8, 152.7, 141.9, 132.5, 129.4, 128.7, 128.5, 117.7, 85.3, 82.5, 75.4, 64.1, 34.5, 33.7, 19.3. IR (neat): 1733, 1672, 1593, 1152 cm^-1. Anal. Calcd for C₂₂H₂₇N₅O₆S: C, 53.98, H, 5.56; N, 14.31. Found: C, 53.84; H, 6.01; N, 14.27.
Compound 3e: yield 90% (111 mg, 234 µmol); mp 167 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 10.88 (s, 1 H), 7.90 (d, J = 5 Hz, 1 H), 6.96 (d, J = 5 Hz, 1 H), 6.69 (dd, J = 5, 4 Hz, 1 H), 6.54 (s, 2 H), 6.44 (t, J = 7 Hz, 1 H), 5.46 (m, 1 H), 4.40 (m, 1 H), 4.22 (m, 1 H), 4.16 (m, 1 H), 3.50 (m, 1 H), 2.57 (m, 2 H), 2.41 (m, 1 H), 1.12 (m, 6 H), 1.03 (m, 6 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 176.6, 176.3, 157.1, 153.9, 152.3, 145.1, 144.7, 138.4, 117.9, 112.9, 112.5, 85.1, 82.3, 75.3, 64.3, 35.0, 33.7, 19.3. IR (neat¹): 1732, 1681, 1153, 1077, 764 cm^-1. Anal. Calcd for C₂₂H₂₇N₅O₇: C, 55.81; H, 5.75; N, 14.79. Found: C, 55.44; H, 6.02; N, 14.67.
Compound 3f: yellow solid, yield 80% (228 mg, 481 µmol). ¹H NMR (500 MHz, DMSO-d ₆): δ = 10.83 (br s, 1 H), 8.14 (s, 1 H), 7.87 (t, J = 1 Hz, 1 H), 6.88 (d, J = 1 Hz, 1 H), 6.50 (br s, 2 H), 6.22 (t, 1 H), 5.49 (quin, J = 7, 4 Hz, 1 H), 4.40 (m, 1 H), 4.24 (m, 1 H), 4.19 (br ddd, J = 7 Hz, 1 H), 3.61 (quin, J = 7 Hz, 1 H), 2.59 (quin, J = 7 Hz, 1 H), 2.52 (br quin, J = 7 Hz, 1 H), 2.43 (ddd, J = 7, 4 Hz, 1 H), 1.12 (dd, J = 7 Hz, 1 H), 1.05 (dd, J = 7 Hz, 1 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 176.4, 176.2, 157.0, 153.5, 152.3, 144.6, 142.7, 140.8, 117.5, 116.7, 111.3, 84.8, 82.1, 75.1, 64.0, 34.4, 33.6, 33.6, 19.2, 19.2, 19.1, 19.1. IR (KBr): 1738, 1687, 1596, 1254, 875 cm^-1.

20

General Procedure for a Stille Coupling Using the Synthesis of Compound 4a as an Example
3′,5′-i-Bu-8-BrdG (50.0 mg, 103 µmol), DPPP (6.35 mg, 15.4 µmol), Pd(OAc)₂ (3.45 mg, 15.4 µmol), Cu₂O (29.5 mg, 206 µmol), and NMP (490 µL) were mixed. After this, compound 6a (115 mg, 206 µmol) was added to the mixture. The mixture was heated to 115 °C for 1 h after which HPLC analysis of the crude reaction mixture showed that the starting material was consumed. Therefore, the mixture was filtered through Celite and the solvents removed under reduced pressure. The product was isolated by column chromatography (50% EtOAc in Et₂O) yielding 4a as a white solid.
Analytical Data
Compound 4a: white solid, yield 74% (47.0 mg, 75.9 µmol); mp 169 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 10.89 (s, 1 H), 8.02 (m, 2 H), 7.58 (m, 2 H), 7.36 (m, 4 H), 7.30 (m, 1 H), 6.54 (s, 2 H), 5.46 (m, 1 H), 4.67 (q, J = 7 Hz, 1 H), 4.53 (s, 1 H), 4.51 (s, 1 H), 4.47 (m, 1 H), 4.31 (m, 1 H), 4.06 (m, 1 H), 3.59 (m, 1 H), 2.50 (m, 2 H), 2.34 (m, 1 H), 1.53 and 1.51 (d, J = 7 Hz, 3 H), 1.15-1.06 (m, 12 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 176.0, 175.5, 161.27, 156.6, 153.2, 152.7, 149.0, 143.7, 143.6, 138.4, 138.1, 128.19, 128.17, 127.39, 127.36, 122.3, 120.1, 117.3, 85.4, 81.4, 77.3, 74.9, 70.1, 63.6, 33.9, 33.1, 21.4, 21.3, 18.7, 18.6, 18.5. IR (neat): 1732, 1690, 1631, 1587, 1156 cm^-1. Anal. Calcd for C₃₂H₃₈N₆O₇: C, 62.12; H, 6.19; N, 13.58. Found: C, 60.88; H, 6.15; N, 12.98.
Compound 4b: white solid, yield 80% (253 mg, 398 µmol); mp 209 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 10.89 (s, 1 H), 8.01 (m, 2 H), 7.55 (m, 2 H), 7.28 (d, J = 8 Hz, 2 H), 6.91 (d, J = 8 Hz, 2 H), 6.54 (s, 2 H), 5.45 (m, 1 H), 4.64 (m, 1 H), 4.48 (m, 1 H), 4.45 (d, J = 14 Hz, 1 H), 4.43 (d, J = 14 Hz, 1 H), 4.07 (m, 1 H), 3.58 (m, 1 H), 2.35 (m, 1 H), 1.49 (t, J = 6 Hz, 3 H), 1.09 (d, J = 7 Hz, 6 H), 1.07 (d, J = 7 Hz, 6 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 176.0, 175.6, 161.4, 158.7, 156.6, 153.2, 149.0, 143.6, 138.2, 130.3, 129.09, 129.07, 122.3, 120.1, 117.4, 113.59, 113.57, 85.4, 81.4, 76.94, 76.90, 74.9, 69.7, 63.7, 55.0, 48.4, 33.9, 33.1, 30.1, 29.0, 21.4, 21.3, 18.6, 18.53, 18.49, 17.2. IR (neat): 1724, 1681, 1635, 1566, 1153, 817 cm^-1. Anal. Calcd for: C₃₃H₄₀N₆O₈: C, 61.10; H, 6.22; N, 12.96. Found: C, 60.61; H, 6.20; N, 12.88.
Compound 4c: white solid, yield 60% (192 mg, 302 µmol); mp 182 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 10.91 (s, 1 H), 8.00 (m, 2 H), 7.54 (m, 2 H), 7.33 (d, J = 8 Hz, 2 H), 6.93 (d, J = 8 Hz, 2 H), 6.57 (s, 2 H), 5.50 (m, 1 H), 4.65 (s, 2 H), 4.58 (s, 2 H), 4.88 (dd, J = 12, 6 Hz, 1 H), 4.29 (dd, J = 12, 7 Hz, 1 H), 4.09 (m, 1 H), 3.76 (s, 3 H), 3.50 (m, 1 H), 2.52 (m, 2 H), 2.35 (m, 1 H), 1.10 (d, J = 7 Hz, 6 H) 1.07 (d, J = 7 Hz, 6 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 176.0, 175.5, 158.8, 157.3, 156.7, 153.3, 152.7, 149.1, 143.5, 138.1, 130.0, 129.2, 122.4, 121.1, 117.3, 113.7, 85.1, 81.4, 74.8, 71.9, 71.6, 63.8, 55.0, 34.4, 33.12, 33.09, 18.7, 18.6. IR (neat): 1734, 1691, 1629, 1588, 1571, 1249 cm^-1. Anal. Calcd for C₃₂H₃₈N₆O₈: C, 60.56; H, 6.03; N, 13.24. Found: C, 60.65; H, 6.00; N, 13.12.
Compound 4d: white solid, yield 61% (187 mg, 305 µmol); mp 193 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 10.88 (s, 1 H), 7.99 (m, 2 H), 7.56 (t, J = 7 Hz, 1 H), 7.47 (d, J = 7 Hz, 1 H), 6.55 (br s, 2 H), 5.50 (m, 1 H), 4.59 (s, 1 H), 4.47 (dd, J = 12, 6 Hz, 1 H), 4.26 (dd, J = 12, 7 Hz, 1 H), 4.09 (m, 1 H), 3.66 (t, J = 8 Hz, 2 H), 3.49 (m, 1 H), 2.60 (m, 1 H), 2.52 (m, 1 H), 2.37 (m, 1 H), 1.14 (dd, J = 7, 3 Hz, 6 H), 1.06 (d, J = 7 Hz, 6 H), 0.99 (t, J = 8 Hz, 2 H), 0.03 (s, 9 H). ¹³C NMR (125 MHz; DMSO-d ₆): δ = 175.9, 175.5, 157.6, 156.6, 153.3, 152.7, 148.9, 143.5, 138.0, 122.2, 120.6, 117.3, 85.1, 81.4, 74.8, 72.4, 67.6, 63.8, 34.5, 33.2, 33.1, 18.69, 18.65, 17.7, -1.30. IR (neat): 1731, 1671, 1564, 1460, 1189 cm^-1. Anal. Calcd for C₂₉H₄₂N₆O₇Si: C, 56.66; H, 6.89; N, 13.67. Found: C, 56.59; H, 6.89; N, 12.85.