Synlett 2008(10): 1510-1514  
DOI: 10.1055/s-2007-1077795
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

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.

    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.