A Versatile Synthetic Approach to Isoguanine Derivatives

Abstract

5-Amino-4-(N-ethoxycarbonyl)formamidino imidazoles were prepared from 5-amino-4-(N-ethoxycarbonyl)cyanoform­imidoyl imidazoles and primary alkyl amines, under mild experimental conditions. The product imidazoles were selectively cyclized to N ₆-substituted isoguanines by reflux in acetonitrile with one equivalent of sulfuric acid, followed by neutralization. The same imidazoles led to N ₁-alkylisoguanines as the major product upon reflux in ethanol.

heterocycles - rearrangements - ring closure - imidazole - isoguanine

References and Notes

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17

Compounds 3 Aqueous methylamine (for 3a and 3b, 14 equiv), or benzylamine (for 3c and 3d, 2-3 equiv) was added to a suspension of imidazole 2 in CH₂Cl₂ (for 3a and 3b), EtOH (for 3c), or MeCN (for 3d, 2-12 mL). The mixture was stirred at r.t. for 10 min to 18 h. The product precipitated from the reaction mixture (3c and 3d) or the solvent was removed in the rotary evaporator (3a and 3b) and EtOH was added to the residue. The white solid was filtered and washed with EtOH (3a-c), or MeCN(3d), and Et₂O. The structure of the products obtained was confirmed by elemental analysis, ¹H NMR and ¹³C NMR spectroscopy.
Characterization of 3a
¹H NMR (300 MHz, DMSO-d ₆, 20 °C): δ (mixture of conformers A and B, ratio A/B = 3:2) = 9.90 (br s, 1 H, A), 8.00 (br s, 1 H, B), 7.40 (d, J = 9.0 Hz, 2 H), 7.39 (s, 1 H), 7.12 (d, J = 9.0 Hz, 2 H), 6.94 (br s, 2 H, A), 5.98 (br s, 2 H, B), 3.97 (q, J = 7.2 Hz, 2 H), 3.81 (s, 3 H), 3.41 (s, 3 H, A), 2.74 (s, 3 H, B), 1.17 (t, J = 7.2 Hz, 3 H); ¹H NMR (300 MHz, DMSO-d ₆, 50 °C): δ (only one set of bands is present) = 10.20-9.20 (br s, 1 H), 7.37 (d, J = 8.7 Hz, 2 H), 7.34 (s, 1 H), 7.11 (d, J = 8.7 Hz, 2 H), 6.80-6.30 (br s, 2 H), 3.99 (q, J = 7.2 Hz, 2 H), 3.82 (s, 3 H), 3.20 (s, 3 H), 1.18 (t, J = 7.2 Hz, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 163.49 (br, A), 159.20, 156.80 (br, B), 147.08 (br), 142.70, 130.99, 126.91, 126.72, 114.99, 110.00-114.00 (br), 59.47 (br), 55.55, 32.31 (br, A), 23.45 (br, B), 14.68. Anal. Calcd for C₁₅H₁₉N₅O₃: C, 56.77; H, 6.04; N, 22.07. Found: C, 56.97; H, 6.06; N, 21.57. IR (mull): 3251 (m), 3116 (m), 1640 (s), 1598 (s).

18

Compounds 5 A suspension of 3a-d in EtOH (20-60 mL) was refluxed for 5 h to 4 d. The resulting suspension was filtered and washed with MeCN (4 and 5a), EtOH (4 and 5b and d) or Et₂O (4 and 5c) to give a mixture of compounds 4 and 5 in a ratio of 4.5:5.5 (4a:5a), 3:7 (4b:5b), 2.5:7.5 (4c:5c) and 2:8 (4d:5d). The mixture 4a:5a (4.5:5.5) was suspended in H₂O and combined with KOH (1 N). The suspension was stirred at r.t. for 45 min to give a 2:8 mixture of 4a:5a. A suspension of these solid mixtures in EtOH (for a and c) or DMF (for b and d) was combined with DBU (1 equiv in relation to the amount of compound 4). The suspension was stirred at 40 °C for 6-18 h (a and b), or at r.t. for 30 min (c and d). The white solid was filtered and washed with EtOH and Et₂O to give compound 5a-d. The structure of the products obtained was confirmed by elemental analysis, ¹H NMR and ¹³C NMR spectroscopy.
Characterization of 5a
¹H NMR (300 MHz, DMSO-d ₆): δ = 8.16 (br s, 2 H), 8.07 (s, 1 H), 7.66 (d, J = 8.7 Hz, 2 H), 7.07 (d, J = 9.0 Hz, 2 H), 3.80 (s, 3 H), 3.36 (s, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 158.03, 154.18, 152.39, 151.49, 137.66, 128.13, 124.35, 114.36, 109.00-110.00(br), 55.06, 30.01. Anal. Calcd for C₁₃H₁₃N₅O₂: C, 57.56; H, 4.83; N, 25.82. Found: C, 57.60; H, 5.06; N, 25.78. IR (mull): 3385 (m), 3208 (s), 3120 (s), 3052 (s), 1883 (w), 1698 (s), 1640 (s), 1601 (s), 1584 (s).

19

Compounds 4
To a suspension of imidazole 3a-d in MeCN (8-10 mL) was added H₂SO₄ (1 equiv), and the mixture was refluxed for 18 h to 11 d. The resulting suspension was filtered and washed with MeCN (6a) or EtOH (6b) and Et₂O. Then, DBU (1 equiv) was added to a suspension of compound 6a,b in MeCN (3-20 mL). The mixture was stirred at r.t. for 30 min to 3 h, when the white solid was filtered and washed with MeCN and Et₂O, to give compounds 4a,b. The structure of the products obtained was confirmed by elemental analysis, ¹H NMR and ¹³C NMR spectroscopy.
Characterization of 4a
¹H NMR (300 MHz, DMSO-d ₆): δ = 10.70 (v br s, 1 H), 8.08 (s, 1 H), 8.00 (br s, 1 H), 7.64 (d, J = 9.0 Hz, 2 H), 7.08 (d, J = 9.0 Hz, 2 H), 3.80 (s, 3 H), 2.93 (br s, 3 H). The compound 4a was not soluble in DMSO-d ₆ and the ¹³C NMR spectrum was obtained from the salt form. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 160.16, 151.85, 149.94, 141.98, 139.87, 127.31, 125.55, 115.10, 110.62, 55.86, 29.25. Anal. Calcd for C₁₃H₁₃N₅O₂·0.4H₂O: C, 56.07; H, 4.99; N, 25.15. Found: C, 55.95; H, 4.92; N, 25.12. IR (mull): 3234 (s), 3126 (m), 3053 (m), 2733 (m), 1681 (s), 1626 (s), 1596 (s).