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Synlett 2007(8): 1231-1234  
DOI: 10.1055/s-2007-977419
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Versatile Synthetic Approach to Isoguanine Derivatives

Alice M. Dias, A. Sofia Vila-Chã, Isabel M. Cabral, M. Fernanda Proença*
Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
e-Mail: fproenca@quimica.uminho.pt;
Further Information

Publication History

Received 8 February 2007
Publication Date:
03 April 2007 (online)

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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.

Key words

heterocycles - rearrangements - ring closure - imidazole - isoguanine

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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).

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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).

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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).