Synthesis of Medicinally Interesting 2,4-Diamino-9H-pyrimido[4,5-b]indol-6-ols via Extension of the Nenitzescu Reaction

Abstract

The title compounds 6 were prepared by a one-step procedure from 1,4-benzoquinone (1) and pyrimidine-2,4,6-triamines 2 via an extension of the Nenitzescu reaction. Formation of 9H-­pyrimido[4,5-b]indoles 6 can be calculated by ¹³C NMR values of C-5 of the pyrimidine-2,4,6-triamines 2.

N-heterocycles - cyclizations - Nenitzescu reaction - 1,4-quinones - nucleophilic additions

References

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The 6-aminopyrimidines 2 were prepared according to the following literature:

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23

Typical Procedure for the Preparation of 6a and 9d.
2,4-Diamino-9 H -pyrimido[4,5- b ]indol-5-ol ( 6a):
To a clear solution of 1.27 g (10 mmol) pyrimidine-2,4,6-triamine(2a) in 50 mL boiling glacial acetic acid 1.3 g (12 mmol) of 1,4-benzoquinone(1) was added, and the mixture refluxed for 6 h. The solvent was removed in vacuo and the dark residue purified by MPLC (silica gel) using CHCl₃/MeOH 4:1 as eluent. Colorless powder, yield 695 mg (31.8%); mp >300 °C.
IR (NaCl): ν_max = 3127, 1589, 1471, 1409, 1199 cm^-1. UV (CH₃OH): λ_max (log ε) = 209 nm (4.205), 237 (3.255), 259 (4.330), 293 (2.005), 316 (1.409), 324 (1.307). ¹H NMR (360 MHz, d ₆-DMSO): δ = 5.82 (s, 2 H, NH₂, with D₂O exchangeable), 6.49 (s, 2 H, NH₂, with D₂O exchangeable), 6.63 (dd, 1 H, H-7, J ₁ = 8.5 Hz, J ₂ = 2.2 Hz), 7.01 (d, 1 H, H-8, J = 8.5 Hz), 7.35 (d, 1 H, H-5, J = 2.2 Hz), 8.66 (s, 1 H, OH, with D₂O exchangeable), 10.76 (s, 1 H, NH, with D₂O exchangeable). ¹³C NMR (90.6 MHz, d ₆-DMSO): δ = 89.0 (C-4a), 105.7 (C-5), 110.0 (C-7), 110.3 (C-8), 122.3 (C-4b), 129.5 (C-8a), 151.2 (C-6), 159.0 (C-2), 158.3, 161.7 (C-4, C-9a). MS: m/z (%) = 215 (100) [M⁺], 198 (19.4), 173 (30.8). Found: C, 55.68; H, 413; N, 32.69. For C₁₀H₉N₅O (215.22) calcd: C, 55.81; H, 4.22; N, 32.54.
7,9-Bis(dimethylamino)-11 H -pyrimido[5′,4′:4,5]pyr-rolo[2,3- f ]quinoxalin-5-ol ( 9d): A mixture of 181 mg (1 mmol) of N ²,N ²,N ⁴,N ⁴-tetramethylpyrimidine-2,4,6-triamine (2d) and 160 mg (1 mmol) of quinoxaline-5,8-dione (8d) were dissolved in 25 mL of absolute EtOH. After addition of 0.5 mL glacial acetic acid the mixture was refluxed for 6 h. The solvent was removed in vacuo and the residue purified by MPLC (silica gel) using CHCl₃/MeOH 95:5 as eluent. Light green powder, yield 112 mg (34.6%); mp >300 °C.
IR (NaCl): ν_max = 3747, 3226, 2927, 2852, 1662, 1556, 1182, 1070 cm^-1. ¹H NMR (360 MHz, d ₆-DMSO): δ = 3.20 (s, 12 H, NMe₂), 7.58 (s, 1 H, H-6), 8.75 (d, 1 H, J = 1.8 Hz), 8.87 (d, 1 H, J = 1.8 Hz), 9.63 (s, 1 H, OH, with D₂O exchangeable), 12.2 (s, 1 H, NH, with D₂O exchangeable). MS: m/z (%) = 323 (100) [M⁺], 308 (25.8), 294 (78.8), 161,7 (14.5). Found: C, 59.61; H, 5.23; N, 30.39. For C₁₆H₁₇N₇O (323.36) calcd: C, 59.43; H, 5.30; N, 30.32.