A Base-Catalyzed Cascade Route to Phenolic 6-Cyanopurines via O-Alkylformamidoximes

Abstract

N-[1,2-Dicyano-2-(hydroxyphenylideneamino)vinyl]-O-alkylformamidoximes were prepared from the reaction of N-(2-amino-1,2-dicyanovinyl)-O-alkylformamidoximes with phenolic aldehydes. These compounds generated 2-hydroxyphenyl-4,5-dicyano-N-(N'-alkoxyformimidoyl)imidazoles in the presence of manganese oxide, whereas in triethylamine 6-cyano-8-hydroxy-phenylpurines were isolated. The reaction was followed by ¹H NMR spectroscopy and a plausible mechanism is presented.

Key words

nitrogen heterocycles - purines - imidazoles - amidoximes - phenols

• References and Notes

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• 20 Synthesis of (Z)-N-[1,2-Dicyano-2-(arylideneamino)-vinyl]-O-alkylformamidoximes (2); General Procedure: Toluenesulfonic acid (cat.) was added to a suspension of either 1a (3.31 mmol) or 1b (1.23–2.45 mmol) and the phenolic aldehyde (1.23–3.31 mmol, 1 equiv) in either MeOH, CH₂Cl₂–EtOH (10:1), or EtOH (2–7 mL). The reaction was complete after 15 min stirring on an ice bath, and the yellow solid was collected by filtration and washed with cold Et₂O to afford products 2a–f. (Z)-N-[1,2-Dicyano-2-(2'-hydroxybenzylidenamino)-vinyl]-O-benzylformamidoxime (2a): Yield: 1.11 g (3.20 mmol, 97%); mp 183–185 °C. IR (NaCl): 3407, 3280, 2234, 2222, 1646, 1623, 1606, 1560, 1494, 1459, 1403 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ (major tautomer: M) = 10.75 (s, 1 H), 9.33 (s, 1 H), 8.77 (s, 1 H), 7.66 (d, J = 7.80 Hz, 1 H), 7.64 (s, 1 H), 7.30–7.45 (m, 6 H), 6.98 (d, J = 8.40 Hz, 1 H), 6.83 (t, J = 7.80 Hz, 1 H), 5.08 (s, 2 H); δ (minor tautomer: m) = 10.58 (s, 1 H), 8.73 (s, 1 H), 8.24 (s, 1 H), 4.98 (s, 2 H); Ratio M/m = 7:1. ¹³C NMR (300 MHz, DMSO-d ₆): δ (major tautomer: M) = 159.53, 157.63, 137.25, 136.94, 135.06, 128.34, 128.12, 127.95, 127.72, 120.58, 119.72, 117.89, 116.86, 113.23, 112.49, 112.31, 75.48; δ (minor tautomer: m) = 159.06, 156.70, 134.50, 129.24, 128.29, 128.21, 127.79, 121.00, 119.44, 116.56, 75.29. Anal. Calcd for C₁₉H₁₅N₅O₂: C, 66.1; H, 4.4; N, 20.3. Found: C, 66.2; H, 4.4; N, 20.1. Synthesis of 2-Aryl-4,5-dicyano-N-(N'-alkoxyformi-midoyl)imidazoles (3); General Procedure: A solution of 2 (0.25 g, 0.72 mmol) in THF was combined with MnO₂ (25–50 equiv). The reaction was complete after 1–29 days heating at reflux and the mixture was filtered through glass fiber paper. The solvent was concentrated under reduced pressure and a yellow solid precipitated by addition of chloroform and n-hexane. The solid was filtered to afford products 3a–f. 4,5-Dicyano-2-(2′-hydroxyphenyl)-N-(N′-benzyloxifor-mimidoyl)imidazole (3a): Yield: 0.16 g (0.46 mmol, 64%); mp 171–174 °C. IR (NaCl): 3195, 3089, 3035, 2248, 2237, 1631, 1605, 1581, 1550, 1518, 1483, 1392 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 11.00–15.00 (s, <1 H), 7.95 (d, J = 7.50 Hz, 1 H), 7.46 (s, 1 H), 7.24–7.42 (m, 6 H), 7.00 (d, J = 8.40 Hz, 1 H), 6.94 (t, J = 8.10 Hz, 1 H), 5.02 (s, 2 H). 13C NMR (300 MHz, DMSO-d6): δ = 155.51, 151.49, 142.72, 137.61, 131.73, 128.65, 128.33, 128.24, 127.87, 119.53, 116.43, 114.29, 112.12, 109.26, 75.42. Anal. Calcd for C19H13N5O2·0.1H2O: C, 66.0; H, 3,9; N, 20.3. Found: C, 66.0; H, 3.9; N, 20.1. 6-Cyano-8-(2'-hydroxyphenyl)purine (4a): Et₃N (1.0 mL) was added to a suspension of 2a (0.10 g, 0.29 mmol) in MeCN (25 mL) leading to a red solution. The mixture was heated to reflux for 3 h, then the solvent was concentrated on a rotary evaporator. Addition of CH₂Cl₂ and n-hexane led to the formation of a yellow solid that was filtered to give 4a. Yield: 0.04 g (0.17 mmol, 58%); mp >300 °C (dec.). IR (NaCl): 3532, 3280, 2244, 1665, 1625, 1604, 1585, 1514, 1398 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 10–15 (s, 2 H), 9.00 (s, 1 H), 8.12 (dd, J = 7.80, 1.50 Hz, 1 H), 7.45 (dt, J = 7.80, 1.50 Hz, 1 H), 7.06 (d, J = 7.80 Hz, 1 H), 7.01 (dt, J = 7.80, 0.90 Hz, 1 H). ¹³C NMR (300 MHz, DMSO-d ₆): δ = 158.57, 158.40, 155.91, 151.93, 134.08, 133.64, 128.63, 125.20, 119.74, 117.40, 114.70, 112.24. Anal. Calcd for C₁₂H₇N₅O·0.9H₂O: C, 56.9; H, 3.5; N, 27.6. Found: C, 57.2; H, 3.5; N, 27.3. 6-Cyano-8-(3′-hydroxyphenyl)purine (4b): Et₃N (0.52 mL) was added to a solution of 2e (0.10 g, 0.37 mmol) in DMSO (0.5 mL) and the mixture was stirred at r.t. for 4 days. A white solid was formed after addition of CHCl₃ and n-hexane. The product was filtered and washed with n-hexane to give 4b. Yield: 0.06 g (0.27 mmol, 72%); mp >300 °C (dec.). IR (NaCl): 3404, 3153, 2243, 1625, 1613, 1598, 1583, 1527, 1406 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 9.91 (s, >1 H, NH), 8.98 (s, 1H), 7.75 (d, J = 1.20 Hz, 1 H), 7.74 (d, J = 7.80 Hz, 1 H), 7.41 (t, J = 7.80 Hz, 1 H), 7.01 (dt, J = 8.10, 1.80 Hz, 1 H). ¹³C NMR (300 MHz, DMSO-d ₆): δ = 158.45, 157.94, 156.78, 151.77, 135.49, 130.39, 129.38, 126.03, 119.41, 118.67, 114.88, 114.41. Anal. Calcd for C₁₂H₇N₅O·0.6H₂O: C, 58.0; H, 3.4; N, 28.2. Found: C, 58.3; H, 3.7; N, 28.0. 6-Cyano-8-(4′-hydroxyphenyl)purine (4c): Et₃N (1.50 mL) was added to a suspension of 2f (0.10 g, 0.37 mmol) in MeCN (9 mL), leading to an orange solution. After 3 h heating to reflux, the solvent was concentrated on a rotary evaporator to give a yellow solid that was filtered and washed with Et₂O to give 4c. Yield: 0.06 g (0.25 mmol, 67%); mp >300 °C (dec.). IR (NaCl): 3454, 3379, 3144, 2236, 1656, 1615, 1592, 1563, 1481, 1437 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 13.50–15.00 (s, 1 H), 10.45 (s, 1 H), 8.93 (s, 1 H), 8.17 (d, J = 8.70 Hz, 2 H), 6.97 (d, 2 H, J = 8.70 Hz). ¹³C NMR (300 MHz, DMSO-d ₆): δ = 161.60, 158.35, 156.69, 151.46, 144.83, 130.12, 124.93, 118.52, 116.18, 115.01. HRMS: m/z [M + H]⁺ calcd for C₁₂H₇N₅O: 238.0684; found: 238.0732.