General Synthetic Approach to 2-Phenolic Adenine Derivatives

Abstract

A simple and general ‘one-pot’ procedure for the synthesis of 2,9-diarylpurines with one or multiple hydroxyl groups in the 2-aryl unit is described, from the reaction of 5-amino-4-amidinoimidazoles with phenolic aldehydes.

Key words

nucleobases - phenols - condensations - aldehydes - ring closure

• References and Notes

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• 6 Procedure for the Synthesis of Imine 4a (Scheme 1) To a stirred suspension of imidazole 1a (0.14 g, 0.49 mmol) in EtOH (0.4 mL), aldehyde 2a (0.09 g, 1.1 equiv) and TFA (75 μL, 2 equiv) were added at 0 °C. A yellow solution developed, and a yellow solid started to precipitate after 25 min. When the TLC indicated the absence of starting material (4 h), EtOH was added (0.8 mL), and the yellow solid was filtered. The solid was washed with EtOH and Et₂O and identified as compound 4a (0.22 g, 0.40 mmol, 82%); mp 124–126 °C. IR (mull): 3498, 3352, 3210, 1665, 1626, 1604, 1586, 1521 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.62 (s, 6 H, CH₂), 2.37 (s, 3 H, CH₃), 3.58 (br s, 4 H, CH₂), 6.82 (s, 2 H, ArH), 7.30–7.45 (m, 4 H, ArH), 8.17 (s, 2 H, 2-H, N=CH), 8.80–9.60 (m, 5 H, NH, HO, D₂O exchangeable). Anal. Calcd for C₂₃H₂₅N₅O₃·TFA·H₂O: C, 54.44; H, 5.08; N, 12.70. Found: C, 54.68; H, 5.41; N, 12.45

Procedure for the Synthesis of Dihydropurine 5c (Scheme 1)
• 7a Method i Aldehyde 2a (0.07 g, 1.0 equiv) and TFA (40 μL,1.3 equiv) were added to a stirred suspension of imidazole 1a (0.11 g, 0.40 mmol) in EtOH (2.0 mL) at r.t. The yellow solution became light yellow, and when TLC showed the absence of imine 4 (5 d), the solution was concentrated in the rotary evaporator. The off-white solid was filtered, washed with EtOH and Et₂O and identified as compound 5c (0.09 g, 0.16 mmol, 41%)
• 7b Method iiA yellow ethanolic solution of 4a (0.09 g, 0.16 mmol) was stirred at 8 °C until TLC showed the absence of starting material (10 d). The solution was concentrated in the rotary evaporator leading to an off-white solid that was filtered and washed with Et₂O and identified as compound 5c (0.08 g, 0.15 mmol, 91%); mp 218–220 °C. IR (mull): 3535, 3202, 1679, 1613, 1530 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.69 (s, 6 H, CH₂), 2.39 (s, 3 H, CH₃), 3.70 (m, 4 H, CH₂), 5.71 (t, 1 H, J = 4.8 Hz, 2-H), 6.28 (s, 2 H, ArH), 7.40–7.46 (m, 4 H, ArH), 7.88 (s, 1 H, 8-H), 8.07 (d, 1 H, J = 4.8 Hz, NH, D₂O exchangeable), 8.23 (br s, 1 H, HO, D₂O exchangeable), 8.88 (d, 1 H, J = 4.8 Hz, NH, D₂O exchangeable), 8.99 (s, 2 H, HO, D₂O exchangeable). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 20.62 (CH₃), 23.32, 25.80, 48.82, 64.77 (2-C), 105.12, 110.60, 124.14, 129.16, 130.32, 130.88, 133.39, 135.14 (8-C), 138.65, 145.73, 145.84, 150.00. Anal. Calcd for C₂₃H₂₅N₅O₃·TFA·2.1H₂O: C, 52.56; H, 5.29; N, 12.26. Found: C, 52.55; H, 5.10; N, 12.07
• 8 Procedure for the Synthesis of Purine 6f (Table 1) Aldehyde 2g (0.18 g, 1.1 equiv) and TFA (166 μL, 1.3 equiv) were added to a stirred suspension of imidazole 1b (0.30 g, 1.08 mmol) in EtOH (0.3 mL) at r.t. during 1 d. Then, the solvent was removed in the rotary evaporator, and DMSO (0.3 mL) was added to the crude solid followed by Et₃N (1.35 mL, 10 equiv), and the reaction was stirred at 40 °C during 6 d. Addition of H₂O and cooling for 10 min led to a brown solid that was filtered and washed with H₂O and Et₂O (0.42 g). The brown solid was purified by dry flash chromatography on silica gel using 500 mL of Et₂O as eluent to give an off-white solid identified as 6f (0.25 g, 0.60 mmol, 59%); mp >300 °C. IR (mull): 3550, 3465, 3337, 3101, 1637, 1624, 1581, 1528 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 2.41 (s, 3 H, CH₃), 3.85 (s, 4 H, CH₂), 4.30 (br s, 4 H, CH₂), 6.36 (d, 1 H, J = 9.0 Hz, ArH), 7.43 (d, 2 H, J = 8.4 Hz, ArH), 7.64 (d, 2 H, J = 8.7 Hz, ArH), 7.68 (d, 1 H, J = 9.0 Hz, ArH), 8.24 (br s, 1 H, HO, D₂O exchangeable), 8.45 (s, 1 H, 8-H), 9.16 (br s, 1 H, HO, D₂O exchangeable), 13.45 (s, 1 H, HO, D₂O exchangeable). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 20.64 (CH₃), 45.52, 66.13, 107.05, 111.53, 117.57, 119.45, 123.82, 130.17, 131.99, 132.69, 137.77, 139.18 (8-C), 148.54, 148.93, 149.36, 152.66, 158.86 (2-C). Anal. Calcd for C₂₂H₂₁N₅O₄·0.5H₂O: C, 61.68; H, 5.14; N, 16.36. Found: C, 61.75; H, 5.06; N, 16.20