An Improved Route to Purin-6-yl Magnesium Halides by Metal–Halogen Exchange in Dichloromethane

Abstract

Treatment of a solution of 9-benzyl or 9-phenyl 6-iodopurine in dichloromethane with an ethereal solution of ethylmagnesium bromide at ambient temperature generates the corresponding purin-6-yl magnesium halides which react with aldehydes to give carbinols in 55–80% yield. Performing the same procedure with THF as solvent gave carbinols in much lower yields (≤15%).

Key words

nucleobases - purin-6-yl magnesium halides - Grignard - dichloromethane - carbinols

• References and Notes

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• 13 Reactions with ketones proceed in much lower yields. For example, the purin-6-yl magnesium halide derived from 2 reacts with acetophenone to give the corresponding carbinol in 12% yield. Efforts are currently under way to try and improve this reaction.
• 14 General Experimental Procedure for the Metal–Halogen Exchange in Dichloromethane Dry CH₂Cl₂ (10 mL) was added to the iodopurine 1 ⁹ or 2 ¹⁰ (1.0 mmol) under an inert atmosphere of dry argon, and the mixture was stirred at rt until the purine was completely dissolved. A solution of EtMgBr (1.2 eq, 3 M in Et₂O, 0.4 mL) was then instilled into the solution over a period of 30 s. The resulting mixture was stirred at rt for 15 min, and then neat aldehyde (3 mmol) was instilled into the mixture over 30 s, and the reaction mixture was stirred at rt overnight (16 h). The reaction was quenched with sat. aq NH₄Cl (5 mL), and then diluted with sat. aq NaHCO₃ (15 mL). The organic phase was separated off, and the aqueous phase extracted thrice with CH₂Cl₂ (20 mL). The combined organic phases were dried over Mg₂SO₄, filtered, and concentrated in vacuo at 40 °C. The crude product was purified by column chromatography to afford pure carbinols 3a–f and 4a–f (see Table 1 for yields).
• 15 Characterization Data The ¹H NMR and ¹³C NMR spectra for compounds 3a–d were identical to those reported previously in the literature.⁸ (9-Benzyl-9H-purin-6-yl)(cyclopropyl)methanol (3e) Colourless solid (223 mg, 0.80 mmol, 80% theory). ¹H NMR (600 MHz, CDCl₃): δ = 0.45–0.55 (m, 2 H), 0.57–0.62 (m, 1 H), 0.73–0.78 (m, 1 H), 1.39–1.45 (m, 1 H), 4.91 (d, J = 6.8 Hz, 1 H), 5.47 (s, 2 H), 7.32–7.39 (m, 5 H), 8.10 (s, 1 H), 8.99 (s, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 2.3, 2.8, 17.8, 47.7, 72.6, 128.2, 129.0, 129.4, 130.4, 134.9, 144.8, 151.6, 151.8, 161.7 ppm. IR (solid): ν_m = 3309, 3114, 3054, 2998, 2715, 1799, 1582, 1440, 1281, 1145, 1023, 953 cm^–1. HRMS (ESI/QTOF): m/z [MH]⁺ calcd for C₁₆H₁₇N₄O: 281.1402; Found: 281.1396. 1-(9-Benzyl-9H-purin-6-yl)butan-1-ol (3f) Colourless solid (155 mg, 0.55 mmol, 55% theory). ¹H NMR (600 MHz, CDCl₃): δ = 0.95 (t, J = 7.4 Hz, 3 H), 1.47–1.59 (m, 2 H), 1.83–1.90 (m, 1 H), 2.06–2.13 (m, 1 H), 4.95 (br s, 1 H), 5.33 (dd, J = 4.1, 8.3 Hz, 1 H), 5.47 (s, 2 H), 7.31–7.39 (m, 5 H), 8.09 (s, 1 H), 8.98 (s, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 14.1, 18.8, 39.9, 47.7, 70.6, 128.1, 128.9, 129.4, 130.2, 134.9, 144.5, 151.6, 162.4 ppm. IR (solid): ν_m = 3224, 3069, 2955, 2872, 1877, 1587, 1455, 1403, 1237, 1153, 939 cm^–1. HRMS (ESI/QTOF) m/z [MH]⁺ calcd for C₁₆H₁₉N₄O: 283.1559; found: 283.1559. Phenyl(9-phenyl-9H-purin-6-yl)methanol (4a) Colourless solid (227 mg, 0.75 mmol, 75% theory). ¹H NMR (600 MHz, CDCl₃): δ = 5.47 (br s, 1 H), 6.48 (s, 1 H), 7.24–7.28 (m, 1 H), 7.32–7.36 (m, 2 H), 7.47–7.51 (m, 1 H), 7.57–7.61 (m, 2 H), 7.66–7.70 (m, 4 H), 8.35 (s, 1 H), 9.04 (s, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 72.6, 123.7, 127.0, 128.1, 128.7, 128.9, 130.1, 130.9, 134.1, 141.8, 144.0, 151.5, 152.3, 161.1 ppm. (IR, solid): ν_m = 3438, 3088, 2893, 1595, 1451, 1378, 1182, 1090, 940 cm^–1. HRMS (ESI/QTOF): m/z [MH]⁺ calcd for C₁₈H₁₅N₄O 303.1246; found: 303.1238. (9-Phenyl-9H-purin-6-yl)[4-(trifluoromethyl)phenyl]-methanol (4b) Colourless solid (268 mg, 0.72 mmol, 72% theory). ¹H NMR (600 MHz, CDCl₃): δ = 5.08 (br s, 1 H), 6.55 (s, 1 H), 7.49–7.53 (m, 1 H), 7.58–7.62 (m, 4 H), 7.66–7.70 (m, 2 H), 7.57–7.61 (d, J = 8.4 Hz, 2 H), 8.38 (s, 1 H), 9.05 (s, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 71.9, 123.8, 125.6 (q, J _C–F = 3.2 Hz), 127.3, 129.1 (q, J _C–F = 33.5 Hz), 130.2, 130.4, 130.8, 131.3, 134.0, 144.4, 145.5, 151.7, 152.1, 160.1 ppm. (IR, solid): ν_m = 3293, 3115, 1598, 1572, 1414, 1404, 1179, 1070, 894 cm^–1. HRMS (ESI/QTOF): m/z [MH]⁺ calcd for C₁₉F₃H₁₄N₄O: 371.1120; found: 371.1103. Benzo[d][1,3]dioxol-5-yl(9-phenyl-9H-purin-6-yl)methanol (4c) Colourless solid (233 mg, 0.67 mmol, 67% theory). ¹H NMR (600 MHz, CDCl₃): δ = 5.18 (br s, 1 H), 5.89 (d, J = 7.9 Hz, 2 H), 6.40 (s, 1 H), 6.78 (d, J = 7.9 Hz, 1 H), 7.12 (d, J = 1.6 Hz, 1 H), 7.16 (dd, J = 1.6, 7.9 Hz, 1 H), 7.48–7.51 (m, 1 H), 7.58–7.62 (m, 2 H), 7.66–7.70 (m, 2 H), 8.37 (s, 1 H), 9.04 (s, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 72.2, 101.2, 107.5, 108.5, 120.8, 123.8, 129.0, 130.2, 130.7, 134.0, 135.4, 144.3, 147.6, 148.0, 151.7, 152.0, 161.0 ppm. (IR, solid): ν_m = 3205, 3063, 2789, 1869, 1590, 1499, 1397, 1377, 1208, 1045, 942 cm^–1. HRMS (ESI/QTOF): m/z [MH]⁺ calcd for C₁₉H₁₅N₄O₃: 347.1144; found: 347.1129. 2-Methyl-1-(9-phenyl-9H-purin-6-yl)propan-1-ol (4d) Colourless solid (163 mg, 0.61 mmol, 61% theory). ¹H NMR (600 MHz, CDCl₃): δ = 0.85 (d, J = 6.8 Hz, 3 H), 1.16 (d, J = 6.8 Hz, 3 H), 2.49–2.58 (m, 1 H), 4.64 (br s, 1 H), 5.25 (d, J = 4.3 Hz, 1 H), 7.49–7.53 (m, 1 H), 7.59–7.63 (m, 2 H), 7.71–7.74 (m, 2 H), 8.38 (s, 1 H), 9.03 (s, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 15.9, 20.0, 34.7, 75.2, 123.8, 128.9, 130.2, 131.3, 134.3, 143.3, 151.1, 152.3, 162.5 ppm. (IR, solid): ν_m = 3234, 3055, 2969, 1935, 1751, 1592, 1572, 1407, 1324, 1185, 1035, 920 cm^–1. HRMS (ESI/QTOF): m/z [MH]⁺ calcd for C₁₅H₁₇N₄O 269.1402; found: 269.1397. Cyclopropyl(9-phenyl-9H-purin-6-yl)methanol (4e) Colourless solid (198 mg, 0.74 mmol, 74% theory). ¹H NMR (600 MHz, CDCl₃): δ = 0.49–0.58 (m, 2 H), 0.61–0.65 (m, 1 H), 0.78–0.83 (m, 1 H), 1.43–1.49 (m, 1 H), 4.55 (br s, 1 H), 4.99 (d, J = 6.9 Hz, 1 H), 7.49–7.52 (m, 1 H), 7.59–7.63 (m, 2 H), 7.71–7.74 (m, 2 H), 8.38 (s, 1 H), 9.02 (s, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ 2.4, 2.7, 17.9, 72.7, 123.8, 128.9, 130.2, 131.1, 134.2, 143.8, 151.4, 152.3, 162.3 ppm. (IR, solid): ν_m = 3102, 2879, 1939, 1892, 1788, 1598, 1515, 1398, 1342, 1161, 916 cm^–1. HRMS (ESI/QTOF): m/z [MH]⁺ calcd for C₁₅H₁₅N₄O: 267.1246; found: 267.1244. 1-(9-Phenyl-9H-purin-6-yl)butan-1-ol (4f) Colourless solid (147 mg, 0.55 mmol, 55% theory). ¹H NMR (600 MHz, CDCl₃): δ = 0.98 (t, J = 7.4 Hz, 3 H), 1.48–1.63 (m, 2 H), 1.88–1.94 (m, 1 H), 2.12–2.19 (m, 1 H), 4.36 (br s, 1 H), 5.39 (dd, J = 4.1, 8.2 Hz, 1 H), 7.48–7.53 (m, 1 H), 7.59–7.63 (m, 2 H), 7.71–7.74 (m, 2 H), 8.37 (s, 1 H), 9.00 (s, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 14.1, 18.8, 39.9, 70.6, 123.8, 129.0, 130.2, 130.9, 134.2, 143.7, 151.2, 152.1, 163.0 ppm. (IR, solid): ν_m = 3220, 2929, 1930, 1767, 1595, 1510, 1403, 1334, 1259, 1117, 1037, 934 cm^–1. HRMS (ESI/QTOF): m/z [MH]⁺ calcd for C₁₅H₁₇N₄O: 269.1402; found: 269.1398.