Microwave-Promoted Michael Addition in Neat Water: A Rapid, Efficient and Green Method for the Preparation of Acyclic Nucleosides

Abstract

Syntheses of acyclic nucleosides were achieved in water with the aid of microwave irradiation, providing a rapid, efficient and convenient method for the preparation of acyclic nucleosides in high yields.

Key words

acyclic nucleoside - microwave irradiation (MWI) - Michael addition - green solvent

References and Notes

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11

General Procedure for the Michael Addition of Uracil to Acrylonitrile.
To a mixture of uracil (2 mmol, 0.224 g) and Et₃N (0.85 mL, 6 mmol) in neat H₂O (5 mL), acrylonitrile (6 mmol, 0.4 mL) was added. Then the mixture was put into the cavity of a commercially available single-mode microwave synthesis apparatus equipped with a high sensitivity infrared sensor for temperature control and measurement (MAS-I, Sineo Microwave Chemical Technology Co. Ltd., Shanghai, P. R. of China) and irradiated at 250 W (internal temperature: 100 °C) for 5 min. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure and the residue was purified by column chromatography using EtOAc-cyclohexane (9:1) as the eluent to afford 6a in 82% yield.

12

Compound 6e: yield 74%; yellow crystals; mp 164-165 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.940 (t, 2 H, J = 6.4 Hz), 3.982 (t, 2 H, J = 6.4 Hz), 6.318 (d, 1 H, J = 7.2 Hz), 7.606 (d, 1 H, J = 7.2 Hz) 12.766 (s, 1 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 17.07, 44.46, 112.86, 118.65, 141.39, 148.63, 191.05 ppm. IR (KBr): 3188, 3102, 3073, 3042, 2965, 2926, 2252, 1681, 1622, 1451, 1355, 1317, 1255, 1149, 1094, 866, 855, 638 cm^-1. HRMS: m/z calcd for C₇H₇N₃OS: 181.0310; found: 181.0320. Anal. Calcd for C₇H₇N₃OS: C, 46.40; H, 3.89; N, 23.19. Found: C, 46.37; H, 3.85; N, 23.11.
Compound 8d: yield 80%; white powder; mp 226-228 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.920 (t, 2 H, J = 6.4 Hz), 3.928 (t, 2 H, J = 6.4 Hz), 6.993 (s, 1 H), 7.842 (s, 1 H), 8.147 (s, 1 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 17.14, 45.07, 85.98, 118.82, 147.05, 154.52, 162.81 ppm. IR (KBr): 3364, 3107, 2963, 2945, 2247, 1674, 1650, 1500, 1438, 1410, 1377, 1333, 1280, 1207, 1099, 1028, 988, 824, 778, 653, 628 cm^-1. HRMS: m/z calcd for C₇H₇BrN₄O: 241.9803; found: 241.9810. Anal. Calcd for C₇H₇BrN₄O: C, 34.59; H, 2.90; N, 23.05. Found: C, 34.54; H, 2.85; N, 22.97.
Compound 10c: yield 86%; white powder; mp 220 °C (dec.). ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.145 (t, 2 H, J = 6.4 Hz), 4.354 (t, 2 H, J = 6.4 Hz), 6.980 (s, 2 H), 8.181 (s, 1 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 18.17, 39.26, 118.62, 123.65, 143.23, 150.01, 154.37, 160.20 ppm. IR (KBr): 3494, 3291, 3168, 3155, 3113, 2961, 2947, 2927, 2246, 1631, 1568, 1520, 1481, 1418, 1363, 1326, 1172, 905, 867, 781, 636 cm^-1. HRMS: m/z calcd for C₈H₇ClN₆: 222.0421; found: 222.1410. Anal. Calcd for C₈H₇ClN₆: C, 43.16; H, 3.17; N, 37.75. Found: C, 43.14; H, 3.14; N, 37.69.
Compound 10d: yield 77%; pale yellow powder; mp >300 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.141 (t, 2 H, J = 6.4 Hz), 4.412 (t, 2 H, J = 6.4 Hz), 7.821 (s, 2 H), 8.211 (s, 1 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 18.58, 39.79, 118.19, 118.65, 141.61, 150.94, 153.53, 157.25 ppm. IR (KBr): 3494, 3418, 3308, 3148, 3087, 3070, 3021, 2979, 2936, 2930, 2860, 2257, 1654, 1597, 1570, 1515, 1479, 1449, 1423, 1409, 1360, 1311, 1257, 644 cm^-1. HRMS: m/z calcd for C₈H₇ClN₆: 222.0421; found: 222.0411. Anal. Calcd for C₈H₇ClN₆: C, 43.16; H, 3.17; N, 37.75. Found: C, 43.13; H, 3.11; N, 37.70.
Compound 10g: yield 78%; white powder; mp 144-145 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.166 (t, 2 H, J = 6.4 Hz), 3.605 (s, 4 H), 4.455 (t, 2 H, J = 6.4 Hz), 4.712 (s, 1 H), 7.514 (s, 1 H), 8.184 (s, 1 H), 8.230 (s, 1 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 18.18, 42.84, 59.99, 118.24, 119.07, 140.44, 149.18, 152.58, 154.83 ppm. HRMS: m/z calcd for C₁₀H₁₂N₆O: 232.1072; found: 232.1081. Anal. Calcd for C₁₀H₁₂N₆O: C, 51.72; H, 5.21; N, 36.19. Found: C, 51.70; H, 5.15; N, 36.11.
Compound 10h: yield 73%; white powder; mp 152-154 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.134 (t, 2 H, J = 6.4 Hz), 3.498-3.597 (m, 4 H), 4.414 (t, 2 H, J = 6.4 Hz), 4.771 (t, 1 H, J = 5.2 Hz), 8.169 (s, 1 H), 8.208 (s, 1 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 18.39, 42.90, 45.28, 59.46, 60.67, 118.37, 141.14, 149.78, 153.45, 155.38 ppm. HRMS: m/z calcd for C₁₀H₁₁ClN₆O: 266.0683; found: 266.0692. Anal. Calcd for C₁₀H₁₁ClN₆O: C, 45.04; H, 4.16; N, 31.51. Found: C, 45.02; H, 4.15; N, 31.48.
Compound 10i: yield 76%; white powder; mp 163-164 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.087 (t, 2 H, J = 6.4 Hz), 3.572 (s, 4 H), 4.254 (t, 2 H, J = 6.4 Hz), 4.707 (s, 1 H), 5.852 (s, 2 H), 6.958 (s, 1 H), 7.747 (s, 1 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 17.97, 38.47, 42.66, 60.35, 113.39, 118.38, 136.95, 151.28, 155.20, 160.35 ppm. HRMS: m/z calcd for C₁₀H₁₃N₇O: 247.1182; found: 247.1174. Anal. Calcd for C₁₀H₁₃N₇O: C, 48.58; H, 5.30; N, 39.65. Found: C, 48.51; H, 5.21; N, 39.55.
Compound 12b: yield 83%; pale yellow crystals; mp 72-74 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.094 (t, J = 6.8 Hz, 3 H), 3.014 (t, J = 6.8 Hz, 2 H), 4.013 (q, J = 7.2 Hz, 2 H), 4.532 (t, J = 6.8 Hz, 2 H), 8.689 (s, 1 H), 8.783 (s, 1 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 14.04, 33.36, 60.47, 130.98, 147.78, 149.09, 151.58, 152.08, 170.54 ppm. HRMS: m/z calcd for C₁₀H₁₁ClN₄O₂: 254.0571; found: 254.0562. Anal. Calcd for C₁₀H₁₁ClN₄O₂: C, 47.16; H, 4.35; N, 22.00. Found: C, 47.08; H, 4.29; N, 21.91.