Ionic Liquid Promoted Aza-Diels-Alder Reaction of Danishefsky’s Diene with Imines

Abstract

A highly efficient procedure for the synthesis of 2-substituted-2,3-dihydro-4-pyridone derivatives through the aza-Diels-Alder reaction under ‘green chemistry’ conditions is described. The reaction of Danishefsky’s diene with imines has been found to ­perform better at room temperature in ionic liquids without an acid catalyst and organic solvent: the ionic liquids are recycled while their efficiency is preserved.

Key words

ionic liquids - aza-Diels-Alder reaction - Danishefsky’s diene - imines - green chemistry

References

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15

General Procedure for the Aza-Diels-Alder Reaction of Danishefsky’s Diene with Imines A mixture of imine 2 (1 mmol), ionic liquid (0.5 equiv) and Danishefsky’s diene 1 (1.2 equiv added in two phases) was stirred at 30 °C for the period of time reported in Table [3] . The reaction mixture was extracted from the ionic liquid phase with Et₂O (3 × 10 mL). The ether layer was dried over anhydrous MgSO₄ and evaporated under reduced pressure. The residue was purified by flash column chromatography (EtOAc-pentane, 10:90→70:30) to provide 3.
The ionic liquid was dissolved in CH₂Cl₂ (20 mL) and then recycled by washing with H₂O (2 × 10 mL). The organic phase was dried over anhydrous MgSO₄, filtered and evaporated in vacuo to afford the recycled ionic liquid. Spectra data (IR, ¹H and ¹³C) were identical to the initial ionic liquid sample. This was reused without loss of efficiency (Table [3] , entry 1).
1-Benzyl-2,3-dihydro-2-phenylpyridin-4(1 H )-one (3a) IR (neat): 2926, 1635, 1591, 1494, 1453, 1382, 1205, 1078, 760, 700 cm^-1. ¹H NMR (CDCl₃): δ = 2.68 (dd, 1 H, J = 8.6 Hz, 16.6 Hz), 2.84 (dd, 1 H, J = 7.2 Hz, 16.6 Hz), 4.12 (d, 1 H, J = 15.5 Hz), 4.35 (d, 1 H, J = 15.5 Hz), 4.50 (t, 1 H, J = 7.2 Hz), 5.10 (d, 1 H, J = 7.9 Hz), 7.13 (d, 1 H, J = 7.2 Hz), 7.24-7.36 (m, 10 H). ¹³C NMR (CDCl₃): δ = 43.2, 57.1, 60.3, 98.2, 126.9, 127.5, 128.1, 129.3, 135.6, 138.2, 154.5, 190.4. HRMS (EI): m/z calcd for C₁₈H₁₇NO (M⁺), 263.1310; found, 263.1310.
1-Benzyl-2,3-dihydro-2-(4-methoxyphenyl)pyridin-4(1 H )-one (3b) IR (neat): 3050, 1634, 1574, 1514, 1383, 1254, 1030, 833, 739, 699 cm^-1. ¹H NMR (CDCl₃): δ = 2.63 (dd, 1 H, J = 8.8 Hz, 16.5 Hz), 2.76 (dd, 1 H, J = 7.0 Hz, 16.8 Hz), 3.78 (s, 3 H), 4.10 (d, 1 H, J = 15.0 Hz), 4.28 (d, 1 H, J = 15.0 Hz), 4.41 (t, 1 H, J = 8.5 Hz), 5.04 (d, 1 H, J = 7.5 Hz), 6.83 (d, 1 H, J = 8.7 Hz), 7.10-7.32 (m, 9 H). ¹³C NMR (CDCl₃): δ = 43.6, 55.3, 57.0, 60.1, 98.4, 114.3, 128.0, 128.6, 128.8, 129.3, 130.4, 135.8, 154.4, 159.5, 190.8. HRMS (EI): m/z calcd for C₁₉H₁₉NO₂ (M⁺), 293.1416; found, 293.1410.

1-Benzyl-2,3-dihydro-2-(4-chlorophenyl)pyridin-4(1 H )-one (3c) IR (neat): 3063, 1644, 1574, 1490, 1382, 1205, 1091, 825, 734, 699 cm^-1. ¹H NMR (CDCl₃): δ = 2.62 (dd, 1 H, J = 8.0 Hz, 16.8 Hz), 2.84 (dd, 1 H, J = 7.4 Hz, 16.6 Hz), 4.10 (d, 1 H, J = 15.2 Hz), 4.38 (d, 1 H, J = 15.2 Hz), 4.47 (t, 1 H, J = 7.4 Hz), 5.10 (d, 1 H, J = 8.0 Hz), 7.12 (d, 1 H, J = 8.2 Hz), 7.15-7.35 (m, 9 H). ¹³C NMR (CDCl₃): δ = 43.3, 57.3, 59.7, 98.6, 127.6, 128.3, 128.9, 135.4, 136.8, 136.9, 154.2, 190.0. HRMS (EI): m/z calcd for C₁₈H₁₆ClNO (M⁺), 297.0920; found, 297.0910.
1-Benzyl-2,3-dihydro-2-(4-nitrophenyl)pyridin-4(1 H )-one (3d) Mp 104 °C. IR (neat): 3032, 1711, 1645, 1582, 1516, 1455, 1347, 1206, 1157, 1030, 856, 734, 699 cm^-1. ¹H NMR (CDCl₃): δ = 2.60 (dd, 1 H, J = 6.8 Hz, 16.6 Hz), 2.93 (dd, 1 H, J = 7.2 Hz, 16.2 Hz), 4.12 (d, 1 H, J = 15.2 Hz), 4.44 (d, 1 H, J = 15.2 Hz), 4.61 (t, 1 H, J = 7.2 Hz), 5.13 (d, 1 H, J = 8.0 Hz), 7.12-7.45 (m, 9 H), 8.22 (d, 1 H, J = 9.0 Hz). ¹³C NMR (CDCl₃): δ = 42.8, 57.8, 59.5, 99.2, 124.2, 128.1, 128.3, 129.0, 129.6, 135.1, 145.7, 147.7, 153.9, 189.0. HRMS (EI): m/z calcd for C₁₈H₁₆N₂O₃ (M⁺), 308.1161; found, 308.1154.
1-Benzyl-2,3-dihydro-2-hexylpyridin-4(1 H )-one (3e) IR (neat): 2931, 1710, 1574, 1558, 1455, 1352, 1195, 1136, 1061, 970, 740, 699 cm^-1. ¹H NMR (CDCl₃) δ = 0.88 (t, 3 H, J = 5.7 Hz), 1.26 (m, 6 H), 1.62 (m 2 H), 1.78 (m, 2 H), 2.31 (dd, 1 H, J = 3.0 Hz, 16.5 Hz), 2.69 (dd, 1 H, J = 7 Hz, 16.5 Hz), 3.4 (m, 1 H), 4.35 (d, 1 H, J = 15.2 Hz), 4.43 (d, 1 H, J = 15.2 Hz), 4.95 (d, 1 H, J = 7.5 Hz), 7.06 (d, 1 H, J = 7.5 Hz), 7.27-7.45 (m, 5 H). ¹³C NMR (CDCl₃): δ = 14.0, 22.5, 25.5, 28.4, 29.1, 31.6, 39.0, 56.0, 58.0, 96.8, 127.4, 127.8, 128.3, 129.1, 136.4, 153.4, 191.1. HRMS (EI): m/z calcd for C₁₈H₂₅NO (M⁺), 271.1936; found, 271.1942.
1-Benzyl-2,3-dihydro-2-isobutylpyridin-4(1 H )-one (3f) IR (neat): 2960, 1710, 1622, 1575, 1558, 1455, 1352, 1195, 1137, 1059, 970, 738, 699 cm^-1. ¹H NMR (CDCl₃): δ = 0.80 (d, 3 H, J = 6.5 Hz), 0.93 (d, 3 H, J = 6.5 Hz), 1.60 (m, 2 H), 1.79 (m, 1 H), 2.27 (dd, 1 H, J = 3.3 Hz, 16.5 Hz), 2.70 (dd, 1 H, J = 6.7 Hz, 16.7 Hz), 3.5 (m, 1 H), 4.32 (d, 1 H, J = 15.3 Hz), 4.42 (d, 1 H, J = 15.3 Hz), 4.96 (d, 1 H, J = 7.2 Hz), 7.07 (d, 1 H, J = 6.8 Hz), 7.27-7.41 (m, 5 H). ¹³C NMR (CDCl₃): δ = 21.3, 23.4, 24.1, 36.5, 38.3, 53.9, 58.1, 96.0, 127.6, 128.4, 129.1, 136.0, 154.5, 191.3. HRMS (EI): m/z calcd for C₁₆H₂₁NO (M⁺), 243.1623; found, 243.1622.
1-Benzyl-2,3-dihydro-2-isopropylpyridin-4(1 H )-one (3g) IR (neat): 2965, 1713, 1634, 1568, 1558, 1455, 1353, 1195, 1137, 1059, 973, 735, 700 cm^-1. ¹H NMR (CDCl₃): δ = 0.95 (d, 6 H, J = 6.2 Hz), 2.27 (m, 1 H), 2.40 (dd, 1 H, J = 3.5 Hz, 17.0 Hz), 2.63 (dd, 1 H, J = 7.7 Hz, 17.0 Hz), 3.25 (m, 1 H), 4.40 (d, 1 H, J = 15.2 Hz), 4.50 (d, 1 H, J = 15.2 Hz), 4.95 (d, 1 H, J = 7.0 Hz), 7.17-7.40 (m, 6 H), ¹³C NMR (CDCl₃): δ = 17.8, 19.4, 29.0, 35.4, 58.9, 61.0, 96.5, 127.4, 128.4, 129.1, 136.2, 155.8, 192.1. HRMS (EI): m/z calcd for C₁₅H₁₉NO (M⁺), 229.1467; found, 229.1472.