Synthesis of a Library of Indolizines Using Poly(ethylene glycol) as Soluble Support

Abstract

A library of indolizines has been synthesized using poly(ethylene glycol) (PEG) as soluble polymer support. The PEG-supported pyridinium ylide reacted with alkenes or alkynes to give PEG-bound indolizines. Cleavage from the soluble polymer support was induced by KCN/MeOH to afford the indolizines. This synthetic method is simple, the reaction conditions are mild and the yields are high to excellent.

Key words

poly (ethylene glycol) - cycloaddition - pyridinium salt - indolizine - polymer-support

References

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17

Preparation of PEG-Supported Pyridinium Salt 2 To a solution of PEG₃₄₀₀ (8 g, 4.71 mmol OH) and DIPEA (1.6 mL, 9.42 mmol) in dry CH₂Cl₂ (50 mL) was added dropwise a solution of bromoacetyl bromide (0.8 mL, 9.42 mmol) in dry CH₂Cl₂ (2 mL) at 0 °C and stirred at r.t. overnight. The mixture was washed with H₂O to remove NH₄Br, dried over MgSO₄ and concentrated. After precipitation with cold Et₂O, washing with cold Et₂O and drying under vacuum, a white solid 1 was obtained. Into a solution of 1 in dry CH₂Cl₂ (20 mL) was added pyridine (1.52 mL, 9.42 mmol) and stirred at r.t. for 18 h. After precipitation from cold Et₂O, the suspension was filtered and washed with cold Et₂O to give solid 2 (8.8 g, 98%). TLC (EtOAc-petroleum ether, 1:4) showed that the solid was free from any low molecular reactants and by-products.
IR (KBr): 2883, 1750, 1114 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 9.42 (d, 2 H, J = 6.6 Hz, α-pyridine), 8.68 (t, 1 H, J = 8.7 Hz, γ-pyridine), 8.19 (t, 2 H, J = 7.2 Hz, β-pyridine), 6.16 (s, 2 H, -CH₂COO-), 3.77-3.52 [m, 4n H, -O(CH₂CH₂O)_n-].

18

Typical Procedure for Preparation of Indolizines 5 A solution of 2 (2 g, 0.53 mmol), 3 (2.12 mmoL), TPCD (0.65 g, 1.06 mmoL) and DIPEA (0.18 mL, 1.06 mmol) in DMF (30 mL) was stirred at 80-90 °C for 3-4 h. After the solvent was evaporated under vacuum, the residue was added CH₂Cl₂ (50 mL) and filtered. The filtrate was washed with H₂O to remove NH₄Br, dried over MgSO₄, filtered, concentrated and precipitated with cold Et₂O to give 4. Product 4 was treated with a 1% solution of KCN in MeOH (30 mL) and stirred at r.t. overnight, evaporated MeOH and precipitated with cold Et₂O to give the crude products, which were purified by column chromatography on silica gel (EtOAc-petroleum ether, 1:4) to afford the pure 5.
5a: IR (KBr): 1678, 1635 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 9.65 (d, 1 H, J = 7.2 Hz, C-5), 8.08 (d, 1 H, J = 9.0 Hz, C-8), 7.46-7.03 (m, 12 H, C-6, C-7, Ph), 3.62 (s, 3 H,
-COOMe). Anal. Calcd for C₂₃H₁₇NO₃: C, 77.73; H, 4.82; N, 3.94. Found: C, 77.68; H, 4.80; N, 3.97.
5b: IR (KBr): 1684, 1633 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 9.64 (d, 1 H, J = 6.6 Hz, C-5), 8.04 (d, 1 H, J = 9.0 Hz, C-8), 7.47-6.88 (m, 11 H, C-6, C-7, Ph), 3.66 (s, 3 H, -COOMe), 2.22 (s, 3 H, Me). Anal. Calcd for C₂₄H₁₉NO₃: C, 78.03; H, 5.18; N, 3.79. Found: C, 78.00; H, 5.14; N, 3.82.
5c: IR (KBr): 1686, 1627 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 9.64 (d, 1 H, J = 4.2 Hz, C-5), 8.08 (d, 1 H, J = 7.8 Hz, C-8), 7.46-6.61 (m, 11 H, C-6, C-7, Ph), 3.71 (s, 3 H,
-COOMe), 3.67 (s, 3 H, -OMe). Anal. Calcd for C₂₄H₁₉NO₄: C, 74.79; H, 4.97; N, 3.63. Found: C, 74.81; H, 4.94; N, 3.67.
5d: IR (KBr): 1687, 1634 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 9.67 (d, 1 H, J = 6.6 Hz, C-5), 8.11 (d, 1 H, J = 9.0 Hz, C-8), 7.47-6.79 (m, 11 H, C-6, C-7, Ph), 3.67 (s, 3 H, -COOMe). Anal. Calcd for C₂₃H₁₆NFO₃: C, 73.99; H, 4.32; N, 3.75. Found: C, 73.96; H, 4.38; N, 3.79.
5e: IR (KBr): 1681, 1627 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 9.65 (d, 1 H, J = 7.2 Hz, C-5), 8.05 (d, 1 H, J = 9.0 Hz, C-8), 7.45-7.03 (m, 11 H, C-6, C-7, Ph), 3.65 (s, 3 H,
-COOMe). Anal. Calcd for C₂₃H₁₆NClO₃: C, 70.86; H, 4.14; N, 3.59. Found: C, 70.90; H, 4.14; N, 3.62.
5f: IR (KBr): 1686, 1634 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 9.65 (d, 1 H, J = 7.2 Hz, C-5), 8.05 (d, 1 H, J = 9.0 Hz, C-8), 7.45-7.03 (m, 11 H, C-6, C-7, Ph), 3.65 (s, 3 H,
-COOMe). Anal. Calcd for C₂₃H₁₆NBrO₃: C, 63.61; H, 3.71; N, 3.23. Found: C, 63.57; H, 3.74; N, 3,24.
5g: IR (KBr): 1686, 1629, 1531 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 9.66 (d, 1 H, J = 7.8 Hz, C-5), 8.00 (d, 1 H, J = 9.6 Hz, C-8), 7.47-7.09 (m, 11 H, C-6, C-7, Ph), 3.63 (s, 3 H, -COOMe). Anal. Calcd for C₂₃H₁₆N₂O₅: C, 69.00; H, 4.03; N, 7.00. Found: C, 68.71; H, 4.00; N, 6.75.
5h: IR (KBr): 1686, 1625, 1533 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 9.67 (d, 1 H, J = 6.6 Hz, C-5), 8.06 (d, 1 H, J = 7.2 Hz, C-8), 7.44-7.13 (m, 11 H, C-6, C-7, Ph), 3.63 (s, 3 H, -COOMe). Anal. Calcd for C₂₃H₁₆N₂O₅: C, 69.00; H, 4.03; N, 7.00. Found: C, 68.66; H, 4.05; N, 6.73.
5i: IR (KBr): 1682, 1628,1535 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 9.66 (d, 1 H, J = 7.2 Hz, C-5), 8.04 (d, 1 H, J = 8.4 Hz, C-8), 7.47-7.08 (m, 11 H, C-6, C-7, Ph), 3.63 (s, 3 H, -COOMe). Anal. Calcd for C₂₃H₁₆N₂O₅: C, 69.00; H, 4.03; N, 7.00. Found: C, 68.64; H, 4.02; N, 6.71.
5j: IR (KBr): 2226, 1682, 1628 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 9.66 (d, 1 H, J = 6.6 Hz, C-5), 8.03 (d, 1 H, J = 9.0 Hz, C-8), 7.45-7.09 (m, 11 H, C-6, C-7, Ph), 3.63 (s, 3 H, -COOMe). Anal. Calcd for C₂₄H₁₆N₂O₃: C, 75.78; H, 4.24; N, 7.36. Found: C, 75.74; H, 4.22; N, 7.38.
5k: IR (KBr): 1687, 1634 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 9.61 (d, 1 H, J = 6.0 Hz, C-5), 8.15 (d, 1 H, J = 8.4 Hz, C-8), 7.56-6.13 (m, 10 H, C-6, C-7, Ph, -furan), 3.82 (s, 3 H, -COOMe). Anal. Calcd for C₂₁H₁₅NO₄: C, 73.04; H, 4.38; N, 4.06. Found: C, 73.06; H, 4.34; N, 4.09.
5l: IR (KBr): 1688, 1647 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 9.59 (d, 1 H, J = 7.2 Hz, C-5), 8.65 (d, 1 H, J = 9.0 Hz, C-8), 7.62-6.49 (m, 5 H, C-6, C-7, -furan), 3.74 (s, 3 H,
-COOMe), 2.02 (s, 3 H, -Me). Anal. Calcd for C₁₆H₁₃NO₄: C, 67.84; H, 4.63; N, 4.94. Found: C, 67.88; H, 4.60; N, 4.87.
5m: IR (KBr): 1676, 1637 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 9.60 (d, 1 H, J = 6.6 Hz, C-5), 8.66 (d, 1 H, J = 9.0 Hz, C-8), 7.76-7.03 (m, 7 H, C-6, C-7, Ph, -furan), 3.52 (s, 3 H, -COOMe), 1.82 (s, 3 H, -Me). Anal. Calcd for C₁₈H₁₅NO₃: C, 73.71; H, 5.15; N, 4.78. Found: C, 73.76; H, 5.11; N, 4.82.
5n and 8b: IR (KBr): 1702, 1637 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 9.56 (d, 1 H, J = 7.2 Hz, C-5), 8.37 (d, 1 H, J = 7.8 Hz, C-8), 8.02 (s, 1 H, C-2), 7.36 (t, 1 H, J = 7.8 Hz, C-7), 7.03 (t, 1 H, J = 6.6 Hz, C-6), 3.95 (s, 3 H, -COOMe), 3.94 (s, 3 H, -COOMe). Anal. Calcd for C₁₂H₁₁NO₄: C, 61.80; H, 4.75; N, 6.01. Found: C, 61.77; H, 4.71; N, 6.00.

19

Typical Procedure for Preparation of Indolizines 8 A solution of 2 (2 g, 0.53 mmol), 6 (2.12 mmoL) and DIPEA (0.18 mL, 1.06 mmol) in toluene was stirred at 90 °C for 2 h. After solvent was removed, the residue was dissolved in CH₂Cl₂ (50 mL) washed, dried, filtered, concentrated, precipitated and cleaved by using the procedure described above for 5. The crude product was purified by column chromatography on silica gel (EtOAc-petroleum ether, 1:2) to afford pure 8.
8a: IR (KBr): 1736, 1715, 1697 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 9.53 (d, 1 H, J = 6.6 Hz, C-5), 8.35 (d, 1 H, J = 9.0 Hz, C-8), 7.40 (t, 1 H, J = 7.8 Hz, C-7), 7.07 (t, 1 H, J = 7.2 Hz, C-6), 4.03 (s, 3 H, -COOMe), 3.92 (s, 3 H,
-COOMe), 3.92 (s, 3 H, -COOMe). Anal. Calcd for C₁₄H₁₃NO₆: C, 57.73; H, 4.50; N, 4.81. Found: C, 57.77; H, 4.51; N, 4.85.