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Synlett 2004(7): 1231-1234  
DOI: 10.1055/s-2004-822922
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Zuxing Chen*, Guizhou Yue, Cuifen Lu, Guichun Yang
Faculty of Chemistry and Material Science, Hubei University, Wuhan, Hubei, 430062, P. R. China
Fax: +86(27)88663043; e-Mail: chzux@tom.com;
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Publication History

Received 22 February 2004
Publication Date:
10 May 2004 (online)

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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

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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-].

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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.

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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.