Microwave-Assisted Synthesis of Indolizino[1,2-b]quinolines

Abstract

An improved preparation of indolizinoquinolines using microwave-assisted synthesis is described. The process involves the Friedländer reaction of o-aminobenzaldehydes or imine with tetrahydroindolizinediones to form the quinoline structure.

Key words

microwave irradiation - indolizinoquinoline - Fried­länder reaction

References

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• For papers on microwave utilization see:
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8

Conventional heating procedure: Tetrahydroindolizinediones 2, [11] 3, [12] or 4 [12] (2.1 mmol) and 2-aminobenzaldehydes 1a, [12] 1b, [12] or imine 1c [13] (2.6 mmol) were added to acetic acid (20 mL) and heated while stirring under reflux for 8 h (TLC control). The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was diluted in methanol and hydrogen chloride was bubbled. The products were purified by flash chromatography (dichloromethane-methanol 8:2→7:3) before recrystallization.

9

Microwave irradiation procedure: The reaction was carried out in a open monomod Prolabo Synthewave S402 microwave oven,^® (equipped with a probe that regulates the temperature of the reaction medium) along with a built-in mechanic stirrer. Quartz vessel was used equipped with a reflux condenser. Tetrahydroindolizinediones 2-4 (2.1 mmol) and 2-aminobenzaldehydes 1a, [12] 1b, [12] or imine 1c [13] (2.6 mmol) were added to acetic acid (20 mL) and heated at reflux while stirring under microwave irradiation (60 W) for 15 min (optimized time). Hydrochlorides were prepared and purified as in the conventional procedure.
7-Methyl-9-oxo-3-(2-piperidinyl-1-ylethoxy)-9,11-dihydroindolizino[1,2- b ]quinoline-8-carbonitrile Hydrochloride(5a): ¹H NMR (300 MHz, CDCl₃): δ = 1.48 (m, 2 H), 1.65 (m, 4 H), 2.93 (m, 2 H), 4.34 (m, 2 H), 5.25 (s, 2 H), 7.18-7.82 (m, 4 H), 8.32 (s, 1 H). MS: m/z = 274 [M⁺]. Anal. Calcd. for C₂₄H₂₄N₄O₂ ·1HCl·2H₂O: C, 60.95; H, 6.18; N, 11.85; Cl, 7.50. Found: C, 61.02; H, 6.26; N, 11.58; Cl, 7.32.
7-Methyl-9-oxo-3-(2-piperidinyl-1-ylethoxy)-9,11-dihydroindolizino[1,2- b ]quinoline-8-carboxamide Hydrochloride(6a): ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.42 (m, 2 H), 1.82 (m, 4 H), 2.50 (s, 3 H), 3.05 (m, 2 H), 3.59 (m, 4 H), 4.63 (m, 2 H), 5.23 (s, 2 H), 7.10 (s, 1 H), 7.42 (dd, 1 H), 7.49 (s, 1 H),7.60 (d, 1 H), 8.09 (d, 1 H), 8.24 (s, 1 H), 8.64 (s, 1 H), 10.22 (s, 1 H). MS: m/z = 418 [M⁺]. Anal. Calcd. for C₂₄H₂₆N₄O₃ ·1HCl·2.5H₂O: C, 57.65; H, 6.45; N, 11.21; Cl, 17.09. Found: C, 57.89; H, 6.20; N, 11.53; Cl, 17.11.
N -[7-Methyl-9-oxo-3-(2-piperidinyl-1-ylethoxy)-9,11-dihydroindolizino[1,2- b ]quinolin-8-ylmethyl]acetamide Hydrochloride(7a): ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.70 (m, 2 H), 1.83 (m, 4 H), 1.95 (s, 3 H), 2.46 (s, 3 H), 3.05 (m, 2 H), 3.58 (m, 4 H), 4.35 (d, 2 H), 4.68 (m, 2 H), 5.26 (s, 2 H), 6.80 (m, 1 H), 7.16 (s, 1 H), 7.43 (dd, 1 H), 7.58 (d, 1 H), 8.09 (d, 1 H), 8.08 (d, 1 H), 8.65 (s, 1 H), 10.85 (s, 1 H). MS: m/z = 446 [M⁺]. Anal. Calcd. for C₂₆H₃₀N₄O₃ ·1HCl·2H₂O: C, 60.17; H, 6.80; N, 10.79; Cl, 6.83. Found: C, 60.03; H, 7.05; N, 10.41; Cl, 7.12.

12

Perzyna, A.; Marty, C.; Facompré, M.; Goossens, J.-F.; Pommery, N.; Colson, P.; Houssier, C.; Houssin, R.; Hénichart, J.-P.; Bailly, C. J. Med. Chem., accepted for publication.