An Efficient Protocol for the Liquid-Phase Synthesis of Furanoquinolines and Pyranoquinolines

Abstract

A three-step liquid-phase protocol for the synthesis of furanoquinolines and pyranoquinolines is described. The one-pot three-component aza-Diels-Alder reaction of PEG-supported benzaldehyde, anilines and 2,3-dihydrofuran or dihydropyran under TFA gave PEG-supported tetrahydroquinolines, which was assuredly oxidized by DDQ and then cleaved from the support to afford the corresponding furanoquinolines and pyranoquinolines with ­reasonable yields and purity.

tetrahydroquinolines - quinolines - liquid-phase synthesis - polyethylene glycol (PEG)

References

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<A NAME="RU04404ST-8">8</A>

Typical Spectral Data. For compound 4a: IR (KBr): 3361, 1702 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.67 (m, 1 H), 2.01 (m, 1 H), 2.46 (m, 1 H), 3.85 (m, 2 H), 3.93 (s, 3 H), 4.04 (m, 1 H), 4.60 (d, J = 5.0 Hz, 1 H), 6.67 (d, J = 8.0 Hz, 1 H), 6.84 (t, J = 7.3 Hz, 1 H), 7.15 (t, J = 7.0 Hz, 1 H), 7.41 (d, J = 6.6 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 2 H), 8.06 (d, J = 8.4 Hz, 2 H). MS (EI): m/z = 309 [M⁺]. HRMS: m/z [M + H]⁺ calcd for C₁₉H₁₉NO₃: 310.1443; found: 310.1505. For compound 4a′: IR (KBr): 3370, 1713 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.46 (m, 1 H), 2.15 (m, 1 H), 2.80 (m, 1 H), 3.72 (m, 2 H), 3.93 (s, 3 H), 4.76 (d, J = 3.0 Hz, 1 H), 5.28 (d, J = 7.8 Hz, 1 H), 6.62 (d, J = 7.9 Hz, 1 H), 6.90 (t, J = 7.2 Hz, 1 H), 7.12 (t, J = 7.2 Hz, 1 H), 7.36 (d, J = 7.0 Hz, 1 H), 7.52 (d, J = 8.3 Hz, 2 H), 8.05 (d, J = 8.3 Hz, 2 H). MS (EI): m/z = 309 [M⁺]. HRMS: m/z [M + H]⁺ calcd for C₁₉H₁₉NO₃: 310.1443; found: 310.1486.

<A NAME="RU04404ST-9">9</A>

Typical Procedure for the Synthesis of 6a: To a solution of PEG-bound aldehyde (0.5 mmol) and aniline (5 mmol) in TFA-CH₃CN (1:50, 6 mL) was added 2,3-dihydrofuran (10 mmol). The mixture was stirred at r.t. for 12 h. The resulting PEG-bound cycloadduct 3a was crystallized from i-PrOH (30 mL) and was separated by filtration and washing. A solution of 3a and DDQ (2 mmol) in CH₂Cl₂ (5 mL) was stirred at r.t. for 24 h. Upon completion of the reaction, the PEG-bound furanquinoline 5a was precipitated in i-PrOH (30 mL) and was separated by filtration and washed. The resulting 5a was dissolved in 0.1 N MeONa-MeOH and stirred at r.t. for 6 h to cleave the product from the PEG support. The detached PEG-OH was precipitated by cold Et₂O and filtered. The combined filtrate was evaporated to offer crude product. Pure 6a for structure assay was obtained by flash-column chromatography (EtOAc-n-hexane, 1:5). All the compounds listed in the Table [2] gave satisfactory IR, ¹H NMR, MS and HRMS data. For compound 6a these data are as follows: IR (KBr): 1719 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 3.61 (t, J = 8.9 Hz, 2 H), 3.97 (s, 3 H), 4.95 (t, J = 8.9 Hz, 2 H), 7.53 (m, 1 H), 7.72 (m, 1 H), 8.01 (m, 3 H), 8.20 (m, 3 H). MS (EI): m/z = 304 [M - H]⁺. HRMS: m/z [M + H]⁺ calcd for C₁₉H₁₉NO₃: 306.1130; found: 306.1185.