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

1a Gravert DJ. Janda KD. Chem. Rev.  1997,  97:  489 

1b Wentworth P. Janda KD. Chem. Commun.  1999,  1917 

1c Toy PH. Tanda KD. Acc. Chem. Res.  2000,  33:  546 

1d Sun CM. Comb. Chem. High Throughput Screening  1999,  2:  299 

2 Nefzi A. Otresh JM. Houghten RA. Chem. Rev.  1997,  97:  449 

3a Yeh CM. Tung CL. Sun CM. J. Comb. Chem.  2000,  2:  341 

3b Zhao X. Metz WA. Sieber F. Janda KD. Tetrahedron Lett.  1998,  39:  8433 

3c Blettner CG. Konig WA. Quhter G. Stenzel W. Schotten T. Synlett  1999,  307 

3d Luisa G. Giorgio M. Pietro C. J. Chem. Soc., Perkin Trans. 1  2002,  2504 

3e Racker R. Doring K. Reiser O. J. Org. Chem.  2000,  65:  6932 

3f Annunziata R. Benaglia M. Cinquini M. Cozzi F. Chem.-Eur. J.  2000,  6:  133 

3g Guo HC. Ding KL. Tetrahedron Lett.  2003,  44:  7103 

4a Weinreb SM. In Comprehensive Organic Synthesis   Vol. 5:  Trost BM. Fleming I. Paquette LA. Pergamon; Oxford: 1991.  p.401 

4b Boger DL. Weinreb SM. Hetero Diels-Alder Methodology in Organic Synthesis   Academic; San Diego: 1987.  Chap 2.

4c Boger DL. Weinreb SM. Hetero Diels-Alder Methodology in Organic Synthesis   Academic; San Diego: 1987.  Chap 9.

4d Qiang LG. Baine NH. J. Org. Chem.  1988,  53:  4218 

5a Katritzky AR. Rachwal S. Rachwal B. Tetrahedron  1996,  52:  15031 

5b Larock RC. Yang H. Pace P. Tetrahedron Lett.  1998,  39:  1885 

5c Padwa A. Brodney MA. Liu B. Satake K. Wu T. J. Org. Chem.  1999,  64:  3595 

5d Bunce RA. Herron DM. Johnson LB. Kotturi S. J. Org. Chem.  2001,  66:  2822 

5e Zhang W. Jia X. Yang L. Zhao G. Liu Z.-L. Tetrahedron Lett.  2002,  43:  9433 

5f Romuald B. Patricia M. Benoit D. Andre T. Tetrahedron  1998,  54:  4125 

5g Spanedda MV. Hoang VD. Crousse B. Bonnet-Delpon D. Bégué J.-P. Tetraheron Lett.  2003,  44:  217 

6a Alexander SK. Robert WA. Tetrahedron Lett.  1997,  35:  6163 

6b Alexander SK. Leon SI. Robert WA. Tetrahedron  1998,  54:  5089 

6c Alexander SK. Leon SI. Alex V. Robert WA. Tetrahedron  1998,  54:  7987 

7a Shang YJ. Wang YG. Tetrahedron Lett.  2002,  43:  2247 

7b Xia M. Wang YG. Tetrahedron Lett.  2002,  43:  7703 

7c Lin XF. Zhan J. Wang YG. Tetrahedron Lett.  2003,  44:  4113 

7d Wang YG. Zhang J. Lin XF. Ding HF. Synlett  2003,  1467 

8

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.

9

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.