New Efficient Synthesis of Pyrido[2,3-c] and Pyrido[3,2-c]coumarin Derivatives

Grégoire Pavé; Pierre Chalard; Marie-Claude Viaud-Massuard; Yves Troin; Gérald Guillaumet

doi:10.1055/s-2003-39302

LETTER

New Efficient Synthesis of Pyrido[2,3-c] and Pyrido[3,2-c]coumarin Derivatives

Grégoire Pavé^a, Pierre Chalard^b, Marie-Claude Viaud-Massuard^c, Yves Troin^b, Gérald Guillaumet*^a
^a Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d’Orléans, BP 6759, 45067 Orléans Cedex 2, France
e-Mail: gerald.guillaumet@univ-orleans.fr ;
^b Laboratoire de Chimie des Hétérocycles et des Glucides, EA 987, Ecole Nationale Supérieure de Chimie de Clermont Ferrand, Université Blaise Pascal, BP 187, 63174 Aubière Cedex, France
^c Groupe de Recherche en Chimie Hétérocyclique et Thérapeutique, EA 3247, UFR Sciences Pharmaceutiques, Université de Tours, 31 avenue Monge, 37200 Tours, France

Abstract

All articles of this category

Abstract

Various substituted pyrido[2,3-c] and pyrido[3,2-c]coumarins are efficiently prepared in three steps from 3- and 4-hydroxycoumarins, respectively and protected β-aminoketones.

Key words

pyridocoumarins - tetrahydropyridocoumarins - disproportionation - oxidative cyclization - Santiagonamine

Full Text

References

1 Valencia E. Patra A. Freyer AJ. Shamma M. Fajardo V. Tetrahedron Lett. 1984, 25: 3163

2 Lewis WH, Stonard RJ, Porras-Reyes B, Mustoe TA, and Thomas A. inventors; US Patent 5156847.

3a Khan MA. Gemal AL. J. Heterocyclic Chem. 1977, 14: 1009

3b Tabakovic K. Tabakovic I. Trkovnik M. Juric A. Trinajstic N. J. Heterocycl. Chem. 1980, 17: 801

3c Sagi M. Wada K. Konno S. Yamanaka H. Heterocycles 1990, 30: 1009

4a Dean FM. Robertson A. Whalley WB. J. Chem. Soc. 1950, 895

4b Trivedi KN. Sethna S. J. Org. Chem. 1960, 25: 1817

5 Islam AM. Raphael RA. J. Chem. Soc. 1955, 3151

6a Ciblat S. Calinaud P. Canet J.-L. Troin Y. J. Chem. Soc., Perkin Trans. 1 2000, 353

6b Rougnon-Glasson S. Canet J.-L. Troin Y. Tetrahedron Lett. 2000, 41: 9797

7 Greenhill JV. Mohamed MI. J. Chem. Soc., Perkin Trans. 1 1979, 1411

8 Heber D. Berghaus T. J. Heterocycl. Chem. 1994, 31: 1353

9

General procedure for the synthesis of pyrido[2,3- c ]coumarins 5. In a round bottom flask equipped with a Dean-Stark apparatus, 3-hydroxycoumarins 3 in toluene, CSA (cat.) and amines 4 (1.1 equiv) were added. The solution was refluxed 5 h. The solution was cooled to r.t and 1.5 equiv of BF₃˙Et₂O was added. The solution was refluxed 18 h and the solvent was evaporated. The residue was hydrolyzed by a saturated aqueous NaHCO₃ solution, extracted by CH₂Cl₂ and dried over MgSO₄. After concentration under reduced pressure, the residue was dissolved in CH₂Cl₂ and 1 equiv of DDQ was added. The solution was stirred 18 h and hydrolyzed by a saturated aqueous K₂CO₃ solution. After extraction with CH₂Cl₂, the organic layers were washed, dried over MgSO₄, evaporated under reduced pressure and purified by flash chromato-graphy (SiO₂) to furnish pyrido[2,3-c]coumarins 5. Compound 5a: Yield: 54%; mp = 133 °C; IR (KBr): 1748 cm^-1; MS : 212 (M + 1); ¹H NMR (CDCl₃, 250 MHz) δ 2.95 (s, 3 H, CH₃), 7.34-7.58 (m, 4 H, 4CH_Ar), 8.26 (d, 1 H, J = 8.2 Hz, CH_Ar), 8.78 (d, 1 H, J = 4.6 Hz, H-6); ¹³C NMR (CDCl₃, 62.5 MHz) δ 24.9 (CH₃, ArCH₃), 116,4 (C, C_Ar), 118.1 (CH, CH_Ar), 124.5 (CH, CH_Ar), 127.4 (CH, CH_Ar), 130.6 (CH, CH_Ar), 132.0 (CH, CH_Ar), 139.1 (C, C_Ar), 145.1 (C, C_Ar), 150.1 (CH, CH_Ar), 150.7 (C, C_Ar), 159.2 (C, C=O).; Anal. Calcd for C₁₃H₉NO₂: C, 73.92; H, 4.29; N, 6.63. Found C, 73.82; H, 4.31; N, 6.72.

10

General procedure for the synthesis of tetrahydro-pyrido[2,3- c ]coumarins 6. In a round bottom flask equipped with a Dean-Stark apparatus, 3-hydroxy-coumarins 3 in toluene, CSA (cat.) and amines 4 (1.1 equiv) were added. The solution was refluxed 6 h. The solution was cooled to r.t. and 1.5 eq of BF₃˙Et₂O was added. The solution was refluxed 18 h and the solvent was evaporated. The residue was hydrolyzed by a saturated aqueous NaHCO₃ solution, extracted by CH₂Cl₂ and dried over MgSO₄. After concentration under reduced pressure, the residue was dissolved in AcOH and 1 equiv of NaBH₃CN was added. The solution was stirred 8 h and hydrolyzed by a saturated aqueous K₂CO₃ solution. After extraction with CH₂Cl₂, organic layers were washed, dried over MgSO₄, evaporated under reduce pressure and purified by flash chromatography (SiO₂, CH₂Cl₂/MeOH, 98:2) to furnish tetrahydro-pyrido[2,3-c]coumarins 6. Compound 6a: Yield: 63%; mp = 108 °C; IR (KBr): 1705 cm^-1; MS : 216 (M + 1); ¹H NMR (CDCl₃, 250 MHz) δ 1.31 (d, 3 H, J = 7.0 Hz, CH₃), 1.79-2.02 (m, 2 H, H-5), 3.17-3.24 (m, 1 H, H-4), 3.41-3.47 (m, 2 H, H-6), 4.87 (brs, 1 H, NH), 7.19-7.51 (m, 4 H, 4CH_Ar); ¹³C NMR (CDCl₃, 62.5 MHz) δ 21.2 (CH₃, CH₃), 25.3 (CH, C-4), 26.8 (CH₂, C-5), 36.1 (CH₂, C-6), 116.7 (CH, CH_Ar), 120.3 (C, C_Ar), 121.1 (CH, CH_Ar), 121.1 (C, C_Ar), 124.5 (CH, CH_Ar), 125.6 (CH, CH_Ar), 127.8 (C, C_Ar), 148.1 (C, C_Ar), 159.0 (C, C=O).; Anal. Calcd for C₁₃H₁₃NO₂: C, 72.54; H, 6.09; N, 6.51. Found C, 72.61; H, 6.23; N, 6.72.

11

General procedure for the synthesis of pyrido[3,2- c ]coumarins 10. Following the same protocol described for the synthesis of pyrido[2,3-c]coumarins 5, pyrido[3,2-c]coumarins 10 were obtained starting from 4-hydroxy-coumarin. Compound 10a: Yield: 61%; mp = 160 °C; IR (KBr): 1731 cm^-1; MS: 212 (M + 1); ¹H NMR (CDCl₃, 250 MHz) δ 2.85 (s, 3 H, CH₃), 7.26-7.37 (m, 3 H, 3 CH_Ar), 7.53 (td, 1 H, J = 7.6 Hz, 1.7 Hz, CH_Ar), 8.53 (dd, 1 H, J = 7.6 Hz, 1.7, CH_Ar), 8.75 (d, 1 H, J = 4.9 Hz, CH_Ar); ¹³C NMR (CDCl₃, 62.5 MHz) δ 23.0 (CH₃, ArCH₃), 116.5 (CH, CH_Ar), 116.7 (C, C_Ar), 119.5 (C, C_Ar), 124.6 (CH, CH_Ar), 125.3 (CH, CH_Ar), 126.7 (CH, CH_Ar), 132.1 (CH, CH_Ar), 152.4 (C, C_Ar), 153.0 (C, C_Ar), 153.5 (C, C_Ar), 154.2 (CH, CH_Ar), 160.5 (C, C=O); Anal. Calcd for C₁₃H₉NO₂: C, 73.92; H, 4.29; N, 6.63. Found C, 73.78; H, 4.32; N, 6.68.