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

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

References

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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.