Hydroxylated Polyfunctionalized Benzo[c]coumarins by an Organocatalyzed Tandem 1,4-Conjugate Addition, Decarboxylation and Aromatization Reaction

Abstract

Novel hydroxylated polyfunctionalized benzo[c]coumarins were synthesized by a new one-pot reaction of an unprotected monohydroxy-3-(acetoacetyl)coumarin as an active methylene ­Michael donor with 4-oxo-4H-chromene-3-carboxylic acid as a ­Michael acceptor in the presence of a catalytic amount of 4-pyrrolidin-1-ylpyridine. An organobase-catalyzed tandem 1,4-conjugate addition, decarboxylation and aromatization reaction mechanism is proposed.

Key words

heterocycles - polycycles - ketones - tandem reactions - addition reactions - catalysis

• References

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• 11 8-Acetyl-7-hydroxy-10-(2-hydroxybenzoyl)-6H-benzo[c]chromen-6-ones (3a–d) Carboxylic acid 2 (1.0 g, 5.26 mmol) was added to a soln of the appropriate 3-(acetoacetyl)coumarin 1a–d (5.26 mmol) in CHCl₃ (20 mL). A catalytic amount of 4-PPy (0.26 mmol, 0.04 g) was added dropwise, and the mixture was refluxed with stirring for 24 h. Incomplete consumption of the starting materials was observed (TLC), even after an extended reaction time. The solvent was evaporated and the resulting gummy solid was directly purified by column chromatography [silica gel, PE–CH₂Cl₂ (gradient 3:1 to 2:1 to 1:1 to 0:1)]. Pure fractions were combined and precipitated in PE.
• 12 8-Acetyl-7-hydroxy-10-(2-hydroxybenzoyl)-6H-benzo[c]chromen-6-one (3a)
  White powder; yield: 1.371 g (70%); mp 197–198 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 2.79 (s, 3 H, H-2′), 6.79 (ddd, J = 8.2, 7.2, 1.1 Hz, 1 H, H-5′′′), 7.20–7.10 (m, 2 H, H-2 and H-3′′′), 7.28 (dd, J = 8.2, 1.4 Hz, 1 H, H-6′′′), 7.42 (dd, J = 8.3, 1.1 Hz, 1 H, H-4), 7.58–7.49 (m, 2 H, H-3 and H-4′′′), 7.65 (dd, J = 8.3, 1.3 Hz, 1 H, H-1), 8.19 (s, 1 H, H-9), 11.99 (s, 1 H, 2′′′-OH), 13.24 (s, 1 H, 7-OH). ¹³C NMR (75.47 MHz, CDCl₃): δ = 31.9 (C-2′), 108.0 (C-6a), 116.2 (C-10b), 118.0 (C-4), 118.8 (C-3′′′), 119.3 (C-1′′′), 119.6 (C-5′′′), 124.2 (C-8), 125.4 (C-2), 125.7 (C-10), 127.5 (C-1), 132.4 (C-3), 132.8 (C-6′′′), 137.7 (C-10a), 137.9 (C-4′′′), 138.3 (C-9), 151.0 (C-4a), 163.6 (C-2′′′), 163.8 (C-7), 165.3 (C-6), 196.2 (C-1′), 202.3 (C-1′′). HRMS (ESI⁺): m/z calcd for [C₂₂H₁₄O₆ + Na]⁺: 397.0688; found: 397.0688.
• 13 8-Acetyl-3,7-dihydroxy-10-(2-hydroxybenzoyl)-6H-benzo[c]chromen-6-one (3b) White-yellowish powder; yield: 0.920 g (45%); mp 279–280 °C. ¹H NMR [300.13 MHz, DMSO-d ₆–CDCl₃ (1:2)]: δ = 2.72 (s, 3 H, H-2′), 6.64 (dd, J = 9.0, 2.5 Hz, 1 H, H-2), 6.76–6.85 (m, 2 H, H-4 and H-5′′′), 7.07 (dd, J = 8.5, 1.0 Hz, 1 H, H-3′′′), 7.32 (dd, J = 8.0, 1.7 Hz, 1 H, H-6′′′), 7.39 (d, J = 9.0 Hz, 1 H, H-1), 7.55 (ddd, J = 8.5, 7.2, 1.7 Hz, 1 H, H-4′′′), 8.05 (s, 1 H, H-9), 10.34 (s, 1 H, 3-OH), 11.98 (s, 1 H, 2′′′-OH), 13.30 (s, 1 H, 7-OH). ¹³C NMR [75.47 MHz, DMSO-d ₆–CDCl₃ (1:2)]: δ = 31.2 (C-2′), 103.1 (C-4), 106.0 (C-6a), 107.3 (C-10b), 113.8 (C-2), 117.9 (C-3′′′), 119.1 (C-5′′′), 119.5 (C-1′′′), 121.7 (C-8), 124.6 (C-10), 128.3 (C-1), 132.4 (C-6′′′), 137.0 and 137.3 (C-4′′′ and C-9), 138.1 (C-10a), 152.3 (C-4a), 161.3 (C-3), 162.2 (C-2′′′), 163.3 (C-7), 164.8 (C-6), 195.4 (C-1′), 201.4 (C-1′′). HRMS (ESI⁺): m/z calcd for [C₂₂H₁₄O₇ + Na]⁺: 413.0637; found: 413.0622.
• 14 8-Acetyl-4,7-dihydroxy-10-(2-hydroxybenzoyl)-6H-benzo[c]chromen-6-one (3c) White-yellowish powder; yield: 1.091 g (53%); mp 272–273 °C. ¹H NMR [300.13 MHz, DMSO-d ₆–CDCl₃ (1:2)]: δ = 2.74 (s, 3 H, H-2′), 6.80 (ddd, J = 8.1, 7.3, 1.1 Hz, 1 H, H-5′′′), 6.93–7.12 (m, 4 H, H-1, H-2, H-3 and H-3′′′), 7.32 (dd, J = 8.1, 1.7 Hz, 1 H, H-6′′′), 7.54 (ddd, J = 8.7, 7.3, 1.7 Hz, 1 H, H-4′′′), 8.07 (s, 1 H, H-9), 10.28 (s, 1 H, 4-OH), 11.68 (s, 1 H, 2′′′-OH), 13.33 (s, 1 H, 7-OH). ¹³C NMR [75.47 MHz, DMSO-d ₆–CDCl₃ (1:2)]: δ = 31.3 (C-2′), 107.7 (C-6a), 116.7 (C-10b), 116.9 (C-1), 117.9 (C-3′′′), 118.3 (C-3), 119.2 (C-5′′′), 119.6 (C-1′′′), 123.3 (C-8), 124.5 (C-2), 126.1 (C-10), 132.5 (C-6′′′), 137.0 (C-4′′′), 137.6 (C-9), 139.5 (C-10a), 145.64 (C-4 and C-4a), 162.0 (C-2′′′), 162.9 (C-7), 164.5 (C-6), 195.5 (C-1′), 201.1 (C-1′′). HRMS (ESI⁺): m/z calcd for [C₂₂H₁₄O₇ + Na]⁺: 413.0637; found: 413.0617.
• 15 8-Acetyl-2,7-dihydroxy-10-(2-hydroxybenzoyl)-6H-benzo[c]chromen-6-one (3d) White-yellowish powder; yield: 0.474 g (23%); mp 134–135 °C. ¹H NMR [300.13 MHz, DMSO-d ₆–CDCl₃ (1:2)]: δ = 2.72 (s, 3 H, H-2′), 6.84 (t, J = 7.8 Hz, 1 H, H-5′′′), 7.02 (dd, J = 8.9, 2.7 Hz, 1 H, H-3), 7.06–7.10 (m, 2 H, H-1 and H-3′′′), 7.30 (d, J = 8.9 Hz, 1 H, H-4), 7.36 (d, J = 7.8 Hz, 1 H, H-6′′′), 7.53–7.61 (m, 1 H, H-4′′′), 8.04 (s, 1 H, H-9), 9.78 (s, 1 H, 2-OH), 11.70 (s, 1 H, 2′′′-OH), 13.33 (s, 1 H, 7-OH). ¹³C NMR [75.47 MHz, DMSO-d ₆–CDCl₃ (1:2)]: δ = 31.3 (C-2′), 107.7 (C-6a), 112.0 (C-1), 116.3 (C-10b), 117.9 (C-3′′′), 118.3 (C-4), 119.1 (C-5′′′), 120.0 (C-1′′′), 120.3 (C-3), 123.3 (C-8), 126.2 (C-10), 132.6 (C-6′′′), 136.9 and 137.0 (C-4′′′ and C-9), 137.1 (C-10a), 143.6 (C-4a), 154.1 (C-2), 162.1 (C-2′′′), 162.9 (C-7), 165.0 (C-6), 195.4 (C-1′), 200.6 (C-1′′). HRMS (ESI⁺): m/z calcd for [C₂₂H₁₄O₇ + Na]⁺: 413.0637; found: 413.0627.