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.

Coumarins (2H-benzopyran-2-ones) are an interesting class of oxygen-containing heterocycles and they are recognized as an outstanding category of polyphenolic compounds with valuable biological activities. They are a common and important family of natural products and, to date, more than one thousand coumarin derivatives have been described, most of which were isolated from over 800 plant species.[1] Coumarin derivatives exhibit useful pharmaceutical properties,[2] including antioxidant,[3] antiinflammatory,[4] anticancer,[5] and molluscicidal activities.[6] There is particular interest in the benzo[c]coumarin scaffold, because several of its hydroxylated derivatives and analogues have shown considerable medicinal benefits, the most interesting of which are a significant lipid-lowering potential and antioxidant activities.[7a] Other benzo[c]coumarin structures have been described as potent and selective antagonists of estrogen receptor subtype β.[7b]

Because of the natural occurrence and range of biological activities associated with coumarin scaffolds, various methods have been developed for their synthesis, of which the Pechmann reaction is among the most widely used.[8] Benzo[c]coumarins, however, constitute a sub-class that have received less attention as synthetic targets. Several challenges remain in synthesizing these compounds in optimal yields and by short reactions sequences, particularly those derivatives bearing free hydroxy and other functional groups that are most likely to have biological effects.[7b] [c] [d] A good example of such a synthesis is the total synthesis of the fungal product graphislactone G (a natural benzo[c]coumarin) in a global yield of 22% from 5-methylbenzene-1,3-diol (orcinol) and 2,4,6-trihydroxybenzoic acid (phloroglucinic acid) in 13 steps, most of which involve protection–deprotection procedures.[7c] Lubbe and co-workers[7d] synthesized 7-hydroxy-2-(2-hydroxybenzoyl)-6H-benzo[c]chromen-6-ones by sequential domino reactions of 1,3-bis(silylenol) ethers with benzopyrylium triflates. Recently, a conjugate addition approach with electron-deficient C-2 chromones has been applied in the preparation of a wide range of oxygen-containing heterocyclic systems, such as functionalized 2-hydroxybenzophenones, 6H-benzo[c]chromenes, and benzo[c]coumarins. Despite its reliability, this method is strongly dependent on the nature of the substituents at the 3-position of the chromone starting material (the Michael acceptor), and is not free from the need for additional protecting steps.[8b]

Our group has long been involved in studying the synthesis of coumarins as well as their reactivities and related photophysical properties.[9] A particular focus has been on the synthesis of 3-(acetoacetyl)coumarins, which are obtained from substituted salicylaldehydes and 4-hydroxy-6-methyl-2H-pyran-2-one (triacetic acid lactone) through a tandem microwave-assisted Knoevenagel condensation and intramolecular translactonization process in an organobasic medium (Scheme [1]).[10]

The resulting 3-acetoacetylcoumarins 1a–e are strategic starting materials, as they contain a coumarin nucleus as well as the active methylene group of the acetoacetyl moiety, which is poised to undergo further useful chemical transformations. In a continuation of our studies on the establishment of new synthetic routes to biologically active coumarins, we developed an efficient one-pot synthesis of hydroxylated polyfunctionalized benzo[c]coumarins 3a–d.

The first part of our synthetic strategy involved covalently connecting a chromone (benzopyran-4-one) ring with a coumarin (benzopyran-2-one) to form a bridged dyad. For this purpose, we selected electron-deficient 4-oxo-4H-chromene-3-carboxylic acid (2) because of its strong Michael-acceptor character, and we examined its reaction with the 1,3-dicarbonyl branch of 3-acetoacetylcoumarins 1a–e in refluxing chloroform containing a catalytic amount of 4-pyrrolidin-1-ylpyridine (4-PPy); the reaction was performed without protecting the free hydroxy groups of coumarins 1b–d. Monitoring by thin-layer chromatography indicated incomplete consumption of the starting reagents (1a–e and 2) after 24 hours of reaction. The reactions were therefore worked up after the formation of substantial amounts of product had been observed in all cases except that of derivative 1e, which contains a 5,6-benzo[f] group. The products were isolated by column chromatography. We expected the reaction to give the corresponding Michael adducts, but ¹H NMR spectroscopic analysis of the products indicated that, instead, the hydroxylated polyfunctionalized benzo[c]coumarins 3a–d had been formed in moderate to good yields (23–70%) by a tandem pathway involving 1,4-conjugate addition, decarboxylation and aromatization (Scheme [2]).[11] [12] [13] [14] [15]

This unexpected tandem pathway presumably involves an initial organobase-catalyzed 1,4-conjugate addition of the nucleophilic 1,3-dicarbonyl reagent 1 to the electron-deficient carboxylic acid 2 to give the intermediate A after cleavage of the chromone ring and decarboxylation. Intermediate A then undergoes a base-promoted intramolecular 1,6-cyclization to give intermediate B. The final step of the tandem process is oxidative aromatization of B to give the corresponding benzo[c]coumarin 3, functionalized with both acetyl and 2-hydroxybenzoyl groups (Scheme [3]).

Attempts to apply the same strategy with the unsubstituted chromone as a Michael acceptor for the acid 2 were unsuccessful, demonstrating the importance of the 3-carboxy functionality. This carboxylic group therefore promotes the conjugate addition, but can subsequently be readily eliminated by decarboxylation under mild conditions.

The structures of benzo[c]coumarins 3a–d was established by means of extensive 2-dimensional NMR analyses (HSQC, HMBC, and NOESY; see the Supporting Information). The connectivities found in the HMBC spectra allowed us to assign the quaternary carbon resonances and to confirm the assignments of some of the proton-bearing carbons (Figure [1]). Moreover, the NOESY experiment led us to conclude that there is free rotation of the 2-hydroxybenzoyl substituents, as evidenced by the NOE effects between the signals for the H-6′′′ and H-5′′′ atoms and those of the H-1 and H-9 atoms of the benzo[c]coumarin (Figure [1]). This free rotation would not be possible if bulky substituents were present at positions C-1 and/or C-9 of the benzo[c]coumarin skeleton, which goes some way toward explaining why derivative 3e, possessing a fused 1,2-benzo[f] group (Scheme [2]), was not formed, and indicates a limitation of this new methodology.

In conclusion, we have established a new and convenient route to hydroxylated polyfunctionalized benzo[c]coumarins in acceptable yields by a one-pot reaction of electron-deficient 4-oxo-4H-chromene-3-carboxylic acid with ­unprotected monohydroxy-3-(acetoacetyl)coumarins, avoiding the need to protect free hydroxy groups in the starting materials. We have therefore replaced the multistep reaction methods reported in the literature by a two-step process that proceeds under mild conditions in the presence of an organobase catalyst.

Acknowledgment

Thanks are due to the University of Aveiro,the Fundação para a Ciência e a Tecnologia (FCT, Portugal), the European Union, QREN, FEDER, and COMPETE for funding the Organic Chemistry Research Unit (QOPNA) (project PEst-C/QUI/ UI0062/2013), and the Portuguese National NMR Network (RNRMN). We also acknowledge the receipt of financial support from European Community’s Seventh Framework Programme (FP7/2007-20139; grant agreement No. 215009).

• References

• 1 Murray DH, Méndez J, Brown SA. The Natural Coumarins: Occurrence, Chemistry and Biochemistry . Wiley; Chichester: 1982
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• 2a Kitagawa H, Iwaki R. J. Pharm. Soc. Jpn. 1963; 83: 1124
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• 2b O’Kennedy R, Thornes RD. Coumarins: Biology, Applications and Mode of Action . Wiley; Chichester: 1997
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• 3a Kostova I. Mini-Rev. Med. Chem. 2006; 6: 365
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• 3b Lin HC, Tsai SH, Chen CS, Chang YC, Lee CM, Lai ZY, Lin CM. Biochem. Pharmacol. 2008; 75: 1416
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• 3c Yuce B, Danis O, Ogan A, Sener G, Bulut M, Yarat A. Arzneim. Forsch. 2009; 59: 129
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• 4 Kontogiorgis C, Hadjipavlou-Litina D. J. Med. Chem. 2005; 48: 6400
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• 5a Harvey RG, Cortez C, Ananthanarayan TP, Schmolka SJ. J. Org. Chem. 1988; 53: 3936
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• 5b Wang C.-J, Hsieh Y.-J, Chu C.-Y, Lin Y.-L, Tseng T.-H. Cancer Lett. 2002; 183: 163
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• 5c Musa MA, Cooperwood JS, Khan MO. Curr. Med. Chem. 2008; 15: 2664
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• 6 Schönberg A, Latif N. J. Am. Chem. Soc. 1954; 76: 6208
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• 7a Sashidhara K, Rosaiah JN, Kumar A, Bhatia G, Khanna AK. Bioorg. Med. Chem. Lett. 2010; 20: 3065
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• 7b Sun W, Cama LD, Birzin ET, Warrier S, Locco L, Mosley R, Hammond ML, Rohrer SP. Bioorg. Med. Chem. Lett. 2006; 16: 1468
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• 7c Cudaj J, Podlech J. Tetrahedron Lett. 2010; 51: 3092
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• 7d Lubbe M, Appel B, Flemming A, Fischer C, Langer P. Tetrahedron 2006; 62: 11755
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• 8a Rodríguez-Domínguez JC, Kirsch G. Synthesis 2006; 1895
  Thieme Connect
• 8b Rajitha B, Kumar VN, Someshwar P, Madhav JV, Reddy PN, Reddy YT. ARKIVOK 2006; (xii): 23
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• 8c Karami B, Kiani M. Catal. Commun. 2011; 14: 62
  CrossrefSearch in Google Scholar
• 8d Daru J, Stirling A. J. Org. Chem. 2011; 76: 8749
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• 8e Iaroshenko VO, Savych I, Villinger A, Sosnovskikh VY, Langer P. Org. Biomol. Chem. 2012; 10: 9344
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• 9a Boutemeur-Kheddis B, Hamdi M, Sellier N, Silva AM. S. J. Heterocycl. Chem. 2000; 38: 227
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• 9b Hamdi M, Cottet S, Tedeschi C, Spéziale V. J. Heterocycl. Chem. 1997; 34: 1821
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• 9c Elligsen G, Vercruysse K, Spéziale V, Hamdi M, Fery-Forgues S. Acta Chem. Scand. 1997; 51: 521
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• 9d Boutemeur-Kheddis B, Bendaas A, Hamdi M, Sakellariou R, Spéziale V. Org. Prep. Proced. Int. 1994; 26: 360
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• 9e Hamdi M, Spéziale V, Jaud J. Z. Kristallogr. 1994; 209: 495
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• 9f Makhloufi-Chebli M, Hamdi SM, Hamdi M, Rabahi A, Silva AM. S. J. Mol. Liq. 2013; 181: 89
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• 10 Makhloufi-Chebli M, Hamdi M, Silva AM. S, Balegroune F. J. Soc. Alger. Chim. 2008; 18: 91
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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.

• References

• 1 Murray DH, Méndez J, Brown SA. The Natural Coumarins: Occurrence, Chemistry and Biochemistry . Wiley; Chichester: 1982
  Search in Google Scholar
• 2a Kitagawa H, Iwaki R. J. Pharm. Soc. Jpn. 1963; 83: 1124
  Search in Google Scholar
• 2b O’Kennedy R, Thornes RD. Coumarins: Biology, Applications and Mode of Action . Wiley; Chichester: 1997
  Search in Google Scholar
• 3a Kostova I. Mini-Rev. Med. Chem. 2006; 6: 365
  CrossrefPubMedSearch in Google Scholar
• 3b Lin HC, Tsai SH, Chen CS, Chang YC, Lee CM, Lai ZY, Lin CM. Biochem. Pharmacol. 2008; 75: 1416
  CrossrefSearch in Google Scholar
• 3c Yuce B, Danis O, Ogan A, Sener G, Bulut M, Yarat A. Arzneim. Forsch. 2009; 59: 129
  Search in Google Scholar
• 4 Kontogiorgis C, Hadjipavlou-Litina D. J. Med. Chem. 2005; 48: 6400
  CrossrefSearch in Google Scholar
• 5a Harvey RG, Cortez C, Ananthanarayan TP, Schmolka SJ. J. Org. Chem. 1988; 53: 3936
  CrossrefSearch in Google Scholar
• 5b Wang C.-J, Hsieh Y.-J, Chu C.-Y, Lin Y.-L, Tseng T.-H. Cancer Lett. 2002; 183: 163
  CrossrefSearch in Google Scholar
• 5c Musa MA, Cooperwood JS, Khan MO. Curr. Med. Chem. 2008; 15: 2664
  CrossrefSearch in Google Scholar
• 6 Schönberg A, Latif N. J. Am. Chem. Soc. 1954; 76: 6208
  Search in Google Scholar
• 7a Sashidhara K, Rosaiah JN, Kumar A, Bhatia G, Khanna AK. Bioorg. Med. Chem. Lett. 2010; 20: 3065
  CrossrefSearch in Google Scholar
• 7b Sun W, Cama LD, Birzin ET, Warrier S, Locco L, Mosley R, Hammond ML, Rohrer SP. Bioorg. Med. Chem. Lett. 2006; 16: 1468
  CrossrefSearch in Google Scholar
• 7c Cudaj J, Podlech J. Tetrahedron Lett. 2010; 51: 3092
  CrossrefSearch in Google Scholar
• 7d Lubbe M, Appel B, Flemming A, Fischer C, Langer P. Tetrahedron 2006; 62: 11755
  CrossrefSearch in Google Scholar
• 8a Rodríguez-Domínguez JC, Kirsch G. Synthesis 2006; 1895
  Thieme Connect
• 8b Rajitha B, Kumar VN, Someshwar P, Madhav JV, Reddy PN, Reddy YT. ARKIVOK 2006; (xii): 23
  Search in Google Scholar
• 8c Karami B, Kiani M. Catal. Commun. 2011; 14: 62
  CrossrefSearch in Google Scholar
• 8d Daru J, Stirling A. J. Org. Chem. 2011; 76: 8749
  CrossrefSearch in Google Scholar
• 8e Iaroshenko VO, Savych I, Villinger A, Sosnovskikh VY, Langer P. Org. Biomol. Chem. 2012; 10: 9344
  CrossrefSearch in Google Scholar
• 9a Boutemeur-Kheddis B, Hamdi M, Sellier N, Silva AM. S. J. Heterocycl. Chem. 2000; 38: 227
  Search in Google Scholar
• 9b Hamdi M, Cottet S, Tedeschi C, Spéziale V. J. Heterocycl. Chem. 1997; 34: 1821
  CrossrefSearch in Google Scholar
• 9c Elligsen G, Vercruysse K, Spéziale V, Hamdi M, Fery-Forgues S. Acta Chem. Scand. 1997; 51: 521
  CrossrefSearch in Google Scholar
• 9d Boutemeur-Kheddis B, Bendaas A, Hamdi M, Sakellariou R, Spéziale V. Org. Prep. Proced. Int. 1994; 26: 360
  CrossrefSearch in Google Scholar
• 9e Hamdi M, Spéziale V, Jaud J. Z. Kristallogr. 1994; 209: 495
  CrossrefSearch in Google Scholar
• 9f Makhloufi-Chebli M, Hamdi SM, Hamdi M, Rabahi A, Silva AM. S. J. Mol. Liq. 2013; 181: 89
  CrossrefSearch in Google Scholar
• 10 Makhloufi-Chebli M, Hamdi M, Silva AM. S, Balegroune F. J. Soc. Alger. Chim. 2008; 18: 91
  Search in Google Scholar
• 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.

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