Abstract
Dihydropyrano[3,2-b]chromenedione derivatives were synthesized in moderate-to-high yields in one-pot three-component reaction from the corresponding aromatic aldehydes, kojic acid, and dimedone, in the presence of catalytic amount of /SiO2 as a nontoxic, reusable, inexpensive, and easily available reagent, under solvent-free conditions.
1. Introduction
Molecules containing a kojic acid core have been shown to have a broad range of important biological activities including antifungal [1, 2], antineoplastic [3], antiproliferative [4], anti-HIV [5], anticonvulsant [6], anti-inflammatory [7], antioxidative [8], antibacterial [9], and tyrosinase inhibitory activities [10]. Consequently, the synthesis of this heterocycle has attracted considerable attention and a wide variety of methods have been used for its assembly. Recently InCl3 has been used for the synthesis of dihydropyrano[3,2-b]chromenediones [11]. However, the methods are associated with one or more disadvantages such as use of expensive, toxic, and nonrecyclable catalyst and harsh reaction conditions. Thus, there is still need of a simple and general procedure for one-pot synthesis of dihydropyrano[3,2-b]chromenedione under mild conditions.
The development of promoted organic reactions using air-stable and water-tolerant lanthanide salts as Lewis acid catalyst is one of the important and challenging subjects in synthesis organic chemistry. In the past few years, Cerium(III) chloride heptahydrate adsorbed on silica gel (CeCl3·7H2O/SiO2) has emerged as a potential catalyst in affecting various organic transformations due to its high catalytic ability, water tolerance, economic viability, and reusability [12, 13]. Herein we report an efficient, green, and simple method for the synthesis of dihydropyrano[3,2-b]chromenediones via the condensation of aromatic aldehydes, kojic acid, and dimedone, in the presence of catalytic amount of CeCl3·7H2O/SiO2 at 110°C under solvent-free conditions (Scheme 1).
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2. Experimental
1H NMR and 13C NMR spectra were determined on Bruker AV-400 spectrometer (100 MHz for 13C NMR) at room temperature using tetramethylsilane (TMS) as an internal standard (CDCl3 solution); coupling constants were measured in Hz; IR spectra were determined on FTS-40 infrared spectrometer; elemental analyses were performed by a Vario-III elemental analyzer; mass spectra were taken on a macromass spectrometer (Waters) by electrospray method (ES); melting points were determined on a XT-4 binocular microscope and were uncorrected; CeCl3·7H2O/SiO2 was prepared according to the literature [12]; commercially available reagents were used throughout without further purification unless otherwise stated.
General Procedure for the Preparation of 4. A mixture of kojic acid (1 mmol), aldehyde (1 mmol), dimedone (1 mmol), and CeCl3·7H2O/SiO2 (0.05 mmol) was heated at 110°C for an appropriate time (TLC). After completion, ethyl acetate (2 × 20 mL) was added, and the solid catalyst was removed by filtration. The solvent was evaporated and the crude product was puried by silica gel column chromatography using ethyl acetate-hexane (7 : 3) as eluents.
2-(Hydroxymethyl)-7,7-dimethyl-10-phenyl-7,8-dihydropyrano[3,2-b]chromene-4,9(6H,10H)-dione (4a). 1H NMR (CDCl3, 400 MHz) δ: 7.32–7.21 (m, 5H), 6.50 (s, 1H), 4.87 (s, 1H), 4.43–4.32 (m, 2H), 2.71–2.59 (m, 2H), 2.29–2.19 (m, 2H), 1.11 (s, 3H), 1.04 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.2, 171.3, 167.3, 163.9, 151.7, 140.5, 137.5, 128.8, 128.1, 127.8, 112.3, 112.2, 60.6, 50.4, 40.9, 38.4, 32.3, 29.0, 27.4; IR (KBr)ν: 3362, 3080, 2952, 2890, 1667, 1637, 1441, 1378, 1219, 1193, 1078, 990, 950, 712; MS (ESI): m/z 353 [M+H]+; Anal. calcd for C21H20O5: C 71.58, H 5.72; found: C 71.65, H 5.68.
2-(Hydroxymethyl)-7,7-dimethyl-10-(4-chlorophenyl)-7,8-dihydropyrano[3,2-b]chromene-4,9(6H,10H)-dione (4b). 1H NMR (CDCl3, 400 MHz) δ: 7.28–7.18 (m, 4H), 6.52 (s, 1H), 4.87 (s, 1H), 4.41–4.37 (m, 2H), 2.66–2.60 (m, 2H), 2.30–2.21 (m, 2H), 1.11 (s, 3H), 1.03 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.3, 171.4, 168.3, 164.1, 151.2, 138.9, 137.5, 133.6, 129.4, 129.0, 112.0, 111.9, 60.4, 50.3, 40.8, 37.8, 32.3, 28.9, 27.4; IR (KBr)ν: 3325, 2961, 2930, 2870, 1672, 1640, 1600, 1490, 1442, 1377, 1218, 1190, 1076, 1014, 952, 850; MS (ESI): m/z 387 [M+H]+; Anal. calcd for C21H19ClO5: C 65.20, H 4.95; found: C 65.12, H 4.88.
2-(Hydroxymethyl)-7,7-dimethyl-10-(4-florophenyl)-7,8-dihydropyrano[3,2-b]chromene-4,9(6H,10H)-dione (4c). 1H NMR (CDCl3, 400 MHz) δ: 7.24–7.20 (m, 2H), 6.99–6.95(m, 2H), 6.52 (s, 1H), 4.87 (s, 1H), 4.40–4.36 (m, 2H), 2.65–2.61 (m, 2H), 2.25–2.22 (m, 2H), 1.10 (s, 3H), 1.03 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.4, 171.5, 168.3, 164.0, 160.9, 151.5, 137.4, 136.2, 129.7, 129.6, 115.8, 115.6, 112.2, 112.0, 60.4, 50.3, 40.8, 37.7, 32.3, 28.9, 27.4; IR (KBr)ν: 3363, 2953, 2930, 2853, 1 675, 1638, 1601, 1509, 1443, 1378, 1219, 1192, 1157, 1075, 962, 845, 683; MS (ESI): m/z 371 [M+H]+; Anal. calcd for C21H19FO5: C 68.10, H 5.17; found: C 68.20, H5.12.
2-(Hydroxymethyl)-7,7-dimethyl-10-(4-nitrophenyl)-7,8-dihydropyrano[3,2-b]chromene-4,9(6H,10H)-dione (4d). 1H NMR (CDCl3, 400 MHz) δ: 8.18 (d, 2H, J = 8.8 Hz), 7.47 (d, 2H, J = 8.4 Hz), 6.53 (s, 1H), 5.03 (s, 1H), 4.42–4.37 (m, 2H), 2.69–2.65 (m, 2H), 2.27–2.23 (m, 2H), 1.13 (s, 3H), 1.04 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.0, 170.8, 167.0, 164.4, 150.0, 147.4, 137.9, 129.1, 124.1, 112.6, 111.5, 60.6, 50.3, 40.9, 38.4, 32.3, 28.9, 27.5; IR (KBr) ν: 3334, 2960, 2928, 2855, 1675, 1633, 1596, 1520, 1375, 1347, 1216, 1123, 1058, 1003, 946, 867, 622; MS (ESI): m/z 398 [M+H]+; Anal. calcd for C21H19NO7: C 63.47, H 482, N 3.52; found: C 63.35, H 4.850, N 3.57.
2-(Hydroxymethyl)-7,7-dimethyl-10-(3-nitrophenyl)-7,8-dihydropyrano[3,2-b]chromene-4,9(6H,10H)-dione (4e). 1H NMR (CDCl3, 400 MHz) δ: 8.11–8.09 (m, 2H), 7.63 (d, 1H, J = 8.0 Hz), 7.50 (t, 1H, J = 8.0 Hz), 6.53 (s, 1H), 5.03 (s, 1H), 4.45–4.33 (m, 2H), 274–2.61 (m, 2H), 2.30–2.20 (m, 2H), 1.12 (s, 3H), 1.05 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.3, 171.3, 168.2, 164.7, 150.2, 148.4, 142.4, 137.7, 134.3, 129.8, 123.4, 122.9, 112.2, 111.3, 60.4, 50.3, 40.8, 38.3, 32.3, 28.9, 27.5; IR (KBr) ν: 3393, 2955, 2922, 2851, 1669, 1637, 1599, 1530, 1448, 1377, 1350, 1213, 1143, 1080, 678; MS (ESI): m/z 398 [M+H]+; Anal. calcd for C21H19NO7: C 63.47, H 482, N 3.52; found: C 63.39, H 4.80, N 3.55.
2-(Hydroxymethyl)-7,7-dimethyl-10-(2-chlorophenyl)-7,8-dihydropyrano[3,2-b]chromene-4,9(6H,10H)-dione (4f). 1H NMR (CDCl3, 400 MHz) δ: 7.36 (dd, 1H, J = 0.8, 8.0 Hz), 7.20–7.16 (m, 3H), 6.49 (s, 1H), 5.44 (s, 1H), 4.40–4.34 (m, 2H), 2.67–2.64 (m, 2H), 2.26–2.22 (m, 2H), 1.12 (s, 3H), 1.08 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.1, 171.3, 168.0, 164.7, 150.9, 137.8, 137.5, 133.7, 130.1, 129.0, 127.3, 112.0, 111.5, 60.4, 50.3, 40.8, 35.7, 32.2, 29.0, 27.5; IR (KBr) ν: 3291, 2956, 2931, 2860, 1673, 1634, 1600, 1468, 1445, 1378, 1221, 1116, 1080, 758; MS (ESI): m/z 387 [M+H]+; Anal. calcd for C21H19ClO5: C 65.20, H 4.95; found: C 65.30, H 4.82.
2-(Hydroxymethyl)-7,7-dimethyl-10-(2,4-dichlorophenyl)-7,8-dihydropyrano[3,2-b]chromene-4,9(6H,10H)-dione (4g). 1H NMR (CDCl3, 400 MHz) δ: 7.39 (s, 1H), 7.21–7.18 (m, 1H), 7.14–7.12 (m, 1H), 6.50 (s, 1H), 5.39 (s, 1H), 4.41–4.37 (m, 2H), 2.71–2.65 (m, 2H), 2.26–2.22 (m, 2H), 1.13 (s, 3H), 1.08 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.0, 171.1, 167.6, 164.8, 150.3, 137.7, 134.4, 134.2, 130.9, 129.9, 127.7, 112.2, 111.2, 60.5, 50.3, 40.8, 37.5, 32.2, 28.9, 27.6; IR (KBr) ν: 3296, 2952, 2863, 1676, 1637, 1600, 1445, 1376, 1221, 1101, 1079, 854; MS (ESI): m/z 422 [M+H]+; Anal. calcd for C21H18Cl2O5: C 59.87, H 4.31; found: C 59.90, H 4.28.
2-(Hydroxymethyl)-7,7-dimethyl-10-(3,4,5-trimethoxyphenyl)-7,8-dihydropyrano[3,2-b]chromene-4,9(6H,10H)-dione (4h). 1H NMR (CDCl3, 400 MHz) δ: 6.50–6.44 (m, 3H), 4.81 (s, 1H), 4.45–4.37 (m, 2H), 3.80 (s, 6H), 3.79 (s, 3H), 2.68–2.63 (m, 2H), 2.28–2.27 (m, 2H), 1.14 (s, 3H), 1.11 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.3, 171.3, 167.7, 164.0, 153.4, 151.5, 137.3, 136.1, 112.1, 105.0, 60.8, 60.6, 56.1, 50.3, 40.9, 38.5, 32.2, 29.3, 27.1; IR (KBr) ν: 3296, 2960, 2923, 2869, 1673, 1637, 1598, 1508, 1422, 1375, 1329, 1220, 1126, 1076, 956; MS (ESI): m/z 443 [M+H]+; Anal. calcd for C24H26O8: C 65.15, H 5.92; found: C 65.20, H 5.89.
2-(Hydroxymethyl)-7,7-dimethyl-10-(2,6-dimethoxyphenyl)-7,8-dihydropyrano[3,2-b]chromene-4,9(6H,10H)-dione (4i). 1H NMR (CDCl3, 400 MHz) δ:6.77–6.74 (m, 3H), 6.47 (s, 1H), 5.17 (s, 1H), 4.40–4.35 (m, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 2.63–2.61 (m, 2H), 2.24–2.20 (m, 2H), 1.11 (s, 3H), 1.04 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.3, 171.3, 167.3, 164.6, 153.7, 151.7, 151.6, 137.8, 129.4, 116.1, 113.4, 112.7, 112.1, 111.4, 60.6, 56.6, 55.6, 50.4, 40.9, 33.8, 32.2, 29.2, 27.1; IR (KBr) ν: 3284, 2950, 2930, 2854, 1672, 1636, 1594, 1503, 1449, 1379, 1226, 1194, 1148, 1080, 1047, 819, 709; MS (ESI): m/z 413 [M+H]+; Anal. calcd for C23H24O7: C 66.98, H 5.87; found: C 67.05, H 5.80.
2-(Hydroxymethyl)-7,7-dimethyl-10-4-methylphenyl-7,8-dihydropyrano[3,2-b]chromene-4,9(6H,10H)-dione (4j). 1H NMR (CDCl3, 400 MHz) δ: 7.13 (d, 2H, J = 8.0 Hz), 7.08 (d, 2H, J = 8.0 Hz), 6.50 (s, 1H), 4.83 (s, 1H), 4.38–4.34 (m, 2H), 2.64–2.61 (m, 2H), 2.28 (s, 3H), 2.23–2.20 (m, 2H), 1.10 (s, 3H), 1.03 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.4, 171.5, 168.2, 163.9, 152.0, 137.6, 137.5, 137.3, 129.5, 127.9, 112.4, 111.9, 60.4, 50.4, 40.8, 37.9, 32.2, 29.0, 27.4, 21.1; IR (KBr) ν: 3368, 2953, 2931, 2847, 1668, 1636, 1442, 1376, 1219, 1189, 1120, 1076, 950, 862, 624; MS (ESI): m/z 367 [M+H]+; Anal. calcd for C22H22O5: C 72.12, H 6.05; found: C 72.20, H 6.00.
2-(Hydroxymethyl)-7,7-dimethyl-10-4-methoxyphenyl-7,8-dihydropyrano[3,2-b]chromene-4,9(6H,10H)-dione (4k). 1H NMR (CDCl3, 400 MHz) δ: 7.18–7.16 (m, 2H), 6.83–6.80 (m, 2H), 6.50 (s, 1H), 4.83 (s, 1H), 4.40–4.35 (m, 2H), 3.75 (s, 3H), 2.65–2.61 (m, 2H), 2.23–2.22 (m, 2H), 1.10 (s, 3H), 1.04 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.4, 171.5, 168.0, 16.7, 159.0, 152.0, 137.3, 132.7, 129.1, 114.2, 112.5, 129.1, 60.5, 55.2, 50.4, 40.8, 37.5, 32.2, 29.0, 27.4; IR (KBr) ν: 3355, 2958, 2922, 2836, 1672, 1637, 1511, 1443, 1377, 1219, 1193, 1120, 1029, 950, 860; MS (ESI): m/z 383 [M+H]+; Anal. calcd for C22H22O6: C 69.10, H 5.80; found: C 69.20, H5.72.
3. Results and Discussion
First, to achieve suitable conditions for the synthesis of dihydropyrano[3,2-b]chromenediones, we tested the reaction of kojic acid, benzaldehyde, and dimedone as a simple model system with or without the presence of various catalysts (Table 1). As can be seen in Table 1, the best result was obtained with 5 mol% of CeCl3·7H2O/SiO2 as the catalyst at 110°C under solvent-free conditions (entry 12). Using less catalyst resulted in lower yields, whereas higher amounts of catalyst did not affect reaction times and yields (significantly) (Table 1). When this reaction was carried out without CeCl3·7H2O/SiO2 or with other catalysts such as p-TsOH, HOAc, I2, and H2SO4, the yield of the expected product was low (Table 1). In the presence of CeCl3 or ZnCl2 as catalyst, the product was obtained in moderate yields.
Encouraged by this success, a variety of aromatic aldehydes were employed under similar conditions to evaluate the substrate scope of this reaction. When a mixture of aromatic aldehydes, kojic acid, and dimedone, and a catalytic amount of CeCl3·7H2O/SiO2 was stirred at 110°C under solvent-free conditions, the corresponding dihydropyrano[3,2-b]chromenediones were obtained in excellent yield (Table 2). The reactions were completed smoothly within 40 to 60 min, and the product was isolated by filtration and washing the solid residues with ethyl acetate, the remaining catalyst being reused for the fresh reactions. There is little decrease in the better yield of products even though the reaction has also been observed in its absence. When this reaction was carried out with aliphatic aldehyde such as butanal or pentanal, TLC and 1H NMR spectra of the reaction mixture showed a combination of starting materials and numerous products; the yield of the expected product was very poor.
4. Conclusion
In summary, we have described a successful strategy, efficient and convenient green synthesis for the preparation of dihydropyrano[3,2-b]chromenediones in valuing cyclocondensation reaction of aromatic aldehydes, kojic acid, and dimedone using the inexpensive, nontoxic, and easily available CeCl3·7H2O/SiO2 catalyst. The method offers several advantages including high yield of products, recyclable of the catalyst and easy experimental work-up procedure, which makes it a useful process for the synthesis of dihydropyrano[3,2-b]chromenediones.
Acknowledgment
The authors are pleased to acknowledge the financial support from Xinxiang Medical University.