Abstract
A concise and efficient one-pot synthesis of 3-functionalized 4-hydroxycoumarin derivatives via a three-component domino reaction of 4-hydroxycoumarin, phenylglyoxal and 3-arylaminocyclopent-2-enone or 4-arylaminofuran-2(5H)-one under catalyst-free and microwave irradiation conditions is described. This synthesis involves a group-assisted purification process, which avoids traditional recrystallization and chromatographic purification methods.
Keywords: 3-functionalized 4-hydroxycoumarin, multi-component domino reaction, catalyst-free, group-assisted purification process
1. Introduction
Heterocyclic compounds are important because of their presence in a broad range of natural products and synthetic organic molecules with various biological activities [1,2]. Coumarin scaffolds are commonly found in diverse natural products, biologically active compounds and pharmaceuticals [3,4]. Among the various coumarin derivatives, substituted 4-hydroxycoumarin derivatives are of much importance because they exist in many natural products and exhibit a wide range of biological activities such as anti-HIV [5], anticancer [6], anti-coagulant [7] and antioxidant [8] activities. Warfarin I and coumatetralyl II are used for pesticides, specifically as a rodenticide and anticoagulant [9]. (Figure 1)
Figure 1.
Biologically active coumarin derivatives.
The development of a simple and eco-friendly protocol for the construction of heterocycles libraries of medical motifs is an attractive area of research in both academia and the pharmaceutical industry. Multicomponent reactions (MCRs) are promising and powerful tools in organic, combinatorial, and medicinal chemistry, because of their atom economy, complexity and diversity of products, multiple bond formation efficiency, and environmental friendliness [10]. These features make MCRs suitable for the easy construction of complex heterocyclic scaffolds from readily available starting materials [11]. In the past decade, some MCRs have been used for the construction of 4-hydroxycoumarin derivatives [12,13,14,15,16].
Microwave irradiation has been increasingly used in organic synthesis in recent years. Compared with traditional methods, this method has the advantages of higher yields, shorter reaction time, mild reaction conditions and environmentally friendliness. To date, a large number of organic reactions can be carried out under microwave irradiation conditions [17,18,19,20].
The development of environmentally friendly synthetic methods is a challenge in modern organic synthesis. The need to reduce the amount of toxic waste and byproducts arising from chemical processes has resulted in an increasing emphasis on the use of less-toxic and environmentally compatible materials in the design of new synthetic methods. Traditional purification methods such as recrystallization and column chromatography have problems in terms of consumption of organic solvents and energy, waste generation, and pollution. The concept of group-assisted purification (GAP) techniques, which avoid traditional crystallization and chromatographic purification methods and reduce waste generation from silica and solvents, particularly toxic solvents, was first developed by Li’s group in the design of asymmetric synthesis of new imine reagents [21,22]. To date, GAP chemistry has been used in many asymmetric reactions [23,24,25] and MCRs [26,27,28]. As part of our current studies on the development of environmentally friendly routes to heterocyclic compounds [29,30,31,32], we now report an efficient and clean synthesis of 3-functionalized 4-hydroxycoumarin derivatives under catalyst-free conditions.
2. Results and Discussion
We initially evaluated the three-component reaction of a 1:1:1 mixture of 4-hydroxycoumarin (1), phenylglyoxal monohydrate (2a) and 3-(p-tolylamino)cyclopent-2-enone (3a) for the optimization of the reaction conditions. The results are summarized in Table 1. The desired product 4a was obtained in 89% yield when the reaction was carried out in ethanol at 100 °C for 30 min. under catalyst-free and microwave irradiation conditions (Table 1, entry 1). Various solvents were then evaluated to determine the impact of the solvent on the yield. Of all the solvents tested, i.e., anhydrous ethanol, water, DMF, acetonitrile, and a mixture of anhydrous ethanol-water (1:1 and 3:1, v/v), ethanol gave the best result (Table 1, entries 1–6). To improve the yield, several catalysts were evaluated: sodium hydrate, diethyl amine, p-toluenesulfonic acid (p-TSA), benzoic acid and L-proline (Table 1, entries 7–11). The results revealed that none of the catalysts could catalyze this reaction. The reaction was then conducted at different temperatures, such as 80, 90, 100 and 110 °C, to determine the optimum temperature for this transformation. All of these experiments were conducted in ethanol under catalyst-free and microwave irradiation conditions, and the desired product 4a was obtained in yields of 69%, 76%, 89% and 87%, respectively (Table 1, entries 1 and 12–14). Finally, the reaction was performed at different reaction times to determine the optimum reaction time. The results showed that the best reaction time was 30 min (Table 1, entries 1 and 15–17). When the reaction was carried out in ethanol at refluxing temperature for 4 h in the absence of microwave, the desired product was obtained in 60% yield (Table 1, entry 18). These indicate that the microwave irradiation can improve the yield and shorten the reaction times. Accordingly, the best temperature for this transformation was 100 °C. On the basis of all of these experiments, the optimum reaction conditions were identified as ethanol at 100 °C for 30 min. under catalyst-free and microwave irradiation conditions.
Table 1.
Optimization of the reaction conditions.
| Entry | Catalyst (mol %) | Solvent (v/v) | Temperature (°C) | Time (min) | Yield (%) a |
|---|---|---|---|---|---|
| 1 | No | EtOH | 100 | 30 | 89 |
| 2 | No | H2O | 100 | 30 | 36 |
| 3 | No | DMF | 100 | 30 | 70 |
| 4 | No | CH3CN | 100 | 30 | 80 |
| 5 | No | EtOH-H2O (1:1) | 100 | 30 | 54 |
| 6 | No | EtOH:H2O (3:1) | 100 | 30 | 72 |
| 7 | NaOH (20) | EtOH | 100 | 30 | 33 |
| 8 | Et2NH (20) | EtOH | 100 | 30 | 50 |
| 9 | p-TSA (20) | EtOH | 100 | 30 | 80 |
| 10 | Benzoic Acid (20) | EtOH | 100 | 30 | 51 |
| 11 | L-Proline (20) | EtOH | 100 | 30 | 81 |
| 12 | No | EtOH | 80 | 30 | 69 |
| 13 | No | EtOH | 90 | 30 | 76 |
| 14 | No | EtOH | 110 | 30 | 87 |
| 15 | No | EtOH | 100 | 10 | 57 |
| 16 | No | EtOH | 100 | 20 | 65 |
| 17 | No | EtOH | 100 | 40 | 86 |
| 18 | No | EtOH | Reflux (absence of microwave) | 240 | 60 |
a Yield was determined by HPLC-MS.
With optimal conditions in hand, various substituted phenylglyoxal monohydrate (2) and 3-arylaminocyclopent-2-enone (3) were explored to investigate the generality of this three- component reaction for the synthesis of 3-functionalized 4-hydroxycoumarin derivatives (4). The results are tabulated in Table 2. The reaction seemed to be tolerant of substitution of the phenylglyoxal and 3-arylaminocyclopent-2-enone with either electron-withdrawing or electron-donating groups. Overall, yields in the range of 70%–95% were obtained.
Table 2.
Synthesis of 3-functionalized 4-hydroxycoumarin derivatives 4.
| Entry | R1 | R2 | Product | Isolated Yield (%) |
|---|---|---|---|---|
| 1 | H | CH3 | 4a | 86 |
| 2 | CH3 | Br | 4b | 90 |
| 3 | CH3 | Cl | 4c | 79 |
| 4 | CH3O | Br | 4d | 85 |
| 5 | CH3O | CH3 | 4e | 86 |
| 6 | CH3O | CH3O | 4f | 81 |
| 7 | Cl | Br | 4g | 95 |
| 8 | Cl | CH3 | 4h | 72 |
| 9 | Cl | CH3O | 4i | 83 |
| 10 | Br | Br | 4j | 70 |
| 11 | Br | CH3 | 4k | 77 |
To our delight, under optimal conditions, further experiments showed that when the 3-arylaminocyclopent-2-enone (3) was replaced by 4-arylaminofuran-2(5H)-one (5), the corresponding 3-functionalized 4-hydroxycoumarin derivatives (6) were obtained in good yields (Table 3).
Table 3.
Synthesis of 3-functionalized 4-hydroxycoumarin derivatives 6.
| Entry | R1 | R2 | Product | Isolated Yield (%) |
|---|---|---|---|---|
| 1 | H | Br | 6a | 89 |
| 2 | H | CH3O | 6b | 84 |
| 3 | Cl | CH3 | 6c | 92 |
| 4 | Cl | Cl | 6d | 70 |
| 5 | Cl | Br | 6e | 91 |
| 6 | Br | CH3 | 6f | 91 |
| 7 | Br | CH3O | 6g | 77 |
| 8 | CH3O | CH3O | 6h | 91 |
| 9 | CH3O | Cl | 6i | 72 |
It is important that this synthesis followed the GAP chemistry (group-assisted-purification chemistry) process, which can avoid traditional recrystallization or column chromatographic purification methods. Pure products were obtained simple by filtration and washing of the solid with a little cold ethanol.
The structures of compounds 4 and 6 were identified from their 1H NMR, and 13C NMR spectra, and by HRMS analysis. The structure of compound 4a was further confirmed using single-crystal X-ray diffraction analysis (Figure 2).
Figure 2.
Crystal structure of compound 4a.
Although the detailed mechanism of this reaction remains to be fully clarified, the formation of compound 4 could be explained by the reaction sequence in Figure 3. First, a Knoevenagel condensation of 4-hydroxycoumarin 1 with phenylglyoxal 2 is proposed to give intermediate A. Michael addition of enaminone 3 to intermediate A then occurs to provide the intermediate B, which undergoes isomerization to form the desired product 4.
Figure 3.
Proposed mechanism for the synthesis of compound 4.
3. Experimental
3.1. General
All reagents were commercial and used without further purification, unless otherwise indicated. Melting points were measured using an XT-4 micro melting point apparatus from Beijing Tech Instrument Co., Ltd., Beijing, China and were uncorrected. 1H NMR and 13C NMR spectra were recorded on Bruker Avance III HD-400 MHz spectrometer from Billerica, MA, USA in DMSO-d6 solution. J values are in hertz (Hz). Chemical shifts are expressed in δ downfield from internal tetramethylsilane (TMS). High-resolution mass spectra (HRMS) were obtained using Bruker MicrOTOF-Q II instrument from Billerica, MA, USA. X-ray crystal diffraction analysis was performed with a Bruker APEX-II CCD X-ray diffractometer from Billerica, MA, USA. Microwave irradiation was carried out with Initiator 2.5 Microwave Synthesizers from Biotage, Uppsala, Sweden. The reaction temperatures were measured by an infrared detector (external sensor type) during microwave heating.
3.2. General Procedure for the Synthesis of 3-Functionalized 4-Hydroxycoumarin Derivatives 4 and 6
4-Hydroxycoumarin (1) (0.5 mmol), substituted phenylglyoxal monohydrate (2) (0.5 mmol), and 3-arylaminocyclopent-2-enone (3) or 4-arylaminofuran-2(5H)-one (5) (0.5 mmol) were placed in a 10 mL Initiator reaction vial, followed by anhydrous ethanol (2 mL). The reaction vial was then sealed and prestirred for 15 s before being irradiated in the microwave (time, 30 min; temperature, 100 °C; absorption level, high; fixed hold time). The reaction mixture was then cooled to room temperature to give a precipitate, which was collected by Büchner filtration. The solid material was then washed with a little cold ethanol to afford the desired products 4 or 6.
4-Hydroxy-3-(2-oxo-1-(5-oxo-2-(p-tolylamino)cyclopent-1-en-1-yl)-2-phenylethyl)-2H-chromen-2-one (4a). White solid, yield 86%, m.p. 134–135 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H, OH), 7.78–7.71 (m, 3H, NH + ArH), 7.57–7.23 (m, 11H, ArH), 6.10 (s, 1H, CH), 3.03–2.96 (m, 1H, CH2), 2.71–2.64 (m, 1H, CH2), 2.47–2.42 (m, 2H, CH2), 2.32 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6) δ 203.6, 196.4, 176.9, 164.8, 163.6, 152.0, 136.4, 135.5, 132.4, 132.2, 129.8, 128.0, 127.7, 124.0, 123.8, 123.7, 117.6, 115.9, 111.5, 105.0, 40.3, 31.7, 26.7, 20.4. HRMS (ESI) m/z: Calcd. for C29H22NO5 [M − H]+ 464.1498. Found: 464.1515.
3-(1-(2-((4-Bromophenyl)amino)-5-oxocyclopent-1-en-1-yl)-2-oxo-2-(p-tolyl)ethyl)-4-hydroxy-2H-chromen-2-one (4b). Brown solid, yield 90%, m.p. 139–140 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H, OH), 7.76–7.67 (m, 3H, NH + ArH), 7.67–7.17 (m, 10H, ArH), 6.09 (s, 1H, CH), 3.09–3.02 (m, 1H, CH2), 2.76–2.70 (m, 1H, CH2), 2.48–2.38 (m, 2H, CH2), 2.25 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6) δ 204.5, 195.6, 175.8, 164.3, 163.6, 160.3, 151.9, 142.7, 137.8, 133.6, 132.2, 128.7, 127.9, 125.4, 124.1, 123.8, 118.1, 117.5, 116.0, 112.5, 105.3, 99.5, 31.9, 26.7, 21.0. HRMS (ESI) m/z: Calcd. for C29H23BrNO5 [M + H]+ 544.0760. Found: 544.0754.
3-(1-(2-((4-Chlorophenyl)amino)-5-oxocyclopent-1-en-1-yl)-2-oxo-2-(p-tolyl)ethyl)-4-hydroxy-2H-chromen-2-one (4c). Brown solid, yield 79%, m.p. 142–143 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H, OH), 7.77–7.67 (m, 3H, NH + ArH), 7.58–7.17 (m, 10H, ArH), 6.08 (s, 1H, CH), 3.09–3.01 (m, 1H, CH2), 2.75–2.69 (m, 1H, CH2), 2.47–2.41 (m, 2H, CH2), 2.25 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6) δ 204.4, 195.7, 175.9, 164.4, 163.6, 151.9, 142.7, 137.4, 133.6, 132.2, 129.9, 129.3, 128.7, 127.9, 125.1, 124.1, 123.8, 117.5, 116.0, 112.5, 105.3, 99.5, 31.9, 30.6, 26.7, 21.0. HRMS (ESI) m/z: Calcd. for C29H23ClNO5 [M + H]+ 500.1265. Found: 500.1252.
3-(1-(2-((4-Bromophenyl)amino)-5-oxocyclopent-1-en-1-yl)-2-(4-methoxyphenyl)-2-oxoethyl)-4-hydroxy-2H-chromen-2-one (4d). Green solid, yield 85%, m.p. 222–223 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H, OH), 7.77–7.74 (m, 3H, NH + ArH), 7.63–6.91 (m, 10H, ArH), 6.05 (s, 1H, CH), 3.74 (s, 3H, CH3O), 3.08–3.02 (m, 1H, CH2), 2.77–2.70 (m, 1H, CH2), 2.48–2.43 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6) δ 204.5, 194.4, 175.7, 164.3, 163.6, 162.5, 152.0, 137.8, 132.2, 130.1, 128.7, 125.3, 124.1, 123.8, 118.0, 117.5, 116.0, 113.4, 112.7, 105.4, 55.3, 32.0, 26.7. HRMS (ESI) m/z: Calcd. for C29H23BrNO6 [M + H]+ 560.0709. Found: 560.0706.
4-Hydroxy-3-(2-(4-methoxyphenyl)-2-oxo-1-(5-oxo-2-(p-tolylamino)cyclopent-1-en-1-yl)ethyl)-2H-chromen-2-one (4e). Blue solid, yield 86%, m.p. 144–146 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H, OH), 7.78–7.73 (m, 3H, NH + ArH), 7.58–6.90 (m, 10H, ArH), 6.05 (s, 1H, CH), 3.74 (s, 3H, CH3O), 3.01–2.95 (m, 1H, CH2), 2.71–2.64 (m, 1H, CH2), 2.47–2.37 (m, 2H, CH2), 2.41 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6) δ 203.7, 194.5, 176.6, 164.7, 163.6, 162.5, 152.0, 135.7, 135.5, 132.1, 130.1, 129.8, 128.9, 124.0, 123.8, 123.7, 117.8, 115.9, 113.3, 111.8, 105.4, 55.3, 31.8, 26.7, 20.5. HRMS (ESI) m/z: Calcd. for C30H26NO6 [M + H]+ 496.1760. Found: 496.1757.
4-Hydroxy-3-(2-(4-methoxyphenyl)-1-(2-((4-methoxyphenyl)amino)-5-oxocyclopent-1-en-1-yl)-2-oxoethyl)-2H-chromen-2-one (4f). Brown solid, yield 81%, m.p. 138–139 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H, OH), 7.77–7.72 (m, 3H, NH + ArH), 7.58–6.90 (m, 10H, ArH), 6.03 (s, 1H, CH), 3.77 (s, 3H, CH3O) 3.74 (s, 3H, OCH3), 2.94–2.88 (m, 1H, CH2), 2.65–2.58 (m, 1H, CH2), 2.45–2.36 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6) δ 207.4, 194.5, 177.2, 164.9, 163.6, 162.5, 157.5, 152.0, 132.1, 130.9, 130.1, 128.8, 125.7, 124.0, 123.8, 117.9, 115.9, 114.5, 113.3, 111.3, 96.9, 55.3, 31.6, 26.7. HRMS (ESI) m/z: Calcd. for C30H26NO7 [M + H]+ 512.1709. Found 512.1693.
3-(1-(2-((4-Bromophenyl)amino)-5-oxocyclopent-1-en-1-yl)-2-(4-chlorophenyl)-2-oxoethyl)-4-hydroxy-2H-chromen-2-one (4g). White solid, yield 95%, m.p. 140–141 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H, OH), 7.79–7.73 (m, 3H, NH + ArH), 7.64–7.25 (m, 10H, ArH), 6.10 (s, 1H, CH), 3.09–3.02 (m, 1H, CH2), 2.77–2.70 (m, 1H, CH2), 2.48–2.43 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6) δ 204.8, 195.8, 176.5, 165.0, 164.1, 163.0, 152.5, 138.2, 137.8, 135.5, 132.7, 130.0, 128.8, 125.8, 124.3, 118.7, 117.8, 116.5, 113.9, 112.7, 105.3, 55.8, 40.8, 32.4, 27.2. HRMS (ESI) m/z: Calcd. for C28H20BrClNO5 [M + H]+ 564.0213. Found: 564.0203.
3-(2-(4-Chlorophenyl)-2-oxo-1-(5-oxo-2-(p-tolylamino)cyclopent-1-en-1-yl)ethyl)-4-hydroxy-2H-chromen-2-one (4h). Brown solid, yield 72%, m.p. 145–146 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H, OH), 7.79–7.72 (m, 3H, NH + ArH), 7.58–7.24 (m, 10H, ArH), 6.10 (s, 1H, CH), 3.02–2.96 (m, 1H, CH2), 2.71–2.65 (m, 1H, CH2), 2.46–2.39 (m, 2H, CH2), 2.31 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6) δ 206.2, 195.5, 177.0, 163.5, 152.0, 137.2, 135.6, 135.1, 132.2, 129.8, 129.6, 128.3, 124.0, 123.8, 123.6, 116.0, 111.4, 93.7, 40.3, 31.7, 26.5, 20.5. HRMS (ESI) m/z: Calcd. for C29H23ClNO5 [M + H]+ 500.1265. Found 500.1257.
3-(2-(4-Chlorophenyl)-1-(2-((4-methoxyphenyl)amino)-5-oxocyclopent-1-en-1-yl)-2-oxoethyl)-4-hydroxy-2H-chromen-2-one (4i). Brown solid, yield 83%, m.p. 140–141 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H, OH), 7.79–7.72 (m, 3H, NH + ArH), 7.57–6.99 (m, 10H, ArH), 6.08 (s, 1H, CH), 3.77 (s, 3H, CH3O), 2.96–2.90 (m, 1H, CH2), 2.66–2.59 (m, 1H, CH2), 2.44–2.37 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6) δ 203.1, 195.5, 177.5, 165.2, 163.5, 157.6, 152.0, 137.2, 135.1, 132.1, 130.7, 129.5, 128.3, 125.6, 123.9, 123.8, 117.8, 115.9, 114.5, 110.9, 104.6, 55.3, 40.3, 31.6, 26.6. HRMS (ESI) m/z: Calcd. for C29H23ClNO5 [M + H]+ 500.1265. Found 500.1257.
3-(2-(4-Bromophenyl)-1-(2-((4-bromophenyl)amino)-5-oxocyclopent-1-en-1-yl)-2-oxoethyl)-4-hydroxy-2H-chromen-2-one (4j). Blue solid, yield 70%, m.p. 159–160 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H, OH), 7.76–7.68 (m, 3H, NH + ArH), 7.64–7.25 (m, 10H, ArH), 6.08 (s, 1H, CH), 3.09–3.02 (m, 1H, CH2), 2.77–2.71 (m, 1H, CH2), 2.47–2.38 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6) δ 204.3, 195.5, 176.0, 164.6, 163.5, 152.0, 137.7, 135.4, 132.3, 132.2, 131.3, 129.7, 126.4, 125.3, 124.1,123.8, 118.2, 117.4, 116.0, 112.3, 104.7, 89.6, 40.3, 31.9, 26.7. HRMS (ESI) m/z: Calcd. for C28H20Br2NO5 [M + H]+ 607.9708. Found 607.9698.
3-(2-(4-Bromophenyl)-2-oxo-1-(5-oxo-2-(p-tolylamino)cyclopent-1-en-1-yl)ethyl)-4-hydroxy-2H-chromen-2-one (4k). Brown solid, yield 77%, m.p. 161–162 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H, OH), 7.75–7.69 (m, 3H, NH + ArH), 7.63–7.24 (m, 10H, ArH), 6.09 (s, 1H, CH), 3.02–2.96 (m, 1H, CH2), 2.71–2.65 (m, 1H, CH2), 2.45–2.38 (m, 2H, CH2), 2.31 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6) δ 203.5, 195.6, 177.0, 165.0, 163.5, 152.0, 135.6, 135.4, 132.2, 131.2, 139.8, 129.7, 126.3, 124.0,123.8, 123.6, 117.7, 116.0, 111.4, 89.7, 40.3, 31.7, 26.8, 20.5. HRMS (ESI) m/z: Calcd. for C29H23BrNO5 [M + H]+ 544.0760. Found 544.0762.
3-(1-(4-((4-Bromophenyl)amino)-2-oxo-2,5-dihydrofuran-3-yl)-2-oxo-2-phenylethyl)-4-hydroxy-2H-chromen-2-one (6a). Pink solid, yield 89%, m.p. 221–223 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H, OH), 7.96–7.80 (m, 3H, NH + ArH), 7.62–7.07 (m, 10H, ArH), 5.94 (s, 1H, CH), 5.25 (d, J = 15.6Hz, 1H, CH2), 5.15 (d, J = 16.0 Hz, H, CH2). 13C NMR (400 MHz, DMSO-d6) δ 195.8, 174.7, 163.4, 162.8, 162.2, 152.0, 138.6, 132.6, 132.3, 128.3, 127.7, 124.2, 123.7, 122.0, 116.4, 116.3, 115.8, 104.3, 94.6, 66.6, 40.4. HRMS (ESI) m/z: Calcd. for C27H19BrNO6 [M + H]+ 532.0396. Found 532.0402.
4-Hydroxy-3-(1-(4-((4-methoxyphenyl)amino)-2-oxo-2,5-dihydrofuran-3-yl)-2-oxo-2-phenylethyl)-2H-chromen-2-one (6b). Brown solid, yield 84%, m.p. 116–118 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H, OH), 7.93–7.79 (m, 3H, ArH + NH), 7.62–6.91 (m, 11H, ArH), 5.95 (s, 1H, CH), 5.08 (d, J = 16.0 Hz, 1H, CH2), 4.89 (d, J = 16.0 Hz, 1H, CH2), 3.73 (s, 3H, CH3O). 13C NMR (400 MHz, DMSO-d6) δ 196.0, 175.6, 163.7, 163.2, 162.6, 156.5, 151.9, 136.3, 132.4, 131.6, 128.2, 127.6, 124.1, 123.6, 123.2, 116.3, 114.9, 114.6, 104.6, 92.0, 66.5, 55.2, 40.2. HRMS (ESI) m/z: Calcd. for C27H19BrNO6 [M + H]+ 484.1396. Found 484.1402.
3-(2-(4-Chlorophenyl)-2-oxo-1-(2-oxo-4-(p-tolylamino)-2,5-dihydrofuran-3-yl)ethyl)-4-hydroxy-2H-chromen-2-one (6c). White solid, yield 92%, m.p. 219–220 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H, OH), 7.97–7.80 (m, 3H, NH + ArH), 7.62–7.03 (m, 10H, ArH), 5.94 (s, 1H, CH), 5.16 (d, 1H, J = 15.6 Hz, CH2), 5.06 (d, J = 16.0 Hz, 1H, CH2), 2.25 (s, 3H, CH3). 13C NMR (400 MHz, DMSO-d6) δ 194.9, 174.8, 163.1, 162.8, 152.0, 137.2, 136.4, 135.1, 133.5, 132.4, 129.9, 129.4, 128.4, 124.1, 123.6, 120.6, 116.3, 104.0, 92.7, 66.5, 56.0, 40.4, 20.3, 18.5. HRMS (ESI) m/z: Calcd. for C28H21ClNO6 [M + H]+ 502.1057. Found 502.1068.
3-(2-(4-Chlorophenyl)-1-(4-((4-chlorophenyl)amino)-2-oxo-2,5-dihydrofuran-3-yl)-2-oxoethyl)-4-hydroxy-2H-chromen-2-one (6d). Pink solid, yield 70%, m.p. 208–210 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H, OH), 7.96–7.79 (m, 3H, NH + ArH), 7.62–7.12 (m, 10H, ArH), 5.87 (s, 1H, CH), 5.21 (d, J = 16.0 Hz, 1H, CH2), 5.12 (d, J = 16.0 Hz, 1H, CH2). 13C NMR (400 MHz, DMSO-d6) δ 194.8, 174.3, 163.1, 162.1, 152.1, 138.1, 137.2, 135.1, 132.4, 129.4, 128.4, 127.7, 124.1, 123.6, 121.7, 116.4, 103.7, 94.2, 66.4, 40.2. HRMS (ESI) m/z: Calcd. for C27H18Cl2NO6 [M + H]+ 522.0521. Found 522.0523.
3-(1-(4-((4-Bromophenyl)amino)-2-oxo-2,5-dihydrofuran-3-yl)-2-(4-chlorophenyl)-2-oxoethyl)-4-hydroxy-2H-chromen-2-one (6e). Pink solid, yield 91%, m.p. 190–191 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H, OH), 7.97–7.80 (m, 3H, NH + ArH), 7.62–7.08 (m, 10H, ArH), 5.91 (s, 1H, CH), 5.24 (d, J = 16.0 Hz, 1H, CH2), 5.14 (d, J = 16.0 Hz, 1H, CH2). 13C NMR (400 MHz, DMSO-d6) δ 195.2, 174.8, 163.8, 163.3, 162.6, 152.5, 139.0, 137.8, 135.5, 132.8, 132.6, 129.9, 128.9, 124.6, 124.1, 122.5, 116.8, 116.2, 104.3, 94.8, 67.0, 19.0. HRMS (ESI) m/z: Calcd. for C27H18BrClNO6 [M + H]+ 566.0006. Found 566.0026.
3-(2-(4-Bromophenyl)-2-oxo-1-(2-oxo-4-(p-tolylamino)-2,5-dihydrofuran-3-yl)ethyl)-4-hydroxy-2H-chromen-2-one (6f). Pink solid, yield 91%, m.p. 218–219 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H, OH), 7.96–7.71 (m, 3H, NH + ArH), 7.65–7.02 (m, 10H, ArH), 5.91 (s, 1H, CH), 5.15 (d, J = 16.0 Hz, 1H, CH2), 5.05 (d, J = 16.0 Hz, 1H, CH2), 5.25 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6) δ 195.2, 174.7, 163.1, 162.9, 152.0, 136.4, 135.5, 133.4, 132.4, 131.3, 129.9, 129.5, 126.3, 124.1, 123.6, 120.6, 116.4, 103.9, 92.7, 66.4, 20.3, 18.5. HRMS (ESI) m/z: Calcd. for C28H21BrNO6 [M + H]+ 546.0552. Found 546.0543.
3-(2-(4-Bromophenyl)-1-(4-((4-methoxyphenyl)amino)-2-oxo-2,5-dihydrofuran-3-yl)-2-oxoethyl)-4-hydroxy-2H-chromen-2-one (6g). White solid, yield 77%, m.p. 155–157 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H, OH), 7.93–7.70 (m, 3H, NH + ArH), 7.73–6.90 (m, 10H, ArH), 5.86(s, 1H, CH), 5.05 (d, J = 15.6 Hz, 1H, CH2), 4.95 (d, J = 16.0 Hz, 1H, CH2), 3.73 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6) δ 195.1, 175.2, 163.7, 163.1, 162.6, 156.5, 152.0, 135.5, 132.4, 131.6, 131.3, 129.5, 126.4, 124.1, 123.6, 123.2, 116.3, 114.6, 104.2, 91.7, 66.3, 55.2, 40.7. HRMS (ESI) m/z: Calcd. for C28H21BrNO7 [M + H]+ 562.0501. Found 562.0493.
4-Hydroxy-3-(2-(4-methoxyphenyl)-1-(4-((4-methoxyphenyl)amino)-2-oxo-2,5-dihydrofuran-3-yl)-2-oxoethyl)-2H-chromen-2-one (6h). White solid, yield 91%, m.p. 170–172 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H, OH), 7.94–7.77 (m, 3H, NH + ArH), 7.63–6.91 (m, 10 H, ArH), 5.92(s, 1H, CH), 5.19 (d, J = 15.6 Hz, 1H, CH2), 4.97 (d, J = 15.6 Hz, 1H, CH2), 3.76 (s, 3H, CH3O), 3.73 (s, 3H, CH3O). 13C NMR (100 MHz, DMSO-d6) δ 194.3, 176.0, 163.7, 163.3, 162.6, 156.5, 151.9, 132.4, 131.6, 129.9, 128.7, 124.1, 123.6, 123.1, 116.3, 114.6, 113.5, 105.0, 92.4, 66.6, 55.2, 39.7. HRMS (ESI) m/z: Calcd. for C29H24NO8 [M + H]+ 514.1502. Found 514.1495.
3-(1-(4-((4-Chlorophenyl)amino)-2-oxo-2,5-dihydrofuran-3-yl)-2-(4-methoxyphenyl)-2-oxoethyl)-4-hydroxy-2H-chromen-2-one (6i). Brown solid, yield 72%, m.p. 206–207. 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H, OH), 7.97–7.78 (m, 3H, NH + ArH), 7.61–6.94 (m, 10H, ArH), 5.93 (s, 1H, CH), 5.25 (d, J = 16.0 Hz, 1H, CH2), 5.14 (d, J = 16.0 Hz, 1H, CH2), 3.76 (s, 3H, CH3O). 13C NMR (100 MHz, DMSO-d6) δ 194.1, 174.9, 163.4, 162.6, 162.1, 152.0, 138.2, 132.4, 129.9, 129.4, 128.7, 127.6, 124.1, 123.6, 121.5, 116.3, 113.5, 104.4, 94.8, 66.6, 55.3, 40.0. HRMS (ESI) m/z: Calcd. for C28H21ClNO7 [M + H]+ 518.1007. Found 518.1018.
4. Conclusions
In summary, we have developed a novel, highly efficient, catalyst-free, green protocol for the one-pot three-component synthesis of 3-functionalized 4-hydroxycoumarin derivatives. This protocol has the advantages of mild reaction conditions, high yields, convenient operation, and environmental friendliness.
Acknowledgments
Financial support of this research provided by the National Natural Science Foundation of China (81473098, 81473099, 81703366) and CAMS Innovation Fund for Medical Sciences (CIFMS 2016-I2M-3-014, CIFMS 2016-I2M-1-011, CIFMS 2016-I2M-3-022, and CIFMS 2017-I2M-3-019) is greatly acknowledged.
Supplementary Materials
Supplementary materials are available online. 1H NMR and 13C NMR spectrum of compounds 4a–4k and 6a–6i.
Author Contributions
Juxian Wang, Yiliang Li and Yucheng Wang conceived and designed the experiments. Yang Gao, Guoning Zhang and Xiaoguang Bai performed the experiments. Yiliang Li wrote the manuscript. Juxian Wang and Yucheng Wang revised the manuscript. All authors read and approved the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
Footnotes
Sample Availability: Samples of the compounds 4a–4k and 6a–6i are available from the authors.
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