Ultrasound-Assisted Preparation of Furo[3,2-c]Coumarin in the Presence of the N- GQDs-Sensitized NiO/Co3O4 Composite as a Robust Catalyst

INTRODUCTION
Furo[3,2-c]coumarines are classified as an important natural and heterocyclic compounds [1] due to  their biological activities, for instance, antibacterial [2], antifungal [3], vasorelaxant [4], nuclear factor kappa B (NF-κB) inhibitors [5, 6], HIV-1 integrate inhibitors [6]. Todays, the use of multicomponent reactions (MCRs) was developed by both medical and synthetic chemists. In fact, MCRs are known as a powerful protocol to preparation of bioactive heterocyclic compounds [7]. Thus, finding the concise and efficient methods for the preparation of the fure[3,2-c]coumarines via MCRs are a significant challenge. 
Some methods have been reported for the preparation of the fure[3,2-c]coumarine compounds using various catalysts such as pyridine or a mixture of AcONH4/AcOH [8], [BMIm]OH ionic liquids [9], Pd (CF3CO2)2 [10], CuBr2 [10], Rh2(OAc)4 [11], triethylamine and PBu3 [12], and N-methyl imidazole [13]. However, a number of these reports have disadvantages: harsh reaction conditions, long reaction times, non-reusable catalysts, and use of toxic materials. Therefore, to overcome these limitations, the development of an efficient and facile available catalyst with high catalytic performance and short reaction time for the synthesis of furo[3,2-c]coumarines is still favored. 
Using ultrasound irradiation (US) technique as a green and safe source in multicomponent reactions could be improved their effectiveness from operating cost and ecological points of views [14, 15]. US technique is applied for a variety of heterocyclic compounds synthesis owing to excellent yields, short reaction times, and facile workup. Ultrasound energy is the result of the cavitation phenomenon. This energy not only extreme heating but also high pressure by imploding of bubbles which can accelerate an organic transformation at the synthesis pathway. Recently, nanocatalysts have emerged as an alternating method for the improvement of many important organic reactions. However, when the size of active site is reduced to nanoscale dimensions, the surface free energy is increased significantly [16]. Among them, graphene quantum dots (GQDs), which are unique fragment of carbon nanomaterials [17] have been revealed splendid properties such as excellent biocompatibility [18],emission and low cytotoxicity [19, 20],extremely soluble in various solvents [21],and photoluminescence (PL) [22].Interestingly, GQDs due to their high specific surface area and functionalized with –OH, -CO2H and etc. are capable to cover nanocomposites and carry different chiral small-molecules as a chemical catalysts [23-25]. 
Based on above results, we used nano-sized NiO/Co3O4@N-doped GQDs composite for the preparation of the furo[3,2-c]coumarine compounds. In this work, we report the successful preparation of NiO/Co3O4@N-doped GQDs nanocomposites as a robust and green catalyst. The NiO/Co3O4@N-GQDs nanostructure have been interested because of their unique properties and applications in diverse fields. Herein, we wish to report the use of NiO/Co3O4@N-GQDs nanocomposites as a robust catalyst for the synthesis of the furo[3,2-c]coumarine compounds via MCRs of 2,4’-dibromoacetophenon, various substituted benzaldehydes, and 4-hydroxycoumarine under US conditions (Fig.  1).  

 
MATERIALS AND METHODS
Synthesis of NiO/Co3O4 nanocomposites (NiO/Co3O4 NCs)
The mixture of nickel(II) hexahydrate (1 g) and cobalt(II) acetate tetrahydrate (3 g) were dissolved completely in deionized water (40 mL). Next, the aqueous ammonia solution was droply added to set the pH to 9.0. After 5 min, the mixture was moved to autoclave at 160 °C for 6 h. After that, the obtained solid was filtered, washed with distilled water (2×20 mL), and dried at 50 °C for 5. To give NiO/Co3O4 NCs, the dried solid was calcined for 2 h at 550 °C [26].

Synthesis of NiO/Co3O4@N-GQDs NCs
0.3 mL of ethylenediamine was droply added to citric acid solution (0.25 M). The clear solution was stirred for 30 s. The prepared NiO/Co3O4 NCs (1 g) was then added to above solution and stirred for 5 min at room temperature. The mixture was moved to autoclave and heated for overnight at 180 °C. At completion, the as-prepared NiO/Co3O4/GQDs NCs was collected, washed with distilled water (2×15 mL), and dried in a vacuum oven until a constant weight was achieved [26]. 

General method for the synthesis of furo[3,2-c]coumarine
In 25 mL round bottom flask and in the presence of NiO/Co3O4@N-GQDs NCs as a catalyst, pyridine, 4-bromophenacyl bromide, various aromatic aldehydes, and 4-hydroxycoumarine were mixed in a 1:1:1:1 ratio in ethanol medium (10 mL). The mixture was refluxed for appropriate time. The completion of the reaction was controlled by TLC. At completion, the resulting solid was collected and recrystallized from ethanol to give pure product. The characteristics of products were determined by FT-IR and 1H NMR spectroscopy.

Spectral Data
trans-2-4’-bromo-benzoyl-3-phenyl-2H-furo[3,2-c]chromen-4(3H)-one (4a): White powder, m.p 243-244 ºC, IR (KBr) cm-1: 2931, 2853, 1718, 1644, 1452, 1404, 1025, 753, 576; 1H NMR (400 MHz, CDCl3): δ (ppm) 4.82 (CH, 1H, d, J= 5.2 Hz), 6.11 (CH, 1H, d, J= 5.2 Hz), 6.88-7.03 (m, 7H), 7.34 (m, 1H), 7.55 (m, 2H), 7.84 (m, 3H); 13C NMR (100 MHz, CDCl3): δ (ppm) 48.32, 92.19, 105.22, 112.22, 117.32, 121.25, 122.38, 123.98, 127.24, 128.62, 129.22, 130.50, 131.96, 133.20, 134.42, 138.88, 155.62, 159.41, 166.34, 192.03; Anal. Calcd for C24H15BrO4:C, 64.45; H, 3.38; Found: C, 64.33; H, 3.27.

trans-2-4’-bromo-benzoyl-3-(3-methylphenyl)-2H-furo[3,2-c]chromen-4(3H)-one (4b): White powder, m.p 222-224ºC, IR (KBr) cm-1: 2927, 2854, 1720, 1648, 1455, 1405, 1026, 753, 576; 1H NMR (400 MHz, CDCl3): δ (ppm) 2.50 (CH3, 3H), 4.80 (CH, 1H, d, J= 4.4 Hz), 6.09 (CH, 1H, d, J= 4.4 Hz), 7.04 (m, 6H), 7.34 (m, 1H), 7.60 (m, 2H), 7.99 (m, 3H);13C NMR (100 MHz, CDCl3): δ (ppm) 21.2, 48.78, 92.11, 104.54, 112.02, 117.22, 120.93, 122.31, 124.25, 127.23, 127.99, 128.32, 128.45, 129.11, 130.51, 132.46, 133.25, 134.40, 139.12, 155.61, 159.42, 166.36, 192.02; Anal. calcd forC25H17BrO4: C, 65.09; H, 3.71; Found: C, 65.16; H, 3.88; 

trans-2-4’-bromo-benzoyl-3-(2-methylphenyl)-2H-furo[3,2-c]chromen-4(3H)-one (4c): White powder,m.p 171-173 ºC, IR (KBr) cm-1:2923, 2851, 1721, 1645, 1453, 1407, 1029, 575; 1H NMR (400 MHz, CDCl3): δ (ppm) 2.43 (CH3, 3H), 5.20 (CH, 1H, d, J = 5.6 Hz), 6.02 (CH, 1H, d, J = 5.6 Hz), 6.89 (m, 1H), 7.27 (m, 7H), 7.60 (d, J= 8.8 Hz, 2H), 7.83 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 22.3, 48.79, 92.14, 104.63, 112.05,117.25, 120.95, 122.33, 124.26, 127.25, 128.08, 128.48, 129.14, 130.57, 130.59, 132.46, 133.27, 134.44, 139.15, 155.64, 159.44, 166.37, 192.10; Anal. calcd forC25H17BrO4: C, 65.09; H, 3.71; Found: C,65.12; H, 3.82; 

trans-2-4’-bromo-benzoyl-3-(4-chlorophenyl)-2H-furo[3,2-c]chromen-4(3H)-one (4d): White powder, m.p 250-252 ºC, IR (KBr) cm-1: 2924, 2824, 1722, 1646, 1412, 1024, 752, 534; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 4.77 (CH, 1H, J= 5.0 Hz), 6.63 (CH, 1H, J= 5.0 Hz), 7.22-7.26 (m, 2H), 7.29-7.32 (m, 2H), 7.32 (m, 3H), 7.50-8.03 (m, 5H); 13C NMR (100 MHz, DMSO-d6): δ (ppm) 49.66, 93.51, 105.22, 112.20, 117.35, 121.28, 122.45, 124.32, 127.25, 128.63, 129.19, 130.59, 133.04, 133.21, 135.14, 139.15, 155.60, 159.42, 166.42, 192.24;  Anal. calcd for C24H14BrClO4: C, 59.84; H, 2.93; Found: C, 59.75; H, 2.82; 

trans-2-4’-bromo-benzoyl-3-(2-chlorophenyl)-2H-furo[3,2-c]chromen-4(3H)-one (4e): White powder, m.p 219-221º C, IR (KBr) cm-1:2922, 2853, 1718, 1644, 1453, 1402, 1024, 755, 574; 1H NMR (400 MHz, CDCl3): δ (ppm) 5.58 (CH, 1H, J= 5.2 Hz), 6.08 (CH, 1H, J= 5.2 Hz), 7.17-7.31 (m, 6H), 7.37 (m, 3H), 7.43 (d, J= 8 Hz, 1H), 7.96 (m, 2H);  13C NMR (100 MHz, CDCl3): δ (ppm) 48.82, 92.19, 105.12, 112.14, 117.28, 121.08, 122.36, 124.28, 127.28, 128.17, 128.57, 129.24, 130.58, 130.69, 132.54, 133.27, 134.41, 139.14, 155.62, 159.42, 166.38, 192.18; Anal. calcd forC24H14BrClO4:C, 59.84; H, 2.93; Found: C, 59.72; H, 2.79; 

trans-2-4’-bromo-benzoyl-3-(4-nitrophenyl)-2H-furo[3,2-c]chromen-4(3H)-one (4f): White powder, m.p 250-252 ºC, IR (KBr) cm-1: 2932, 2834, 1734, 1636, 1432, 1025, 762, 535; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 5.15 (CH, 1H, J= 4.8 Hz), 6.04 (CH, 1H, J= 4.8 Hz), 7.28 (m, 2H), 7.32 (t, J = 7.2 Hz, 1 H), 7.40 (m, 1H), 7.45 (d, J = 7.6 Hz, 2H), 7.49 (d, J = 7.6 Hz, 2H)  7.92- 8.12 (m, 4H); 13C NMR (100 MHz, CDCl3): δ (ppm) 48.05, 91.97, 104.35, 111.73, 117.28, 123.17, 124.48, 124.60, 128.75, 130.33, 130.65, 132.01, 132.57, 133.54, 146.47, 147.76, 155.48, 159.01, 166.38, 190.61; Anal. calcd forC24H14BrNO6: C, 58.56; H, 2.87; N, 2.85;Found: C, 58.47; H, 2.79; N, 2.80;

trans-2-4’-bromo-benzoyl-3-(4-methylthiophenyl)-2H-furo[3,2-c]chromen-4(3H)-one (4g): White powder, m.p 206-208 ºC, IR (KBr) cm-1: 2925, 2829, 1724, 1647, 1406, 1027, 754, 538;1H NMR (400 MHz, CDCl3): δ (ppm) 2.66 (s, CH3, 3H), 4.77 (CH, 1H, d, J= 4.8 Hz), 6.07 (CH, 1H, d, J= 4.8 Hz), 7.16 (m, 4H), 7.30 (m, 1H), 7.41-7.87 (m, 7H);  13C NMR (100 MHz, CDCl3): δ (ppm) 15.68, 48.80, 92.04, 104.52, 112.03, 117.21, 120.94, 122.31, 124.24, 127.22, 127.99, 128.32, 130.53, 132.46, 133.25, 134.40, 139.17, 155.61, 159.42, 166.38, 192.03. Anal.calcd for C25H17BrO4S: C, 60.86; H, 3.47; Found: C, 60.74; H, 3.54.

trans-2-4’-bromo-benzoyl-3-(4-bromophenyl)-2H-furo[3,2-c]chromen-4(3H)-one (4h): White powder, m.p 256-258 ºC, IR (KBr) cm-1:2919, 2821, 1718, 1644, 1402, 1024, 751, 535; 1H NMR (400 MHz, CDCl3): δ (ppm) 4.86 (CH, 1H, J =5.2 Hz), 6.05 (CH, 1H, J = 5.2 Hz), 7.18 (m, 2H), 7.23 (m, 2H), 7.34 (m, 1H), 7.50-7.93 (m, 7H); 13C NMR (100 MHz, CDCl3): δ (ppm) 48.51, 92.28, 105.24, 112.24, 117.31, 121.25, 122.38, 124.21, 127.22, 128.51, 129.17, 130.57, 132.53, 133.21, 134.42, 139.14, 155.62, 159.43, 166.44, 192.16;  Anal. calcd for C24H14Br2O4: C, 54.78; H, 2.68; Found: C, 54.61; H, 2.55.

trans-2-4’-bromo-benzoyl-3-(3-nitrophenyl)-2H-furo[3,2-c]chromen-4(3H)-one (4i): White powder, m.p 250-252 ºC, IR (KBr) cm-1: 2934, 2853, 1727, 1647, 1522, 1410, 747, 575;1H NMR (400 MHz, CDCl3): δ (ppm) 5.17 (CH, 1H, J= 4.8 Hz), 6.07 (CH, 1H, J= 4.8 Hz), 7.34-7.39 (m, 2H), 7.42-7.47 (m, 4H),  7.92- 8.12 (m, 5H); 8.17 (m, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 49.04, 93.50, 105.24, 112.28, 117.38, 121.29, 122.43, 124.33, 124.54, 127.37, 128.33, 128.39, 129.44, 131.73, 132.54, 133.35, 134.65, 139.16, 155.71, 159.48, 166.52, 193.10; Anal. calcd forC24H14BrNO6: C, 58.56; H, 2.87; N, 2.85;Found: C, 58.47; H, 2.79; N, 2.80;

trans-2-4’-bromo-benzoyl-3-(4-methylphenyl)-2H-furo[3,2-c]chromen-4(3H)-one (4j): White powder, m.p 204-206ºC, IR (KBr) cm-1: 2932, 2862, 1721, 1646, 1458, 1403, 1025, 756, 1H NMR (400 MHz, CDCl3): δ (ppm) 2.45 (CH3, 3H), 5.58 (CH, 1H, d, J= 5.4 Hz), 6.08 (CH, 1H, d, J= 5.4 Hz), 7.02-7.12 (m, 4H), 7.16-7.20 (m, 2H), 7.36-7.55 (m, 3H), 7.77-7.95 (m, 3H);13C NMR (100 MHz, CDCl3): δ (ppm) 21.5, 48.65, 92.05, 104.52, 111.95, 117.18, 120.82, 124.22, 127.83, 128. 45,128.65, 129.14, 130.32, 132.42, 133.18, 134.32, 139.02, 155.55, 159.44, 166.30, 192.14; Anal.calcd for C25H17BrO4: C, 65.09; H, 3.71; Found: C, 65.21; H, 3.85. 

trans-2-4’-bromo-benzoyl-3-(2-fluorophenyl)-2H-furo[3,2-c]chromen-4(3H)-one (4k): White powder, m.p 186-188º C, IR (KBr) cm-1: 2922, 2853, 1718, 1644, 1453, 1402, 1024, 755, 574; 1H NMR (400 MHz, CDCl3): δ (ppm) 5.50 (CH, 1H, J = 5.2 Hz), 6.18 (CH, 1H, J = 5.2 Hz), 7.27-7.51 (m, 6H), 7.47 (m, 3H), 7.53 (d, J= 7.6 Hz, 1H), 7.96 (m, 2H);  13C NMR (100 MHz, CDCl3): δ (ppm) 48.93, 92.31, 105.22, 113.02, 117.22, 121.18, 122.45, 124.20, 127.28, 128.17, 128.61, 129.31, 130.65, 131.72, 133.54, 133.71, 135.52, 139.21, 155.81, 159.52, 166.56, 192.30; Anal. calcd for C24H14BrFO4: C, 61.96; H, 3.03; Found: C, 61.82; H, 2.92; 

2-Benzoyl-3-p-chlorophenyl-2,3-dihydrofuro[3,2-c]chromen-4-one (4l): White powder, m.p 170-172º C, IR (KBr) cm-1: 2924, 2855, 1717, 1643, 1454, 1406, 1024, 756, 572; 1H NMR (400 MHz, CDCl3): δ (ppm) 4.85 (d, J = 5.2 Hz, 1H, CH), 6.06 (d, J = 5.2 Hz, 1H, CH), 7.20-7.89 (m, 13 H); 13C NMR (100 MHz, CDCl3): δ (ppm) 48.72, 92.44, 104.92, 112.12, 117.14, 123.22, 124.23, 129.04, 129.10, 129.52, 133.12, 133.22, 134.15, 134.17, 134.60, 138.12, 155.43, 159.27, 166.58, 191.84; Anal. calcd for C24H15ClO4: C, 71.56; H, 3.75; Found: C, 71.45; H, 3.69;

2-Benzoyl-3-3-fluorophenyl-2,3-dihydrofuro[3,2-c]chromen-4-one (4m): White powder, m.p 210-212º C, IR (KBr) cm-1: 3052, 1704, 1648, 1605, 1500, 1449, 1410, 1326, 887, 756; 1H NMR (400 MHz, CDCl3): δ (ppm) 4.90 (d, J = 5.2 Hz, 1H, CH), 6.07 (d, J = 5.2 Hz, 1H, CH), 7.12-7.87 (m, 13 H); 13C NMR (100 MHz, CDCl3): δ (ppm) 48.30, 92.21, 104.32, 111.83, 117.22, 122.52, 123.34, 124.44, 129.28, 129.32, 130.34, 133.21, 133.39, 133.45, 134.24, 134.75, 141.64, 148.96, 155.54, 159.18, 166.76, 191.48; Anal. calcd for C24H15FO4: C, 74.61; H, 3.91; Found: : C, 74.55; H, 3.87;

trans-2-4’-bromo-benzoyl-3-phenyl-8-methoxy-2H-furo[3,2-c]chromen-4(3H)-one (4o): White powder, m.p 218-220º C, IR (KBr) cm-1: 3045, 1701, 1645, 1603, 1503, 1448, 1412, 1325, 882, 754; 1H NMR (400 MHz, CDCl3): δ (ppm) 3.61 (s, 3H, OCH3), 5.20 (d, J = 5.6 Hz, 1H, CH), 6.03 (d, J = 5.6 Hz, 1H, CH), 6.88-7.83 (m, 12 H); 13C NMR (100 MHz, CDCl3): δ (ppm)  48.62, 55.25, 92.36, 105.27, 112.29, 115.09, 121.29, 122.48, 123.99, 127.35, 128.76, 129.37, 131.15, 131.97, 133.34, 134.55, 138.78, 155.59, 159.48, 166.51, 192.08; Anal. Calcd for C25H17BrO5: C, 62.91; H, 3.59; Found: C, 62.89; H, 3.61.

RESULTS AND DISCUSSION
Initially, we fabricated NiO/Co3O4 and NiO/Co3O4@N-GQDs NCs via hydrothermal method [25]. The FT-IR graphs of NiO/Co3O4 and NiO/Co3O4@N-GQDs NCs are revealed in Fig. 1. The peaks at 3330 and 1635 cm-1 correspond to the stretching and bending absorptions of hydroxyl group, respectively. The absorption peaks at 460, 570, and 655 cm-1 are related to Ni-O, Co(II)-O, and Co(III)-O, respectively (Fig. 2a). In addition, the characteristics bands at 1703, 1125, and 1475-1590 cm-1 are belong to C=O, C-O-C, and C=C functional groups in N-GQDs structure (Fig. 2b). 
The XRD patterns of each step displayed if Fig. 2. The first pattern confirms the presence of NiO (Code. No. 22-1189) and Co3O4 (Code. No. 65-3103) (Fig. 3a). Besides, the new peak located at 2θ= 24.3° is assigned reflection of [002] plane of N-GQDs (Fig. 3b).
Besides of FT-IR and XRD results, the Energy-dispersive X-ray graph (EDS) confirms the presence of Ni, Co, O, C, and N elements in the structure of NiO/Co3O4@N-GQDs nanocomposites (Fig. 4). Also, to study of the morphology and particle size of as-prepared nanocomposites, the FE-SEM technique and Digimizer software were applied, respectively. The FE-SEM images of NiO/Co3O4 and NiO/Co3O4@N-GQDs NCs are shown in Fig. 5a-c. Moreover, the average particles size of final structure was measured about nm (Fig. 4d).
We investigated the systematic evaluation of various catalysts for the reaction of benzaldehyde, 4-hydroxycoumarine, 2,4’-dibromoacetophenone, and pyridine as a model reaction. The slected reaction was done in the presence of various catalysts, which are tabulated in Table 1. When the reaction was done using NiO/Co3O4@N-GQDs nanoomposites, the product could be obtained in a good to excellent yield. The NiO/Co3O4 nanostructure covered by N-GQDs shows good catalytic activity due to their large number of active sites which are mainly responsible for their catalytic activity. The most ideal results were seen under ultrasound irradiations (50 W) in ethanol medium and the reaction gave satisfy results in the presence of the NiO/Co3O4@N-GQDs as a new catalyst. When the amount of catalyst was raised, the yield of the reaction was increased. Consequently, 10 mol% of NiO/Co3O4@N-GQDs were an expedient and an excessive amount of NiO/Co3O4@N-GQDs did not change the yield, remarkably (Table 1). When the reaction was done under ultrasound irradiations (US) conditions, the rate of the reaction increased considerably. In this research, US is applied as a green method for the synthesis of the furo[3,2-c]coumarines. 
With these helpful data in hand, we turned to study the scope of the reaction by different aryl aldehydes, 4-hudroxycoumarine, and 2,4’-dibromoacetophenone as starting chemicals under optimized conditions (Table 2). It was observed that the electron-withdrawing groups reacted faster than electron-donation groups. In the interim, it is shown that the best yield are obtained with starting materials having electron-withdrawing groups. The all prepared product was summarized in Table 2. In the recovering method of NiO/Co3O4@N-GQDs nanocatalyst, chloroform was added to curd product after terminating the reaction. The nanocatalyst was not dissolve in chloroform and was separated by simple filtering. The reusing ability of the nanocatalyst was checked for 5 runs, proving almost similar yield of the desired product (Fig. 6).
A proposed mechanism was revealed in Fig. 7. We supposed that the reaction occurs via Knoevenagel condensation between 4-hydroxycoumarine and substituted aryl aldehydes to form intermediate (I). After that, the Michael addition of pyridinium yield with enones affords the zwitterions intermediate and followed by cyclization affords the product. The final step includes classical SN2 reaction. Besides, pyridine plays an important role. It acts as a nucleophilic tertiary amine to form zwitterionic salt and acts as a leaving group to finish the intermolecular substitutions reaction. In this proposed mechanism, NiO/Co3O4@N-GQDs was introduced as an acid catalyst and active the carbonyl group. 

CONCLUSION
As a result, we have developed the green, flexible, and highly efficient method for the synthesis of furo[3,2-c]coumarines catalyzed by NiO/Co3O4@N-GQDs nanocomposites. The present protocol tolerates most of the substrates and the designed catalyst can be recovered at least 5 runs without remarkable loss of activity. The advantage of this research are using ultrasound irradiations as a green and clean source, efficient and recoverable catalyst, little catalyst loading, and facile separation of product. This job reveals the advantage of ultrasound irradiations-assisted heterogeneous catalyst in the preparation of furo[3,2-c]coumarines.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interests regarding the publication of this manuscript.