Nickel oxide nanoparticles: a green and recyclable catalytic system for the synthesis of diindolyloxindole derivatives in aqueous medium

Abstract

This study focuses on the use of nano-NiO particles as green and inexpensive nanocatalysts for the synthesis of diindolyl oxindoles, an important class of potentially bioactive compounds. The oxindole derivatives were prepared by the condensation of indole and isatin compounds in water, an excellent solvent in terms of environmental impact and reduction of waste production.

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1. Introduction

Recently, the environmental and economic aspects of the use of heterogeneous solid acid catalysts for various organic transformations have received great attention.^1,2 Heterogeneous catalysts are always superior to their homogeneous counterparts in terms of many aspects such as operational simplicity, reusability, environmental compatibility and high selectivity. With the advancement of nanoscience and nanotechnology, nanoparticulate heterogeneous catalysts have received significant attention in organic transformations owing to their ability to enhance faster rates of organic reactions, high catalytic activity and higher yield of products, which is due to their ability to afford high particle size-to-volume ratio along with greater surface area.³ During recent years, nickel oxide nanoparticles have attracted considerable attention as an inexpensive and nonhazardous catalysts or as an effective promoter that can enhance the reactivity and selectivity of various organic reactions.^4,5

In many cases, organic solvents, which are used in huge amounts for many different applications, have a negative impact on the health and the environment. One of the key areas of green chemistry is the elimination of solvents in chemical processes or the replacement of hazardous solvents with environmentally benign solvents. Water emerged as a useful alternative solvent for several organic reactions owing to many of its potential advantages such as safety, economy and environmental benefits. Occasionally, it shows higher reactivity and selectivity compared to other conventional organic solvents owing to its strong hydrogen bonding ability.^6,7

On a different note, oxindole derivatives often appear as important structural components in biologically active and natural compounds. Among the various oxindole systems, spirooxindoles have received considerable attention owing to their wide range of useful biological properties, which include antibacterial, antiprotozoal, anti-inflammatory activities and owing to their role as progesterone receptors (PR) agonists.^8–13 Because of the pharmacological properties of oxindoles, the development of synthetic methods enabling easy access to these compounds is desirable. In continuation of our work on the synthesis of biologically important compounds using simple, efficient and nontoxic catalysts,^14–17 in this paper we report the synthesis of diindolyloxindole derivatives by the coupling of indole and isatin derivatives in the presence of nano-NiO, an inexpensive and green catalyst in aqueous medium.

2. Results and discussion

Initially, nickel oxide nanoparticles were synthesized by the reaction of nickel nitrate hexahydrate with urea in deionized water and this mixture was heated at 115 °C for 1.5 h in an oil bath. The resulting compound was dried and calcined at 400 °C for 1 h. Then, nano-NiO particles were characterized using XRD, DLS and TEM. XRD patterns of the products were obtained after calcining the precursors at 400 °C. Of all the diffraction peaks observed in Fig. 1, the peak positions appearing at 2θ = 37.37, 43.43, 62.97, 75.52, and 79.48 as well as their lattice parameters were quite consistent with those of the standard JCPDS card no. 04-0835 for the standard spectrum of pure NiO. The average size of the NiO particles was estimated to be about 9 nm using the Debye–Scherrer equation.

Fig. 1 XRD pattern of NiO nanoparticles.

The TEM analysis of NiO nanoparticles (Fig. 2) provided information on the size of NiO nanoparticles. The mean particle size determined by TEM is very close to that of the average particle size calculated using the Debye–Scherer formula from the XRD pattern. The particle size distribution of NiO showed that the average diameter of the particles was 11 nm (Fig 3).

Fig. 2 TEM pattern of NiO nanoparticles.

Fig. 3 Particle size distribution of NiO nanoparticles.

The average hydrodynamic size of NiO NPs in water is determined by dynamic light scattering (DLS). Size dispersion by number patterns obtained before and after the precursors were calcined at 400 °C (Fig. 4 and 5). When the NiO NPs were calcined, the number of large-sized nanoparticles decreased.

Fig. 4 Size dispersion by number NiO nanoparticles before calcination.

Fig. 5 Size dispersion by number NiO nanoparticles after calcination.

In order to show the merits of a synthesized heterogeneous catalyst in organic reactions, nano NiO was used as an efficient and inexpensive catalyst for the synthesis of a series of analogues of oxindole using various isatins and indoles. Indole and isatin were selected as the model substrates and reacted under different experimental variants (Scheme 1).

Scheme 1 Synthesis of 3,3-diindolyloxindole.

To obtain the optimized reaction conditions, we changed the amount of catalyst. The results are summarized in Table 1. Consequently, among the tested temperatures and amounts of the catalyst, the condensation of indole and isatin was best catalyzed by 0.004 g of nano NiO at 70 °C. The reaction provided a high yield. In the presence of 0.0004 g of catalyst, the model reaction was not completed for 30 min and only 50% of the product was obtained. Further increases in the amount of nano NiO (0.008 g) in the aforementioned reaction did not show any significant effect on the product yield.

Table 1 Effect of the amount of catalyst on the synthesis of oxindole catalyzed by nano-NiO^a

Entry	Cat. (g)	Time (min)	Yield^b (%)
a Reaction conditions: isatin (1 mmol), indole (2 mmol) and water (2 mL) at 70 °C.b The yield corresponds to that of the pure isolated product.
1	0.008	15	92
2	0.004	15	87
3	0.0008	120	88
4	0.0004	120	83

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To evaluate the catalytic activity of nano-NiO, the model reaction was separately carried out in water (2 mL) at 70 °C for 30 min in the presence of different catalytic systems (0.004 g). The results are shown in Table 2. As evident from the results, nano-NiO was the most effective catalyst in terms of the yield of the oxindole (98%), whereas other catalysts formed the product with the yields of 33–68% (Table 2, entries 2–8). To establish the catalytic role of nano NiO, indole was treated with isatin in the absence of the catalyst. In this case, the reaction proceeded with a lower yield as compared to that for the model reaction time (30 min) (Table 2, entry 9).

Table 2 Synthesis of 3,3-diindolyloxindole in the presence of various catalytic systems^a

Entry	Catalyst	Yield^b (%)
a Reaction conditions: isatin (1 mmol), indole (2 mmol), catalyst (0.004 g) and water (2 mL) at 70 °C for 30 min.b The yield refers to that of the pure isolated product.
1	Nano NiO	98
2	NiO	45
3	CdO	52
4	PbO	65
5	As2O3	67
6	CuO	68
7	CaO	38
8	Al2O3	33
9	None	10

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We further explored the scope and limitation of this protocol under the optimized conditions (0.004 g catalyst in H₂O at 70 °C), particularly in regard to the library construction, and carried out the evaluation using various isatin and indole compounds (Table 3). In all the cases, the reaction proceeded readily to afford the corresponding oxindoles in good to excellent yields (60–98%) with very short reaction times (0.5–1.5 h).

Table 3 Preparation of 3,3-diindolyloxindole derivatives^a

Entry	Reactant				Time (h)	Yield^b (%)
	Indole		Isatin
	R1	R2	R3	R4
a Reaction conditions: isatin compounds (1 mmol), indole compounds (2 mmol), nano NiO (0.004 g) and water (2 mL) at 70 °C.b The yield refers to that of the pure isolated product.
1	H	H	H	H	0.5	98
2	H	H	H	NO2	0.5	95
3	H	H	H	Br	0.5	92
4	H	H	Me	NO2	0.5	95
5	H	H	Me	H	1.5	90
6	H	H	Me	Br	1.5	80
7	H	H	PhCH2	Br	1.5	93
8	H	H	PhCH2	H	1.5	60
9	H	H	PhCH2	NO2	1.5	75
10	Me	H	H	H	1	90
11	Me	H	PhCH2	H	1.5	85
12	Me	H	H	Br	1	95
13	Me	H	H	OMe	1.5	80
14	Me	H	Et	Br	1.5	90

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These reactions also proceeded with 3-methyl indole (Table 4). In these cases, the reaction time is longer than that for 2-methyl indole/indole.

Table 4 Synthesis of 2,2-diindolyloxindole derivatives^a

Entry	R1	R2	Time (h)	Yield^b (%)
a Reaction conditions: isatin compounds (1 mmol), 3-methyl indole (2 mmol), nano NiO (0.004 g) and water (2 mL) at 70 °C.b The yield refers to that of the pure isolated product.
1	H	H	1	80
2	PhCH2	Br	0.5	85
3	H	Br	0.5	90
4	PhCH2	H	1	98
5	Me	H	1.5	80
6	PhCH2	NO2	1.5	82

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In Table 5, the efficiency of our method for the synthesis of diindolyloxindole is compared to the reported efficiencies published in literature. Each of these methods have their own advantages, but they often suffer from some difficulties, including the use of organic solvent (entries 2–4), long reaction time (entries 2, 4 and 5) and the use of non-recyclable catalyst (entry 5).

Table 5 Comparison of the results obtained using nano NiO with results obtained by other works for the synthesis of diindolyloxindole

Entry	Catalyst	Yield (%)	Time (h)	Condition	Solvent	Ref
1	Current	98	0.5	70	H2O	—
2	Bi(OTf)3	92	3.0	r.t.	CH3CN	18
3	Ru-Y	93	0.5	Reflux	C2H4Cl2	19
4	PEG-OSO3H	93	2.5	r.t.	CH3CN	20
5	CAN	95	3.0	U.S.	EtOH	21

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On the completion of the reaction, the catalyst could be recovered by centrifugation. The recycled catalyst was washed with dichloromethane and subjected to another reaction process. The results show that the yield of the product after five runs was only slightly reduced (Fig. 6).

Fig. 6 Recyclability of the nano-NiO catalyst used in the synthesis of oxindoles.

A reasonable pathway for the reaction of indole with isatin compounds conducted in the presence of nano NiO is presented by Scheme 2. The first step involves the formation of activated isatin (1) followed by its reaction with indole to generate compound 2 that subsequently undergoes elimination reaction to produce compound 4. Intermediate 4 undergoes further addition with the second indole molecule to afford oxindole derivatives.

Scheme 2 The proposed mechanism for the synthesis of diindolyl oxindole in the presence of nano NiO.

3. Experimental

3.1. General methods

Indole and isatin derivatives were purchased from Merck Chemical Company. Purity determinations of the products were accomplished with TLC using silica-gel polygram SILG/UV 254 plates. The melting points were measured on an Electro thermal 9100 apparatus. The IR spectra were obtained on a Perkin Elmer 781 spectrometer in KBr pellets and reported in cm⁻¹. ¹H NMR and ¹³C NMR spectra were measured on a Bruker DPX-250 Avance instrument at 250 MHz and 62.9 MHz in CDCl₃ or DMSO-d₆ with chemical shift given in ppm relative to TMS as internal standard. The morphology of the products was determined using CMPhilips10 model. Transmission Electron Microscopy (TEM) at the accelerating voltage of 100 kV. Power X-ray diffraction (XRD) was performed using a Bruker D₈-advance X-ray diffractometer with Cu K_α (λ = 0.154 nm) radiation.

3.2. Preparation of nano NiO

Nickel oxide nanoparticles were prepared through the following process. By maintaining the molar ratio of nickel nitrate hexahydrate to urea at 1 : 4, a stoichiometric amount of Ni(NO₃)₂·6H₂O (0.08 mol) and CO(NH₂)₂ (0.32 mol) were accurately weighed and dissolved into 60 mL of deionized water, respectively. The two solutions were mixed in a beaker and stirred with a magnetic stirrer at room temperature to obtain a homogeneous solution. Thereafter, the mixture was transferred into a round bottom flask, sealed and heated at 115 °C for 1.5 h in an oil bath. In this process, a light green sediment (i.e., the precursor) was formed. After the reaction was completed, the precipitated powders were filtered and washed with deionized water to make them neutral and colorless. This step was undertaken to remove the possibly adsorbed ions and chemicals for reducing the potential of agglomeration. After being dried in an oven at 90 °C for 6 h, the precursors were calcined in a muffle furnace at 400 °C for 1 h to obtain dark-colored products (i.e., NiO nanoparticles). The calcined products were then collected for further analyses.⁵

3.3. General procedure for the preparation of oxindol derivatives

A mixture of indole (2 mmol), isatin (1 mmol), nano-NiO (0.004 g) and water (2 mL) was stirred for the appropriate time at 70 °C, as shown in Tables 3 and 4. Completion of the reaction was indicated by TLC monitoring. After the completion of the reaction, the reaction mixture was dissolved in acetone and the catalyst was isolated by centrifugation. The product was afforded by evaporating the solvent and was recrystallized from EtOH to afford the pure products in high purity and yield. Structural assignments of the products are based on their ¹H NMR, ¹³C NMR and IR spectra.

3.4. Spectral data for selected products

3,3-Diindolyloxindole (compound 1, Table 3). White solid, m.p > 250 °C; ¹H NMR (250 MHz, DMSO-d₆) 6.79 (2H, m, ArH), 6.84 (2H, m, ArH), 6.92 (1H, m, ArH), 6.97–7.02 (3H, m, ArH), 7.22 (4H, m, ArH), 7.35 (2H, m, ArH), 10.58 (1H, s, N–H), 10.94 (2H, br s, N–H); ¹³C NMR (62.9 MHz, DMSO) 53.4, 110.4, 112.4, 115.2, 119.1, 121.6, 121.8, 122.3, 125.1, 125.8, 126.6, 128.7, 135.5, 137.8, 142.2, 179.6; IR (KBr, cm⁻¹) 3420, 3300, 1704, 1610, 1105, 737 cm⁻¹; Anal. calcd for C₂₄H₁₇N₃O: C, 79.32; H, 4.72; N, 11.56. Found: C, 79.39; H, 4.68; N, 11.63.

3,3-Diindolyl-5-bromooxindole (compound 3, Table 3). White solid, mp > 250 °C; ¹H NMR (DMSO-d₆) 6.81 (2H, t, ArH), 6.88 (2H, s, ArH), 6.96 (1H, m, ArH), 7.03 (2H, m, ArH), 7.21 (2H, m, ArH), 7.30 (1H, s, ArH), 7.38 (2H, m, ArH), 7.43 (1H, m, ArH), 10.77 (1H, s, NH), 11.03 (2H, s, NH) ppm; ¹³C NMR (DMSO-d₆) 53.64, 112.65, 114.00, 114.35, 119.23, 119.35, 121.35, 121.94, 125.21, 125.35, 126.34, 128.22, 137.79, 137.84, 141.53, 179.11 ppm; IR (KBr, cm⁻¹): 3340, 3120, 1699 cm⁻¹; anal. calcd for C₂₄ H₁₆BrN₃O: C, 65.17; H, 3.65; N, 9.50. Found: C, 65.11; H, 3.49; N, 9.62.

3,3-Bis(2-methylindolyl)oxindole (compound 9, Table 3). White solid, mp > 250 °C; ¹H NMR (DMSO-d₆) 1.95 (3H, s, Me), 2.09 (3H, s, Me), 6.47 (1H, m, ArH), 6.61–6.66 (2H, m, ArH), 6.71 (1H, m, ArH), 6.85–6.92 (3H, m, ArH), 6.96 (1H, m, ArH), 7.16 (1H, m, ArH), 7.21–7.24 (3H, m, ArH), 10.57 (1H, s, NH), 10.87 (1H, s, NH), 10.90 (1H, s, NH) ppm; ¹³C NMR (DMSO-d₆) 13.87, 14.05, 53.28, 110.21, 110.29, 111.21, 111.27, 118.78, 118.84, 120.15, 120.21, 120.46, 120.63, 122.13, 126.32, 127.90, 128.54, 128.68, 132.84, 134.81, 135.76, 135.83, 136.44, 142.06, 180.21 ppm; IR (KBr, cm⁻¹) 3400, 3250, 1700 cm⁻¹; anal. calcd for C₂₆H₂₁N₃O: C, 79.77; H, 5.41; N, 10.73. Found: C, 79.85; H, 5.32; N, 10.64.

Conclusions

In summary, we describe an efficient protocol for the preparation of diindolyloxindole derivatives. The procedure offers several advantages, including the use of an inexpensive and readily available catalyst, mild reaction conditions and high yields of the products, as well as simple experimental and isolation procedures. All these advantages make this protocol a useful and attractive procedure for the synthesis of oxindole derivatives.

Acknowledgements

We gratefully acknowledge the support of this work by the Birjand University Research Council.

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