A pseudo six-component process for the synthesis of tetrahydrodipyrazolo pyridines using an ionic liquid immobilized on a FeNi₃ nanocatalyst

Abstract

A highly efficient method for the synthesis of tetrahydrodipyrazolopyridines by a multicomponent reaction of ethyl acetoacetate, an aldehyde, hydrazine and ammonium acetate using an ionic liquid (IL) supported on a FeNi₃ nanocatalyst is described. This method provides several advantages including mild reaction conditions, applicability to a wide range of substrates, reusability of the catalyst and little catalyst loading.

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1. Introduction

Pyrazolopyridines represent a common scaffold in numerous bioactive compounds and have a number of pharmacological properties. The pyrazolopyridines exhibit important biological properties such as anti-virual,¹ anti-leishmania,² protein kinase inhibition,³ PDE4B inhibition,⁴ HIF 1-α-prolyl hydroxylase inhibition,⁵ B-Raf^V600E inhibition,⁶ and dopaminergic properties.⁷ The synthesis of pyrazolopyridines has been reported using MCRs in the presence of diverse catalysts including carbonaceous material (C–SO₃H),⁸ L-proline,⁹ acetic acid,¹⁰ and p-TSA.¹¹ Many methods for the synthesis of pyrazolopyridines are known, but some of these methods have certain drawbacks, including long reaction times, use of toxic and non-reusable catalyst and utilize of specific conditions. Therefore, looking for efficient and simple methods for the synthesis of pyrazolopyridines is an attractive challenge. For this reason, multicomponent reactions (MCRs) are particularly well suited for diversity-oriented synthesis.^12,13 Thus; the synthesis pyrazolopyridines by the multicomponent reactions with a heterogeneous catalyst could enhance their efficiency from economic and ecological points of view. To overcome the separation problems of the nanocatalysts, magnetic materials have emerged as recoverable catalysts. Separation of magnetic nanoparticles is easy, convenient, economical and environmentally benign.^14,15 One of the most attractive alternatives to catalyst supports are magnetic nanoparticles (MNPs), which have witnessed increasing popularity due to their high surface areas and improved disperse ability in the reaction medium. In recent years, ionic liquids (ILs) as being environmental-friendly reaction media had attracted significant attention for their unique properties, such as high thermal stability, negligible vapor pressure, suitable solvents, high viscosity, and catalysis activities.^16–18 Although ILs possess some advantages but their useful applications have been limited by some difficulties in its recovery which lead to economical and environmental problems. These problems can be overcome by immobilization of ILs onto solid supports to obtain heterogeneous catalysts.¹⁹ FeNi₃ core–shell nanoparticles were used as a suitable catalyst in many reactions including synthesis of 1,3-thiazolidin-4-one,²⁰ triazolo[1,2-a]indazole-triones,²¹ and synthesis of 4H-benzo[b]pyrans.²² Recently, immobilized functional ionic liquids as efficient, green, and reusable catalysts have been described by Yang et al. and the results are compared with those of traditional ILs.²³ Herein, we reported the use of ionic liquid (ILs) supported on FeNi₃ nanocatalysis as an efficient catalyst for the preparation of tetrahydrodipyrazolo pyridines by multicomponent reaction of ethyl acetoacetate, aldehydes, hydrazine and ammonium acetate under reflux conditions in ethanol (Scheme 1).

Scheme 1 Synthesis of tetrahydrodipyrazolo pyridines by FeNi₃-ILs nanocatalyst.

2. Results and discussion

At first FeNi₃ nanoparticles were prepared according to method reported in the literature with some modifications.^20,24 (Scheme 2). Nano-FeNi₃ was capped with SiO₂ generated from the hydrolyzation of tetraethyl orthosilicate (TEOS). After being coated with a SiO₂ and organic layer, the typical core–shell structure of the FeNi₃-ILs MNPs can be observed. The structural properties of synthesized FeNi₃-ILs MNPs were analyzed by X-ray power diffraction (XRD). As shown in Fig. 1.

Scheme 2 Schematic illustration of the synthesis for FeNi₃-ILs MNPs.

Fig. 1 XRD analysis of FeNi₃-ILs MNPs.

In order to investigate the morphology and particle size of nanoparticles, SEM image of nanoparticles was presented in Fig. 2. The SEM image shows particles with diameters in the range of nanometers. The results show that FeNi₃-ILs MNPs were obtained with an average diameter of 30–35 nm as conformed by XRD analysis.

Fig. 2 SEM images of FeNi₃-ILs MNPs.

This structure was further supported by the FT-IR spectra. The FT-IR spectrum of FeNi₃-ILs MNPs showed the typical bands at 2920 and 2850 cm⁻¹ attributed to C–H stretching vibrations of alkyl chains. Moreover, the broad peak at 1053 cm⁻¹ belonged to S=O stretching vibrations in the sulphonate functional groups. Bands at 1628 and 1506 cm⁻¹ were related to N–H bending vibrations in the ammonium groups. These results indicated that IL was successfully immobilized on FeNi₃ MNPs (Fig. 3).

Fig. 3 FTIR spectra of FeNi₃-ILs MNPs.

The magnetic properties of the nanoparticles were characterized using a vibrating sample magnetometer (VSM). Magnetic measurement shows that FeNi₃, and FeNi₃-ILs MNPs have saturation magnetization values of 59.2, and 39.1 emu g⁻¹ respectively (Fig. 4). These results exhibit that catalyst can be easily separated and recovered by an external magnetic field.

Fig. 4 Room-temperature magnetization curves of the nanocatalysis.

Initially, we carried out the MCR between hydrazine hydrate, ethyl acetoacetate, 4-nitrobenzaldehyde and ammonium acetate under reflux condition in ethanol as a model reaction in the presence of different catalyst. Meanwhile, we observed the effect of different solvents on the progress of reaction. Ethanol was found to be the best solvent, in which the product was obtained in 92% yield. Unfortunately, when the model reaction was carried out in water, the desired product was only obtained in 58% yield.

The model reaction was carried out in the presence of various nanocatalysts such as Et₃N, K₂CO₃, ZnO, CuO, FeCl₃, FeNi₃ NPs, ZnO-ILs and CuO-ILs NPs and FeNi₃-ILs MNPs. When the reaction was carried out using FeNi₃-ILs MNPs (0.002 g) as the catalyst, the products were obtained in good to high yields.

Table 1 shows the influence of particles size on the activity of FeNi₃-ILs MNPs in the synthesis of tetrahydrodipyrazolopyridines. However, the activity of catalysts is influenced by the acid–base properties and many other factors such as size, surface area, geometric structure (particularly pore structure), the distribution of sites and the polarity of the surface sites.²⁵ In this work, we evaluates an example in solid-based heterogeneous catalytic systems that have been developed with the aid of ILs. FeNi₃–SO₃^{− +}NH₃–CH₂CH₂–OH composed of FeNi₃–SO₃⁻ as anion and ⁺NH₃–CH₂CH₂–OH as cation.

Table 1 Optimization of reaction conditions using different catalysts^a

Entry	Catalyst	Solvent (reflux)	Time (min)	Yield^b, %
a Hydrazine hydrate (2 mmol), ethyl acetoacetate (2 mmol), 4-nitrobenzaldehyde (1 mmol) and ammonium acetate (4 mmol).b Isolated yield.
1	—	EtOH	300	53
2	—	H2O	360	35
3	Et3N (10 mol%)	EtOH	600	58
4	K2CO3 (5 mol%)	EtOH	600	62
5	ZnO NPs (3 mol%)	EtOH	480	65
6	CuO NPs (3 mol%)	EtOH	480	62
7	FeCl3 (5 mol%)	EtOH	250	65
8	FeNi3 NPs (2 mol%)	EtOH	280	74
9	ZnO-ILs NPs (0.003 g)	EtOH	50	85
10	CuO-ILs NPs (0.003 g)	EtOH	50	80
11	FeNi3-ILs MNPs ≈ 30–35 nm (0.001 g)	EtOH	50	87
12	FeNi3-ILs MNPs ≈ 30–35 nm (0.002 g)	EtOH	40	92
13	FeNi3-ILs MNPs ≈ 50–55 nm (0.002 g)	EtOH	40	88
14	FeNi3-ILs MNPs ≈ 30–35 nm (0.003 g)	EtOH	40	92
15	FeNi3-ILs MNPs ≈ 30–35 nm (0.002 g)	H2O	70	58
16	FeNi3-ILs MNPs ≈ 30–35 nm (0.002 g)	CH3CN	60	72
17	FeNi3-ILs MNPs ≈ 30–35 nm (0.002 g)	DMF	60	63
18	HO–CH2–CH2–NH3^+ −OOCH (20 mol%)	EtOH	80	68
19	HO–CH2–CH2–NH3^+ −OOCH (30 mol%)	Solvent-free	80	73
20	HO–CH2–CH2–NH3^+ −OOCH3 (30 mol%)	Solvent-free	80	78
21	[HO3SO–CH2–CH2–NH2^+–SO3H]HSO4^− (30 mol%)	Solvent-free	80	84

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We also investigated recycling of FeNi₃-ILs MNPs as catalyst under reflux conditions in ethanol. After completion of the reaction, the catalyst was separated using an external magnet, washed with methanol and dried with a vacuum pump. The catalyst could be reused for eight times with a minimal loss of activity. Perhaps, activity of FeNi₃-ILs MNPs is decreased by the number of the regeneration (yields 92 to 89%) (Fig. 5).

Fig. 5 Reusability of FeNi₃-ILs MNPs as catalyst for the synthesis of 5a.

The extreme stability of the FeNi₃-ILs MNPs is mainspring of the continuous and high catalytic activity. The morphology of FeNi₃-ILs MNPs was investigated by scanning electron microscopy (SEM) before use and after reuse of seven times with images shown in Fig. 6. Interestingly, the shape and size of the nanoparticles remained unchanged before and after reaction. We suppose that, this is also the possible reason for the extreme stability of the FeNi₃-ILs MNPs presented herein.

Fig. 6 SEM of FeNi₃-ILs MNPs (a) before use (b) after reuse of seven times.

With these hopeful results in hand, we turned to explore the scope of the reaction using diverse aromatic aldehydes as substrates under the optimized reaction conditions (Table 2). In general the reactions are clean and high-yielding. Several functional groups, such as Br, Cl, OH, NO₂, OMe, N(CH₃)₂, and CH₃, are compatible under the reaction conditions. Interestingly, a variety of aromatic aldehydes, including ortho, meta and para-substituted aryl aldehydes, participated well in this reaction and gave the corresponding products in a good to excellent yield (Table 2). The influence of electron-withdrawing and electron-donating substituents on the aromatic ring of aldehydes upon the reaction yields was investigated. It was shown that aromatic aldehydes with electron-withdrawing groups reacted faster than those with electron-releasing groups. Meanwhile, the practicable synthetic efficiency of this reaction was highlighted by the reaction of terephthaldehyde, hydrazine hydrate, and ammonium acetate and ethyl acetoacetate to give 5l (Scheme 3).

Table 2 Synthesis of tetrahydrodipyrazolo pyridines by FeNi₃-ILs nanocatalyst^a

Entry	5a–5l	Aldehyde	Product	Time (min)	Yield%	Mp (ref.)
a Isolated yield.
1	5a			40	92	>300 (26)
2	5b			45	84	286–288 (26)
3	5c			52	78	244–246 (26 and 28)
4	5d			50	80	185–187 (26)
5	5e			48	86	240–242 (26)
6	5f			54	82	290–292
7	5g			44	90	254–256 (26 and 28)
8	5h			47	88	165–167 (27)
9	5i			43	85	240–242 (26)
10	5g			50	82	267–268 (27)
11	5k			53	84	187–188 (27)
12	5l			55	89	>300

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Scheme 3 Synthesis of 1,4-bis[(1,4,7,8-tetrahydro-3,5-dimethyldipyrazolo[3,4-b:4′,3′-e]pyridin-4-yl)] benzene by FeNi₃-ILs nanocatalyst.

A plausible mechanism for the preparation of tetrahydrodipyrazolo pyridines using FeNi₃-ILs MNPs is shown in Scheme 4. The mechanism involves the initial nucleophilic attack of hydrazine on the ethyl acetoacetate and subsequent cyclization to form the pyrazolone and then, the reaction of pyrazolone with an aldehyde to give intermediate II. In the next step, the reaction can be followed by attack of the second pyrazolone ring that leads to the formation of III. Finally, nucleophilic attack of ammonia on intermediate III followed by intramolecular cyclization leads to product 5. The FeNi₃-ILs MNPs has the active sites of NH₃⁺ as cation and FeNi₃–SO₃⁻ as anion.

Scheme 4 Proposed mechanism for the pseudo six-component process.

3. Experimental

3.1. Chemicals and apparatus

The products were isolated and characterized by physical and spectral data. ¹H NMR and ¹³C NMR spectra were recorded on Bruker Avance-400 MHz spectrometers in the presence of tetramethylsilane as internal standard. The IR spectra were recorded on FT-IR Magna 550 apparatus using with KBr plates. Melting points were determined on Electro thermal 9200, and are not corrected. The elemental analyses (C, H, N) were obtained from a Carlo ERBA Model EA 1108 analyzer. FeNi₃ and FeNi₃-ILs MNPs have been measured with a vibrating sample magnetometer (VSM, PPMS-9T) at 300 K in Iran (Kashan University). Powder X-ray diffraction (XRD) was carried out on a Philips diffractometer of X'pert Company with monochromatized Cu Kα radiation (λ = 1.5406 Å). Microscopic morphology of products was visualized by SEM (ZEISS).

3.2. Preparation of FeNi₃ nanoparticles

FeCl₂·4H₂O and NiCl₂·6H₂O (the total amount of Fe²⁺ and Ni²⁺ was 0.04 mol) were dissolved into 200 mL deionized water to form a preliminary reaction solution. Certain amounts of sodium hydroxide (NaOH) solution were added into the former solution with moderate stirring. Adjust the amount of added NaOH solution carefully so that the pH value was in the range 10 ≤ pH ≤ 13. At this moment, a dark brown suspension was formed. 0.16 mol aqueous hydrazine (N₂H₄·H₂O, 80% concentration) was then added into the above suspension. This reaction was continued for about 24 h. During this period, the pH value was kept in the range 10 ≤ pH ≤ 13 by adding NaOH. Final resulting particles were separated magnetically and washed repeatedly until the pH value was 7. The suspension was repeatedly washed, filtered for several times and dried at 100 °C in the air.

3.3. General procedure for the preparation of FeNi₃/SiO₂ nanoparticles

FeNi₃-ILs MNPs was prepared according to the procedure reported in the literature with some modification.²⁰ Firstly, a mixture of ethanol (100 mL) and distilled water (20 mL) was added to magnetic nanoparticles (FeNi₃ NPs) (1 g), and the resulting dispersion was sonicated for 15 min. After adding ammonia water (3 mL), tetraethyl orthosilicate (TEOS, 2.2 mL) was added to the reaction solution. The resulting dispersion was under mechanically stirred continuously for 20 h at room temperature. The magnetic FeNi₃/SiO₂ nanoparticles were collected by magnetic separation and washed with ethanol and deionized water in sequence.

3.4. General procedure for the preparation of FeNi₃/SiO₂/SO₃H nanoparticles

To a round-bottomed flask (100 mL) FeNi₃/SiO₂ MNPs (0.40 g) in CH₂Cl₂ (50 mL), was added chlorosulfonic acid (12 mmol) dropwise over a period of 20 min at room temperature (Fig. 1). After vigorous stirring for 24 h, the magnetic FeNi₃/SiO₂/SO₃H nanoparticles were collected by magnetic separation and washed with ethanol and deionized water in sequence.

3.5. General procedure for the preparation of FeNi₃-ILs nanoparticles

Ethanolamine (5 mmol) was dispersed in dry CH₂Cl₂ (20 mL) and FeNi₃/SiO₂/SO₃H (0.1 g) nanoparticles were added. Then the mixture was heated to 60 °C for 15 h under nitrogen atmosphere. The resulting solid was separated by an external magnet and washed 4 times with CH₂Cl₂, ethanol and H₂O. After drying at room temperature in vacuum, FeNi₃-ILs was obtained as reddish-brown powder.

3.6. General procedure for the preparation of tetrahydrodipyrazolopyridines

A mixture of hydrazine hydrate 80% (2.0 mmol) and ethyl acetoacetate (2.0 mmol) and FeNi₃-ILs MNPs (0.002 g) in EtOH (5 mL) was magnetically stirred at 25 °C followed by addition of aldehyde (1.0 mmol) and ammonium acetate (4.0 mmol). The reaction mixture was heated at reflux for 40–50 min and then cooled to 25 °C. After completion of the reaction monitored by TLC, 10 mL ethanol was added to the reaction mixture and the catalyst FeNi₃-ILs MNPs was separated by external magnetic field. The precipitate was washed with EtOH to afford the pure product and then dried well under vacuum pump.

3.7. Spectral data

3,5-Dimethyl-4-(4-nitro-phenyl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b;4′,3′-e]pyridine (5a). Cream solid; mp 295–297 °C; IR (KBr): ν_max 3400, 2963, 1603, 1511, 1348, 1177, 846 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 2.07 (s, 6H), 4.95 (s, 1H), 7.34–7.36 (d, 2H, J = 8 Hz), 8.09–8.11 (d, 2H, J = 8 Hz), 11.25 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 10.75, 33.43, 103.62, 123.46, 129.25, 140.18, 146.09, 152.24, 161.34 ppm; anal. calcd for C₁₅H₁₄N₆O₂: C, 58.06; H, 4.55; N, 27.08; found C, 58.12; H, 4.50; N, 27.15.

3,5-Dimethyl-4-(3-nitro-phenyl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b;4′,3′-e]pyridine (5b). Cream solid; mp 286–288 °C; IR (KBr): ν_max 3200, 2963, 2855, 1599, 1347 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 2.05 (s, 6H), 4.97 (s, 1H), 7.52 (m, 2H), 7.93 (s, 1H), 8.02 (d, 1H, J = 8 Hz), 11.25 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 10.74, 33.11, 103.74, 121.22, 122.32, 129.72, 135.20, 140.22, 146.26, 148.05, 161.3 ppm; anal. calcd for C₁₅H₁₄N₆O₂: C, 58.06; H, 4.55; N, 27.08; found C, 58.16; H, 4.48; N, 27.14.

3,5-Dimethyl-4-(4-methyl-phenyl)-1,4,7,8-tetrahydro dipyrazolo[3,4-b;4′,3′-e]pyridine (5c). White solid; mp 243–245 °C; IR (KBr): ν_max 3300, 2924, 1602, 1512 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 2.04 (s, 6H), 2.21 (s, 3H), 4.74 (s, 1H), 6.98–7.00 (m, 4H), 11.24 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 10.84, 20.95, 32.84, 104.82, 127.81, 128.80, 134.68, 140.21, 140.72, 161.52 ppm; anal. calcd for C₁₆H₁₇N₅: C, 68.79; H, 6.13; N, 25.07; found C, 68.71; H, 6.22; N, 25.12.

3,5-Dimethyl-4-(4-methoxy-phenyl)-1,4,7,8-tetrahydro dipyrazolo[3,4-b;4′,3′-e]pyridine (5d). Cream solid; mp 186–188 °C; IR (KBr): ν_max 3267, 2924, 1597, 1510, 1348, 1239, 792 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 2.04 (s, 6H), 3.69 (s, OCH₃), 4.74 (s, 1H), 6.74–6.76 (d, 2H, J = 8 Hz), 6.99–7.01 (d, 2H, J = 8 Hz), 11.32 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 10.82, 32.40, 55.51, 104.92, 113.53, 128.82, 135.66, 140.12, 140.18, 157.68 ppm; anal. calcd for C₁₆H₁₇N₅O: C, 65.07; H, 5.80; N, 23.71; found C, 65.12; H, 5.89; N, 23.75.

1,4,7,8-Tetrahydro-3,5-dimethyl-4-phenyldipyrazolo-[3,4-b:4′,3′-e]pyridine (5e). White solid; mp 240–242 °C; IR (KBr): ν_max 3181, 2924, 1600, 1523, 1484, 725 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 2.04 (s, 6H), 4.79 (s, 1H), 7.09–7.19 (m, 5H), 11.34 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 10.84, 33.24, 104.65, 125.84, 127.92, 128.16, 140.24, 143.82, 161.54 ppm; anal. calcd for C₁₅H₁₅N₅: C, 67.90; H, 5.70; N, 26.40; found C, 67.95; H, 5.76; N, 26.49.

3,5-Dimethyl-4-(2-methyl-phenyl)-1,4,7,8-tetrahydro dipyrazolo[3,4-b;4′,3′-e]pyridine (5f). White solid; mp 290–292 °C; IR (KBr): ν_max 3300, 2923, 1602, 1527, 1448, 747 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 1.87 (s, 6H), 2.09 (s, 3H), 4.91 (s, 1H), 7.03–7.17 (m, 4H), 10.65 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 10.88, 20.73, 32.83, 104.80, 125.51, 127.80, 128.85, 129.34, 134.69, 140.24, 140.74, 161.69 ppm; anal. calcd for C₁₆H₁₇N₅: C, 68.79; H, 6.13; N, 25.07; found C, 68.88; H, 6.10; N, 25.17.

3,5-Dimethyl-4-(4-chloro-phenyl)-1,4,7,8-tetrahydro di pyrazolo[3,4-b;4′,3′-e]pyridine (5g). White solid; mp 255–257 °C; IR (KBr): ν_max 3180, 2924, 1597, 1487, 1142, 1091 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 2.05 (s, 6H), 4.79 (s, 1H), 7.09–7.11 (d, J = 8 Hz, 2H), 7.24–7.26 (d, J = 8 Hz, 2H), 11.50 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 10.78, 32.67, 104.34, 128.06, 129.85, 130.49, 140.16, 142.78, 161.46 ppm; anal. calcd for C₁₅H₁₄ClN₅: C, 60.10; H, 4.71; N, 23.36; found C, 60.15; H, 4.78; N, 23.29.

3,5-Dimethyl-4-(4-bromo-phenyl)-1,4,7,8-tetrahydro di pyrazolo[3,4-b;4′,3′-e]pyridine (5h). Yellow solid; mp 165–167 °C; IR (KBr): ν_max 3100, 2924, 1598, 1487, 1142, 753 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 2.06 (s, 6H), 4.78 (s, 1H), 7.03–7.05 (d, J = 8 Hz, 2H), 7.39–7.41 (d, J = 8 Hz, 2H), 11.50 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 10.23, 32.43, 104.45, 118.30, 129.62, 130.34, 131.85, 142.66, 157.42 ppm; anal. calcd for C₁₅H₁₄BrN₅: C, 52.34; H, 4.10; N, 20.35; found C, 52.39; H, 4.15; N, 20.31.

4-(1,4,7,8-Tetrahydro-3,5-dimethyldipyrazolo[3,4-b:4′,3′-e]pyridin-4-yl)-N,N-dimethylaniline (5i). Cream solid; mp 240–242 °C; IR (KBr): ν_max 3200, 2950, 1598, 1470, 1145, 751 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 2.04 (s, 6H), 2.98 (s, 6H), 4.64 (s, 1H), 6.56–6.58 (d, J = 8 Hz, 2H), 6.90–6.92 (d, J = 8 Hz, 2H), 11.28 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 10.84, 32.35, 40.92, 105.23, 112.73, 128.35, 131.64, 137.02, 149.05, 161.66 ppm; anal. calcd for C₁₇H₂₀N₆: C, 66.21; H, 6.54; N, 27.25; found C, 66.33; H, 6.59; N, 27.37.

3,5-Dimethyl-4-(4-hydroxy-phenyl)-1,4,7,8-tetrahydro di pyrazolo[3,4-b;4′,3′-e]pyridine (5j). White solid; mp 267–268 °C; IR (KBr): ν_max 3266, 2924, 1562, 1465, 1142, 859 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 2.03 (s, 6H), 4.65 (s, 1H), 6.56–6.58 (d, J = 8 Hz, 2H), 6.88–6.90 (d, J = 8 Hz, 2H), 9.10 (s, OH), 11.50 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 10.32, 31.75, 104.5, 114.42, 128.23, 133.35, 139.76, 155.03, 161.04 ppm; anal. calcd for C₁₅H₁₅N₅O: C, 64.04; H, 5.37; N, 24.90; found C, 64.09; H, 5.30; N, 24.82.

3,5-Dimethyl-4-(2-nitro-phenyl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b;4′,3′-e]pyridine (5k). Cream solid; mp 187–188 °C; IR (KBr): ν_max 3300, 2925, 1604, 1550, 1348, 1177, 846 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 1.90 (s, 6H), 5.43 (s, 1H), 7.36–7.68 (m, 4H), 10.95 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 10.02, 28.94, 101.94, 123.85, 127.12, 130.22, 131.64, 136.24, 138.62, 149.50, 160.54 ppm; anal. calcd for C₁₅H₁₄N₆O₂: C, 58.06; H, 4.55; N, 27.08; found C, 58.15; H, 4.43; N, 27.12.

1,4-Bis[(1,4,7,8-tetrahydro-3,5-dimethyldipyrazolo[3,4-b:4′,3′-e]pyridin-4-yl)] benzene (5l). Orange solid, mp > 300 °C; IR (KBr): ν_max 3186, 1591, 1508, 1200, 785, 608 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 2.05 (s, 12H), 4.70 (s, 2H), 6.94 (4H), 11.25 (s, 6H) ppm; ¹³C NMR (100 MHz, DMSO-d₆) δ 10.70, 33.20, 104.55, 129.34, 134.43, 139.50, 160.20 ppm; anal. calcd for C₂₄H₂₄N₁₀: C, 63.70; H, 5.35; N, 30.95; found C, 63.79; H, 5.44; N, 30.86; MS (EI, 70 eV): m/z 452 (M⁺).

4. Conclusions

In conclusion, we have developed a straightforward and efficient approach to synthesis of tetrahydrodipyrazolopyridines by a simple one-pot pseudo six-component reaction of hydrazine hydrate, ethyl acetoacetate, aldehydes and ammonium acetate in the presence of FeNi₃-ILs nanoparticles as catalyst.

The procedure offers several advantages including short reaction times, a simple procedure, high atom economy; excellent yields, reusability of the catalyst and little catalyst loading. This green nanocatalyst could be used for other significant organic reactions and transformations. Further explorations of similar protocols are underway in our laboratory. Meanwhile, this recoverable catalyst will provide a regular platform for heterogeneous catalysis, green chemistry, and environmentally benign protocols in the near future. We hope that this article will serve to stimulate research in this fascinating and very useful area of organic synthesis.

Acknowledgements

The authors acknowledge a reviewer who provided helpful insights. The authors are grateful to University of Kashan for supporting this work by Grant No. 159196/XXI.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra02906j

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