Pseudo five-component process for the synthesis of 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol) derivatives using ZnAl₂O₄ nanoparticles in aqueous media

Abstract

In the present paper, we report the successful synthesis of zinc aluminate nanoparticles by the co-precipitation method using aqueous ammonia solution as the precipitating agent. ZnAl₂O₄ nanoparticles have been used as an efficient catalyst for the preparation of 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol) derivatives by pseudo five-component reaction of hydrazine hydrate, ethyl acetoacetate and aldehydes at 60 °C in water. Atom economy, wide range of products, excellent yields in short time and environmental benignity are some of the important features of this protocol.

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1. Introduction

The pyrazole ring system is a structural sector of a large number of biologically active compounds. The pyrazole derivatives exhibit important biological properties such as anti-inflammatory and hypnotic activity,¹ antifungal activity against three phytopathogenic fungi, namely Helminthosporium species, Fusarium oxysporum and Alternaria alternate,² suppress A549 lung cancer cell growth,³ nonnucleoside HIV-1 reverse transcriptase inhibitors with enhanced activity versus the P236L mutant,⁴ antibacterial,⁵ and antidepressant.⁶ Some other examples of pyrazole derivatives such as celecoxib, SC-558, mefobutazone, and deracoxib have been reported as potent NSAIDs.⁷ 4,4-(Arylmethylene)bis(1H-pyrazol-5-ols) show excellent antiviral activity against the peste des petits ruminants virus (PPRV).⁸ Therefore, the development of simple methods for the synthesis of pyrazoles is an important challenge. Undoubtedly, the synthesis of pyrazole derivatives through multicomponent reactions (MCR) has been paid much attention owing to excellent synthetic efficiency, inherent atom economy, procedural simplicity, and environmental friendliness. Therefore, the design of novel MCRs for the synthesis of diverse groups of compounds, especially the ones that are biologically active, has commanded vast attention.^9–13

The possibility of accomplishing multicomponent reactions under mild conditions with a heterogeneous catalyst could improve their effectiveness from cost-effectiveness and ecological points of view. Theoretically, nanoscale heterogeneous catalysts should present higher surface areas, which are mainly responsible for their catalytic activity. These surface atoms behave as the centers where the chemical reactions could be catalytically activated. These advances have opened the door for the design of new nanocatalysts for particular applications in synthetic chemistry. Recently, nanoparticle catalysts have emerged as an alternative approach for the development of many significant organic reactions. Ideally, they introduce neat processes and utilize eco-friendly and green catalysts which can simply be recycled at the end of reactions, which has led to them receiving remarkable attention in recent years.^14–18 Among various inorganic solids, spinel-type mixed oxides (AB₂O₄) are well known for their rich catalytic action. ZnAl₂O₄ is generally used as a catalytic, ceramic, electronic material and is emerging as one of the best wide band gap compound semi-conductor (E_g = 3.8 eV) for various optoelectronic applications.¹⁹

ZnAl₂O₄ nanoparticles acting as a lubricating additive can considerably improve the anti-wear and anti-friction performance of lubricant oils and have large potential in lubrication.²⁰ ZnAl₂O₄ has remarkable potential for photocatalytic air purification, particularly for the removal of toxic aromatic compounds.²¹ For stoichiometric materials, the basicity scale is MgO > ZnO > MgA1₂O₄ ≈ ZnAl₂O₄ ≈ A1₂O₃. Thus, the basic site distributions on the two normal spinel aluminates MgA1₂O₄ and ZnAl₂O₄ are apparently very similar to each other.²² Zinc aluminate (ZnAl₂O₄) has been used extensively as a heterogeneous catalyst in many reactions, such as acetylation of amines, alcohols and phenols under solvent-free conditions²³ and the synthesis of xanthene derivatives.²⁴ They can be recovered easily from the reaction mixture by simple filtration, and reused several times without appreciable loss of activity. In general, there are many methods of preparation of ZnAl₂O₄ such as: co-precipitation,²⁵ hydrothermal,^26,27 microwave-hydrothermal,²⁸ combustion,²⁹ and modified sol–gel.³⁰ Compared with other techniques, the co-precipitation method is a simple and attractive procedure for the preparation of ZnAl₂O₄ nanoparticles.

Recently, pyridine trifluoroacetate or acetic acid,³¹ phosphomolybdic acid,³² sulfuric acid ([3-(3-silicapropyl) sulfanyl]propyl)ester (SASPSPE),³³ silica-bonded N-propyltri-ethylenetetramine³⁴ and sodium dodecyl sulfate³⁵ were reported for the synthesis of 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol) derivatives. Herein we report the use of ZnAl₂O₄ nanoparticles as an efficient catalyst for the preparation of 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol) derivatives by the pseudo five-component reaction of hydrazine hydrate, ethyl acetoacetate and aldehydes at 60 °C in water (Scheme 1).

Scheme 1 Synthesis of 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol) derivatives via ZnAl₂O₄ nanoparticle-catalyzed multicomponent reactions of hydrazine hydrate, ethyl acetoacetate and aldehydes.

2. Results and discussion

The catalyst was prepared by the co-precipitation method using aqueous ammonia solution as the precipitating agent. Zn(NO₃)₂·6H₂O and Al(NO₃)₃·9H₂O were used as the starting materials for the synthesis of zinc aluminate nanoparticles (Fig. 1). This method is simple and inexpensive. The XRD patterns for ZnAl₂O₄ are shown in Fig. 2. The particle size of ZnAl₂O₄ nanoparticles was investigated by XRD pattern. The crystallite size diameter (D) of the ZnAl₂O₄ nanoparticles has been calculated using the Debye–Scherrer equation (D = Kλ/β cos θ), where FWHM (full-width at half-maximum) is in radians and θ is the position of the maximum of the diffraction peak, K is the so-called shape factor, which usually takes a value of about 0.9, and λ is the X-ray wavelength. The pattern agrees well with the reported pattern for ZnAl₂O₄ nanoparticles (JCPDS no. 82-1043). The average particle size was estimated by applying the Scherrer formula on the highest intensity peak. An average size of around 21–25 nm was obtained. Fig. 3 shows a FTIR spectrum of nano ZnAl₂O₄. The bands at 682 cm⁻¹, 557 cm⁻¹ and 495 cm⁻¹ were assigned to the stretching and bending mode of Al–O. The morphology and particle size of ZnAl₂O₄ NPs was investigated by scanning electron microscopy (SEM) as shown in Fig. 4. The SEM images show particles with diameters in the nanometer range.

Fig. 1 Flow chart of ZnAl₂O₄ nanoparticle preparation procedure.

Fig. 2 XRD pattern of ZnAl₂O₄ NPs.

Fig. 3 FTIR spectrum of ZnAl₂O₄ nanoparticles.

Fig. 4 SEM image of ZnAl₂O₄ nanoparticles.

The choice of a suitable reaction medium is of vital importance for successful synthesis. Initially, we had explored and optimized different reaction parameters for the synthesis of 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol) derivatives by the pseudo five-component reaction of hydrazine hydrate, ethyl acetoacetate and 4-nitrobenzaldehyde as a model reaction (Scheme 2). As shown in Table 1, the solvent has a great effect on the acceleration of the reactions. Several reactions were scrutinized using various solvents, such as EtOH, CH₃CN, water, and n-propanol.

Scheme 2 Model reaction for the preparation of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols).

Table 1 Optimization of reaction conditions using different catalysts^a

Entry	Solvent	Catalyst (mol%)	Time (min)	Yield^b %
a Reaction conditions: hydrazine hydrate (2 mmol), ethyl acetoacetate (2 mmol) and 4-nitrobenzaldehyde (1 mmol).b Isolated yields.
1	H2O (80 °C)	H2SO4 (2)	240	30
2	EtOH (reflux)	H2SO4 (2)	300	29
3	EtOH (reflux)	Et3N (10)	190	38
4	CH3CN	Et3N (10)	290	32
5	H2O (70 °C)	Pyridine trifluoroacetate	300	87 (ref. 31)
6	n-Propanol	ZnS (7)	150	43
7	H2O (80 °C)	CuO (7)	120	38
8	H2O (reflux)	CaO (10)	150	35
9	H2O (60 °C)	ZnO (8)	150	51
10	EtOH (reflux)	ZnO (8)	150	45
11	EtOH (reflux)	Al2O3 (6)	165	38
12	EtOH (reflux)	ZnAl2O4 NPs (5)	25	78
13	H2O (reflux)	ZnO NPs	50	63
14	H2O (60 °C)	ZnAl2O4 NPs (2)	14	82
15	H2O (60 °C)	ZnAl2O4 NPs (4)	14	92
16	H2O (60 °C)	ZnAl2O4 NPs (6)	14	92
17	H2O (80 °C)	ZnAl2O4 NPs (4)	14	91

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The best results were obtained at 60 °C in H₂O and the reaction gave satisfying results in the presence of ZnAl₂O₄ nanoparticles (Table 1). When 2, 4 and 6 mol% of ZnAl₂O₄ nanoparticles were used, the yields were 82%, 92% and 92%, respectively. Therefore, 4 mol% of ZnAl₂O₄ nanoparticle was appropriate and an excessive amount of catalyst did not increase the yields considerably. Also, the activity and stability of the ZnAl₂O₄ nanoparticles in water is at a maximum amount compared to other solvents. The model reactions were carried out in the presence of various catalysts, such as CaO, ZnO, CuO, Al₂O₃ and ZnS. When the reaction was carried out using ZnS, ZnO NPs and ZnAl₂O₄ NPs as the catalyst, the product could be obtained in a moderate to good yield. Nanoparticles exhibit good catalytic activity because of their large surface area and large number of active sites which are mainly responsible for their catalytic activity.

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 Cl, OH, NO₂, 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. The presence of halogen on the aromatic ring of aldehydes had negligible effect on the reaction results. Aromatic aldehydes having NO₂ group (entries 1 and 2) reacted at a faster rate compared with aromatic aldehydes substituted with other groups. Meanwhile, the practicable synthetic efficiency of this reaction was highlighted by the reaction of terephthaldehyde, hydrazine hydrate and ethyl acetoacetate to give 6j (Scheme 3). Therefore, the synthesis of 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ols) is highly flexible, fruitful, simple and versatile from an organic chemistry viewpoint.

Table 2 Synthesis of 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol) derivatives using ZnAl₂O₄ NPs^a,b

Entry	Aldehyde	Product	Structure (6)	Time (min)	Yield%	M.P °C
a All the reactions were carried out at 60 °C in water.b Isolated yields.
1		6a		14	92	275–278 (ref. 31)
2		6b		16	88	288–291 (ref. 31)
3		6c		23	87	206–207 (ref. 36)
4		6d		28	83	209–211 (ref. 31)
5		6e		22	88	214–216 (ref. 36)
6		6f		28	83	278–280
7		6g		26	85	245–247
8		6h		24	87	267–270 (ref. 31)
9		6i		25	84	265–267
10		6j		28	80	286–288

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Scheme 3 Reaction of terephthaldehyde, hydrazine hydrate and ethyl acetoacetate.

All products were well characterized by IR, ¹H NMR, ¹³C NMR, and elemental analysis. The ¹H NMR spectra in DMSO-d₆ showed a singlet around δ = 11.20–11.58 corresponding to an NH group and a signal around δ = 3.40–3.70 corresponding to an OH group which exchanged with water of DMSO-d₆. Recently, Soleimani and coworkers have developed the synthesis of 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol) derivatives using pyridine trifluoroacetate or acetic acid.³¹ They reported a signal around δ = 3.50–5.50, corresponding to OH and NH groups that are different to our observations.

Meanwhile, short reaction times, excellent yield of products and the use of a green catalyst are some of the important features of this protocol.

A plausible mechanism for the preparation of 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol) derivatives using ZnAl₂O₄ NPs is shown in Scheme 4.

Scheme 4 Proposed reaction pathway for the synthesis of 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol) derivatives by ZnAl₂O₄ NPs.

3. Experimental

3.1. Chemicals and apparatus

All organic materials were purchased commercially from Sigma-Aldrich and Merck, and were used without further purification. All melting points are uncorrected and were determined in capillary tubes on a Boetius melting point microscope. FT-IR spectra were recorded with KBr pellets using a Nicolet Magna-IR 550 spectrometer. NMR spectra were recorded on a Bruker 400 MHz spectrometer with DMSO as the solvent and TMS as the internal standard. Powder X-ray diffraction (XRD) was carried out on a Philips diffractometer from X'pert Company. The microscopic morphology of products was visualized by SEM (MIRA 3 TESCAN).

3.2. Preparation of ZnAl₂O₄ nanoparticles

Nano ZnAl₂O₄ was prepared according to the procedure reported in the literature with some modification.³⁷ The Zn (NO₃)₂·6H₂O aqueous solution (5.94 g (20.0 mmol) in 10 mL) was added to the Al(NO₃)₃·9H₂O aqueous solution (15 g (40.0 mmol) in 10 mL). Then the appropriate amount of aqueous ammonia solution (28 wt%) was added to the above solution, and the mixture was stirred until complete precipitation occurred at pH 9.0. The powder was filtered, washed with distilled water, and dried. Then, the solid was treated at 700 °C for 4 h to obtain the ZnAl₂O₄ nanocrystals.

3.3. General procedure for the preparation of 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ols)

A solution of hydrazine hydrate (2.0 mmol, 1.0 g), ethyl acetoacetate (2.0 mmol, 0.26 g), and ZnAl₂O₄ nanoparticles (4 mol%) as catalyst in water (5 mL) was stirred. (Hydrazine solutions are hazardous because of their toxic, corrosive, flammable or explosive properties. Hydrazine solutions should always be handled with great care. Avoid inhaling the vapours from hydrazine solutions at all times and whenever possible use a reliable fume hood. Avoid skin contact with hydrazine at all times.) After 3 min, aldehyde (1.0 mmol) was added and the mixture stirred at 60 °C for an appropriate time. It was then allowed to cool to room temperature. The formed precipitate was isolated by filtration. The product was dissolved in hot CH₃OH and the catalyst was filtered. After cooling, the crude products were precipitated. The precipitate was washed with EtOH to afford the pure product and then dried well under vacuum pump. The structures of the products were fully established on the basis of their ¹H NMR, ¹³C NMR and FT-IR spectra.

3.4. Spectral data

4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl) (4-nitrophenyl) methyl)-3-methyl-1H-pyrazol-5-ol (6a). White powder, mp 275–278 °C; IR (KBr) (v_max/cm⁻¹): 3392.82, 3104.77, 2931.41, 1600.58, 1515.05, 841.11; ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 2.08 (s, 6H, 2CH₃), 3.38 (2OH exchanged with water of DMSO-d₆), 4.96 (s, 1H, CH), 7.37–8.11 (m, 4H, H-Ar), 11.40 (brs, 2H, 2NH); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 10.3, 33.0, 103.3, 123.0, 128.8, 140.0, 145.6, 151.7, 160.9; anal. calcd for C₁₅H₁₅N₅O₄: C, 54.71; H, 4.59; N, 21.27%. Found: C, 54.65; H, 4.62; N, 21.31%. MS (m/z): 330 (M + 1), 241, 232, 217, 135, 97.

4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl) (3-nitrophenyl) methyl)-3-methyl-1H-pyrazol-5-ol (6b). White powder, mp 288–291 °C; IR (KBr) (v_max/cm⁻¹): 3403.31, 3096.66, 2961.47, 1599.54; ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 2.09 (s, 6H, 2CH₃), 3.42 (2OH exchanged with water of DMSO-d₆), 4.98 (s, 1H, CH), 7.52–8.02 (m, 4H, H-Ar), 11.49 (brs, 2H, 2NH); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 10.2, 32.5, 103.4, 120.8, 121.9, 129.3, 134.6, 140.1, 145.6, 147.6, 160.9. Anal. calcd for C₁₅H₁₅N₅O₄: C, 54.71; H, 4.59; N, 21.27%. Found: C, 54.62; H, 4.46; N, 21.30%. MS (m/z): 330 (M + 1), 241, 232, 217, 135, 97.

4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl) (phenyl)methyl)-3-methyl-1H-pyrazol-5-ol (6c). White solid, mp 206–207 °C; IR (KBr) (v_max/cm⁻¹): 3532.69, 3315.48, 2924.40, 1602.23; ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 2.04 (s, 6H, 2CH₃), 3.36 (2OH exchanged with water of DMSO-d₆), 4.78 (s, 1H, CH), 6.93–7.17 (m, 5H, H-Ar) 11.37 (brs, 2H, 2NH); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 10.20, 33.0, 103.2, 123.0, 128.6, 140.0, 145.4, 151.2, 160.5. Anal. calcd for C₁₅H₁₆N₄O₂: C, 63.37; H, 5.67; N, 19.71%. Found: C, 63.40; H, 5.69; N, 19.65%. MS (m/z): 285 (M + 1), 245, 219, 188, 97.

4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl) (3-hydroxyphenyl) methyl)-3-methyl-1H-pyrazol-5-ol (6d). White powder, mp 209–211 °C; IR (KBr) (v_max/cm⁻¹): 3321.81, 2924.11, 1602.23, 1521.96, 1481.05; ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 2.049 (s, 6H, 2CH₃), 3.372 (2OH exchanged with water of DMSO-d₆), 4.69 (s, 1H, CH), 6.48–6.94 (m, 4H, H-Ar), 9.08 (brs, 1H, OH), 11.34 (brs, 2H, 2NH); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 10.3, 32.5, 104.3, 112.4, 114.5, 118.2, 138.5, 140.1, 144.7, 156.9, 161.1. Anal. calcd for C₁₅H₁₆N₄O₃: C, 59.99; H, 5.37; N, 18.66%. Found: C, 59.96; H, 5.30; N, 18.71%. MS (m/z): 301 (M + 1), 299, 267, 241, 203, 186, 162, 115.

4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl) (4-cholorophenyl) methyl)-3-methyl-1H-pyrazol-5-ol (6e). White solid, mp 214–216 °C; IR (KBr) (v_max/cm⁻¹): 3180.94, 2924.39, 1602.60, 1524.39, 1487.38; ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 2.049 (s, 6H, 2CH₃), 3.40 (2OH exchanged with water of DMSO-d₆), 4.78 (s, 1H, CH), 7.10–7.24 (m, 4H, H-Ar), 11.51 (brs, 2H, 2NH); ¹³C NMR (100 MHz, DMSO-d₆) δ (ppm) 10.3, 33.3, 103.4, 123.4, 128.7, 140.2, 145.8, 151.9, 161.2. Anal. calcd for C₁₅H₁₅ClN₄O₂: C, 56.62; H, 4.74; N, 17.58%. Found: C, 56.49; H, 4.81; N, 17.61%. MS (m/z): 320 (M + 2), 318 (M⁺), 224, 196, 180, 126.

4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl) (o-tolyl)methyl)-3-methyl-1H-pyrazol-5-ol (6f). Pale orange solid, mp 278–280 °C; IR (KBr) (v_max/cm⁻¹): 2923.19, 1602.77, 1529.29, 1484.30, 749.39; ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 1.79 (s, 6H, 2CH₃), 2.11 (s, 3H, CH₃), 3.35 (2OH exchanged with water of DMSO-d₆), 4.93 (s, 1H, CH), 7.04–7.21 (m, 4H, H-Ar), 10.73 (brs, 2H, 2NH); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 10.85, 19.60, 31.47, 103.11, 125.51, 126.05, 128.71, 130.33, 135.86, 138.33, 141.86, 160.89. Anal. calcd for C₁₆H₁₈N₄O₂: C, 64.41; H, 6.08; N, 18.78%. Found: C, 64.50; H, 6.11; N, 18.75%. MS (m/z): 299 (M + 1), 241, 203, 160, 115.

4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl) (m-tolyl)methyl)-3-methyl-1H-pyrazol-5-ol (6g). Pale orange solid, mp 245–247 °C; IR (KBr) (v_max/cm⁻¹): 3350.54, 2922.97, 1602.64, 1455.93; ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 2.05 (s, 6H, 2CH₃), 2.18 (s, 3H, CH₃), 2.75 (2OH exchanged with water of DMSO-d₆), 4.75 (s, 1H, CH), 6.71–7.06 (m, 4H, H-Ar), 11.58 (brs, 2H, 2NH); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 10.82, 21.69, 33.09, 104.80, 125.07, 126.64, 128.13, 128.48, 137.05, 140.45, 143.66, 161.56. Anal. calcd for C₁₆H₁₈N₄O₂: C, 64.41; H, 6.08; N, 18.785%. Found: C, 64.52; H, 6.10; N, 18.73%. MS (m/z): 299 (M + 1), 241, 203, 160, 115.

4-((2,4-Dichlorophenyl) (5-hydroxy-3-methyl-1H-pyrazol-4-yl)methyl)-3-methyl-1H-pyrazol-5-ol (6h). White powder, mp 267–270 °C; IR (KBr) (v_max/cm⁻¹): 3411.32, 2927.52, 1606.81, 1529.31, 1466.81; ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 1.93 (s, 6H, CH₃), 3.36 (2OH exchanged with water of DMSO-d₆), 5.01 (s, 1H, CH), 7.32–7.48 (m, 3H, H-Ar), 11.42 (brs, 2H, 2NH); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 10.3, 31.2, 101.9, 126.6, 128.2, 130.9, 132.0, 133.1, 138.6, 140.1, 160.4. Anal. calcd for C₁₅H₁₄Cl₂N₄O₂: C, 51.01; H, 4.00; N, 15.86%. Found: C, 51.10; H, 4.02; N, 15.77%. MS (m/z): 355 (M + 2), 353 (M⁺), 278, 255, 241, 219, 202, 175, 158, 112.

4-((2-Chlorophenyl) (5-hydroxy-3-methyl-1H-pyrazol-4-yl) methyl)-3-methyl-1H-pyrazol-5-ol (6i). Pale orange solid, mp 265–267 °C; IR (KBr) (v_max/cm⁻¹): 3409.36, 2926.67, 1605.31, 1534.23, 1466.52, 753.07; ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 1.916 (s, 6H, 2CH₃), 3.341 (2OH exchanged with water of DMSO-d₆), 5.06 (s, 1H, CH), 7.19–7.52 (m, 4H, H-Ar), 11.23 (brs, 2H, 2NH); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 10.91, 31.79, 102.87, 126.89, 127.98, 129.51, 131.04, 132.72, 139.38, 141.13, 161.14. Anal. calcd for C₁₅H₁₅ClN₄O₂: C, 56.52; H, 4.74; 17.58%. Found: C, 56.59; H, 4.70; N, 17.62%. MS (m/z): 320 (M + 2), 318 (M⁺), 224, 196, 180, 126.

4-((4-(Bis(3-methyl-1H-pyrazol-4-yl-5-ol)methyl)phenyl) (3-methyl-1H-pyrazol-4-yl-5ol)methyl)-3-methyl-1H-pyrazole-5-ol (6j). Orange solid, mp 286–288 °C; IR (KBr) (v_max/cm⁻¹): 3351.22, 3112.39, 1600.70, 1471.53, 833.03; ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 2.04 (s, 12H, 4CH₃), 3.94 (4OH exchanged with water of DMSO-d₆), 4.70 (s, 2H, 2CH), 6.93 (s, 4H, H-Ar), 11.61 (brs, 4H, 4NH); ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) 10.84, 32.82, 104.85, 127.34, 140.49, 140.91, 161.56. Anal. calcd for C₂₄H₂₆N₈O₄: C, 58.77; H, 5.34; N, 22.84%. Found: C, 58.72; H, 5.36; N, 22.80%. MS (m/z): 491 (M + 1), 395, 298, 285, 188, 147.

4. Conclusions

In conclusion, we have developed a straightforward and efficient approach to synthesis of 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol) derivatives by a simple one-pot pseudo five-component reaction of hydrazine hydrate, ethyl acetoacetate and aldehydes in the presence of ZnAl₂O₄ nanoparticles as catalyst under benign reaction conditions. This ‘green’ methodology can synthesize new substituted pyrazole scaffolds. These compounds will provide promising candidates for biological applications and drug discovery. The advantages offered by this method include short reaction times, a simple procedure, high atom economy, excellent yields, use of no toxic organic solvent in the entire process, no need for chromatographic purification, and the employment of a cost-effective catalyst.

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.

References

1. S. Sugiura, S. Ohno, O. Ohtani, K. Izumi, T. Kitamikado, H. Asai and K. Kato, J. Med. Chem., 1977, 20, 80.
2. O. Prakash, R. Kumar and V. Parkash, Eur. J. Med. Chem., 2008, 43, 435.
3. F. Wei, B. X. Zhao, B. Huang, L. Zhang, C. H. Sun, W. L. Dong, D. S. Shin and J. Y. Miao, Bioorg. Med. Chem. Lett., 2006, 16, 6342.
4. M. J. Genin, C. Biles, B. J. Keiser, S. M. Poppe, S. M. Swaney, W. G. Tarpley, Y. Yagi and D. L. Romero, J. Med. Chem., 2000, 43, 1034.
5. P. C. Lv, J. Sun, Y. Luo, Y. Yang and H. L. Zhu, Bioorg. Med. Chem. Lett., 2010, 20, 4657.
6. D. M. Bailey, P. E. Hansen, A. G. Hlavac, E. R. Baizman, J. Pearl, A. F. Defelice and M. E. Feigenson, J. Med. Chem., 1985, 28, 256.
7. B. P. Bandgar, H. V. Chavan, L. K. Adsul, V. N. Thakare, S. N. Shringare, R. Shaikh and R. N. Gacche, Bioorg. Med. Chem. Lett., 2013, 23, 912.
8. K. Sujatha, G. Shanthi, N. P. Selvam, S. Manoharan, P. T. Perumal and M. Rajendran, Bioorg. Med. Chem. Lett., 2009, 19, 4501.
9. M. Seddighi, F. Shirini and M. Mamaghani, RSC Adv., 2013, 3, 24046.
10. B. Jiang, T. Rajale, W. Wever, S. J. Tu and G. Li, Chem.–Asian J., 2010, 5, 2318.
11. J. P. Wan and Y. Liu, RSC Adv., 2012, 2, 9763.
12. F. Nador, M. A. Volpe, F. Alonso, A. Feldhoff, A. Kirschning and G. Radivoy, Appl. Catal., A, 2013, 455, 39.
13. H. Fujioka, K. Murai, O. Kubo, Y. Ohba and Y. Kita, Org. Lett., 2007, 9, 1687.
14. C. W. Lim and I. S. Lee, Nano Today, 2010, 5, 412.
15. J. Safaei-Ghomi, Z. Akbarzadeh and A. Ziarati, RSC. Adv., 2014, 4, 16385.
16. A. R. Kiasat and J. Davarpanah, J. Mol. Catal. A: Chem., 2013, 373, 46.
17. J. Safaei-Ghomi, H. Shahbazi-Alavi, A. Ziarati, R. Teymuri and M. R. Saberi, Chin. Chem. Lett., 2014, 25, 401.
18. J. Safaei-Ghomi, M. Kiani, A. Ziarati and H. Shahbazi-Alavi, J. Sulfur Chem., 2014, 35, 450.
19. K. Kumar, K. Ramamoorthy, P. M. Koinkar, R. Chandramohan and K. Sankaranarayanan, J. Nanopart. Res., 2007, 9, 331.
20. X. Song, S. Zheng, J. Zhang, W. Li, Q. Chen and B. Cao, Mater. Res. Bull., 2012, 47, 4305.
21. X. Li, Z. Zhu, Q. Zhao and L. Wang, J. Hazard. Mater., 2011, 186, 2089.
22. P. F. Rossi, G. Busca, V. Lorenzelli, M. Waqif, O. Saur and J. C. Lavalley, Langmuir, 1991, 7, 2677.
23. S. Farhadi and S. Panahandehjoo, Appl. Catal., A, 2010, 382, 293.
24. T. R. Mandlimath, B. Umamahesh and K. I. Sathiyanarayanan, J. Mol. Catal. A: Chem., 2014, 391, 198.
25. M. A. Valenzuela, J. P. Jacobs, P. Bosch, S. Reijne, B. Zapata and H. H. Brongersma, Appl. Catal., A, 1997, 148, 315.
26. M. Zawadzki and J. Wrzyszcz, Mater. Res. Bull., 2000, 35, 109.
27. Z. Chen, E. Shi, Y. Zheng, W. Li, N. Wu and W. Zhong, Mater. Lett., 2002, 56, 601.
28. M. Zawadzki, Solid State Sci., 2006, 8, 14.
29. A. K. Adak, A. Pathak and P. Pramanik, J. Mater. Sci. Lett., 1998, 17, 559.
30. F. Davar and M. Salavati-Niasari, J. Alloys Compd., 2011, 509, 2487.
31. E. Soleimani, S. Ghorbani, M. Taran and A. Sarvary, C. R. Chim., 2012, 15, 955.
32. K. R. Phatangare, V. S. Padalkar, V. D. Gupta, V. S. Patil, P. G. Umape and N. Sekar, Synth. Commun., 2012, 42, 1349.
33. S. Tayebi, M. Baghernejad, D. Saberi and K. Niknam, Chin. J. Catal., 2011, 32, 1477.
34. K. Niknam, M. Sadeghi Habibabad, A. Deris and N. Aeinjamshid, Monatsh. Chem., 2013, 144, 987.
35. W. Wang, S. X. Wang, X. Y. Qin and J. T. Li, Synth. Commun., 2005, 35, 1263.
36. J. Xu-dong, D. Hai-feng, L. Ying-jie, C. Jun-gang, L. Da-peng and W. Mao-cheng, Chem. Res. Chin. Univ., 2012, 28, 999.
37. E. L. Foletto, S. Battiston, J. M. Simões, M. M. Bassaco, L. S. F. Pereira, E. M. de Moraes Flores and E. I. Müller, Microporous Mesoporous Mater., 2012, 163, 29.

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