Nano-silica sulfuric acid as an efficient catalyst for the synthesis of substituted pyrazoles

1 Introduction

The synthesis of nitrogen-containing heterocyclic compounds has been a subject of great interest due to their wide application in agrochemical and pharmaceutical fields (Noga et al., 1986; Craig, 1991). Pyrazole derivatives, which belong to this category, fulfill a wide variety of biological functions such as antipyretic (Behr et al., 1967), antibacterial (Mahajan et al., 1991), antipsychotic (Barcelo et al., 2007), antiviral (Larsen et al., 1999), pesticidal (Londershausen, 1996), and insecticidal ones (Windholz, 1976).

Pyrazoles can be synthesized via 1,3-dipolar cycloadditions of diazo compounds (Aggarwal et al., 2003), reaction of chalcones and hydrazines (Bhat et al., 2005), a three-component coupling of hydrazine, aldehyde and ethyl acetoacetate (Kumari et al., 2012), reaction of isocyanides, dialkylacetylenedicarboxylates and diacylhydrazines (Adib et al., 2005), and the direct condensation of 1,3-diketones and hydrazines in the presence of an acidic catalyst (Fustero et al., 2008; Katritzky, 1985). The last one is the most straightforward procedure for the synthesis of pyrazole derivatives. This procedure can be carried out in the presence of various catalysts such as H₂SO₄ (Wang and Qin, 2004), polystyrene-supported sulfonic acid (Polshettiwar and Varma, 2008), layered zirconium sulfophenyl phosphonate [a-Zr(CH₃PO₃)_1.2(O₃PC₆H₄SO₃H)_0.8] (Curini et al., 2005), Sc(OTf)₃ (Xiong et al., 2009), Y-zeolite (Sreekumar and Padmakumar, 1998), and Mg(ClO₄)₂ (Mirjalili et al., 2010).

In recent years, the use of reusable heterogeneous catalysts has received considerable importance in organic synthesis. This is because of their environmental, economic, and industrial benefits. Among these, the application of silica sulfuric acid (SSA) or nano-silica sulfuric acid (nano-SSA), which is a stable and efficient heterogeneous catalyst in organic synthesis, has been widely studied. This catalyst is important from an environmental point of view because it produces little waste. It also has an excellent activity and selectivity even on an industrial scale and, in most cases, can be recovered from reaction mixtures and reused.

Silica sulfuric acid has already gained much interest in the synthesis of substituted pyrroles (Veisi, 2010), β-aminoketones (Wu et al., 2007), N-acylsulfonamides (Massah et al., 2008), triarylmethanes (Mohammad poor-Baltork et al., 2011), imidazo pyridines (Polyakov et al., 2009), and deprotection of oximes to carbonyls (Li et al., 2010), Now, we report an efficient and convenient procedure for the synthesis of substituted pyrazoles using silica sulfuric acid or nano-silica sulfuric acid as a catalyst.

2 Materials and methods

The products were characterized by elemental analysis, IR, ¹H-NMR, and ¹³C-NMR spectra. IR spectra were run on a Bruker, Eqinox 55 spectrometer. ¹H-NMR and ¹³C-NMR spectra were obtained using a Bruker Avance 400 and 500 MHz spectrometers (DRX). The elemental analysis was done by a Costech ECS 4010 CHNS-O analyzer. The melting points were measured by a Buchi melting point B-540 apparatus and the SEM of nano-SSA particles was determined with a VEGA/TESCAN scanning electron microscope.

2.1

2.1 Synthesis of nano-SSA

A 500 mL suction flask containing nano-silica gel (60.0 g) was equipped with a constant pressure dropping funnel containing chlorosulfonic acid (23.3 g, 0.2 mol) and gas inlet tube for conducting HCl gas over an adsorbing solution i.e., water. Chlorosulfonic acid was added dropwise over a period of 30 min at room temperature. HCl gas was evolved from the reaction vessel immediately. After the addition was complete, the mixture was shaken for 30 min and a white solid of nano-SSA (76.0 g) was collected. Fig. 1 is the SEM photograph of the product. The SSA was prepared according to the literature (Zolfigol, 2001).

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Figure 1

The SEM photograph of nano-SSA.

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3 Results and discussion

In order to optimize the reaction conditions, we studied the condensation of 1,3-diphenyl-1, 3-propanedione (1 mmol) with phenylhydrazine (1 mmol) in various reaction conditions. The results are summarized in Table 1.

Table 1 Condensation of 1, 3-diphenyl-1, 3-propanedione with phenylhydrazine under different reaction conditions^a .

Entry	Catalyst (g)	Solvent	Conditions	Time (h)	Yield (%)	Ref.
1	–	Solvent-free	60 °C	2	25	–
2	SSA(0.02)	Solvent-free	r.t	0.5	40	–
3	SSA(0.02)	Solvent-free	60 °C	0.5	68	–
4	SSA(0.04)	Solvent-free	r.t	0.5	45	–
5	SSA(0.04)	Solvent-free	60 °C	0.5	78	–
6	SSA(0.06)	Solvent-free	r.t	0.5	52	–
7	SSA(0.06)	Solvent-free	60 °C	0.5	86	–
8	SSA(0.08)	Solvent-free	r.t	0.5	52	–
9	SSA(0.08)	Solvent-free	60 °C	0.5	88	–
10	Nano-SSA(0.002)	Solvent-free	60 °C	0.5	68	–
11	Nano-SSA(0.006)	Solvent-free	60 °C	0.5	82	–
12	Nano-SSA(0.01)	Solvent-free	60 °C	0.5	93	–
13	Nano-SSA(0.014)	Solvent-free	60 °C	0.5	95	–
14	Nano-SSA(0.01)	Water	60 °C	5	30	–
15	Nano-SSA(0.01)	Ethanol	60 °C	1	80	–
16	Nano-SSA(0.01)	Acetonitrile	60 °C	3	75	–
17	Nano-SSA(0.01)	Ethyl acetate	60 °C	3	70	–
18	Nano-SSA(0.01)	Chloroform	60 °C	3	60	–
19	Nano-SSA(0.01)	Dichloromethane	60 °C	3	55	–
20	Nano-SSA(0.01)	n-Hexane	60 °C	5	40	–
21	SSA(0.01), 2nd run	Solvent-free	60 °C	0.5	76	–
22	H2SO4 (0.1 drop)	Solvent-free	r.t	1	86	Wang and Qin (2004)
23	Polystyrene supported sulfonic acid (0.1 mL of 20% PSSA solution)	Solvent-free	r.t	0.04	92	Polshettiwar et al. (2008)
24	[a-Zr(CH3PO3)1.2(O3PC6H4SO3H)0.8](0.025)	Solvent-free	40 °C	2	95	Curini et al. (2005)
25	Sc(OTf)3 (2 mol%)	Solvent-free	r.t	0.35	94	Xiong et al. (2009)
26	Y-Zeolite (1)	Ethylene dichloride	r.t 2		84	Sreekumar and Padmakumar (1998)

a 1, 3-Diphenyl-1, 3-propanedione (1 mmol) and Phenylhydrazine (1 mmol) were applied.

Initially, the reaction was performed with different amounts of SSA in various conditions. It was found that 0.06 g of SSA as a catalyst would be sufficient and an excessive amount of that would not increase the yield remarkably (Table 1, entry 7). We repeated the above mentioned reaction with various amounts of nano-SSA with the finding that the activity of nano-SSA is six times more, and only 0.01 g of it would be sufficient (Table 1, entry 12). Among the various reaction conditions (Table 1, entries 1–20), the most effective condition in terms of reaction yield and rate was found to be created by SSA (0.06 g) and nano-SSA (0.01 g) in solvent- free media at 60 °C. The nano-SSA is a more effective activation agent because of the vide surface of it and can accelerate the overall reaction rate by a little amount of it.

To examine the reusability of nano-SSA under a solvent- free condition, after each run, the product was dissolved to CHCl₃ and filtered. The catalyst residue was washed with acetone and reused. As a matter of fact, treatment with acetone removes the tar from the catalyst surface more efficiently (Table 1, entry 21). The catalyst was reusable although a gradual decline was observed in its activity.

The general efficiency of this protocol was then studied for the synthesis of a variety of pyrazoles (Table 2). As it can be seen in Table 2, various hydrazines reacted efficiently with 1,3-diketones to afford the desired pyrazoles in good yields. Investigation was made of a series of aromatic hydrazines bearing either electron-donating or electron-withdrawing groups on the aromatic ring. The substitution group on the phenyl ring seemed to affect the reaction significantly neither in the product yield nor in the reaction rate.

Table 2 The condensation of 1, 3-diketones and hydrazines in the presence of silica sulfuric acid or nano-silica sulfuric acid^a .

Entry	R1	R2	R3	R4	Yield (%) Nano-SSA/SSA	Time (min)	Mp (°C) [m.p. reported]	Ref.
1	2,4- O2N-C6H3	CH3	H	CH3	85/79	15	122–124	Xiong et al. (2009)
2	2,4- O2N-C6H3	C6H5	H	CH3	92/93	20	127–129	Curini et al. (2005)
3	2,4- O2N-C6H3	C6H5	H	C6H5	92/90	20	149–150	Mirjalili et al. (2010)
4	2,4- O2N-C6H3	CH3	Cl	CH3	89/80	25	166–168	Mirjalili et al. (2010)
5	C6H5	C6H5	H	C6H5	93/86	30	137–138	Sreekumar and Padmakumar (1998)
6	C6H5	CH3	Cl	CH3	93/86	20	Oil	Polshettiwar et al. (2008)
7	H	C6H5	H	CH3	87/87	25	202–204	Mirjalili et al. (2010)
8	4- Br-C6H4	CH3	Cl	CH3	94/90	15	87–88	Mirjalili et al. (2010)
9	4- Br-C6H4	C6H5	H	C6H5	90/85	40	119–120	Mirjalili et al. (2010)
10	4- Br-C6H4	C6H5	H	CH3	92/88	25	178–180	Mirjalili et al. (2010)
11	4- Me-C6H4	C6H5	H	C6H5	87/94	40	104–105	Mirjalili et al. (2010)
12	4- Me-C6H4	C6H5	H	CH3	89/87	15	82–84	Mirjalili et al. (2010)
13	4-OMe-C6H4	C6H5	H	C6H5	74/78	30	oil	Mirjalili et al. (2010)
14	4-OMe-C6H4	C6H5	H	CH3	88/88	20	oil	Mirjalili et al. (2010)
15	4- Me-C6H4SO2	CH3	H	CH3	83/80	20	94–95	Xiong et al. (2009)
16	4- Me-C6H4SO2	C6H5	H	C6H5	83/85	25	101–103	Mirjalili et al. (2010)
17	4- Me-C6H4SO2	C6H5	H	CH3	84/85	35	86–87	Mirjalili et al. (2010)

a Phenylhydrazine (1 mmol), 1, 3-Diphenyl-1, 3-propanedione (1 mmol) silica sulfuric acid (0.06 g) or nano-silica sulfuric acid (0.01 g).

The reactions of chalkon with hydrazines in the presence of nano-silica sulfuric acid were examined and the corresponding products were produced in high yields (Scheme 1).

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Scheme 1

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Ethylacetoacetate was utilized as substrate and the pyrazole ring was not formed (Scheme 2).

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Scheme 2

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4 Conclusions

This paper reports the development of an efficient procedure for the synthesis of substituted pyrazoles using nano-silica sulfuric acid as a reusable, eco-friendly and efficient heterogeneous catalyst. The major advantages of this procedure include easy work-up, high yields, clean reactions, and low catalyst loading.