Sonochemical synthesis of methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones using Sn^II-montmorillonite

ABSTRACT

Tin exchanged montmorillonite K10 (Sn^II-Mont K10) was prepared by ion exchange between SnCl₂ and montmorillonite K10. The Sn^II-Mont K10 was characterized by X-ray diffraction, scanning electron microscope and energy-dispersive X-ray spectroscopy. The synthesized Sn^II-Mont K10 was used as a recoverable solid catalyst for synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones via one-pot multicomponent cyclocondensation of hydroxylamine hydrochloride, ethyl acetoacetate and benzaldehyde derivatives in water under ultrasound irradiations. The yields of products were obtained 87–96%. The remarkable advantages of this method are a low-cost and eco-friendliness catalyst, rapid completion of the reactions, and avoidance of using organic solvents, excellent yield and mild conditions.

GRAPHICAL ABSTRACT

KEYWORDS:

• Isoxazoles
• ultrasound irradiation
• montmorillonite K10
• heterogeneous catalyst
• SnCl₂

Introduction

One-pot multicomponent reactions have recently been discovered to be a powerful synthetic tool for the synthesis of heterocyclic compounds, since the products are formed in one-pot and the diversity can be achieved simply by varying each component. The simplicity of a one-pot procedure, the possible structural variations, the atom economy and convergent character, operational simplicity and the very large number of accessible organic compounds are among the described advantages of multicomponent reactions ( 1, 2). One such multicomponent reaction that belongs to the latter category is the isoxazole derivatives synthesis.

Isoxazole and isoxasolone derivatives are important organic heterocycles, because of their widespread pharmacological activities such as fungicidal ( 3), analgesic ( 4), antimicrobial ( 5), antioxidant ( 6), nematicidal ( 7), anti-inflammatory compounds ( 8) and hypoglycemic activity ( 9). In recent studies, several reports on the synthesis of isoxasolones heterocycles involves the one-pot reactions of an aldehyde, hydroxylamine hydrochloride and a β-ketoester using various catalytic substrates have been presented ( 10–17). Due to the importance of isoxazole heterocycles, we decided to explore an efficient, simple and fast synthesis of isoxasolones using Tin exchanged montmorillonite K10 as a heterogeneous nanocatalyst under ultrasound irradiation.

In recent years, ultrasound irradiation has been introduced as a green technology for different types of chemical reactions. Ultrasonic energy leads to cavitations, namely, formation, growth and implosive collapse of bubbles in a liquid during a very short period of time. This induces intense local heating with very short lifetimes, which promotes organic reactions to occur. Therefore, chemical transformations under ultrasound irradiation are more advantageous comparing to conventional methods in view of its milder reaction condition, high yields in shorter reaction time, improved selectivity, simple experimental procedure and energy conservation ( 18, 19).

Recent progresses in fine chemical synthesis demonstrate that the field is promising with the newly developed catalysts and methods. Montmorillonite has attracted attention in heterogeneous catalytic processes because of their surface area in the range of 750 m²/g, high structural charge (up to 1000 meq/kg) and catalytic activities. Montmorillonite is one of the most intensively explored as a heterogeneous support for organic reactions due to its physical and chemical properties ( 20). To enhance the acidity property and high catalytic activities, SnCl₂ can be used with montmorillonite to be widely used as a powerful catalyst for various organic transformations under mild conditions ( 21, 22).

However, there are no examples of the use of Sn^II-Mont K10 as a catalyst for the synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones under sonication. Therefore, we like to report, for the first time, a new efficient, and clean methodology for the synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones via a three component condensation of an aromatic aldehyde, ethyl acetoacetate, hydroxylamine hydrochloride, and Sn^II-Mont K10 as a heterogeneous catalyst under ultrasonic irradiation, which is an efficient preparation 3-methyl-4-arylmethylene isoxazole-5(4H)-one (Scheme 1).

Scheme 1. Sonochemical synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones using Sn^II-Mont K10.

Results and discussion

Characterization of montmorillonite Sn^II-Mont K10

Montmorillonite K10 supported Sn^II composite (Sn^II-Mont K10) was prepared by the ion-exchange process. In order to analyze the catalyst, it was studied by powder X-ray diffraction (XRD) which the obtained diffractogram is reported in Figure 1. As shown in this figure, in montmorillonite K10, the positions and relative intensities of all the peaks coincide well with the XRD pattern that are mainly in the amorphous form. When Sn cations are exchanged for other cations in the montmorillonite, the frontier between the interlayer of Sn^II-Mont K10 is different from that of the interlayer of MMT. It is indicated that the Sn cation increases the distance between the sheets and alter the montmorillonite structures (d-spacing MMT – Sn = 11.84 and d-spacing MMT = 9.86). Also, the shifting of the (8.96) peak towards a lower shift peak (7.46) suggests the intercalation of Sn into the clay interlayer.

Figure 1. X-ray diffraction (XRD) pattern of montmorillonite and Sn^II-Mont K10.

Furthermore, the scanning electron microscope (SEM) micrograph of the neat K10 and modified clay was shown in Figure 2((a),(b)), respectively. It is clear that the layered structure of MMT after modification is similar to that of the parent clay.

Figure 2. SEM photographs of (a) montmorillonite and (b) Sn^II-Mont K10.

The EDX spectra of K10 clay and Sn^II-Mont K10 are shown in Figure 3. In the spectrum of montmorillonite in Figure 3, the three sharp peaks were observed which are related to Al, Si and O elements. However, in the Sn^II-Mont K10 in Figure 3(b), in addition to above-mentioned peaks, a peak was observed which verify the Sn element. The content of Sn in the clays is 21.43 Wt %.

Figure 3. EDX spectrum of (a) montmorillonite and (b) Sn^II-Mont K10.

Preparation of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones

We are reporting here an efficient sonochemical Sn^II-Mont K10 catalyzed for the synthesis of isoxasolones. The addition of Sn^II-Mont K10 accelerated this organic reaction which leads to great results. Using 4-methoxy-benzaldehyde, ethyl acetoacetate and hydroxylamine hydrochloride as the model substrates in water, this condensation was studied with Sn^II-Mont K10 catalyst under ultrasound irradiation. Thereafter, the reaction was evaluated by varying the concentrations of catalyst (0.006–0.02 g). Table 1 shows the yield of isoxazolone against catalyst amount data. The use of 0.01 g of Sn^II-Mont K10 in the reaction mixture was sufficient for achieving the best yield (entry 5). Also, it was observed that the reaction in the presence of catalyst and ultrasound irradiation with the power of 90 W leaves the best result as the obtained product has 96% isolated yield during 20 min (entry 11). This shows that both the catalyst as well as ultrasound energy has an important role in the completion of this reaction. The combination of ultrasonic irradiation and heterogeneous catalyst is a standard technology used in this context. Ultrasound provides an unusual mechanism due to the immense temperatures (up to 5000 K) and high pressures (up to 1000 bar) and the extraordinary heating rate generated by the cavitation phenomenon in this medium ( 18).

Table 1. Optimization of reaction conditions in view of catalyst amount and max power intensity.^a

Entry	Catalyst (g)	Power intensity (W)	Time (min)	Yield (%)^b
1	None	–	120	20
2	0.006	90	20	80
3	0.008	90	20	92
4	0.01^c	–	80	45
5	0.01	90	20	96
6	0.02	90	20	96
7	0.03	90	20	93
8	0.04	90	20	90
9	0.01	30	20	32
10	0.01	70	20	74
11	0.01	100	20	96
12	None	90	20	40
13	MMT (0.01)	90	20	65
14	SnCl2 (0.01)	90	20	60

^aReaction conditions: a mixture of hydroxylamine hydrochloride (1 mmol), ethyl acetoacetate (1 mmol), 4-methoxy-benzaldehyde (1 mmol) and distilled water (5 mL).

^bIsolated yield.

^cIn the absence of ultrasound irradiations.

The model reaction for preparation of product 4 under ultrasound irradiations at 30°C was examined using a variety of solvents and the results are summarized in Table 2. As seen in Table 2, the best results were obtained for H₂O in the presence of ultrasound irradiations (entry 2). In the absence of solvent the yields reduced significantly (entry 6) and using solvents such as EtOH, MeOH and DCM was completely unsuccessful (entries 3–5). Therefore, H₂O was chosen as solvent of this system. The application of ultrasound in this reaction has advantages such as shorter reaction times, milder reaction condition and higher yields in comparison with the classical method.

Table 2. Screening of solvent effect on model reaction under ultrasound irradiation at 30°C.^a

Entry	Solvent	Time (min)	Yield (%)^b
1	CH3CN	20	Trace
2	H2O	20	96
3	Ethanol	20	Trace
4	Methanol	20	Trace
5	DCM	20	Trace
6	Solvent free	20	10

^aReaction conditions: a mixture of hydroxylamine hydrochloride (1 mmol), ethyl acetoacetate (1 mmol), 4-methoxy-benzaldehyde (1 mmol), solvent (5 mL) and nanocatalyst (0.01 g).

^bIsolated yield; irradiations.

After optimization of the reaction conditions, we studied the scope of this method, particularly with regard to library construction. We have extended the procedure using a series of aromatic aldehydes with both electron-donating and electron-withdrawing substituents. Most importantly, aromatic aldehydes carrying either electron-withdrawing or electron-donating substituents reacted very well to give the corresponding isoxazoles with excellent yields and high purity. The results are summarized in Table 3.

Table 3. Sn^II-Mont catalyzed synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones under sonication.

Entry	ArCHO	Products	Time (min)	Yield (%)	M.P (°C)		Ref
					Found	Reported
1			20	96	173–175	173–175	( 15)
2			11	94	138–140	137–139	(12d)
3			16	93	135–136	135	( 5)
4			15	90	214–215	213–215	( 15)
5			28	89	201–203	202–203	( 15)
6			50	88	197–198	198–199	( 15)
7			45	87	132–133	130–132	( 15)
8			11	94	188–189	187–189	(12d)
9			10	97	226–227	226–228	( 15)
10			40	92	140–142	141–142	( 15)
11			10	93	242–244	240	( 5)
12			16	91	145–14	144–146	( 15)

Then, we compared our catalytic data with that found in the literature. Comparison of the results shows a better catalytic activity of Sn^II-Mont K10 to the synthesis of isoxazoles (Table 4).

Table 4. Comparison of Sn^II-Mont K10 with some other catalysts for the synthesis of 4a.

Entry	Catalyst (g)	Condition	Yield (%)	Time (min)	Ref
1	Na2S	EtOH/r.t.	88	90	(11a)
2	Pyridine	EtOH/reflux	71	180	(13a)
3	Sodium benzoate	H2O/r.t.	87	90	(16a)
4	Sodium saccharin	H2O/r.t.	91	50	(14a)
5	Potassium phthalimide	H2O/r.t.	96	70	(17a)
6	Boric acid	H2O/r.t.	92	50	(15b)
7	NH2-MMT	H2O/r.t.	96	25	(12d)
8	DL-Tartaric acid	H2O/r.t.	60	85	(12a)
9	Visible light	Aqueous ethanol	82	10	( 5)
10	Imidazole	H2O/U.S	96	20	This work

To explore the advantages of Sn^II-Mont K10 as a catalyst for the synthesis of the model compound 4a, we compared results reported in the literature for this reaction mediated by other catalysts (Table 4). It is clear from this table that Sn^II-Mont K10 is an efficient catalyst which could be useful in the synthesis of isoxazoles.

Next, we have investigated the reusability of Sn^II-Mont K10 ultrasound irradiation. In this process, the model reaction was again studied under optimized conditions. After the completion of the reaction, heterogeneous catalysts were separated by filtration, and reused after dilution with ethyl acetate for the model reaction. As indicated in Figure 4, recycled catalyst showed no efficiency loss with respect to reaction time and yield after six consecutive runs.

Figure 4. Reusability diagram of SnII-Mont K10under ultrasound irradiations.

Mechanisms of the reaction

A possible mechanism for the one-pot cyclocondensation of aromatic aldehyde, ethyl acetoacetate and hydroxylamine hydrochloride, in the presence of Sn^II-Mont K10, is shown in Scheme 2. At first, the tin-exchanged clay acts as a Lewis acid and increases the electrophilic character of the carbonyl groups in ethyl acetate. Also, Sn^II-Mont K10 is given the high Lewis acidity of Sn as well as its ability to produce acid media from coordinated water molecules that this process is accelerated via sonication in the layered structure of MMT. Then the nucleophilic attack of the amino group of hydroxylamine hydrochloride occurs at the activated carbonyl carbon of ethyl acetoacetate to result oxime intermediate A. The catalyst then activates the carbonyl group of oxime intermediate and the nucleophilic attack occurs at the carbonyl carbon of the aromatic aldehyde which is also activated by Sn^II-Mont K10 under sonication. Then, cyclization of intermediate B is done for the synthesis of 3-methyl-isoxazole-5(4H)-one under ultrasound irradiation. In a heterogeneous solid/liquid system, adsorption of intermediate oxime (A) is improved on the Sn^II-Mont K10 surface from the effects of catalyst surface and also ultrasonic irradiation (10b, c, 12c).

Scheme 2. Proposed mechanism for synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones by Sn^II-Mont K10.

Experimental

Materials and methods

Chemicals such as hydroxylamine hydrochloride, ethyl acetoacetate, aldehyde derivatives, montmorillonit-K10, SnCl₂, ethanol, methanol and DCM were purchased from Fluca and Merck chemical companies in high purity. All of the materials were of commercial reagent grade. The products are characterized by comparison of their spectral data (¹³C and ¹H-NMR, IR, UV and R_f) and physical data with authentic samples. ¹H and ¹³C NMR spectra were recorded on an Avance BRUKER (DRX- 400 MHz) in CDCl₃ as solvent. UV–VIS spectra were taken by a double beam Perkin-Elmer 550S spectrophotometer in the range of 200–400 nm, using chloroform as the solvent. IR spectra were determined on a Nicolet Magna series FTIR 550 spectrometer using KBr pellets. The purity determination of the substrates and reaction monitoring were accomplished by thin layer chromatography (TLC) on silica gel polygram SILG/UV 254 plates. A Bandelin Sonorex Super 10P Ultrasonic Bath (water) (with a frequency of 35 kHz and a nominal power 100 W) was used. The melting points were determined by a Yanagimoto micro melting point apparatus. Structures were characterized using a Holland Philips Xpert XRD diffractometer (CuK, radiation, λ = 0.154056 nm), at a scanning speed of 2°/min from 10° to 100° (2θ). The surface morphology of montmorillonite based materials was analyzed by field emission SEM (KYKY-EM3200).

Preparation of Sn^II-Mont K10

Montmorillonite Sn^II-Mont K10 was prepared according to the reported procedure in the literature ( 21). In short, a mixture containing SnCl₂·2H₂O (0.19 g) and montmorillonite clay (0.8 g) in distilled water (10 mL) was stirred at room temperature for 36 h. The product was centrifuged and the modified clay was washed with copious amounts of deionized water until the discarded filtrate was free from chloride ions (checked by 0.1 M AgNO₃). Finally, the prepared catalyst was dried at 110°C for 12 h.

General procedure for the preparation of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones

To a 50 mL round-bottomed flask was added sequentially aromatic aldehyde (1 mmol), ethyl acetoacetate (1 mmol), hydroxylamine hydrochloride (1 mmol), Sn^II-Mont K10 (0.01 g) and distilled water (5 mL). The reaction was irradiated under sonication at 30°C. The precipitate is gradually formed during the reaction. After completion of the reaction (monitored by TLC; petroleum ether-ethyl acetate 1:1), the precipitate was filtered at the pump and dried in oven. Then, the mixture was dissolved in ethyl acetate and the catalyst was separated by filtration. The solvent was removed under reduced pressure. The crude product was crystallized from EtOH to afford the pure product in high yield.

Conclusion

In this study, we have investigated the application of heterogeneous Sn^II-Mont K10 for the synthesis of isoxazole compounds that offer 3-methyl-4-arylmethylene isoxazole-5(4H)-ones under ultrasound irradiation, in high yields and high purity maintaining the advantage of the one-pot approach. The present methodology offers advantages such as mild reaction conditions, reduced reaction times, simple manipulation and economic viability of the catalyst, compared with conventional methods.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes on contributors

Majid Ahmadzadeh received his B.Sc. degree in Chemistry from the University of Zabol, in 2009 and then his M.Sc. degree in Organic chemistry from the Semnan university in 2012. He received his Ph.D. degree in Organic Chemistry from the University of Kashan (Kashan, Iran) in 2017 which included Preparation of pyranopyrazole and isoxazolone hetrocycles using modified montmorillonite nanocatalysts under the supervision of Dr Javad Safari.

Zohre Zarnegar received her BS (2002) in Pure Chemistry from University of Kashan (Iran). Next, she studied her MS (2008) in Organic Chemistry at the Lorestan University. She performed her MS research in the field of nanochemistry which included synthesis of novel dendrimers under the supervision of Prof. Mohsen Adeli. She obtained her PhD degree in Organic Chemistry at University of Kashan (2014) which included development of magnetic nanoparticles and their application in hostguest systems and some of the organic reactions under the supervision of Dr Javad Safari. She added a postdoctoral stage from the Iran Nanotechnology Initiative Council (INIC) in 2016.

Javad Safari was born in Kashan, Iran in 1965. He obtained his B.Sc. degree in Chemistry at the University of Kashan in 1989. He received his M.Sc and Ph.D. degrees in Organic Chemistry at the University of Isfahan in 1992 and 2002. He is teaching as associate professor of Chemistry at the University of Kashan. His research interests focus on heterocyclic chemistry, spectroscopy, catalysis and organic methodology.

Additional information

Funding

This work was supported by the Research Council of the University of Kashan [grant number 256722/21].