Ethyl gallate as an unexplored organocatalyst: unlocking sustainable routes to isoxazolones

Abstract

A simple and effective approach has been established for producing a wide range of pharmaceutically valuable functionalised 3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones. In this method, ethyl gallate (EG) was identified as a previously unexplored and potent organocatalyst, allowing for quick one-pot conversion to isoxazolones. The technique offers several major benefits, including metal-free conditions, good to exceptional yields, the use of readily available starting materials, and overall operational simplicity.

A green one-pot three component synthesis of isoxazolone derivatives using ethyl gallate (EG), an unexplored organocatalyst at room temperature, with broad functional group tolerance.

Introduction

Green chemistry is a growing field in modern science, with researchers investigating new catalysts and solvent systems. Researchers are attempting to develop safer and more ecologically friendly synthetic processes based on the twelve green chemistry principles.¹ As a result, chemists have prioritised the development of environmentally friendly techniques. In this context, multi-component reactions (MCRs) are important in organic transformations because of their numerous advantages in the production of complex molecular structures and bioactive medicinal molecules.^2,3 In recent decades, chemists have created organocatalysts, a new type of catalyst made up of simple organic molecules that may catalyse a variety of processes, particularly those involving MCR synthesis.^4–8

Ethyl gallate (ethyl 3,4,5-trihydroxybenzoate) (EG) is a naturally occurring phenolic ester formed from gallic acid that can be found in plants, fruits, and beverages like tea and wine. EG is a well-known chemical with significant research into its antioxidant, antibacterial, and medicinal effects.⁹ It is affordable, readily available, simple to use, eco-friendly, and biodegradable. The presence of three hydroxyl groups results in mild Brønsted acidity. However, despite its well-documented chemical characteristics and functional groups that could potentially aid catalytic activity via hydrogen bonding and substrate activation, its use as an organocatalyst in organic synthesis has yet to be investigated.

Isoxazole and its derivatives are an important class of chemicals due to their heterocyclic structure, which contains both nitrogen and oxygen atoms. These compounds have a wide range of uses, including organic synthesis, medicinal chemistry, the pharmaceutical sector, optoelectronic device development, and light-conversion molecular systems, with some also finding use in agricultural chemicals.¹⁰ For example, the isoxazole moiety can be found in merocyanine dyes (Fig. 1), which are employed in optical recording, nonlinear optical research, and some liquid crystalline materials.^11–13 Furthermore, isoxazole compounds have a variety of biological actions, such as anti-obesity,¹⁴ anti-inflammatory,¹⁵ antifungal,¹⁶ anticancer,¹⁷ antitumor,¹⁸ antibacterial,¹⁹ anticonvulsant,²⁰ and anti-HIV²¹ properties (Fig. 1). Interestingly, several isoxazole motifs have antagonistic effect²² against human metastatic breast cancer and prostate tumour cells.²³

Fig. 1. Some example of compounds containing isoxazolone moiety.

Various synthetic strategies for producing isoxazolone derivatives have been documented. In general, aryl-3-methylisoxazol-5(4H)-one derivative are synthesised via a one-pot, three-component procedure that includes an aromatic aldehyde, ethyl acetoacetate, and hydroxylamine hydrochloride (Scheme 1).

Scheme 1. One-pot three component synthesis of aryl-3-methylisoxazol-5(4H)-one derivative.

Several catalysts have been used to synthesise isoxazole-5(4H)-ones, including phthalimide-N-oxyl salts,²⁴ sodium sulphide,²⁵ boric acid,²⁶ sulphated polyborate,²⁷ sodium azide,²⁸ potassium sorbate,²⁹ Sn(ii)-montmorillonite,³⁰ β-cyclodextrin,³¹ mesolite,³² Dowex1-X8-OH,³³ citric acid,³⁴ glutamic acid in glycerol,³⁵ sodium benzoate,³⁶ DABCO,³⁷ ChCl-ZnCl₂ DES,³⁸ WEOFPA/glycerol,³⁹ eucalyptol,⁴⁰ sodium malonate,⁴¹ sulfonic graphene oxide (SGO), graphene oxide (GO),⁴²N-bromosuccinimide,⁴³ Cu/AC/r-GO nanohybrid with NaHCO₃,⁴⁴ CuBr₂ with oxone,⁴⁵ Fe(ii) catalyst,⁴⁶ nano-SiO₂-H₂SO₄,⁴⁷ Ag/SiO₂,⁴⁸ salicylic acid,⁴⁹ imidazole,⁵⁰l-valine,⁵¹ glycine,⁵² and guanidine hydrochloride.⁵³ Although these methods have produced promising results, many of them have drawbacks, such as the use of toxic reagents, strongly acidic or basic conditions, expensive catalysts, harsh reaction conditions, tedious procedures, long reaction times, and, in some cases, low product yields, which limit their practical application. As a result, it is very desirable to design a novel procedure that uses an efficient, economical catalyst, has a shorter reaction time, and produces a high yield. As part of our ongoing study, we provide an ecologically friendly organocatalyzed synthesis of substituted isoxazolone derivatives. Organocatalysts have received a lot of interest as non-metal options for essential organic reactions because of their sustainability, low toxicity, and cost-effectiveness.⁵⁴ As a result, in this paper, we describe a novel organocatalytic strategy for the synthesis of isoxazolone derivatives that employs ethyl gallate as an efficient, affordable, and environmentally friendly catalyst.

Result and discussion

We tested the effectiveness of ethyl gallate (EG) as a Brønsted acid catalyst for synthesising isoxazole derivatives. Initially, we focused on the synthesis of 3-methyl-4-arylmethyleneisoxazole-5(4H)-ones. The model reaction for optimising the reaction conditions was benzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), and hydroxylamine hydrochloride (1 mmol). Table 1 summarises the impacts of several reaction parameters such as solvent, temperature, and catalyst loading. To assess the catalyst's water tolerance, the reaction was also performed in an aqueous media (Table 1, entries 2 and 3). The reaction was subsequently investigated in other solvents, including ethanol, acetonitrile, toluene, and DMF (Table 1, entries 4–7). Except for toluene and DMF, the remaining solvents produced the intended output in moderate to good yields. Further investigation revealed that solvent-free stirring at room temperature produced the desired product in high yield (Table 1, entry 8). Encouraged by the results, the catalyst loading was adjusted under solvent-free conditions to find the best reaction conditions (Table 1, entries 9–11). To investigate the influence of temperature, the model reaction was run at higher temperatures; however, no significant increase in product yield was detected (Table 1, entries 12 and 13). Based on reaction duration, yield, temperature, and catalyst loading, 1 mol% of EG was found to offer the best result (Table 1, entry 10), hence it was chosen as the optimum catalyst loading. The reaction was also tested on a gram scale to determine the protocol's scalability. Thus 10 mmol of benzaldehyde, ethyl acetoacetate, and hydroxylamine hydrochloride was mixed at room temperature with 5 mol% ethyl gallate, yielding the desired product in good yield (72%) (Table 1, entry 14). To strengthen the green chemistry, some green metrics such as E-factor, Atom economy, Reaction mass efficiency were calculated for the model reaction under optimised condition. As shown in Fig. 2, the low value of E-factor (0.71), good atom economy (61.31%) and reaction mass efficiency (58.36%) indicated that the present work was environmentally favourable and support the green chemistry aspects. Although numerous catalysts were tested for this reaction (Table 2), 1 mol% ethyl gallate produced the desired product in 95% yield, confirming its great catalytic efficiency.

Table 1. Optimization of reaction parameters for the synthesis of 3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones^a.

Entry	Catalyst amount (mol%)	Solvent	Temperature (°C)	Time (min)	Yieldb (%)
1	—	—	RT	120	Tracec
2	5	Water	RT	60	40%
3	5	Water	100	60	45%
4	5	Ethanol	RT	60	67%
5	5	Acetonitrile	RT	60	53%
6	5	Toluene	RT	60	—
7	5	DMF	RT	60	—
8	5	Neat	RT	60	90%
9	2	Neat	RT	60	91%
10	1	Neat	RT	10	95%
11	0.5	Neat	RT	30	92%
12	1	Neat	60	20	95%
13	1	Neat	80	30	97%
14	5	Neat	RT	60	72%d

^aReaction of benzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), hydroxylamine hydrochloride (1 mmol) at room temperature (RT).

^bIsolated yield after purification through column chromatography on silica gel.

^cNo catalyst was added.

^dFor the scale up reaction, the reactants are taken 10 mmol of each in presence of the 5 mol% mg of catalyst.

Fig. 2. Calculation of green metrics.

Table 2. Comparison of the efficiency of different catalytic system synthesis of substituted isoxazolone derivatives.

Entry	Catalyst	Condition	Yield (%)
1	—	No solvent	Trace
2	Sulfated polyborate	Neat/80 °C/30 min	90 (ref. 27)
3	Mesolite	EtOH : H2O/rt, 40 °C/1 h	89 (ref. 32)
4	DOWEX 1-x8OH	H2O/rt/6 h	95 (ref. 33)
5	Citric acid	Neat/rt/8 h	90 (ref. 34)
6	Glutamic acid in glycerol	EtOH/60 °C/55 min	92 (ref. 35)
7	Guanidine hydrochloride	H2O/rt/90 min	90 (ref. 53)
8	Ethyl gallate	Neat/RT	95 (our work)

After determining the optimal reaction conditions, a wide range of aldehydes were used to synthesise various substituted 3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones. To investigate the scope of the reaction, a range of aromatic aldehydes containing both electron-donating and electron-withdrawing groups were utilised, and the desired products were obtained in high yields in case of both EDG and EWG. The effect of position of substituent (ortho, meta, and para) on the aromatic ring was also studied. The study found that the kind of ED and EW substituent on the aromatic ring at ortho, para and meta position had no effect on product yield. The technique was modified to include heterocyclic, polycyclic, and α,β-unsaturated aldehydes, resulting in high yields of the desired compounds (Table 3, entries 15 and 18–20). Among the polycyclic aldehydes, 2-naphthaldehyde (Table 3, entry 16) yielded desired product, whereas 1-naphthaldehyde (Table 3, entry 17) yielded no product, possibly due to steric hindrance. Aliphatic aldehydes were also employed for this reaction (Table 3, entries 21 and 22) but desired product was not obtained, probably due to their lower reactivity under the reaction circumstances. We have found that under optimised conditions, ethyl gallate can be employed to achieve higher turnover number (TON) and turnover frequency (TOF) values for isoxazolone synthesis from various starting materials.

Table 3. EG catalysed synthesis of different substituted 3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones^a.

Entry	Aldehyde	Product	Time (min)	Yieldb (%)	TON/TOF (h−1)
1		5A	10	95	95/190
2		5B	12	91	91/182
3		5C	15	89	89/178
4		5D	10	90	90/180
5		5E	10	93	93/186
6		5F	20	84	84/168
7		5G	12	91	91/182
8		5H	10	94	94/188
9		5I	15	95	95/190
10		5J	10	97	97/194
11		5K	10	97	97/194
12		5L	10	95	95/190
13		5M	15	90	90/180
14		5N	12	87	87/174
15		5O	20	87	87/174
16		5P	20	90	90/180
17		5Q	—	—	—
18		5R	15	90	90/180
19		5S	15	91	91/182
20		5T	12	90	90/180
21		5U	—	—	—
22		5V	—	—	—

^aReaction of wide variety of aldehyde (1 mmol), ethyl acetoacetate (1 mmol), hydroxylamine hydrochloride (1 mmol), EG (1 mol%) at room temperature.

^bIsolated yield after purification through column chromatography on silica gel.

To broaden the scope of the current technique, the flexibility of the reaction was tested using methyl acetoacetate instead of ethyl acetoacetate at optimised reaction conditions. Aromatic aldehydes having both electron-donating and electron-drawing substituents participated smoothly in the reaction. The influence of substituents on the aromatic ring was also studied. As expected, methyl acetoacetate produced the corresponding isoxazolone compounds in virtually identical yields as ethyl acetoacetate (Table 4).

Table 4. EG catalysed synthesis of different substituted 3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones^a.

Entry	Aldehyde	Product	Time (min)	Yieldb (%)	TON/TOF (h−1)
1		5A	10	95	95/190
2		5B	12	91	91/182
3		5D	10	90	90/180
4		5G	12	91	91/182
5		5H	10	94	94/188
6		5I	15	95	95/190
7		5J	10	97	97/194
8		5K	10	97	97/194
9		5L	10	95	95/190
10		5M	15	90	90/180

^aReaction of various aldehyde (1 mmol), methyl acetoacetate (1 mmol), hydroxylamine hydrochloride (1 mmol), EG (1 mol%) at room temperature.

^bIsolated yield after purification through column chromatography on silica gel.

Mechanism

Scheme 2 depicts a probable process for the EG-catalyzed synthesis of 3-methyl-4-arylmethylene isoxazole-5(4H)-ones. At first, the activated carbonyl carbon of ethylacetoacetate is take part in oximation with hydroxylamine to produce I. Then resultant oxime (I) intermediate undergo enolisation to conduct a Knoevenagel condensation with the activated aromatic aldehyde to provide an intermediate (II). The required product is then obtained via intramolecular cyclisation, which is followed by ethanol elimination.²⁷

Scheme 2. Mechanism of synthesis of functionalised isoxazolone derivatives.

Experimental section

General information

The reactions were monitored by TLC [carried out on Merck silica gel (60 F₂₅₄) by using UV light as visualizing agent]. NMR spectra of all the products were taken in CDCl₃ (TMS as an internal standard) using a Bruker 400 spectrometer operating for ¹H at 400 MHz and for ¹³C at 100 MHz.¹H NMR spectroscopic data are represented as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, dd = doublet of doublets, m = multiplet, brs = broad), integration, coupling constants in Hertz (Hz). ¹³C NMR spectroscopic data are reported in ppm. Coupling constants were reported as J values in Hertz (Hz).The chemicals and reagents were purchased from Merck, Spectrochem, and Sigma-Aldrich.

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

In a 25-mL round-bottomed flask, the three components, various aldehydes (1 mmol), ethyl acetoacetate (1 mmol), and hydroxyl amine (1 mmol), were mixed in the presence of ethyl gallate catalyst. The reaction mixture was stirred for a sufficient amount of time at room temperature in solvent-free conditions. After the reaction was completed as shown by thin layer chromatography (TLC), the organic part was extracted in ethyl acetate and separated using column chromatography. The products were identified using ¹H and ¹³C NMR data given in the literature.

Conclusion

Finally, a green, efficient, and sustainable technique has been established for synthesising a wide range of isoxazole derivatives from easily available various aromatic aldehydes. This paper describes a unique application of ethyl gallate (EG), a naturally occurring and ecologically friendly organocatalyst, to promote the synthesis of 3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones. Under mild reaction conditions, EG efficiently catalyses the condensation process, producing the necessary products in excellent to high yields while maintaining amazing operational simplicity. The catalytic system avoids the need for toxic reagents and harsh reaction conditions, which is consistent with the principles of green chemistry. Overall, this study not only describes a simple and ecologically friendly method for synthesising clinically relevant isoxazole derivatives, but it also identifies ethyl gallate as a viable organocatalyst for acid-catalyzed chemical reactions. Given its economic viability, eco-friendliness, and exceptional catalytic performance, EG is expected to find widespread use in the synthesis of valuable heterocyclic compounds significantly contributing to the advancement of green and sustainable chemistry. It is anticipated that this work will stimulate further research into bio-derived organocatalysts and accelerate the development of greener catalytic processes for the synthesis of structurally diverse and biologically significant organic molecules.

Conflicts of interest

The authors declare no conflicts of interest.

Data availability

We declare that the data used/put in the article is always available with the authors, if requested for.

Supplementary information (SI): Experimental details, green metric calculation, FTIR, ¹H NMR and ¹³C NMR spectra and elemental analysis of all the synthesized compounds (5A–5T). See DOI: https://doi.org/10.1039/d6ra05201k.