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Article

Synthesis of Isoxazol-5-One Derivatives Catalyzed by Amine-Functionalized Cellulose

by
Sanaz Gharehassanlou
1 and
Hamzeh Kiyani
2,*
1
School of Chemistry, Damghan University, Damghan 36715-364, Iran
2
Department of Chemistry, Faculty of Science, Shahrekord University, Shahrekord 64165478, Iran
*
Author to whom correspondence should be addressed.
Organics 2024, 5(4), 378-394; https://doi.org/10.3390/org5040020
Submission received: 18 August 2024 / Revised: 19 September 2024 / Accepted: 8 October 2024 / Published: 12 October 2024
Browse Figures
Versions Notes

Abstract

:
In this contribution, propylamine-functionalized cellulose (Cell-Pr-NH2) was employed as the catalyst in the three-component reaction between hydroxylamine hydrochloride and various types of aryl/heteroaryl aldehydes, ethyl acetoacetate/ethyl 4-chloroacetoacetate, or ethyl 3-oxohexanoate. The result of these experiments was the formation of 3,4-disubstituted isoxazol-5(4H)-one heterocycles. The desired five-membered heterocyclic compounds were obtained in good to high yields at room temperature. The investigation of different solvents led us to the conclusion that water is the best solvent to perform the current one-pot, three-component reactions. Attempts to find the optimal catalyst loading clearly showed that 14 mg of cell-Pr-NH2 seems to be sufficient to carry out the reactions. This method has highlighted some principles of green chemistry including less waste generation, atom economy, use of water as an environmentally friendly solvent, and energy saving. Purification without chromatographic methods, mild reaction conditions, simple work-up, low-cost reaction medium, saving time, and obtainable precursors are other notable features of this one-pot fashion.

1. Introduction

Isoxazoles, as one of the most important five-membered N,O-containing heterocyclic compounds, displays numerous pharmacological activities including anti-inflammatory, anti-obesity, antibacterial, anticonvulsant, antirheumatic, antifungal, antitumor, anti-mycobacterial, and antiviral [1,2,3,4]. Among the heterocyclic rings available in drugs, isoxazole ranks 33rd [5], and among the drugs available in the market that have this attractive heterocyclic ring we can mention oxacillin, cloxacillin, sulfisoxazole, sulfamethoxazole, isocarboxazid, leflunomide, valdecoxib, and dicloxacillin [6]. The arylideneisoxazol-5(4H)-one is present in a vast variety of bioactive compounds, agrochemicals, and nonlinear optical (NLO) materials [7]. Additionally, these heterocycles act as promising drug candidates for anti-ulcer [8], anti-obesity [9], antioxidant [10,11], anti-Alzheimer [12], antimicrobial [13,14], anticancer [15], antifungal [16], antitubercular [16], enzyme inhibitor [17], larvicidal [18], antibacterial [19], and fungicide [20] applications (Figure 1). Furthermore, arylidenesoxazol-5-ones have been used as flexible building blocks for the synthesis of various heterocycles [21,22,23,24], alkynes [25], β-amido-N-allylated products [26], γ-functionalized ketones [27], pyrrole-2-carboxylic acids [28], and other functionalized molecules [29,30]. Since arylideneisoxazol-5(4H)-one derivatives have various applications, accordingly, a variety of methods such as condensation of benzaldoximes with 1,3-dicarbonyls, cyclization of oxoesters with hydroxylamine under basic or acidic conditions, cyclization of O-propioloyl oximes, two-step reaction of 1,3-dicarbonyls with hydroxylamine followed by Knoevenagel condensation with various aldehydes, 1,3-dipolar cycloaddition reactions, and most importantly three-component reactions have been reported for their synthesis. In each of these methods, various reagents and catalysts have been used [29,30,31]. Developing efficient and green procedures in synthesizing these heterocycles remains attractive to organic and medicinal chemists. In recent years, numerous catalysts have been reported for their synthesis, some of which include lipase [32], Stiglich’s base [33], sodium acetate in EtOH [34], sodium malonate [35], guanidine hydrochloride [36], sodium acetate in EtOH under visible light [37], citrazinic acid [38], 2,2′-bipyridine]-1,1′-diium perchlorate [39], eosin-Y using visible light [40], acidic ionic liquid [41], Na2S2O3 [42], hydantoin potassium salt [43], NHC-precursor [44], malic acid [45], triphenylphosphine (TPP) [46], sulfamic acid [47], L-valine [48], sodium lauryl sulfate (SLS) [49], glutamic acid [50], succinic acid [51], eucalyptol [52], urea [53], vitamin B1 [54], nano-SiO2-H2SO4 [55], deep eutectic solvents (DESs) [56,57], nano-ZnO [58], nano-MgO [59], nano-SiO2 [60], potassium bromide (KBr) under microwave irradiation [61], gluconic acid aqueous solution (50 wt % GAAS) [62], NaCl [63], Fe3O4@SiPr@GDL MNPs [64], and magnetic DES [65].
On the other hand, multicomponent reactions (MCRs) are among the most extensive and diverse chemical transformations in organic synthesis and medicinal chemistry, enabling the rapid synthesis of various heterocyclic compounds from at least three starting materials [66]. The majority of the atoms from starting materials are incorporated into final products [67]. Due to the economic cost issue, high efficiency, mild conditions, and atom, step, and pot economy, as well as following principles of green chemistry, MCRs can be considered as significant, environmentally friendly, cost-effective, and the most successful processes in organic synthesis [68,69].
Cellulose-derived materials are used in numerous fields such as biology, medicine, tissue engineering, ultraviolet (UV) protection, and artificial blood vessels due to wide availability, biodegradability, biocompatibility, and inexpensiveness [70,71]. Nano-cellulose-grafted amines are also used in catalytic organic transformations [72,73]. Based on the considerations above, finding a sustainable and environmentally friendly catalyst for the synthesis of heterocycles is desirable for synthetic chemistry scholars, not only from the synthetic point of view but also for aligning with the principles of green chemistry. For this purpose, we tried to utilize a useful and efficient catalyst for the synthesis of isoxazol-5(4H)-one derivatives (Scheme 1).

2. Materials and Methods

2.1. General

The aldehydes, hydroxylamine hydrochloride, β-keto esters, and solvents were purchased from commercial sources and were used without further purification. Thin layer chromatography (TLC) analysis was performed on a silica gel plate and thin layer spots were observed under UV lamp. Melting points were measured using the OIptimelt MPA100 melting-point apparatus. 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance or Varian 300, 400, or 500 MHz spectrometer in DMSO-d6 or CDCl3.

2.2. General Procedure for the Synthesis of arylidenemethyleneisoxazole-5(4H)-ones (4a–4ae)

The mixture of β-keto esters (1a–1c, 1 mmol), hydroxylamine hydrochloride (2, 1 mmol), aldehyde derivatives (3, 1 mmol), and catalytic amount of cell-Pr-NH2 (C, 14 mg, 017 mol%) in water (10 mL) were stirred at room temperature. After the completion of the reaction, monitored through TLC analysis, the formed precipitates were filtered off, washed with ethanol (3 × 10 mL), and air-dried to provide the heterocyclic products (4a–4ae).

2.2.1. 4-(3-Hydroxybenzylidene)-3-methylisoxazol-5(4H)-one (4e) (Figures S1 and S2)

1H NMR (300 MHz, DMSO-d6): δ 2.28 (s, 3H, CH3), 7.08 (d, 1H, J = 8.0 Hz, Ar-H), 7.39 (t, 1H, J = 8.0 Hz, Ar-H), 7.79 (d, 1H, J = 7.6 Hz, Ar-H), 7.85 (s, 1H, H-vinyl), 7.95 (s, 1H, Ar-H), 9.96 (s, 1H, OH); 13C NMR (75 MHz, DMSO-d6): δ 11.7 (H-vinyl), 118.9, 119.9, 121.8, 125.8, 130.2, 134.1, 152.3, 157.8, 162.6 (C=N), 168.2 (C=O).

2.2.2. 3-Methyl-4-(4-(methylthio)benzylidene)isoxazol-5(4H)-one (4i) (Figures S7 and S8)

1H NMR (500 MHz, CDCl3): δ 2.30 (s, 3H, CH3), 2.55 (s, 3H, SCH3), 7.30 (d, J = 8.6 Hz, 2H, Ar-H), 7.33 (s, 1H, H-vinyl), 8.32 (d, J = 8.6 Hz, 2H, Ar-H); 13C NMR (CDCl3, 125 MHz): δ 11.6 (CH3), 14.5 (SCH3), 125.1, 125.3, 128.8, 134.2, 148.6, 148.9, 161.1 (C=N), 167.9 (C=O).

2.2.3. 4-(2-Hydroxy-3-methoxybenzylidene)-3-methylisoxazol-5(4H)-one (4j) (Figures S9 and S10)

1H NMR (300 MHz, DMSO-d6): δ 2.24 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 6.89 (t, J = 8.1 Hz, 1H, Ar-H), 7.26 (dd, J = 1.2, 8.1 Hz, 1H, Ar-H), 8.11 (s, 1H, H-vinyl), 8.32 (dd, J = 1.2, 8.4 Hz, Ar-H), 10.34 (s, 1H, OH); 13C NMR (75 MHz, DMSO-d6): δ 12.5 (CH3), 58.4 (OCH3), 116.8, 118.6, 119.8, 139.3, 145.0, 147.6, 149.5, 152.9, 162.2 (C=N, 176.1 (C=O)).

2.2.4. 4-(3-Ethoxy-4-hydroxybenzylidene)-3-methylisoxazol-5(4H)-one (4k) (Figures S11 and S12)

1H NMR (300 MHz, DMSO-d6): δ 1.41 (t, J = 6.9 Hz, 3H, CH3CH2), 2.27 (s, 3H, CH3), 4.14 (q, J = 6.9 Hz, 2H, CH2O), 6.99 (d, J = 8.4 Hz, 1H, Ar-H), 7.80 (s, 1H, H-vinyl), 7.90 (dd, J = 2.1, 8.4 Hz, 1H, Ar-H), 8.54 (d, J = 2.1 Hz, 1H, Ar-H), 10.72 (s, 1H, OH); 13C NMR (75 MHz, DMSO-d6): δ 11.8 (CH3), 15.1 (CH3CH2), 64.3 (CH2O), 114.1, 116.3, 118.1, 125.5, 132.0, 147.1, 152.4, 154.5, 162.8 (C=N), 169.5 (C=O).

2.2.5. 4-(4-Hydroxy-3-methoxybenzylidene)-3-methylisoxazol-5(4H)-one (4l) (Figures S13 and S14)

1H NMR (500 MHz, DMSO-d6): δ 2.28 (s, 3H, CH3), 3.89 (s, 3H, OCH3), 6.98 (d, J = 8.4 Hz, 1H, Ar-H), 7.90 (s, 1H, H-vinyl), 7.93 (dd, J = 1.8, 8.4 Hz, 1H, Ar-H), 8.56 (d, J = 1.8 Hz, 1H, Ar-H), 10.81 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6): δ 11.9 (CH3), 55.8 (OCH3), 114.1, 116.2, 117.3, 125.6, 132.2, 148.1, 152.3, 154.4, 162.9 (C=N), 169.6 (C=O).

2.2.6. 4-(3,4-Dimethoxybenzylidene)-3-methylisoxazol-5(4H)-one (4m) (Figures S15 and S16)

1H NMR (300 MHz, DMSO-d6): δ 2.29 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 7.22 (d, J = 9.0 Hz, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 8.03 (d, J = 9.0 Hz, 1H, Ar-H), 8.51 (s, 1H, H-vinyl); 13C NMR (75 MHz, DMSO-d6): δ 11.8 (CH3), 55.9 (OCH3), 56.5 (OCH3), 112.1, 115.5, 116.1, 126.5, 131.5, 148.8, 152.2, 154.8, 162.8 (C=N), 169.3 (C=O).

2.2.7. 3-Methyl-4-(3,4,5-trimethoxybenzylidene)isoxazol-5-(4H)-one (4n) (Figures S17 and S18)

1H NMR (500 MHz, CDCl3): δ 2.30 (s, 3H, CH3), 3.96 (s, 6H, OCH3), 3.99 (s, 3H, OCH3), 7.32 (s, 1H, H-vinyl), 7.84 (s, 2H, Ar-H); 13C NMR (125 MHz, DMSO-d6): δ 11.8 (CH3), 56.6 (OCH3), 60.8 (OCH3), 112.4, 117.5, 128.5, 143.5, 152.3, 152.8, 162.6 (C=N), 168.8 (C=O).

2.2.8. 3-Methyl-4-(thiophen-2-ylmethylene)isoxazol-5(4H)-one (4o) (Figures S19 and S20)

1H NMR (300 MHz, CDCl3): δ 2.29 (s, 3H, CH3), 7.39–7.42 (m, 1H, Ar-H), 8.24 (d, J = 3.0 Hz, 1H, Ar-H), 8.27 (s, 1H, H-vinyl), 8.34 (d, J = 6.0 Hz, 1H, Ar-H); 13C NMR (75 MHz, CDCl3): δ 11.6 (CH3), 113.5, 129.5, 136.7, 141.6, 142.1, 143.5, 162.1 (C=N), 169.0 (C=O).

2.2.9. 3-Methyl-4-((1-methyl-1H-pyrrol-2-yl)methylene)isoxazol-5(4H)-one (4p) (Figures S21 and S22)

1H NMR (500 MHz, CDCl3): δ 2.26 (s, 3H, CH3), 3.84 (s, 3H, N-CH3), 6.41 (dd, J = 2.3, 4.5 Hz, 1H, Ar-H), 7.13 (t, J = 2.0 Hz, 1H, Ar-H), 7.16 (s, 1H, H-vinyl), 8.56 (dd, J = 1.5, 4.5 Hz, 1H, Ar-H); 13C NMR (125 MHz, CDCl3 + DMSO-d6): δ 11.1 (CH3), 34.2 (N-CH3), 112.2, 126.0, 129.2, 131.6, 134.9, 160.9 (C=N), 169.2 (C=O).

2.2.10. 3-(Chloromethyl)-4-(4-(dimethylamino)benzylidene)isoxazol-5(4H)-one (4v) (Figures S23 and S24)

1H NMR (400 MHz, CDCl3): δ 3.22 (s, 6H, N(CH3)2), 4.54 (s, 2H, CH2Cl), 6.78 (d, J = 9.2 Hz, 2H, Ar-H), 7.55 (s, 1H, H-vinyl), 8.47 (d, J = 7.2 Hz, 2H, Ar-H); 13C NMR (100 MHz, CDCl3): δ 35.7 (N(CH3)2), 40.3 (CH2Cl), 107. 3, 111.7, 121.6, 125.5, 138.3, 150.4, 154.8, 160.6 (C=N), 169.8 (C=O).

2.2.11. 3-(Chloromethyl)-4-(2-hydroxy-3-methoxybenzylidene)isoxazol-5(4H)-one (4w) (Figures S25 and S26)

1H NMR (300 MHz, DMSO-d6): δ 3.85 (s, 3H, OCH3), 4.89 (s, 2H, CH2Cl), 6.87 (t, J = 8.1 Hz, 1H, Ar-H), 7.26 (d, J = 8.1 Hz, 1H, Ar-H), 8.33 (d, J = 8.2 Hz, 1H, Ar-H), 8.41 (s, 1H, H-vinyl), 10.46 (s, 1H, OH); 13C NMR (75 MHz, DMSO-d6): δ 35.3 (CH2Cl), 56.2 (OCH3), 113.1, 118.2, 118.8, 119.6, 123.4, 146.8, 147.8, 150.1, 161.5 (C=N), 167.7 (C=O).

2.2.12. 3-(Chloromethyl)-4-((1-methyl-1H-pyrrol-2-yl)methylene)isoxazol-5(4H)-one (4aa) (Figures S27 and S28)

1H NMR (500 MHz, DMSO-d6): δ 3.92 (s, 3H, N-CH3), 4.94 (s. 2H, CH2Cl), 6.53–6.54 (m, 1H, Ar-H), 7.72 (t, J = 1.6 Hz, 1H, Ar-H), 7.78 (s, 1H, H-vinyl), 8.44 (dd, J = 1.6, 4.5 Hz, 1H, Ar-H); 13C NMR (125 MHz, DMSO-d6): δ 34.8 (N-CH3), 35.9 (CH2Cl), 103.2, 113.7, 127.0, 130.1, 134.8, 138.5, 161.8 (C=N), 169.6 (C=O).

2.2.13. 3-(Chloromethyl)-4-(3-(4(dimethylamino)phenyl)allylidene)isoxazol-5(4H)-one (4ab) (Figures S29 and S30)

1H NMR (500MHz, CDCl3): δ 3.11 (s, 6H, N(CH3)2), 4.49 (s, 2H, CH2Cl), 6.69 (d, J = 8.6 Hz, 2H, Ar-H), 7.34 (d, J = 3.5, 6.9 Hz, 1H, =CH), 7.55 (dd, J = 3.5, 6.7 Hz, 1H, =CH), 7.61 (d, J = 8.6 Hz, 2H, Ar-H), 8.90 (m, 1H, =CH); 13C NMR (125 MHz, CDCl3): δ 35.5 (CH2Cl), 40.1 (N(CH3)2), 112.0, 118.1, 123.1, 132.3, 150.4, 153.3, 155.4, 159.2, 164.1 (C=N), 169.0 (C=O).

2.2.14. 4-(4-(Methylthio)benzylidene)-3-propylisoxazol-5(4H)-one (4ac) (Figures S31 and S32)

1H NMR (500 MHz, CDCl3): δ 1.01 (t, J = 7.2 Hz, 3H, CH3CH2CH2), 1.81 (sex, J = 7.5 Hz, 2H, CH3CH2CH2), 2.59 (s, 3H, SCH3), 2.68 (t, J = 7.5 Hz, 2H, CH3CH2CH2), 7.45 (d, J = 8.7 Hz, 2H, Ar-H), 7.92 (s. 1H, H-vinyl), 8.42 (d, J = 8.7 Hz, 1H, Ar-H); 13C NMR (125 MHz, CDCl3): δ 13.9 (CH3CH2CH2), 14.5 (SCH3), 19.8 (CH3CH2CH2), 27.6 (CH3CH2CH2), 112.2, 114.9, 116.2, 126.4, 131.4, 148.7, 166.3 (C=N), 169.1 (C=O).

2.2.15. (4-(Dimethylamino)phenyl)allylidene)-3-propylisoxazol-5(4H)-one (4ad) (Figures S33 and S34)

1H NMR( 500 MHz, CDCl3): δ 1.04 (t, J = 7.5 Hz, 3H, CH3CH2CH2), 1.74 (sex, J = 7.3 Hz, 2H, CH3CH2CH2), 2.55 (t, J = 7.3 Hz, 2H, CH3CH2CH2), 3.11 (s, 6H, N(CH3)2), 6.68 (d, J = 8.9 Hz, 2H, Ar-H), 7.22–7.27 (m, 1H, =CH), 7.46–7.51 (m, 1H, =CH), 7.56 (d, J = 8.9 Hz, 2H, Ar-H), 8.09–8.15 (m, 1H, =CH); 13C NMR (125 MHz, CDCl3): δ 13.9 (CH3CH2CH2), 20.2 (CH3CH2CH2), 27.9 (CH3CH2CH2), 40.1 (N(CH3)2), 111.9, 118.2, 123.2, 131.2, 131.7, 148.5, 152.8, 153.3, 163.0 (C=N), 170.5 (C=O).

2.2.16. 4-((1-Methyl-1H-pyrrol-2-yl)methylene)-3-propylisoxazol-5(4H)-one (4ae) (Figures S35 and S36)

1H NMR (500 MHz, DMSO-d6): δ 0.98 (t, J =7.2 Hz, 3H, CH3CH2CH2), 1.68 (sex, J = 7.4, 2H, CH3CH2CH2), 2.67 (t, J = 7.3, 2H, CH3CH2CH2), 3.91 (s, 3H, N-CH3), 6.45 (dd, J = 1.6, 2.4 Hz, 1H, Ar-H), 7.51 (s, 1H, H-vinyl), 7.58 (t, J = 1.7 Hz, 1H, Ar-H), 8.38 (dd, J = 1.6 Hz, 1H, Ar-H); 13C NMR (125 MHz, DMSO-d6): δ 14.2 (CH3CH2CH2), 19.9 (CH3CH2CH2), 27.4 (CH3CH2CH2), 34.7 (N-CH3), 106.5, 112.7, 125.8, 129.7, 133.7, 164.8 (C=N), 170.0 (C=N).

3. Results and Discussion

Propylamine-functionalized cellulose (cell-Pr-NH2, C) was synthesized according to the literature [74,75]. Briefly, microcrystalline cellulose (A, 10 g) and AlCl3·6H2O (10 g) in water (100 mL) was stirred at RT for 12 h. Then, the mixture was filtered, the residue was exposed to ammonia, washed with water, and dried in vacuum to produce the cell-alumina (cell-Al2O3) composite (B). Cell-Al2O3 composite (B, 10.0 g) and (3-aminopropyl)- trimethoxysilane (6.98 mL, 40.0 mmol) were mixed in refluxing toluene for 24 h. After cooling, the mixture was filtered off and washed with toluene. Finally, drying at RT in vacuum led to the formation of the cell-Pr-NH2 (C) (Figure 2). The X-ray diffraction (XRD) pattern of the Cell-Pr-NH2 (C) is shown in Figure 3. The three peaks at 2θ = 15.5°, 22.5° and 34.5°, which are related to crystallographic planes (101), (002), and (040) are due to microcrystalline cellulose [76]. These peaks are also observed in the XRD pattern of other cellulose sources containing an NH2 functional group [77]. Other peaks at 2θ = 16.7° and 21.5° can be attributed to other parts of the catalyst (probably due to incorporation of amino groups on the cellulose surface.) (Figure 3). Of course, the peak located at 2θ = 16.4° is also found in microcrystalline cellulose [78].
The field emission scanning electron microscopy image (FE-SEM) shows the rough structure of cellulose and the presence of new parts. In parts of the micrographs, nano-sized spots can be seen (Figure 4, left) approximately 28 to 36 nm in size.
The one-pot, three-component reaction of ethyl acetoacetate (1a), hydroxylamine hydrochloride (2), and vanillin was initially designated for investigation with the aim of achieving the best conditions for carrying out the reaction. The experimental results of these studies are listed in Table 1. When the reaction was carried out without a catalyst in water at room temperature (RT), a yellow solid product was obtained after 40 min with a yield of 50% (Table 1, Entry 1). Continuation of the reaction did not change the efficiency appreciably. After purification, after measuring the melting point (214–216 °C; Lit. [53] 215–217 °C), and recording the 1H and 13C nuclear magnetic resonance (NMR) spectra, it was determined that the compound formed is the expected heterocycle, i.e., 4-(4-hydroxy-3-methoxybenzylidene)-3-methylisoxazol-5(4H)-one (4l). The 1H NMR spectrum of this compound showed the peaks of CH3, OCH3, H-vinyl, OH as four characteristic singlet signals at δ 2.28, 3.89, 7.90, and 10.81 ppm, respectively. Furthermore, two doublet peaks at δ 6.98 (J = 8.4 Hz) and 8.56 ppm, as well as a doublet of doublets peak at δ 7.93 ppm, were attributed to three protons of the benzene ring. The 1H NMR decoupled spectrum of 4l showed 12 distinct signals in agreement with the desired product. The characteristic signals of CH3, OCH3, C=N, and C=O carbons were observed at δ 11.9, 55.8, 162.9, and 169.6 ppm, respectively. Six carbons of the benzene ring, one carbon of the vinyl group, and the 4-position of the isoxazolone ring appeared in the expected regions (114.1–154.4 ppm). After observing this favorable result, we decided to continue the experiments in order to find the best reaction conditions. In this context, important parameters such as the amount of catalyst, the type of solvent, and reaction temperature were investigated. The reactions were performed under aqueous conditions at RT. Various amounts of cell-Pr-NH2 (C) as the catalyst (2–14 mg) were loaded into the reaction mixture in a water solvent. It was found that using 14 mg (0.17 mol%) of cell-Pr-NH2 (C) led to the best results in terms of reaction time (25 min) and isolated reaction yield (97%) (Table 1, Entry 8). Due to this excellent result, other catalyst loading values were not checked and 14 mg of cell-Pr-NH2 (C) as the catalyst was used to check other parameters. After testing various catalyst loadings in water at RT, some solvents available in our laboratory were investigated. Solvents including ethanol (EtOH), acetone (CH3COCH3), chloroform (CHCl3), dimethylformamide (DMF), n-hexane, and a mixture of EtOH-H2O (1:1, v:v) were screened at room temperature (Table 1, Entries 9–14). It was observed that these solvents did not have a significant and acceptable effect on the reaction times or yields. In some solvents, such as CHCl3 and DMF, small amount of the product 4l was seen (checked with the help of TLC analysis) and the reactants remained almost intact (Table 1, Entries 11 and 12). When the reaction was carried out in solvent-free conditions and using the optimal amount of catalyst at RT, no favorable results were obtained (Table 1, Entry 15). Considering the temperature parameter led us to explore other temperatures in addition to room temperature. The reaction was investigated at different temperatures in water solvent and using the optimal amount of the catalyst. Two results are given in the optimization table (Table 1, Entries 16 and 17). No significant results were obtained in any of these studies. With all this controversy, it can be concluded that the best conditions for carrying out the reaction are water as a solvent, 14 mg of cell-Pr-NH2 (C) as the catalyst, and RT (Table 1, Entry 8).
After optimizing the reaction conditions, the substrate scope of the reaction was explored using ethyl acetoacetate (1a), hydroxylamine hydrochloride (2), and substituted benzaldehydes. Consequently, using 14 mg of cell-Pr-NH2 (C) in H2O at RT, the reaction between ethyl acetoacetate (1a), hydroxylamine hydrochloride (2), benzaldehyde, or structurally diverse substituted benzaldehydes produced a broad spectrum of arylideneisoxzol-5(4H)-ones (4a–4n). The results indicate that aryl aldehydes, with the electron-donating groups, participate better in this three-component reaction and produce the corresponding heterocyclic products in good to excellent yields (Table 2, Entries 1–14). When heteroaryl aldehydes, such as thiophene-2-carboxaldehyde and N-methyl-2-pyrrolecarboxaldehyde were used, the cyclocondensation reaction proceeded well and the corresponding products (4o and 4p) were obtained in high isolated yields and reasonable reaction times (Table 2, Entries 15 and 16). In addition, the scope of the substrate was explored further. In this context, ethyl 4-chloroacetoacetate (1b) was employed instead of ethyl acetoacetate (1a). A good result was obtained when benzaldehyde was used as a precursor (Table 2, Entry 17). When the substituted benzaldehydes containing electron-donating functional groups, including OCH3, CH3, N(CH3)2, and OH, at different positions on the aryl ring were used in this three-component catalytic reaction, the processes proceeded well and the corresponding 3-chloromethyl substituted isoxazole-5(4H)-ones (4r–4y) were obtained in good to excellent yields and in satisfactory reaction times (Table 2, Entries 18–25). We also tested two five-membered heteroaryl aldehydes, thiophene-2-carbaldehyde and 1-methyl-1H-pyrrole-2-carbaldehyde, in a reaction with ethyl 4-chloroacetoacetate (1b) and hydroxylamine hydrochloride (2). Fortunately, the two desired heterocyclic products (4z and 4aa) were synthesized with excellent isolated reaction yields (Table 2, Entries 26 and 27). Under the optimized reaction conditions (as described in Table 1, Entry 8), the use of the α,β-unsaturated aldehyde containing a phenyl ring (4-(dimethylamino)cinnamaldehyde) was also fruitful and the desired heterocyclic product (4ab) was formed in an excellent isolated yield of reaction and short reaction time (Table 2, Entry 28). Moreover, under optimal conditions, the attempt to use ethyl 3-oxohexanoate (1c) as a β-keto ester precursor was fruitful. In this regard, three heterocycles (4ac–4ae), were successfully synthesized and the target compounds were isolated with satisfactory yields along with rational reaction times (Table 2, Entries 29–31).
Cellulose is partially soluble in ethanol [78]. Since the amount of catalyst containing cellulose is very small, it dissolves in ethanol during the washing process. The filtrate containing the catalyst can be reused in subsequent reactions. The catalyst was reused four times (Figure 5).
This reaction is comparable to other similar reactions in several aspects (Table 3). Although each of the methods revealed has its own merits, they frequently suffer from some problems. This cyclocondensation process is comparable with other similar chemical transformations in several aspects such as reaction yield, reaction time, type of reaction medium, amount of catalyst, and reaction temperature. From the efficiency point of view, it is superior to entries 1–4 and 7–10. From the aspect of the reaction medium, it is better than cases 9 and 10 because no organic solvent was used. In comparison with methods 1–4 and 6–10, which are included in Table 3, the current reaction has been implemented in a shorter reaction time. It should also be noted that this reaction was carried out at RT, but when 2,2′-bpy (Table 3, Entry 4), [H2-BiPyr][ClO4]2 (Table 3, Entry 5), 50 wt % aq. GAAS (Table 3, Entry 8), PPTS (Table 3, Entry 10), Na2S2O3 (Table 3, Entry 9), and sulfamic acid (Table 3, Entry 10) were used as catalysts, harsh reaction conditions (70 °C, reflux, 65 °C, and reflux, respectively) were needed.
Although we did not carry out mechanistic investigations, based on the literature [79], the mechanism drawn in Scheme 2 can be proposed for the reaction. The Cell-Pr-NH2 catalyst helps the released hydroxylamine to initiate the oximation reaction and nucleophilic attack of the NH2OH on the carbonyl carbon of the β-keto ester (1a–1c) leading to the formation of oxime intermediate A. Intermediate A was cyclized to generate 3-substituted-isoxazole-5(4H)-ones (B). In the presence of the catalyst, cyclic intermediates B are enolized to intermediates C. Finally, the Knoevenagel condensation reaction between enolized 3-substituted-isoxazole-5(4H)-ones (C) and D leads to the formation of the corresponding heterocycles (4a–4ae) (Scheme 2).

4. Conclusions

In conclusion, this work introduces an efficient and green procedure to synthesize 3,4-disubstituted isoxzol-5(4H)-ones, heterocyclic compounds with potential biological activity, using commercially available starting materials. The reactions have been successfully implemented under aqueous conditions in the presence of cell-Pr-NH2 as a catalyst at RT. Employing this method for the synthesis of isoxazole-5(4H)-one heterocycles has several advantages, including ease of reaction implementation, simplicity of product purification, reasonable yields, acceptable reaction times, performing the reactions in non-organic solvents, as well as the low cost, availability, and abundance of the reaction solvent.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/org5040020/s1 and contains the 1H and 13C NMR spectra for compounds.

Author Contributions

Conceptualization, H.K.; investigation, S.G.; data curation, S.G.; writing—original draft preparation, H.K. and S.G.; writing—review and editing, H.K.; supervision, H.K.; project administration, H.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

The data of this study can be found in the Supplementary Materials section.

Acknowledgments

We would to express our thankfulness to the Shahrekord University.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Representative of some synthetically bioactive heterocycles with isoxazol-5(4H)-one skeleton.
Figure 1. Representative of some synthetically bioactive heterocycles with isoxazol-5(4H)-one skeleton.
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Scheme 1. Synthesis of isoxazol-5(4H)-ones (4a–4ae) using cell-Pr-NH2 (C) as the catalyst.
Scheme 1. Synthesis of isoxazol-5(4H)-ones (4a–4ae) using cell-Pr-NH2 (C) as the catalyst.
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Figure 2. Preparation of cellulose propylamine (cell-Pr-NH2) (C).
Figure 2. Preparation of cellulose propylamine (cell-Pr-NH2) (C).
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Figure 3. XRD pattern of aminopropyl cellulose Cell-Pr-NH2 (C).
Figure 3. XRD pattern of aminopropyl cellulose Cell-Pr-NH2 (C).
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Figure 4. Field emission scanning electron microscopy (FESEM) micrographs of Cell-Pr-NH2 (C).
Figure 4. Field emission scanning electron microscopy (FESEM) micrographs of Cell-Pr-NH2 (C).
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Figure 5. Recycle investigation of catalyst in the model reaction.
Figure 5. Recycle investigation of catalyst in the model reaction.
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Scheme 2. A plausible mechanism for the formation of isoxazol-5(4H)-ones (4a–4ae).
Scheme 2. A plausible mechanism for the formation of isoxazol-5(4H)-ones (4a–4ae).
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Table 1. Optimization of the reaction conditions.
Table 1. Optimization of the reaction conditions.
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Entry SolventCatalyst/mg (mol%) 1Temp. (°C)Time (min)Isolated Yields (%)
1H2O-RT7540
2H2O2 (0.024)RT7550
3H2O4 (0.049)RT6055
4H2O6 (0.073)RT5065
5H2O8 (0.098)RT4570
6H2O10 (0.12)RT3085
7H2O12 (0.15)RT3088
8 2H2O14 (0.17)RT2597
9EtOH14 (0.17)RT4565
10CH3COCH314 (0.17)RT8020
11CHCl314 (0.17)RT80trace
12DMF14 (0.17)RT80Trace
13n-Hexane14 (0.17)RT8045
14H2O:EtOH (1:1)14 (0.17)RT5060
15-14 (0.17)RT8035
16H2O14 (0.17)506070
17H2O14 (0.17)Reflux 6562
1 The mol% is calculated based on 0.122 mmol NH2 group per gram of cellulose [72]. 2 Optimized Conditions.
Table 2. Substrate scope of aldehydes and β-keto esters for the synthesis of isoxazole-5(4H)-ones (4a–4ae) a.
Table 2. Substrate scope of aldehydes and β-keto esters for the synthesis of isoxazole-5(4H)-ones (4a–4ae) a.
EntryCompound’s StructureTime (min)/Isolated Yields (%)Melting Points (Lit. [Ref.])
1Organics 05 00020 i0024a40/85140–142 (141–143 [53])
2Organics 05 00020 i0034b35/94176–178 (175–177 [53])
3Organics 05 00020 i0044c45/90136–137 (134–136 [53])
4Organics 05 00020 i0054d30/85200–202 (198–200 [53])
5Organics 05 00020 i0064e37/92202–204 (201–203 [53])
6Organics 05 00020 i0074f40/94211–212 (211–213 [53])
7Organics 05 00020 i0084g40/90225–227 (226–228 [53])
8Organics 05 00020 i0094h55/8587–89 (88–90 [33])
9Organics 05 00020 i0104i45/89128–130 (128–130 [43])
10Organics 05 00020 i0114j35/93218–220 (217–219 [53])
11Organics 05 00020 i0124k27/94135–137 (135–138 [43])
12Organics 05 00020 i0134l25/97213–214 (212–214 [47])
13Organics 05 00020 i0144m30/91127–128 (126–128 [47])
14Organics 05 00020 i0154n40/92170–172 (171–173 [53])
15Organics 05 00020 i0164o45/90146–148 (145–147 [53])
16Organics 05 00020 i0174p40/96212–214 (213–215 [35])
17Organics 05 00020 i0184q 45/80182–184 (181–183 [53])
18Organics 05 00020 i0194r38/92176–178 (175–177 [53])
19Organics 05 00020 i0204s45/90178–179 (177–178 [53])
20Organics 05 00020 i0214t30/85198–200 (200–201 [53])
21Organics 05 00020 i0224u40/94184–185 (184–186 [53])
22Organics 05 00020 i0234v40/91179–181 (178–181 [53])
23Organics 05 00020 i0244w45/87167–169 (166–168 [53])
24Organics 05 00020 i0254x25/96144–146 (143–144 [53])
25Organics 05 00020 i0264y45/93128–130 (128–130 [53])
26Organics 05 00020 i0274z45/88137–138 (137–139 [53])
27Organics 05 00020 i0284aa50/9282–84 (82–83 [35])
28Organics 05 00020 i0294ab35/92212–215 (New)
29Organics 05 00020 i0304ac35/92146–148 (145–148 [43])
30Organics 05 00020 i0314ad50/93158–160 (New)
31Organics 05 00020 i0324ae50/89145–148 (New)
a The reactions were conducted by means of 1a–1c (1 mmol), 2 (1 mmol), and aldehyde derivatives (3, 1 mmol) in H2O (10 mL) in the presence of the catalyst (14 mg, 0.17 mol%) at RT.
Table 3. Comparison of various catalysts applied in synthesis of 4-(4-methoxybenzylidene)-3-methylisoxazol-5(4H)-one (4b).
Table 3. Comparison of various catalysts applied in synthesis of 4-(4-methoxybenzylidene)-3-methylisoxazol-5(4H)-one (4b).
EntryCatalyst (Amount)/ConditionsTime (min)Yield (%)Refs.
1Silica-TLC grade (1 g)/H2O, RT144091[13]
2Lipase (30 mg)/H2O, RT60–12082[32]
3Guanidine hydrochloride (15 mol%)/H2O, RT7088[36]
42,2′-bpy (10 mg)/H2O, reflux7080[39]
5[H2-BiPyr][ClO4]2/H2O, reflux3096[39]
6Succinic acid (10)/H2O, RT9088[51]
7Eucalyptol (1 mL)/RT18084[52]
850 wt % aq. GAAS (5 mL)/70 °C4592[62]
9Na2S2O3 (30 mol%)/H2O, 65 °C30092[42]
10Sulfamic acid (15 mol%)/H2O, reflux6089[47]
11Cell-Pr-NH2 (14 mg, 0.17 mol%)/H2O, RT3594[This work]
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Gharehassanlou, S.; Kiyani, H. Synthesis of Isoxazol-5-One Derivatives Catalyzed by Amine-Functionalized Cellulose. Organics 2024, 5, 378-394. https://doi.org/10.3390/org5040020

AMA Style

Gharehassanlou S, Kiyani H. Synthesis of Isoxazol-5-One Derivatives Catalyzed by Amine-Functionalized Cellulose. Organics. 2024; 5(4):378-394. https://doi.org/10.3390/org5040020

Chicago/Turabian Style

Gharehassanlou, Sanaz, and Hamzeh Kiyani. 2024. "Synthesis of Isoxazol-5-One Derivatives Catalyzed by Amine-Functionalized Cellulose" Organics 5, no. 4: 378-394. https://doi.org/10.3390/org5040020

APA Style

Gharehassanlou, S., & Kiyani, H. (2024). Synthesis of Isoxazol-5-One Derivatives Catalyzed by Amine-Functionalized Cellulose. Organics, 5(4), 378-394. https://doi.org/10.3390/org5040020

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