Potassium phthalimide as efficient basic ... - CyberLeninka

Journal of Saudi Chemical Society (2013) xxx, xxx–xxx

King Saud University

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ORIGINAL ARTICLE

Potassium phthalimide as efficient basic organocatalyst for the synthesis of 3,4-disubstituted isoxazol-5(4H)-ones in aqueous medium Hamzeh Kiyani *, Fatemeh Ghorbani School of Chemistry, Damghan University, 36715-364 Damghan, Iran Received 27 July 2013; revised 4 October 2013; accepted 8 November 2013

KEYWORDS Potassium phthalimide; Isoxazole-5(4H)-ones; Aryl aldehydes; Three-component; Water

Abstract Potassium phthalimide (PPI) is employed as an efficient and effective basic organocatalyst for the one-pot three-component reaction of b-oxoesters with hydroxylamine hydrochloride and various aromatic aldehydes. This cyclocondensation reaction was performed in water as an environmentally benign solvent at room temperature giving 3,4-disubstituted isoxazol-5(4H)-ones in good to excellent yields. PPI was found to be an effective organocatalyst for the synthesis of isoxazol-5(4H)-one system. The advantages of this method are efficiency, clean, easy work-up, high yields, shorter reaction times, inexpensive, and readily available catalyst. ª 2013 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.

1. Introduction Since the first multicomponent process (MCP) was described by Strecker in 1850 [67] multicomponent processes (MCPs) have been demonstrated to be highly valuable tools for the expedient creation of the numerous chemical compounds including natural products and biologically active compounds [55,71,32,46,63]. Recently, considerable attention has been focused on MCPs owing to their high efficiency, mild conditions, simplistic completing, environmentally friendly, and minimizing * Corresponding author. Tel.: +98 232 523 5431. E-mail address: [email protected] (H. Kiyani). Peer review under responsibility of The Egyptian Society of Chest Diseases and Tuberculosis.

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time-consumption [4,33,34,61,20,6]. In addition to this, the other features of MCPs are the following: (i) simple procedures for the formation of final products in a one-pot process from at least three starting materials, (ii) green of bond-forming, (iii) atom and structural economy, (iv) minimization of waste produced, (v) easy construction of complex organic molecules, as well as (vi) avoiding complicated purification processes [72,73,16,17]. Carrying out MCPs in water as the reaction medium will be one of the most suitable methods, which will be a significant component of green chemistry [9,31,60,7,19]. On the other hand, isoxazol scaffold represents an important class of heterocycles which have a wide range of pharmacological properties. A variety of biological activities have been reported for isoxazol derivatives such as protein-tyrosine phosphatase 1B (PTP1B) inhibitory [21] anticonvulsant [3] antifungal [59] HDAC inhibitory [12] analgesic [22] antitumor [52] antioxidant [50,49] antimicrobial [54] COX-2 inhibitory [69] nematicidal [65] antinociceptive [18] anti-inflammatory [23] anticancer [24] antiviral [35] antituberculosis [43] and

1319-6103 ª 2013 King Saud University. Production and hosting by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jscs.2013.11.002

Please cite this article in press as: H. Kiyani, F. Ghorbani, Potassium phthalimide as efficient basic organocatalyst for the synthesis of 3,4-disubstituted isoxazol-5(4H)-ones in aqueous mediumH)-ones –>, Journal of Saudi Chemical Society (2013), http://dx.doi.org/ 10.1016/j.jscs.2013.11.002

2

H. Kiyani, F. Ghorbani

antimycobacterial [10]. Furthermore, some of compounds containing the isoxazol ring in their structure were used for the treatment of leishmaniasis [68], as well as treatment of patients with active arthritis [30]. Due to the importance of isoxazol derivatives, recently, organic chemists are interested in the synthesis of such compounds [1,39,40,2,41,44,57]. Also, we synthesized arylmethylene-isoxazole-5(4H)-ones in water at room temperature in the presence of various catalysts [25–29]. Water is one of the best solvents due to its features such as being environmentally friendly, safe, non-toxic, non-flammable, clean, green, inexpensive, and readily available in organic transformations has received considerable attention. Also, use of water not only diminishes the risk of organic solvents, but also improves the rate of many chemical reactions [53,38,37,36,7,11]. Development of solid basic catalytic systems utilizing inexpensive, clean, environmentally benign, and commercially available catalysts has been a challenge in organic synthesis [70,13,47]. Potassium phthalimide (PPI) is a mild, green, inexpensive, commercially available, efficient basic recyclable catalyst, and a stable reagent. This reagent has been used in several reactions including synthesis of primary amines by the Gabriel method [58,64] the synthesis of phthalimide derivatives

[66,8,45,51,62,42,74] and the preparation of cyanohydrin trimethylsilyl ethers [14,15]. Our literature survey revealed that there is no report on the use of PPI as a catalyst in the synthesis of isoxazol-5(4H)-one derivatives. Herein, we report the applicability of PPI as a readily available, efficient, and solid basic catalyst for the synthesis of a wide variety of isoxazol-5(4H)-one derivatives via the one-pot three-component process (Scheme 1). 2. Experimental 2.1. General All chemicals, unless otherwise specified, were purchased from commercial sources and were used without further purification, with the exception of furan-2-carbaldehyde and benzaldehyde, which were distilled before using. 4-Hydroxy-3-nitrobenzaldehyde (3m) [5] and chromone-3-carbaldehyde (3n) [48] were synthesized according to the procedures reported in the literature. The products were characterized by comparison of their physical data with those of known samples or by their spectral data. Melting points were measured on a Buchi 510 melting point apparatus and are uncorrected. 1H NMR and 13C NMR spectra O N: -K+

O

O CO 2Et + NH2OH.HCl +

R R = CH3 (1a) = CH2Cl (1b) = Ph (1c)

2

1

Scheme 1

Table 1

H

R Ar

10 mol% O H2O, r.t.

Ar

N

3a-n

O

O

4a-y

Synthesis of 3,4-disubstituted isoxazol-5(4H)-ones catalyzed by PPI.

Solvent effect in the reaction of ethyl acetoacetate (1a) with hydroxylamine hydrochloride (2) and vanillin (3d).a O

O CO2Et

H 3C

+ NH2OH.HCl +

OCH3

H

OH 1a

2

3d

OH

H3C PPI Solvent

N

O 4d

O

OCH3

Entry

Solvent

PPI amount (mol%)

Time (min)

Yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13

H2O H2O H2O H2O C2H5OH Acetone Hexane H2O/C2H5OH (1:1) H2O/acetone (1:1) H2O/dioxane (1:1) 1,4-Dioxane Cyclohexane Solvent-free

5 10 15 20 10 10 10 10 10 10 10 10 10

80 70 70 70 120 120 120 120 120 120 120 120 120

89 95 96 95 55 10 21 70 15 10 Trace Trace 20

a

Reaction conditions: ethyl acetoacetate (1 mmol), hydroxylamine hydrochloride (1 mmol), vanillin (1 mmol), water (4 mL), room temperature. b Isolated yield of product.


Potassium phthalimide as efficient basic organocatalyst

3

were recorded at ambient temperature on a BRUKER AVANCE DRX-500 and 400 MHz using CDCl3 or DMSO-d6 as the solvent. FT-IR spectra were recorded on a PerkinElmer RXI spectrometer. The development of reactions was monitored by thin layer chromatography (TLC) on Merck pre-coated silica gel 60 F254 aluminum sheets, visualized by UV light.

the products can be recrystallized from hot ethanol. After removal of the water from the filtered solution, the catalyst is recovered and used for the subsequent reaction. Spectral data for some compounds are as follows: 2.2.1. 4-Benzylidene-3-methylisoxazol-5(4H)-one (4a) 1

H NMR (400 MHz, CDC13): d 2.34 (s, 3H), 7.46 (s, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.61–7.64 (m, 1H), 8.38 (dd, J = 1.3, 7.4 Hz, 2H).

2.2. General procedure for the synthesis of isoxazol-5(4H)-ones (4a–q)

2.2.2. 3-Methyl-4-(4-methylbenzylidene)isoxazol-5(4H)-one (4b)

A reaction mixture of b-ketoester 1 (1 mmol), hydroxylamine hydrochloride 2 (0.07 g, 1 mmol), aromatic aldehyde 3 (1 mmol), and PPI (10 mol%) in 4 mL of distilled water was stirred at room temperature for the mentioned time shown in Table 2. Precipitate gradually is formed during the reaction. After completion of reaction (monitored by TLC analysis), the precipitate was filtered off, and washed with cold distilled water (3 mL) and dried in the air to obtain the desired products with high purity. If the further purification was needed,

Table 2

1 H NMR (400 MHz, CDC13): d 2.33 (s, 3H), 2.48 (s, 3H), 7.36 (d, J = 8.0 Hz, 2H), 7.42 (s, 1H), 8.32 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDC13): d 11.6, 22.1, 118.2, 129.8, 129.9, 134.2, 145.8, 150.2, 161.4, 168.3.

2.2.3. 4-(3-Hydroxybenzylidene)-3-methylisoxazol-5(4H)-one (4g) 1 H NMR (400 MHz, DMSO-d6): d 2.28 (s, 3H), 7.08 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.79 (d,

Synthesis of 3,4-disubstituted isoxazol-5(4H)-ones (4a–y) catalyzed by PPI in water at room temperature.a O -

N: K+ O

O

CO2Et + NH2OH.HCl + H R R = CH3 (1a) = CH2Cl (1b) = Ph (1c) 2

1

R Ar

10 mol% O H2O, r.t.

N

3a-n

Ar O

O

4a-y

Entry

Aldehyde (3)

R

Product (4)

Time (min)

Yieldb (%)

m.p. (C)

Lit.c m.p. (C)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

C6H5– 3a 4-CH3C6H4– 3b 4-CH3OC6H4– 3c 4-OH-3-CH3OC6H3– 3d 2-OHC6H4– 3e 3-OHC6H4– 3g 4-OHC6H4– 3h 4-(NMe)2C6H4– 3i 2-Furyl 3j 2-Thienyl 3k 3-Thienyl 3l 4-OH-3-NO2-C6H3– 3m 3-Coumarinyl 3n C6H5– 3a 4-CH3C6H4– 3b 4-CH3OC6H4– 3c 4-OHC6H4– 3h 4-(NMe)2C6H4– 3i C6H5– 3a 4-CH3OC6H4– 3c 4-OH-3-CH3OC6H3– 3d 4-OHC6H4– 3h 4-(NMe)2C6H4– 3i 2-Thienyl 3k

CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 Ph Ph Ph Ph Ph CH2Cl CH2Cl CH2Cl CH2Cl CH2Cl CH2Cl

4a 4b 4c 4d 4e 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 4s 4t 4u 4v 4w 4x 4y

130 100 70 70 150 120 130 100 130 100 100 50 110 100 75 70 90 95 60 35 30 30 30 40

90 91 96 95 82 95 95 91 85 90 92 87 90 85 90 91 88 92 88 95 94 92 92 90

140–142 135–135 175–177 213–215 198–200 199–201 210–211 220–221 239–241 143–145 142–144 266–267 242–244 213–215 195–196 168–170 209–211 195–197 183–186 175–177 142–145 183–186 179–180 146–148

141–143 – 174–176 211–214 198–201 – 214–216 – 238–241 – – – 251 215–216 194–196 168–169 210 194–196 – 174–176 – – –

a Reagents and conditions: b-ketoester 1 (1 mmol), hydroxylamine hydrochloride 2 (1 mmol), aryl aldehyde 3 (1 mmol), water (4 mL), room temperature. b All yields are of pure products. c Melting points are listed in Refs. [1,39,40,2,41,44,25–29,56].


4 J = 7.6 Hz, 1H), 7.85 (s, 1H), 7.95 (s, 1H), 9.96 (s, 1H); 13C NMR (100 MHz, DMSO-d6): d 11.7, 118.9, 119.9, 121.8, 125.8, 130.2, 134.1, 152.3, 157.8, 162.6, 168.2. 2.2.4. 4-(4-(Dimethylamino)benzylidene)-3-methylisoxazol5(4H)-one (4i)

H. Kiyani, F. Ghorbani 2.2.12. 3-(Chloromethyl)-4-(4-(dimethylamino)benzylidene) isoxazol-5(4H)-one (4x) 1

H NMR (400 MHz, CDC13): d 3.22 (s, 6H), 4.56 (s, 2H), 6.78 (d, J = 8.6 Hz, 2H), 7.55 (s, 1H), 8.48 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDC13): d 35.7, 40.3, 107.3, 111.7, 121.7, 138.3, 150.4, 154.8, 160.6, 169.9.

1

H NMR (400 MHz, CDC13): d 2.27 (s, 3H), 3.19 (s, 6H), 6.75 (dd, J = 1.2, 8.4 Hz, 2H), 7.24 (s, 1H), 8.43 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDC13): d 11.7, 40.1, 110.9, 111.5, 121.5, 137.7, 149.3, 154.2, 161.7, 170.2. 2.2.5. 3-Methyl-4-(thiophen-2-ylmethylene)isoxazol-5(4H)one (4k)

2.2.13. 3-(Chloromethyl)-4-(thiophen-2-ylmethylene)isoxazol5(4H)-one (4y) 1

H NMR (400 MHz, CDC13): d 4.60 (s, 2H), 7.34–7.36 (m, 1H), 7.98 (s, 1H), 8.06 (d, J = 4.8 Hz, 1H), 8.19 (d, J = 3.6 Hz, 1H); 13C NMR (100 MHz, CDC13): d 35.3, 111.1, 129.2, 136.5, 140.9, 141.0, 142.6, 159.7, 168.3.

1

H NMR (400 MHz, CDC13): d 2.32 (s, 3H), 7.29 (t, J = 4.8 Hz, 1H), 7.64 (s, 1H), 7.95 (d, J = 4.8 Hz, 1H), 8.13 (d, J = 3.6 Hz, 1H); 13C NMR (100 MHz, CDC13): d 11.5, 114.6, 128.9, 136.5, 139.2, 139.6, 141.5, 160. 7, 168.7. 2.2.6. 3-Methyl-4-(thiophen-3-ylmethylene)isoxazol-5(4H)one (4l) 1

H NMR (400 MHz, CDC13): d 2.29 (s, 3H), 7.42 (dd, J = 5.2, 2.8 Hz, 1H), 7.49 (s, 1H), 7.95 (dd, J = 1.6, 4.8 Hz, 1H), 8.99 (dd, J = 0.8, 2.8 Hz, 1H); 13C NMR (100 MHz, CDC13): d 11.6, 117.0, 126.8, 131.5, 135.2, 139.4, 140.9, 161.3, 168.5. 2.2.7. 4-(4-Hydroxy-3-nitrobenzylidene)-3-methyl-4H-isoxazol5-one (4m) 1

H NMR (400 MHz, DMSO-d6): d 2.27 (s, 3H), 7.27 (d, J = 8.8 Hz, 1H), 7.92 (s, 1H), 8.20 (s, 1H), 8.62 (d, J = 9.2 Hz, 1H), 9.2 (s, 1H); 13C NMR (100 MHz, CDCl3 and DMSO-d6): d 11.7, 117.8, 119.9, 124.5, 132.3, 137.2, 140.5, 149.6, 157.0, 162.3, 168.7. 2.2.8. 4-Benzylidene-3-(chloromethyl)isoxazol-5(4H)-one (4t) 1

H NMR (400 MHz, CDCl3): d 4.59 (s, 2H), 7.55–7.59 (m, 2H), 7.63–7.67 (m, 1H), 8.39–8.42 (m, 2H); 13C NMR (100 MHz, CDCl3): d 35.1, 116.1, 129.2, 132.1, 151.9, 160.2, 167.3. 2.2.9. 3-(Chloromethyl)-4-(4-methoxybenzylidene)isoxazol5(4H)-one (4u) 1

H NMR (400 MHz, CDCl3): d 3.96 (s, 3H), 4.57 (s, 2H), 7.05 (dd, J = 2.0, 7.2 Hz, 2H), 7.70 (s, 1H), 8.50 (dd, J = 2.0, 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 35.3, 55.8, 112.6, 114.8, 125.7, 137.6, 151.2, 160.4, 165.3, 168.3. 2.2.10. 3-(Chloromethyl)-4-(3-hydroxy-4-methoxybenzylid ene)isoxazol-5(4H)-one (4v) 1

H NMR (400 MHz, DMSO-d6): d 3.87 (s, 3H), 4.88 (s, 2H), 7.0 (d, J = 8.4 Hz, 1H), 7.92 (dd, J = 2.0, 8.4 Hz, 1H), 8.02 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d 35.6, 56.0, 110.5, 116.5, 117.2, 125.4, 132.9, 148.1, 153.5, 155.3, 162.2, 169.1. 2.2.11. 3-(Chloromethyl)-4-(4-hydroxybenzylidene)isoxazol5(4H)-one (4w) 1 H NMR (400 MHz, DMSO-d6): d 4.90 (s, 2H), 7.10 (d, J = 8.4 Hz, 2H), 8.04 (s, 1H), 8.48 (d, J = 8.8 Hz, 2H), 11.28 (s, 1H); 13C NMR (100 MHz, DMSO-d6): d 35.6, 110.7, 116.9, 124.9, 138.6, 153.3, 162.2, 164.9, 168.9.

3. Results and discussion In the beginning, the optimal conditions for this reaction were investigated. Conducting reaction between ethyl acetoacetate (1a), hydroxylamine hydrochloride (2), and vanillin (3d) in the presence of 10 mol% of PPI for 70–120 min at room temperature in different solvents such as EtOH, H2O, acetone, hexane, and a mixture of H2O–EtOH (V:V, 1:1), H2O–acetone (V:V, 1:1) as well as H2O–1,4-dioxane (V:V, 1:1) resulted in corresponding product 4d in 95%, 55%, 10%, 21%, 70%, 15%, and 10% of yields, respectively (Table 1, entries 2 and 5–10). Among all these solvents, H2O was found to be the best in terms of the yield of the product and time of completion in comparison with other solvents. The amount of PPI required for this transformation was also evaluated. Variation of the amount of PPI from 10 to 15 and 20 mol% led to 95%, 96%, and 95% of yields, respectively. When 5 mol% of catalyst was used, the reaction needed more time to furnish, and yield also decreased. These results indicated that, 10 mol% PPI gives high yield of the product in duration of reaction. Also, performing the reaction in the other organic solvents such as cyclohexane and 1,4-dioxane at room temperature for 2 h provided trace amount of product 4d. On conducting the same reaction in the absence of solvent at room temperature, only 20% yield of 4d was achieved even after a prolonged reaction. Increasing the reaction temperature from r.t. to 50, 70, and 100 C had not only considerable influence on the yield of 4d, but also decreased yield, and no effect on the reaction rate. Hence, using 10 mol% PPI in water is sufficient to push the reaction forward. After optimizing the conditions, the broad view of this process was studied by the reaction of various substituted aryl aldehydes and heterocyclic aldehydes with hydroxylamine hydrochloride (2) and b-ketoesters (1a–c) in the presence of 10 mol% PPI in water at room temperature. The results of this study are presented in Table 2. The reaction was clean, and no chromatographic separation was performed because no impurities were observed. After completion of the reaction, the solid product was collected by simple filtration. The structure of the title compounds was established by spectral data and physical properties. For example, the 1H NMR spectrum of 4k exhibited a sharp singlet signal at d = 2.32 ppm due to the methyl group in the isoxazol unit. One triplet at d = 7.29 (J = 4.8 Hz) and two doublets at d = 7.95 (J = 4.8 Hz) and d = 2.88 (J = 3.6 Hz) integrating for one proton each in 1H NMR spectrum of 4k were assigned to the thiophene ring. Also, the 1H NMR showed one singlet signal at


Potassium phthalimide as efficient basic organocatalyst

5

d = 7.64 ppm for the ‚CH proton between the isoxazol and thiophene rings. The 13C NMR spectrum of 4k displayed the isoxazol ring carbons C‚O and C‚N at d = 168.7 and 160.7 ppm, respectively confirming the isoxazol unit. The signal at d = 11.5 ppm corresponds to the CH3 group. The other carbon signals were observed at the expected chemical shifts. Likewise, in the NMR spectra of compound 4y, which are very similar to compound 4k, the expected signals are observed. The 1H NMR spectrum showed two singlet signals at d = 4.60 and 7.98 ppm for the –CH2Cl and the ‚CH protons. The signals corresponding to the thiophene ring protons appeared at the desired region. In the 13C NMR spectrum, the signals of the C‚O and C‚N carbons of the isoxazol ring are seen at 168.3 and 159.7 ppm. Trace of the signal corresponding to the methyl group is not observed, instead a signal which indicates the presence of –CH2Cl carbon at 35.3 ppm is observed. The other carbon signals appeared at the expected regions. It is found that, aromatic substrates having electron-donating functional groups afforded good to high yields of products (Table 2, entries 2–8, 15–18, and 20–23). Furthermore, the reaction with p-excessive heterocyclic aldehydes also preceded smoothly with high yields in short reaction times (Table 2, entries 9–11 and 24). These results show that the electron-withdrawing groups are not favored under these conditions, whereas, aromatic aldehydes bearing electron-donating functional groups proved to be good substrates and reacted smoothly. However, the aryl aldehydes with the electrondonating group at the ortho-position such as 2-hydroxybenzaldehyde (3e) afforded 4e in relatively longer time and 82% yield probably due to the steric hindrance effects (Table 2, entry 5). Interestingly, when the 4-hydroxy-3-nitrobezaldehyde (3m) containing both electron-accepting (–NO2) and electrondonating (–OH) groups was used, the corresponding product

(4m) was obtained in a shorter reaction time and higher yield (Table 2, entry 12). On the other hand, for aromatic aldehydes bearing electron-deficient groups and p-deficient heterocyclic aldehyde, pyridine-2-carbaldehyde, there was no product formation even after 12 h under the optimized reaction conditions. Accordingly, it is concluded that the electronic nature of the functional groups and their position on aryl aldehydes have many effects on this reaction. Although the exact mechanism of this transformation is not completely clear, a possible reaction mechanism is proposed based on these results and the provided mechanism in the literature (Scheme 2). At first, the nucleophilic attack of the amino group of hydroxylamine hydrochloride on the carbonyl carbon of the b-ketoester (1) resulted in intermediate oxime 5. The removal of hydrogen by PPI, the carbon anion 6 is generated. The aldehyde was attacked by carbon anion 6 and subsequent reaction Knoevenagel, 9 is formed. Then oxygen attacks on carbon of ester moiety to give 10, which undergoes proton transfer and losing one ethanol molecule to corresponding products 4a–y. To compare the effectiveness of PPI with other catalysts in the preparation of 4-arylmethylene-3-methyl-isoxazol-5(4H)ones, results of the reaction of 4-methoxybenzaldehyde, EAA, and NH2OH.HCl are presented in Table 3. As can be seen in Table 3, PPI, comparative to the formerly reported methods, is reasonably better in terms of time reactions and yields. In all reactions, the catalyst is recoverable. The catalyst was recovered by evaporation of solvent from filtrated solution after each run. The catalyst recycled was applied as such for the consecutive runs in four series of the same model reaction under the optimized conditions for up to four runs (1st use: 94%, isolated yield, 2nd use: 91% isolated yield, 3rd use: 87% isolated yield, and 4th use: 82% isolated yield).

O K+ N O

HO

O

R

NH2OH.HCl O

N

HO

O O

R H 5

1

O O

O N

R

- HN

N

O O

R

O

Intramolecular cyclization

O O

R Ar

Ar 10 N

N

O

R

O

N - EtOH

O

H

O O

OH 8

HO

NH

O

Ar

9

OH

- H2O R

Knoevenagel condensation O

N

-

Ar 3

6

O HO

H

+ O

H HO

O

N

O

R Ar

N

O O 7

O

O O

R Ar

Ar

4a-y

11

Scheme 2

Plausible mechanism for the formation of isoxazol-5(4H)-ones (4a–y).


6

H. Kiyani, F. Ghorbani Table 3 Comparison of the results of the reaction of ethyl acetoacetate (1a) with hydroxylamine hydrochloride (2) and 4methoxybenzaldehyde (3c), using PPI with those obtained by reported catalysts. O

O CO2Et

H3C

+ NH2OH.HCl +

OCH3 1a

2

OCH3

H3C Catalyst

H

Conditions

3c

N

O 4c

O

Catalyst/conditions

Catalyst amount (mol%)

Time (min)

Yield (%)

Refs.

Na2S/EtOH/r.t. Pyridine/EtOH/reflux Catalyst free/grinding Pyridine/H2O/ultrasound Sodium benzoate/H2O/r.t. Sodium silicate/H2O/r.t. PPI/H2O/r.t.

5 100 0 100 10 5 10

90 180 48 60 90 90 70

88 71 61 82 87 91 96

[41] [40] [40] [40] [39] [40] This work

Decreasing the yield is probably related to a slight reduction in the catalytic activity of the catalyst or decreasing the amount of catalyst recycled, which is attributed to the handling.

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