KI-Mediated Three-component Reaction of Hydroxylamine Hydrochloride with Aryl / Heteroaryl Aldehydes and Two β-Oxoesters

A KI-mediated multi-component cyclocondensation of hydroxylamine hydrochloride, aromatic/hetero-aromatic aldehydes, and ethyl acetoacetate or 4-chloroethyl acetoacetate to form isoxazole-5(4H)-one heterocycles is described. The reaction employs readily accessible starting reactants and provides a range of synthetically isoxazole-5(4H)-ones in good to high yields. Reactions were performed in water as a green medium at room temperature (rt) without heating, microwave irradiation or sonication. Reusability of the reaction medium is also a noteworthy characteristic of this reaction.

Owing to importance of isoxazole-5(4H)-ones, extensive research has been keen to the development of efficient methods for their synthesis.The conventional methods employed for the synthesis of substituted isoxazole-5(4H)ones, include cyclization of O-propioloyl oximes [27], reaction of ethyl acetoacetate and hydroxylamine hydrochloride followed by the Knoevenagel condensation with aromatic aldehydes in two steps [28][29][30], condensation of substituted benzaldoximes and 1,3-dicarbonyl compounds [31], and reaction of β-oxoesters with hydroxylamine and sodium hydroxide with subsequent addition of aqueous HCl followed by heating [32].One-pot synthesis involving threecomponent reaction (3CR) of β-oxoester compounds, hydroxylamine hydrochloride, and diverse aldehydes has been considered as a unique and attractive approach to access this significant class of heterocycles due to the possibility of forming several bonds in a single operation .The 3CR for the synthesis of 3,4-disubstituted isoxazole-5(4H)-ones is of particular interest to our laboratory [41][42][43][44][45][46][47][48], and this report describes the one-pot synthesis of several derivatives of isoxazole-5(4H)-ones in the presence of KI (Scheme 1).Scheme 1.The three-component reaction of β-oxoesters (1a-b) with aryl/heteroaryl aldehydes (2a-p) and hydroxylamine hydrochloride (3) catalyzed by KI in water at room temperature (rt).

Results and Discussion
Initially, we focused on the optimization of the reaction conditions for the cyclocondensation reaction of ethyl acetoacetate (1a), vanillin (2h), and hydroxylamine hydrochloride (3) as starting substrates, as all of these are commercially available.The results are summarized in Table 1.First of all, we employed water as a solvent; because it is considered the best solvent from the viewpoint of green chemistry and showed the best yields for the reactions showed in Table 1.It was successful to carry out some experiments in water at room temperature (rt) as can be seen in entries 2-5.The addition of catalytic amounts of potassium iodide (3 mol%) was effective in promoting the three-component cyclocondensation leading to 4h in a 55% yield (entry 1).The reaction yield was improved to several times by increasing the amount of catalyst from 3 to 15 mol% (entries 2-5).In fact, the employment of 15 mol% KI at rt gave the best result (entry 5).Other solvents, such as dimethylsulfoxide (DMSO), acetone, methanol, nhexane, ethanol, and a mixed water-ethanol resulted in poor to modest yields of 78% (entries 6-11).Increasing reaction temperature to 50 and 100 ℃ did not improve chemical yields (entries 12 and 13).The reaction was also carried out in the solvent-free conditions in the presence of 15 mol% of the KI; and the corresponding isoxazole (4h) was obtained with the 25% yield at longer reaction time and solvent-free conditions (  With the optimal reaction conditions in hand, to explore the scope of this three-component reaction various aromatic/hetero-aromatic aldehydes and β-oxoesters were employed, and the results are shown in Table 2.All the products synthesized through this method are precipitated in the reaction vessel after standing 12h, and the corresponding isoxazoles (4a-s) were then obtained in reasonable yields without any chromatographic purification methods.Electron-donating substituted phenyl rings and hetro-aromatic aldehydes as starting reactants were well tolerated, providing the desired isoxazole-5(4H)-ones in good to high yields (Table 2, entries 1-10).The reaction also displays good tolerance of various substitution patterns (o-, m-, and p-).Electron-withdrawing substituted phenyl rings containing starting materials remained unreactive towards the reaction conditions.In another attempt, the reusability of the catalyst was also examined on the model reaction.After the completion of the reaction, the solid product was filtered off and washed with water.The filtrate containing the catalyst was used again as the reaction medium for three subsequent cycles (Table 3).Decreased reaction yields and increased reaction times, probably due to the decreased amount of catalysts in the next step the reactions.The reaction conditions are similar to the optimized conditions described for the model reaction.

Material and Methods
All chemicals were purchased from Alfa Aesar and Aldrich as well as were used without further purification, except 4-methylbenzaldehyde, 4methoxylbenzaldehyde, benzaldehyde, thiophene-2-carbaldehyde, and thiophene-3carbaldehyde which were distilled before use.All solvents were distilled before use.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.NMR spectra were recorded at ambient temperature on a BRUKER AVANCE DRX-400 MHz using DMSO-d6 as the solvent.FT-IR spectra were recorded on a Perkin-Elmer RXI spectrometer.The development of reactions was monitored by thin layer chromatography (TLC) analysis on Merck pre-coated silica gel 60 F254 aluminum sheets, visualized by UV light.Elemental microanalyses were performed on an Elementar Vario EL III analyzer.All of the targeted products are reported in the literature and are characterized by comparison of their spectral and physical data on the basis of literature descriptions.

General procedure for the synthesis of isoxazole-5(4H)-ones (4a-s)
A mixture of ethyl acetoacetate/4-chloroethyl acetoacetate (1, 1 mmol), aryl/hetro-aryl aldehyde (2, 1 mmol), hydroxylamine hydrochloride (3, 1 mmol), and 15 mol% of KI was stirred in distilled water (5 mL) at rt.The progress of the reaction was monitored by TLC (EtOAc: n-hexane, 3:10) analysis.After the completion of the reaction, the crude products were obtained by filtration followed by washing with distilled water and the corresponding products were obtained as solid materials.The filtrate containing catalyst was reused for subsequent reactions.Data for representative compound 4r was as follows:

Conclusions
In conclusion, this one-pot 3CR giving good to high yields of isoxazole-5(4H)-ones using KI as the commercially available catalyst.The approach is simple, efficient, and offers an alternative method for the synthesis of valuable heterocycles.Eco-friendliness, cost-effectiveness, no chromatographic purification, not using microwave irradiation or ultrasound waves are another notable characteristic of this reaction.