1. Introduction

The design of multi-component reactions is an important field of research and there has been tremendous developments in three- and four-component reactions. These protocols are performed without isolation of any intermediates, thus reducing time and saving both energy and raw materials. β-Acetamido ketones are important compounds which have been used in the synthesis of other important organic molecules such as 1,3-amino alcohols, nucleoside peptide antibiotics, nikkomycines, and neopolyoxins[1, 2]. The best known route for the synthesis of this important class of compounds is proposed as Dakin–West reaction[3]. This reaction involves the one-pot multicomponent coupling condensation of an enolisable ketone, aldehyde and acetonitrile in the presence of acetyl chloride[4]. A few catalysts have already been applied to synthesis of acetamido ketones such as CoCl₂[5], montmorillonite K10 clay[6], silica sulphuric acid[7], Cu(OTf)₂, transition metal triflates, various metal chlorides[8] and solid acid Hβ-zeolite[9]. However, most of these procedures are not entirely satisfactory and suffer from long reaction time or tedious work up. Hence, the development of new catalysts with more efficiency is of interest[10].

Herein, we developed the applicability of strong super-acidic vanadium(V)-substituted Keggin-type heteropolyacid, H₇SiW₉V₃O₄₀, as catalyst for the efficient and facile synthesis of β-acetamido ketones through one-pot condensation of an aryl aldehyde, acetophenone, acetyl chloride, and acetonitrile (Scheme 1).

Scheme 1.

2. Experimental

All starting materials were purchased commercially and were used as received. All products were characterized by comparison of their spectral and physical data with those reported in the literature. Silica gel 60 (70—230 mesh) was used for column chromatography. Progress of the reactions was monitored by TLC. Infrared spectra were recorded (KBr pellets) on a 8700 Shimadzu Fourier Transform spectrophotometer. ¹HNMR spectra were recorded on a Bruker AVANCE 300-MHz instrument. The catalyst was prepared and characterized according to literature procedures[11-14].

H₇SiW₉V₃O₄₀ was prepared from sodium vanadates precursor. Sodium vanadate (1.9 g; 15.5 mmol) was dissolved in 300 ml of water. Na₁₀[α-SiW₉O₃₄].18H₂O (145 g; 52 mmol) was added to the stirred solution, followed by 185 ml of 6 M sulfuric acid. The solution then was maintained under stirring for 45 min. The pH was adjusted between 6 and 7 by the addition of solid potassium carbonate. An orange potassium salt (∼100 g) was precipitated via the addition of solid potassium chloride (80 g) and recrystallized in water. Calcd (Found): K, 9.34 (9.12); Si, 0.96 (1.12); V, 5.16 (5.28); W, 56.48 (56.73); H₂O, 6.14 (6.32).FT-IR (cm^-1): 1004(w), 960(s), 900(vs), 805(vs), 740(vs). Then, the potassium salt (15 g; 5 mmol) was dissolved in 65 ml of water, and the solution was placed in a separatory funnel. Diethyl ether then was added, followed by the slow addition of concentrated hydrochloric acid (100 ml). The heavy phase was collected and diethyl ether evaporated under vacuum. The resultant solid was dissolved in a minimum amount of water. Finally, the heteropolyacid was slowly crystallized at room temperature.

A mixture of aromatic aldehyde (1 mmol), acetophenone (1 mmol), acetyl chloride (2 mmol) in acetonitrle (4 ml) was treated with a catalytic amount of the desired heteropolyacid at 80 ^◦C. Progress of the reaction was monitored by TLC. The work-up procedure of this reaction is very simple. After completion of the reaction, the mixture was filtered to separate the catalyst. Then, the solid crude product was washed with petroleum ether and filtered. The pure product, if needed, could be obtained by re-crystallization from ethanol-water mixture. All products were identified by means of IR and ¹H NMR spectroscopy and/or comparison of their melting points with those reported in the literature.

3. Results and Discussion

The catalytic proficiency of the corresponding heteropolyacid in the four-component condensation of para- chloro-benzaldehyde with acetophenone and acetyl chloride in refluxing acetonitril was studied. Findings revealed that Keggin H₇SiW₉V₃O₄₀ behaved as active catalyst, due to its bi-functional nature originating from their strong acidic protons and presence of vanadium (V) transition metal ion, as effective electron acceptor resource[15].

The four-component coupling condensation of benzaldehyde, acetophenone, and acetyl chloride was performed in acetonitrile in the absence of catalyst. Findings revealed that the reaction could not be productive, and no reaction was happened even after prolonged reaction time (10 h), indicating that this is indeed a heteropolyacid catalyzed reaction.

At first, the four-component coupling condensation of benzaldehyde, acetophenone, and acetyl chloride was performed in acetonitrile in the absence of catalyst. Findings revealed that the reaction could not be productive, and no reaction was happened even after prolonged reaction time (10 h), indicating that this is indeed a heteropolyacid catalyzed reaction (Table 1).

The catalytic activity and efficacy of the present method can be influenced by miscellaneous parameters such as kind and amount of the employed catalyst, solvent system, and temperature. To establish the optimal reaction condition, a set of experiments varying the amount of the catalyst, quantity of acetyl chloride, and temperature were carried out. Initially, different mol% of H₇SiW₉V₃O₄₀ was taken into account (Table 1). The best condition to prepare the β-acetamido ketones was achieved when 2.5 mol% of vanadium(V)-containing heteropolyacid, H₇SiW₉V₃O₄₀, was accomplished (Table 1). 4-chlorobenzaldehyde led to 76% of product after 3 h); whereas, higher mol% of catalyst (10 mol%) resulted in 82% conversion in short time 0.5 h. Employing smaller amounts of the catalyst (0.5 mol%) diminished the product yield to 53% after 6 h.

Table 1. Synthesis of β-acetamido-β-(4-chlorophenyl)propiophenone in the presence of different catalytic amounts of H7SiW9V3O40 in refluxing acetonitrile. Catalyst Catalyst (mol%) Time (h) Yield (%) - - 10 - H7SiW9V3O40 0.5 6 53 H7SiW9V3O40 2.5 3 76 H7SiW9V3O40 5 2 78 H7SiW9V3O40 10 0.5 82 A mixture of aromatic aldehyde (1 mmol), acetophenone (1mmol), acetyl chloride (2 mmol) in acetonitrle (4 ml) was treated with a catalytic amount of heteropolyacid at 80 ◦C. Progress of the reaction was monitored by TLC.

Effect of temperature was monitored by carrying out the model reaction in the presence of 2.5 mol% H₇SiW₉V₃O₄₀ in acetonitrile at different temperatures (Table 2). It was observed that the yield% was increased when the reaction temperature elevated from 25 to 80 ℃. Therefore, the reflux temperature of acetonitril, 80 ℃, was selected for all the reactions.

Table 2. Synthesis of β-acetamido- β-(4-chlorophenyl)propiophenone in acetonitrile at different temperatures. Catalyst (mol%) Time (min) Yield (%) Temperature (◦C) H7SiW9V3O40 (2.5 mol%) 3 76 80 H7SiW9V3O40 (2.5 mol%) 5 48 50 H7SiW9V3O40 (2.5 mol%) 6 33 25

The productivity of the method was further extended to various substituted aromatic aldehydes (Table 3). The reactions were performed well and the reaction rates as well as the yields of products were satisfactory. The conversion generally furnished the desired product in high yields within an acceptable time.

The superiority of the present protocol over other methodologies can be seen by comparing the results obtained for the vanadium (V) substituted heteropolyacid, H₇SiW₉V₃O₄₀, with some selected previously reported catalysts (Table 4). The reaction of benzaldehyde, acetyl chloride, and acetophenone in acetonitril to afford the corresponding β-acetamido-β-phenylpropiophenone was chosen as a model reaction and the comparison was based on mol% of the catalyst, reaction time and percentage yield. Obviously, H₇SiW₉V₃O₄₀ was the best among the introduced catalysts.

To study the reusability of H₇SiW₉V₃O₄₀, the recycled catalyst was washed with dichloromethane and forwarded to a second run for the preparation of β-acetamido- β-(4-methoxyphenyl)propiophenone. The recovered catalyst was reused for seven times and it was confirmed any considerable loss of activity (Fig. 1). The results of the first run and the subsequent runs were almost consistent in yields.

Table 3. Synthesis of different β-acetamido-β-(aryl)propiophenones in the presence of H7SiW9V3O40 (2.5mol%) in refluxing acetonitrile.

Table 4. Comparison of the catalytic efficiency of H7SiW9V3O40 with some reported catalysts in the synthesis of β-acetamido- β-(4- chlorophenyl)propiophenone.

Figure 1. Studying Reusability of H7SiW9V3O40.

4. Conclusions

In conclusion, this report illustrated a new convenient and efficient method for the preparation of a wide range of β-acetamido ketones by using H₇SiW₉V₃O₄₀. The present methodology offers attractive features, such as easy workup, simple experimental procedure, relatively short reaction times, high yields, and using a recyclable catalyst which will have wide scope in organic synthesis.