An Efficient and Green Procedure for the Synthesis of 2 , 4 , 6-Triarylpyridines Using PPA-SiO 2 as a Reusable Heterogeneous Catalyst Under Solvent-Free Conditions

Abstract: Silica gel-supported polyphosphoric acid (PPA-SiO2) was found to be highly efficient, eco-friendly and recyclable heterogeneous catalyst for the synthesis of 2,4,6-triarylpyridines through one-pot three-component reaction of acetophenone, aryl aldehydes, and ammonium acetate under solvent-free conditions. This method has several advantages, such as simple procedure with an easy work-up, short reaction times, and high yields. Furthermore, the catalyst could be recycled after a simple work-up, and used at least three times without substantial reduction in its catalytic activity.


Introduction
Multicomponent reactions (MCRs) have emerged as efficient and powerful tools in modern synthetic organic chemistry because the synthesis of complex organic molecules from simple and readily available substrates can be achieved in a very fast and efficient manner without the isolation of any intermediate [1][2][3] .Therefore, developing new MCRs and improving known MCRs are popular areas of research in current organic chemistry.One such reaction is the synthesis of 2,4,6-triarylpyridines.Pyridines are of interest because of occurrence of their saturated and partially saturated derivatives in biologically active compounds and natural products such as NAD nucleotides, pyridoxol (vitamin B 6 ) and pyridine alkaloids 4 .Literature reports have already established pyridines as antimalarials, vasodilators, anesthetics, anticonvulsants, antiepileptics, and agrochemicals such as fungicides, pesticides, and herbicides [5][6][7][8] .2,4,6-Triarylpyridines (Kröhnke pyridines) are structurally related to symmetrical triaryl-thiopyrylium, triarylselenopyrylium, and triaryl-telluropyrylium photosensitizers, which have been recommended for photodynamic cellspecific cancer therapy 9 .These compounds have already been synthesized by reaction of N-phenacylpyridinium salts with α,β-unsaturated ketones in the presence of ammonium acetate 10,11 .However, the pyridinium salts and the unsaturated ketones have to be synthesized first, so this method is relatively expensive.More recently, several new improved methods and procedures for preparation of 2,4,6triarylpyridines have been reported, for example reaction of N-(diphenylphosphinyl)-1phenylethanimine with aldehydes 12 , solvent-free reaction of chalcones with ammonium acetate 13 , and solvent-free reaction between acetophenones, benzaldehydes, and NH 4 OAc in the presence of various catalysts, for example HClO 4 -SiO 2 14 , Brønsted-acidic ionic liquid 15 , and I 2 16 .Recently, solid-supported reagents, such as silica gel-supported acids, have gained considerable interest in organic synthesis because of their unique properties of the reagents such as high efficiency due to more surface area, more stability and reusability, low toxicity, greater selectivity and ease of handling [17][18][19][20] .Although, the catalytic applications of silica supported reagents for organic synthesis have been established, to the best of our knowledge, there is no report in the literature on the use of silica gel-supported polyphosphoric acid (PPA-SiO 2 ) in the synthesis of 2,4,6-triarylpyridines.As part of our current studies on the development of new routes for the synthesis of organic compounds using reusable catalysts, [21][22][23][24][25][26][27] herein we wish to report an efficient, and green method for the synthesis of 2,4,6-triarylpyridines by one-pot three-component reaction of acetophenone, aryl aldehydes, and ammonium acetate using PPA-SiO 2 as a solid acid supported catalyst under solvent-free conditions (Scheme 1).Scheme 1. Synthesis of 2,4,6-triarylpyridines catalyzed by PPA-SiO 2 .

Experimental
All chemicals were available commercially and used without additional purification.Melting points were recorded on a Stuart SMP3 melting point apparatus.The IR spectra were obtained using a Tensor 27 Bruker spectrophotometer as KBr disks.The 1 H NMR (500 MHz) spectra were recorded with a Bruker DRX500 spectrometer.

Preparation of PPA-SiO 2
The PPA-SiO 2 was prepared following the procedure reported by Aoyama and co-workers 28 .PPA (2.1 g) was transferred into a round-bottom flask and CHCl 3 (100 ml) was added.After the mixture was stirred at 50 °C for 1 h, SiO 2 (200-400 mesh, 4.9 g) was added to the solution, and the mixture was stirred for a further 1 h.The CHCl 3 was removed using a rotary evaporator and the resulting solid was dried in vacuum at laboratory temperature for 3 h.The amount of H + in the PPA-SiO 2 determined by acid-base titration was 0.50 mmol g -1 .
General procedure for the synthesis of 2,4,6-triarylpyridines 4a-j using PPA/SiO2 as catalyst A mixture of acetophenone 1 (2 mmol), aryl aldehyde 2a-j (1 mmol), NH 4 OAc 3 (1.3 mmol) and PPA-SiO 2 (0.05 g, 0.025 mmol of H + ) was heated on the oil bath at 120 °C for 30-80 min.During the procedure, the reaction was monitored by TLC.Upon completion, the reaction mixture was cooled to room temperature and then boiling ethanol was added.The catalyst was removed by filtration under hot conditions.After cooling the filtrate, the precipitated solid was filtered and recrystallised from ethanol to give compounds 4a-j in high yields.

Recycling and reusing of the catalyst
Due to the fact that the catalyst was insoluble in hot ethanol, it could therefore be recycled by a simple filtration.The separated catalyst was washed with cold ethanol, dried at 100 °C under vacuum for 2 h and reused in another reaction.The results show that there is not any significant loss of activity in using recycled catalyst after three times in the model reaction.

Results and Discussion
The use of heterogeneous catalysts especially under solvent-free conditions presented itself as a remarkable technique toward environmentally clean synthesis of organic compounds.Therefore, we decided to investigate the efficiency of PPA-SiO 2 as a solid acid supported catalyst for the synthesis of 2,4,6-triarylpyridines under solvent-free conditions.At first, the synthesis of compound 4d was selected as a model reaction to determine suitable reaction conditions.The reaction was carried out by heating a mixture of acetophenone 1 (2 mmol), 4-chlorobenzaldehyde 2d (1 mmol), and NH 4 OAc 3 (1.3 mmol) in the presence of PPA-SiO 2 in different solvents and under solvent-free conditions (Table 1).As can be seen from Table 1, the shortest time and best yield was achieved in solventfree conditions (entry 7).It was also found that the yield of compound 4d was strongly affected by the catalyst amount and reaction temperature in solvent-free conditions.Only a trace amount of the product was obtained in the absence of the catalyst (entry 1) or in the presence of the catalyst at room temperature (entry 2) indicating that the catalyst and temperature are necessary for the reaction.Increasing the amount of the catalyst and reaction temperature up to 0.05 g and 120 °C, respectively, increased the yield of the product 4d, whereas further increase in both catalyst amount and temperature was found to have an inhibitory effect on the formation of the product (entries 8-12).To evaluate the generality of this model reaction we then prepared a range of 2,4,6triarylpyridines under the optimized reaction conditions.In all cases, aromatic aldehydes with substituents carrying either electron-donating or electron-withdrawing groups reacted successfully and gave the products in high yields.It was found that aromatic aldehydes with electron-withdrawing groups reacted faster than those with electron-donating groups, as would be expected.The results are shown in Table 2. b All the products were characterized by IR spectral data and comparision of their melting points with those of authentic samples.Also, the structures of some products were confirmed by 1 H NMR spectral data. c The yields were calculated based on aryl aldehyde and refer to the pure isolated product.
The principle advantage of the use of heterogeneous catalysts in organic transformations is their reusability.Hence, we decided to study the catalytic activity of recycled PPA-SiO 2 in the synthesis of compound 4d under the optimized conditions.After the completion of the reaction, the catalyst was recovered according to the procedure mentioned in experimental section and reused for a similar reaction.The catalyst could be used at least three times with only slight reduction in the catalytic activity (90% for 1st use; 89% for 2nd use; 87% for 3rd use).

Table 1 .
Effect of PPA-SiO 2 amount, solvent and temparature on the model reaction a .The yields were calculated based on 4-chlorobenzaldehyde and refer to the pure isolated product. b