An adapted route to efficient synthesis of 1,8-dioxooctahydro-xanthene derivatives using InCl3 and (HPO3)n as recyclable catalysts

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Introduction
][8][9][10] Furthermore, they can be easily separated from the organic components. 11Among organic compounds, xanthenes and its derivatives have received significant attention in recent years due to their wide range of biological and therapeutic properties. 12,13The importance of xanthene derivatives clearly was realized from their usage as dyes, 14 sensitizers in photodynamic therapy for destroying the tumor cells, 15 pH-sensitive fluorescent materials for visualization of biomolecules, 16 and in laser technologies. 17Furthermore, some of the xanthene based compounds have found applications as antagonists for paralyzing the action of zoxalamine and in photodynamic therapy. 18Several polycyclic compounds containing the xanthene skeleton are isolated from natural sources. 19Xanthenes and its derivatives are prepared by different methods, including the reaction of aryloxymagnesium halides with triethylorthoformate, 20 cyclodehydration, 21 trapping of benzynes by phenols, 22 intramolecular phenyl carbonyl coupling reactions of benzaldehydes and acetophenones, 23 and cyclocondensation between 2-hydroxy aromatic aldehydes and 2-tetralone. 24n view of the importance of xanthene derivatives, many methods for the synthesis of these compounds were reported including condensation of β-naphthol and aldehydes or acetals catalyzed by silica sulfuric acid, HCl/CH3COOH or H3PO4. 25However some of these methods involved long reaction times, harsh reaction conditions and unsatisfactory yields.Therefore improvements in these syntheses have been sought continuously.In scope of our study on the catalytic synthesis of heterocyclic compounds, [26][27][28] In this work an efficient and adapted route to synthesis of 1,8-dioxooctahydroxanthenes (4) was obtained by condensation of 1,3-cyclohexanediones (1) and aromatic aldehydes (2) using Indium (III) chloride and metaphosphoric acid (when an average of one molecule of water per phosphoric unit has been driven off, the resulting substance is a glassy solid having an empirical formula of (HPO3)n and is called metaphosphoric acid) as effective, inexpensive and recoverable catalysts (Scheme 1).
The structures of the products 4 were deduced from their IR, 1 H, 13 CNMR spectroscopic data and their melting points.To find the optimum conditions for synthesis of xanthenes derivatives in the presence of InCl3 and (HPO3)n as two efficient catalysts, firstly, synthesis of 3,3,6,6-tetramethyl-9phenyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8 (2H)-dione (4a) was chosen as a model reaction.In model reaction, in the presence of InCl3 and (HPO3)n as catalyst separately, the reaction carried out in different solvents such as water, ethanol, methanol, chloroform, acetonitrile and solvent-less conditions.From these experiments, found that the reaction was compeleted with short time and high yield under solvent free condition (Table 1).Therefore, the reaction carry out in solvent free condition which has very advantage in chemistry such as reduce pollution, and help to decrease costs due to the simplification of experimental procedure, work up technique and saving in labour. 29Evaluated quantity of required catalysts in synthesis 1,8-dioxooctahydroxanthene derivatives for model reaction (compound 4a) was shown that maximum yield obtained, when the reaction was loaded with 10 mol% of InCl3 and 8 mol% (HPO3)n (Table 2).As can be seen from Table 2, the best molar ratios of the catalysts for this reaction were found to be 10 mol% for InCl3 and 8 mol% for (HPO3)n for the model reaction whereas the larger amounts of the catalysts did not improve the results.In the following study on the model reactions, we examined the reactions at various temperatures to find out the effect of temperature on the progress of reaction in the presence of optimized amount of catalysts.The maximum rate of reaction was obtained at 80 °C in the presence of both InCl3 and (HPO3)n (Table 3).As can be seen from Table 3, at room temperature, reaction was completed slowly.Increasing temperature to 80 °C increased the yield of reaction and decreased the time of reaction.When, the reaction was heated above 80 °C, so high temperatures did not further improved yield and decrease time of reaction.According to the archived optimal condition, we conducted the synthesis of xanthenes derivatives in the presence of InCl3 (10 mol%) and (HPO3)n (8 mol%) in solvent-free condition at 80 °C.
[32][33][34][35][36][37][38][39][40][41][42]  At the end of the reactions, the catalysts were filtered, washed with diethyl ether, dried at 120 °C for 1 h, and reused in another reaction.We found that both InCl3 and (HPO3)n showed high catalytic activity with very short reaction times.Moreover, can be recovered and reused five times without significant loss of activity (Fig. 1).The results of these observations for the model reaction are shown in Table 5.6  These results show that these catalysts prepared good to excellent conditions for the synthesis of xanthene derivatives than other catalysts and methods that were reported.This method not only affords the products with high yields but also avoids the problems associated with handling, pollution and catalysts cost.

Conclusions
In conclusion, new application of indium (III) chloride (InCl3) and metaphosphoric acid (HPO3)n as two effective and reusable solid acid catalysts in the preparation of 9-aryl substituted 1,8dioxooctahydro xanthene derivatives are presented.All products in the presence of catalytic amount of InCl3 and (HPO3)n were obtained in excellent yields.The presence of InCl3 and (HPO3)n in condensation between cyclic 1,3-diketones with aromatic aldehydes is a key factor to progress of reaction.(HPO3)n not only prepared cheap and facile procedure but also developed the green chemistry.Other advantages of these methods are simple experimental procedure, utilization of clean and recyclable catalysts, the use of ready available starting materials, and short period of reaction.

Materials and Methods
Melting points were measured on an elecrtothermal KSB1N apparatus.IR spectra were recorded in the matrix of KBr with JASCO FT-IR-680 plus spectrometer. 1 H NMR and 13 C NMR spectra were determined on a FT-NMR Bruker Avance Ultra Shield Spectrometer at 400.13 and 100.62 MHz in CDCl3 as solvent in the presence of tetramethylsilane as internal standard.TLC was performed on TLC-Grade silica gel-G/UV 254 nm plates (n-hexane, ethyl acetate 2:1).Chemicals were purchased from Fluka and Merck chemical companies.

General procedure for the Preparation of 9-Aryl-substituted 1,8-Dioxooctahydroxanthenes
A mixture of cyclic 1,3-diketone (2 mmol), aromatic aldehyde (1 mmol) and InCl3 (0.022 g, 0.1 mmol) or (HPO3)n (0.003 g, 0.08 mmol) was heated at 80 °C for the time indicated in Table 4.The progress of the reaction was monitored by TLC on silica gel (SILG/UV 254) plates (n-hexane, ethyl acetate 2:1).After completion of the reaction, the reaction mixture was cooled to room temperature and was washed with CHCl3 (10 mL), then was filtered to remove the catalyst and the filtrate was concentrated in vacuum to afford the crude product.Crude product was recrystallized from EtOH to afford the crystalline pure product.The catalyst was washed with ethanol, dried at 120 °C for 1 h, and reused five times in other reactions.3,3,6,6-tetramethyl-9-phenyl-3,4,5,6,7,9-

Table 1 .
Effect of solvents in synthesis of xanthenes derivatives (model reaction)

Table 2 .
Optimization of molar ratio of the catalysts in synthesis of 1,8-dioxooctahydroxanthene

Table 3 .
Optimization of temperature for model reaction

Table 5 .
Reusability results of catalysts on the reaction process for the model reaction.