Investigation of efficient synthesis of 1 , 8-dioxo-octahydroxanthene derivatives under solvent-free grinding method

Article history: Received March 27, 2013 Received in Revised form July 27, 2013 Accepted 22 August 2013 Available online 24 August 2013 In these studies, we had observed polyaniline (PANI) supported p-toluene sulfonic acid (TsOH) and FeCl3(PANI-TsOH, PANI-FeCl3) as excellent reusable solid acid catalysts for the synthesis of 1, 8-dioxo-octahydroxanthene derivatives 4(a-g) under solvent-free grinding method at mild conditions. Additionally, in the same optimized condition ferric nitrate nonahydrate also acted as (non-reusable) very reactive inexpensive Lewis acid catalyst. The ferric nitrate nonahydrate lost its activity in the form of Clayfen (Clay-supported ferric nitrate) catalyst. © 2013 Growing Science Ltd. All rights reserved.


Introduction
The combined application of solvent-free mechanochemical process 1 and reusable solid acid catalyst in organic synthesis will reduce pollution and cost, simplify the work-up steps, and eliminate excessive and wasteful heating.The flexibility in choice of all types of reagent pairs at room temperature is an important aspect of mechanochemical processes.The potential use of reusable supported solid acid catalysts 2,3 in organic synthesis make reaction methods more convenient, economic and environmentally benign, since the product purification is simple due to easy separation of insoluble support from the reaction medium 4,5 .
The syntheses of xanthene derivatives are important in medicinal chemistry as antibacterials, antioxidant, antifungal, antiviral and anti-inflammatory agents 6 , photodynamic therapy and antagonists for the paralyzing action of zoxazolamine. 7In material science, they are applied as leuco dye 8 in laser technologies, and as pH sensitive fluorescence materials for visualization of biomolecules. 9Some xanthene derivatives are presented in natural products with different biological activities, e.g.strong and selective inhibition of MAO-A, antitumor activity. 10,11For 1,8-dioxooctahydroxanthene derivatives, the inherent reactivity of pyran ring 12 makes them building block of several natural products.In literature, a number of synthetic approaches 13,14 have been developed for the preparation of 1,8-dioxo-octahydroxanthenes involving acid or base catalyzed condensation of aldehydes and 5, 5-dimethyl-1,3-cyclohexanedione (Scheme 1) in solvent-free condition, ionic liquid and aqueous medium.Each of these methods have their own merits but also suffers from one or more drawbacks such as longer reaction time, high temperature, tedious work-up processes, low yield and non-recycling of catalysts.Therefore, the synthesis of 1, 8-dioxo-octahydroxanthene derivatives require the investigation of novel routes with efficient recyclable catalyst at mild condition, short reaction time and simple work-up procedure for isolation of product.

Results and Discussion
In continuation [15][16][17] of our development of environmentally benign syntheses, we examined the catalytic activity of supported acids (PANI-TsOH, PANI-FeCl 3 , Clayfen) and conventional Brønsted or Lewis acid (TsOH, FeCl 3 , Fe(NO 3 ) 3 .9H 2 O) catalysts in the synthesis of xanthenedione derivatives from aromatic aldehydes and 5,5-dimethyl-1,3cyclohexanedione in solution under reflux and solventfree grinding condition at ambient temperature.In this context, to study the activity of various catalysts in solution and solvent-free grinding conditions we selected the reactions of pchlorobenzaldehyde (1 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (2 mmol) which led to xanthenedione derivative 4. The results are shown in Table 1 ----40 B 90 14 --90 a, Method A : Using 3 ml of chloroform under reflux condition ; Method B : Solvent-free grinding method.
We have observed that with all catalysts (Table 1, Entries 3-4) the product selectivity for 4b in solvent-free grinding method increases as compared to reactions (Entries 1, 2) in chloroform.The above reaction was also observed in other polar (ethanol, acetone, THF) and non-polar solvents (dichloromethane, toluene) in presence of 0.1 mmol of catalysts.We observed less reactive or non selective nature of the supported/traditional form of TsOH, FeCl 3 and ferric nitrate nonahydrate in solution.The catalysts TsOH and FeCl 3 transformed into more reactive and selective catalysts on PANI support (Table 1, entries 4) under solvent-free medium for the formation of product 4b as compared to Clayfen(Clay-supported ferric nitrate) catalyst.It was observed that ferric nitrate nonahydrate lost its activity and selectivity in the form of Clayfen catalyst.The optimized condition utilized 0.1 mmol of polyaniline supported acids (TsOH, FeCl 3 ) and Fe(NO 3 ) 3 .9H 2 O catalysts in solvent-free grinding method (entries 3-4).We observed incompletion of the reactions with 0.05 mmol of unsupported TsOH, FeCl 3 and Fe(NO 3 ) 3 .9H 2 O catalysts (Table 1, Entry 5).
To see the feasibility of the reaction in solvent-free method we had extended the above standard condition with other aromatic aldehydes containing both electron withdrawing and donating groups using supported acid (PANI-TsOH, PANI-FeCl 3 ) and unsupported acid (TsOH, FeCl 3 , Fe(NO 3 ) 3 .9H 2 O) catalysts.All these results are summarized in Table 2 The results in Table 2 indicated that the PANI supported TsOH and FeCl 3 catalysts are superior regarding the time of reaction and product selectivity with all aromatic aldehydes (Table 2) as compared to unsupported catalysts.The activity of the PANI supported acid catalyst depends on the strength of non-bonding interaction between the -NH group of support and acid catalyst by the donation of lone pair of electron on the nitrogen atom.The strong interaction of ferric ion with the Montmorillonite clay decreases the reactivity of ferric nitrate nonahydrate in the supported form (Entry 2).The three supported catalysts were found to be inactive with pentanal.Furaldehyde forms polymeric product with these catalysts.The FT-IR studied the progress of reaction between p-chlorobenzaldehyde and 5, 5-dimethyl-1, 3cyclohexanedione (Fig. 1) under the optimized condition with ferric nitrate nonahydrate as catalyst at different time intervals from the beginning.The spectra B-D did not show any prominent signal for the catalyst Fe(NO 3 ) 3 .9H 2 O during the course of reaction, which may be due to the lower concentration of catalyst and its interaction with the reaction mixture.The reusability of the three supported catalysts (PANI-TsOH, PANI-FeCl 3 , Clayfen) were investigated for three times (Fig. 2) with the reaction of p-chlorobenzaldehyde and dimedone in solvent-free method which were further supported by FT-IR spectra of reused catalyst up to 3 rd cycles (Fig. 3).The reusability of Fe(NO 3 ) 3 .9H 2 O catalyst in organic solvents was studied by dissolving the reaction mixtures in chloroform, dichloromethane, ethanol, ethyl acetate and diethyl ether after completion.The hygroscopic nature of the catalyst changed its state from solid to liquid in these solvents and made it very difficult to filter as solid residue from the solution for recycling.

Conclusion
This article investigates the activities of three reusable supported acid catalysts PANI-TsOH, PANI-FeCl 3 and Clayfen for the synthesis of xanthenedione derivatives in mild conditions with different aromatic aldehydes and dimedone under solvent-free grinding method.The ferric nitrate nonahydrate was found as an efficient and selective catalyst for this reaction in absence of support.The advantage of this protocol lies in the avoidance of organic solvent, high yield, energy efficiency, variation of substrates, and use of inexpensive reusable catalyst.
constant stirring at ambient temperature for 4 h.The supported catalyst was isolated through filtration, washed with acetone and dried at 100 º C till a constant weight.Amount of acid group present in the polymeric chain was calculated based on the weight of redoped polyaniline salt obtained and the weight of polyaniline base used.Amount of dopant present in PANI-TsOH and PANI-FeCl 3 were found to be 40.2% and 27.1% respectively.

General procedure for the Synthesis of 1,8-dioxo-octahydroxanthene Derivatives 4 in Organic Solvent and solvent-free grinding method :
A mixture of 0.5 mmol of 4-chlorobenzaldehyde and 1 mmol of 5, 5-dimethyl-1, 3cyclohexanedione in organic solvent (3 mL) is taken in a 25 mL round bottom flask containing 0.1 mmol of acid catalyst.For solvent-free method, the above mixture is grinded continuously with the help of mortar and pestle.The progress of the reaction in both conditions is monitored with the help of TLC technique.After completion, the reaction mixture is diluted with ethyl acetate and filtered to get the catalysts as residue.During the work-up step, the filtrate is diluted with aqueous sodium bicarbonate (NaHCO 3 ) solution and the organic part is extracted with ethyl acetate.The organic extract is dried over anhydrous sodium sulfate.The solvent ethyl acetate is distilled under reduced pressure to get the crude product.Recrystallization of crude product from ethanol yielded the pure product.The used catalyst is dried at 100 º C and made ready for reuse.

Fig. 1
Fig. 1 FT-IR monitoring on the progress of reaction .A: Spectra of Fe(NO 3 ) 3 .9H 2 O catalyst; B: Initial reaction mixture without grinding; C: Reaction mixture after 5 min of grinding; D: Reaction mixture after 10 min of grinding; E: Spectra of pure product

Table 1 .
. Optimization of conditions of the reaction of 4-chlorobenzaldehyde and 5, 5-dimethyl 1, 3cyclohexanedione in chloroform under reflux and solvent-free grinding.