Sulfated Tungstate as a Heterogeneous Catalyst for Synthesis of 3-Functionalized Coumarins under Solvent-Free Conditions

Abstract A novel sulfated tungstate catalyzed synthesis of 3-functionalized coumarins from substituted salicylaldehydes and β-ketoesters under solvent-free conditions described. The library of 3-acyl coumarin products obtained in excellent yield by employing substituted salicylaldehydes and β-ketoesters under optimal reaction conditions. This new method has numerous merits such as using green and nontoxic catalyst, displaying broad substrate scope, shorter reaction time, excellent yield, functional group compatibility, operational simplicity, and outstanding catalyst recyclability.


Introduction
The coumarin scaffold is a key structural motif and essential in the synthesis of many natural products and pharmaceutically active compounds. 1 Coumarin and its derivatives exhibits the broad spectrum of biological properties. 2 In addition, coumarin analogous have been used in food and cosmetic additive, in perfumes, in agrochemical and in material chemistry. 3 Coumarin, on the other hand, is an important component in a number of well-known natural and synthetic drugs used in clinical practice ( Figure 1). As a result, coumarin plays an important role in the development of combinatorial libraries.
In particular, the 3-carbonyl coumarins shows the wide range of biological activities and it has been used as luminous chemosensor. 4 3-carbonyl coumarins are also key intermediates in the synthesis of a variety of heterocyclic-fused coumarin compounds with different biological activities. 5 As a result, numerous researchers have focused their efforts on developing 3-functionalized coumarins. In addition to the conventional methods of Perkin/Knoevenagel condensation, Pechmann reaction, Mizorogi-Heck reaction, Kostanecki reaction, and witting reaction, several efficient strategies for the synthesis of coumarin derivatives have been published. 6 Among the classical procedures, Knoevenagel condensations, which use salicylaldehydes and b-ketoesters as starting materials, are the most widely used method for the synthesis of 3-carbonyl coumarins. 7 Despite its many advantages, the aforementioned reaction has a number of disadvantages, including the need for a basic or acidic environment, low yields, a limited substrate range, and/or a lengthy synthetic procedure. As a result, the development of an efficient, one-pot, solvent-free, and ecologically friendly methodology for obtaining 3-carbonyl coumarins is still in great demand.
The main goals of green chemistry is to design the waste-less and by-product less chemical process using the ecofriendly reagent with minimizing work-up and energy consumption as much as possible. 8 To achieve this green chemistry goals, the application of solvent-free reaction by using nontoxic heterogeneous catalyst are the most common strategies. 9 Solvent-free transformation has a variety of advantages from the perspective of both academia and industry. 10 The idea of solvent-free catalytic transformation has sparked a lot of attention in the field of green synthesis in recent years. Organic syntheses that do not use solvents are both economically and environmentally beneficial. Solvent-free transformation has a variety of advantages from the perspective of both academia and industry. It provides a number of benefits, including ease of use, economic effectiveness, and reduced energy consumption.
The sulfonic acid and ionic liquids in which sulfonic group bonded to with positive nitrogen in organic compounds has been effectively used as catalysts and reagent in organic transformation. 11 In recent years, a number of research groups have introduced sulfated tungstate, a moderately acidic, easy-to-prepare, nontoxic, recyclable, efficient, and heterogeneous green catalyst. At room temperature and under solvent-free circumstances, it is used as a heterogeneous and ecologically friendly catalyst in a range of chemical reactions. The sulfated tungstate was effectively used as catalyst in number of organic transformation for synthesis of various organic compounds. 12 To examine the catalytic potential of sulfated tungstate, we effectively synthesized 3-functionalized coumarin from substituted salicylaldehydes and b-keto esters under solvent-free conditions at ambient temperature (Scheme 1).

Experimental
All reactions were performed in oven-dried glassware. All reagents and solvents were obtained from commercial suppliers and used as received. Analytical thin-layer chromatography (TLC) was performed on precoated Merck silica gel plates (60 F-254), visualized with a UV254 lamp and stained with KMnO 4 . Melting points are uncorrected and were determined in open capillary tubes using paraffin oil bath. The NMR spectra were recorded on a Brucker Advance Digital 400 & 300 MHz (1 H) and 100 & 75 MHz ( 13 C) in CDCl 3 using tetramethylsilane as an internal standard. The following abbreviations were used to explain the multiplicities: General procedure for the synthesis of 3-acyl coumarins A mixture of salicylaldehydes (1 mmol), b-keto ester (1 mmol) and sulfated tungstate (10 wt%) was heated in an oil bath at 60 C with constant stirring till the reaction was completed. After completion of the reaction (monitored by TLC), the reaction mixture was cooled at room temperature. Then ethyl acetate was (5 mL) added, the catalyst was separated by filtration and solvent evaporated under the reduced pressure to get crude product. The crude product was purified by recrystallization from hot ethanol to give the pure product in good to excellent yields.

Result and discussion
We choose the reaction between salicylaldehyde (1a), and ethyl acetoacetate (2a) as a model reaction to assess the catalytic effectiveness of the sulfated tungstate and to optimize the reaction conditions. The model reaction was carried out at various temperatures and with varying mol% of catalyst in the presence of various solvents, as well as in solvent-free conditions, in order to optimize the reaction conditions. The findings summarize in Table 1. The desired product (3a) was not generated in the absence of a catalyst, at different reaction temperatures, and for varied reaction times ( Table 1, entries [1][2][3][4]. We repeated the model reaction at room temperature in the presence of a 10 wt% catalyst for further research. Surprisingly, a reasonable quantity of the intended product (3a) was detected (Table 1 entry 5). We were so excited by this result that we continued to run the model process at several temperatures with the 10 wt% catalyst (Table 1, entry 6-9). To our pleasure, increasing the temperature smooth's out the reaction, and the desired product (3a) was obtained in 98% yield at 60 C (Table 1, entry 7). At 60 C, the highest yield of product (3a) was found (Table 1, entry 7). Above that temperature, there was no substantial improvement in reaction time or yield of product (Table 1, entries 8-10), hence 60 C was chosen as the reaction temperature. To evaluate the catalyst's efficiency in the presence of several solvents, we conducted a model reaction with H 2 O, EtOH, MeOH, MeCN, DMF, and DMSO. The attempted reactions were carried out in reflux conditions, and the corresponding results are summarized in Table 1 (entry 11-16). The solvent study showed that the solvent-free system provides the highest results in terms of yield% and reaction time when compared to all other solvents used. We optimize the amount of catalyst required for the title reaction after optimizing the reaction temperature. The yield of the target product (3a) increased from 69% to 98% as the catalyst amount was increased from 5 mol% to 20 mol% (Table 1, entries [16][17][18]. Increases in catalyst quantity over 10 wt% had no discernible influence on the yield of the target product (Table 1, entry [17][18][19]. As a result, the 10 wt% catalyst was chosen as the optimal level for further exploration of the scope of this unique approach. We also looked into the possibility of repurposing sulfated tungstate from the post-reaction mixture for future trials. Experiments on catalyst recyclability revealed that the recycle catalyst was very effective, with no discernible loss of catalytic activity after five reuses ( Table 2). The catalyst's catalytic activity was found to be substantially identical to that of a newly used catalyst.
With these results in hand, we then examined the substrate scope and limitations of synthesis of 3-acyl coumarins derivatives in the presence of 10 mol% sulfated tungstate as catalyst under the solvent-free condition. The generality of the current protocol was probed in the reaction of differently substituted salicylaldehydes, containing either electron-donating or electron-withdrawing groups in the ortho, meta, and para positions with ethyl acetoacetate under secured optimal conditions. The scope of this novel approch is illustrated in Table 3. The corresponding 3-acyl coumarin derivatives were obtained in good to excellent yields in relatively short times without formation of any by-products. It was found that the salicylaldehydes containing the electron-donating groups reacted faster than those with electron-withdrawing group. In general, salicylaldehyde and salicylaldehydes bearing electron-donating groups produced a slightly higher yield than bearing an electron-withdrawing group within 5-10 min (Table 3, entries 3a-3d). The chloroand bromo-salicylaldehydes also reacts under the optimized reaction condition and afforded the desired product in good yield in short reaction time (Table 3, entries 3f-3h).
The salicylaldehyde with strongly electron-withdrawing groups could also reacted in slow rate under the optimized conditions and afford the desired product with moderate yield (Table 3, entry 3i). Notably, there is significant effect of steric hindrance on yields desired products. The ortho-substituted salicylaldehyde provided the desired product in moderate yields (Table 3, entry 3d-3f). The reaction of 1-formyl-2-naphthol with ethyl acetoacetate could also afford the product with good yield in shorter reaction time under the optimized conditions (Table 3, entry 3j).
Next, we use the various substituted b-keto ester under the optimized condition. The reaction of various substituted b-keto esters with salicylaldehyde afforded the 3-acyl coumarin derivatives in good yield with faster rate (Table 3, entries 3k-3t). The heteroaryl group bearing b-keto esters could also reacts under the optimized conditions and afforded the corresponding 3-acyl coumarin derivatives in good yield (Table 3, entries 3s and 3t).
Finally, a comparison was made between the present work and already reported methods for the synthesis of compound 3k. The result presented in the Table 4. The comparative study showed that reported methods has its own advantages, but some they suffer from disadvantages such as low yield, long reaction time, and use of organic solvents and employment of expensive catalyst. So present method furnishes green reaction medium, takes shorter reaction time and a small quantity of this inexpensive and readily available catalyst is sufficient to get excellent yield of 3-carbonyl coumarins derivatives.
On the basis of previous related literature reports a plausible mechanism for the synthesis of 3-acyl coumarins using sulfated tungstate shown in the (Figure 2).

Conclusion
To summarize, we have described an environmentally friendly and efficient synthesis of 3-acyl coumarins by condensation of substituted salicylaldehydes and b-keto esters under solvent-free      conditions employing a sulfated tungstate catalyst. This technique not only improves reaction rates and yields significantly, but it also avoids the use of harmful catalysts or solvents. This approach has several advantages, including a low-cost catalyst, a quicker reaction, clean reaction profiles, high yield, facile product isolation, no column purification, high catalytic activity, catalyst recyclability, easy handling, low corrosiveness, and environmental compatibility. The demonstrated method, we believe, is important in organic, material, pharmaceutical, and industrial chemistry.