STARCH SULFURIC ACID: AN ALTERNATIVE, ECO-FRIENDLY CATALYST FOR BIGINELLI REACTION

The one-pot multicomponent synthesis of 3,4-dihydropyrimidinone derivatives using starch sulfuric acid as an environmentally friendly biopolymer-based solid acid catalyst from aldehydes, β-keto esters and urea/ thiourea without solvent is described. Compared with classical Biginelli reaction conditions, this new method has the advantage of minimizing the cost operational hazards and environmental pollution, good yields, shorter reaction times and simple work-up.

In recent years, the direction of science and technology has been shifting more towards eco-friendly, natural product resources and reusable catalysts. Thus, natural biopolymers are attractive candidates in the search for such solid support catalysts [39]. Starch as a one of the most common and easy to recover biopolymer become in the scope of many research [40,41].
We now report an effi cient catalyzed method for the synthesis of dihydropyrimidinones via the three-component reaction of β-dicarbonyl compounds with aldehydes and urea or thiourea under mild conditions (Scheme 1). To the best of our knowledge, the use of starch sulfuric acid (SSA) as a catalyst for the synthesis of dihydropyrimidinones previously has not been reported.

Experimental
All chemicals and analytical grade solvents were purchased from Merck or Fluka chemical company. Melting points were determined in open glass capillaries on Mettler 9100 melting point apparatus. Infrared (IR) spectra were recorded using a 4300 Shimadzu FT-IR spectrometer. 1 H NMR and 13 C NMR spectra were recorded on a Bruker 250MHz spectrometer. Mass spectra were recorded on a Shimadzu QP 1100 BX mass spectrometer. All products were known compounds and identifi ed by comparing their physical data to their authentic samples.

General procedure for the Preparation of starch sulfuric acid
To a magnetically stirred mixture of 5.0 g of starch in 20 mL of n-hexane, 1.0 g of chlorosulfonic acid (9 mmol) was added drop wise at 0 ºC during 2 h. HCl gas was removed from the reaction vessel immediately. After the addition was complete, the mixture was stirred for 2 h. Then the mixture was fi ltered and washed with 30 mL of acetonitrile and dried at room temperature to afford 5.25 g of starch sulfuric acid as a white powder. Sulfur content of the samples by conventional elemental analysis, was 0.55 mmol/g for starch sulfuric acid. The number of H + sites on the starch-SO 3 H was determined by acid-base titration was 0.50 meq/g. This value corresponds to about 90% of the sulfur content, indicating that most of the sulfur species on the sample are in the form of the sulfonic acid groups.
General procedure for the synthesis of dihydropyrimidinones SSA (0.05 g) was added to a mixture of aldehyde (1 mmol), β-dicarbonyl compound (1 mmol) and urea or thiourea (1.5 mmol). The neat reaction mixture was heated with stirring for appropriate time at 80 ºC (progress of the reaction was monitored by TLC). At the end of reaction, SSA washed and fi ltered off with water and ethanol to remove urea (or thiourea) from the surface of the catalyst. Then, the catalyst dried and was maintained for new runs. The fi ltrate was concentrated and the crude product was recrystallized from ethanol to afford the pure product. Products were identifi ed by comparison with melting points of the authentic compounds. The isolated catalyst was dried at 70 °C overnight and was reused in the next runs without further purifi cation. The catalyst could be reused at least three times without an appreciable decrease of the yield and reaction rate.

Results and discussion
SSA is readily prepared by the dropwise addition of chlorosulfonic acid to mixture of starch in n-hexane at 0 ºC. It is important to note that, this reaction is easy and clean without any work-up procedure due to HCl gas is evolved from the reaction vessel immediately. This white homogeneous, nonhygroscopic solid acid is stable under reaction conditions (Scheme 2).

Scheme 2.
We are interested in studying Biginelli reaction with the aim to develop an operationally simple method for the synthesis of some DHPMs. We started our study of the one-pot three-component Biginelli condensation using SSA as the catalyst (Scheme 1), by examining the conditions for the reaction using benzaldehyde, ethylacetoacetate and urea to afford the corresponding DHPM product. In order to optimize the reaction conditions we conducted this reaction in different solvents (Table 1). By using water and ethanol as solvent, the catalyst led to the good conversion but in longer reaction times. The best results were obtained under solvent-free conditions yielding Biginelli products in excellent conversion in shorter reaction times (entry 7, Table 1). No product was formed in the absence of the catalyst (entry 5, Table 1) whereas in the presence of starch sulfuric acid (0.05 g), under the same conditions yield increased to 60% (entry 6, Table 1). The yield of dihydropyrimidinone increased with increasing the amounts of the catalyst from 0.05 to 0.1 g. The use of 0.15 g of SSA permitted the reaction time to be decreased to 5 min, the yield unexpectedly decreased to 75% (entry 8, Table 1). A possible explanation for the low product yield is that the starting material or the product may have been destroyed during the reaction when an excess amount (0.15 g) of SSA was used in the exothermic reaction and that 0.1 g SSA was suffi cient to catalyze the reaction effectively. The reaction temperature was also optimized, below 80 °C the reaction proceeded slow giving a relatively low yield and no improvement was observed above 80 °C (entries 9-10, Table 1). All further studies were carried out under solvent-free conditions with 0.1g catalyst at 80 °C. Varying the amount of reactants, the best result was obtained when the molar ratio of benzaldehyde, ethyl acetoacetate and urea was 1.0:1.0:1.2. The structural variations in the aldehydes had no signifi cant effect on the yield and with aldehydes bearing sensitive functional groups like Cl, NO 2 , and OCH 3 the reaction proceeded smoothly to afford the corresponding products in excellent yields (entries2-4 Table 2). SSA also worked well even with an acid-sensitive aldehyde such as furfural without leading to the formation of any side products (entry 7, Table 2). The reaction of other 1,3-dicarbonyl compounds such as acetylacetone was also run with benzaldehyde and urea in the presence of SSA under solvent-free conditions and the corresponding dihydropyrimidinone was obtained in high yields (entry 8 Table 2). Thiourea has been also used with success to provide the corresponding dihydropyrimidin-2-(1H)-thiones in high yields (entries 9-11, Table  2). It is well known that for Biginelli reaction, aromatic aldehyde works very well, but aliphatic aldehyde works hard, however it is noteworthy that catalyzed the reaction with aliphatic aldehyde. Reaction was very slow and practically did not give any product at 80 °C. The mechanism of the Biginelli reaction established by Kappe proposed that the key step in this cyclocondensation process should involve the formation of N-acyliminium ion intermediate. The suggested mechanism for the Biginelli reaction catalyzed by SSA under solvent-free conditions is outlined in Scheme 3.
A comparative study was performed for the use of SSA with some of the reported catalysts for the Biginelli reaction (Table 3). In most methods, the reaction was performed in solvent such as acetic acid, dioxane and toluene. Thus, SSA promoted the reactions more effectively than the other catalysts and should be considered as one of the best choice for selecting an economically convenient, user friendly catalyst. In conclusion, we have shown an effi cient SSA catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones and thione analogs by multicomponent Biginelli reactions under solvent-free conditions, using commercially available substrates. The attractive features of this protocol are its green-ness with respect to solvent-free reaction, recyclability of catalyst, mild reaction conditions, short reaction times and high yield.