An Economic and Green Prospect For the Synthesis of Dihydropyrimidinones Using Microwave and Solid Acid Catalyst Under Solvent Free Condition-A Comparative Study

MCRs have great contribution in convergent synthesis of complex and important organic molecules from simple and readily available starting materials, and have emerged as powerful tools for drug discovery [1-4]. MW-assisted chemistry has blossomed into a useful technique for a variety of applications in drug discovery [5] and organic synthesis. Dihydropyrimidinones belong to an important class of heterocyclic compounds with pharmacological and biological properties. DHPs act as potent vasodilators, antihypertensives, antiatherosclerotics, antitumor, antimutagenic, and antidiabetic agents [6-12]. They are also useful as cognition enhancers, neuroprotectants, and platelet antiaggregatory agents [13, 14]. Biginelli reaction is one of the most studied reactions in the area of multicomponent reactions [15] The application of Brönsted and Lewis acids such as silica-based nanocatalysts and silica sulphuric acid (SSA) as heterogeneous catalysts in organic transformations is very important to avoid wastes as well as improving the greenness of the processes [16-17]. In the recent years, has shown immense potentiality as an efficient and easily retrievable solid catalyst in various important organic syntheses under solvent-free conditions [18]. Herein we wish to report a green methodology for the construction of 3, 4- Dihydropyrimidin-2-(1H)ones, using SSA as a solid-supported acid catalyst under solvent-free conditions.Various catalysts have been used to catalyse this reaction like protic acids [19], Lewis acids [20], heterogeneous acidic catalyst [21] and reagents like iodine [22] NBS [23] etc. But many of these protocols are still suffering from different drawbacks such as longer reaction time, high catalyst loading, expensive reagents, corrosive reagents and low yields of products.

The model reaction to synthesize 1e by the reaction of ethyl acetoacetate, benzaldehyde and urea was investigated with different amounts of solid silica-based sulfonic acid (0-5 mol %). And the best results were obtained (95% yield) with 3% of catalyst. Then the reactions were carried out at different MW power (250-900W) and different time of irradiation (5-8 min). The maximum yield (95%) was obtained in 7min at 900W.

best results in terms of time and yield are obtained using the present protocol.

Materials and method: Silica gel (K100, 0.063–0.200 mm) was purchased from Merck (Germany) and 3-aminopropyltrimethoxy silane from Aldrich Chemical Company. All melting points were determined on a perfit melting point apparatus and areuncorrected. 1H NMR spectra were registered on a Brucker DPX-200NMR spectrometer (200 MHz) in CDCl3+DMSO-d6 using tetramethylsilane as an internal standard and IR spectra were recorded on Perkin-Elmer FTIR spectrophotometer using KBr discs. Mass spectral data was recorded on Jeol JMS D-300 mass spectrometer at 70 eV. All yields refer to the isolated yields.

Solid silica-based sulfonic acid: To a mixture of 3-aminopropylsilica (5 g) in chloroform (20 mL) chlorosulfonic acid (1 g, 0.6 mL) was added dropwise at 00 C. After addition was complete, the mixture was stirred for 2 h until HCl gas evolution stopped. Then, the mixture was filtered and washed with ethanol (30 mL) and dried at room temperature to obtain silica solid-based sulfonic acid as a cream powder (5.13 g). Sulfur content of the samples determined by conventional elemental analysis was 9.29%.

Table-3: Physical data of 4,6-diaryl-3,4-dihydropyrimidin-2(1H)-ones 1(a-f) based sulfonic acid (3 mmol) in microwave irradiation of 900W at 90oC under solvent free condition. bIsolated yields. cProducts were characterized by comparison of their physical and spectroscopic data with those reported in the literature (Anil et al., 2007)

aReaction conditions: aldehyde (2.5 mmol), ethyl acetoacetate (2.5 mmol), urea/thiourea (2.5 mmol), solid silica based sulfonic acid (3 mmol) in microwave irradiation 990W at 90oC under solvent free condition. bIsolated yields. cProducts were characterized by comparison of their physical and spectroscopic data with those reported in the literature (AtulChaskaret al., 2009; Hitendraet al., 2007) The reusability of the catalyst was also investigated. For this purpose, the same model reaction to synthesize the compound 2e was again studied under the optimized conditions. After completion of the reaction, the catalyst was filtered, washed with worm ethanol, dried at 1000C under vacuum for 2 h and reused for the same reaction process. As shown in Fig. 1, the catalyst could be reused for eight times without reduction in the catalytic activity of the catalyst.

The demand for green and economic synthetic methods in the fields of healthcare and fine chemicals pose significant challenges to the synthetic chemical community. This objective can be achieved, in part, through the development of solvent free protocols using MW heating. The synthesized products show antihypertensive and calcium channel blocking activity.

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