Environmentally Benign Syntheses and Characterization of 4-Aryldihydropyrimidin-2 ( 1 H )-ones

A general, simple, efficient, cost-effective and environmental benign procedure for the syntheses of 4-aryl-3,4-dihydropyrimidin-2(1H)-ones (DHPMs) has been developed. The reaction is efficiently catalysed by using various amino acids viz., glycine, L-proline, L-cysteine, leucine and tryptophan. Reactions give excellent yields under reflux conditions. The chemical structures of these compounds were identified by Fourier Transform-Infra Red Spectroscopy (FT-IR), Gas Chromatography-Mass Spectroscopy (GC-MS) and Nuclear Magnetic Resonance Spectroscopy (H NMR). Physical parameters such as m.p., mixed m.p. as well as TLC also helped to characterize the expected products. The progress of the reaction time and purity was checked by TLC and the products were purified by recrystallization using ethyl acetate as a solvent. The synthesized molecule has numerous biological applications as it is anti-microbial, anti-inflammatory and anti-hypertensive in character.


Introduction
The synthesis of dihydropyrimidinones (DHPMs) has gained importance in recent years due to structural similarities between dihydropyrimidinones and pyrimidine [1].Pyrimidines are one of biologically important families.Pyrimidine bases such as cytosine (C), thymine (T), are basic constituents in nucleic acids [2].This class of heterocyclic compounds has also very important pharmaceutical activities such as antimicrobial [3], anti-inflammatory [4], antitumor [3]antihypertensive agents [5], chemical modulators, calcium channel modulators as well as melanin concentrating hormone receptor, antagonists [6], antifungal [7], as inhibitors to replicate hepatitis B, and inhibitors of specific organic acid transporters [8], [9].In1893, Pietro Biginelli reported synthesis of 4dihydropyrimidin-2(1H)-one by cyclocondensation of ethyl acetoacetate, benzaldehyde, and urea by simply heating a mixture of these three components in the presence of acid as a catalysts under reflux conditions [10].

Scheme I: General Scheme of Biginelli condensation
Now Biginelli reaction is an important multicomponent reaction for the preparation of biologically active dihydropyrimidinone derivatives.
Many of these classical methods, however, suffer from drastic reaction conditions, lower yields, difficult workup process, excessive use of chemicals as well as catalyst and environmental impact such as carcinogenic solvents and non-biodegradable catalysts [17].Although a variety of methods are reported for the synthesis of DHPMs, only few examples were developed with the aim of replacing conventional toxic and polluting Bronsted and Lewis acid catalysts with efficient and green catalysts such as recyclable catalyst under solvent-free conditions [18] , amino acid catalyzed [19], [20], 21], Mesoporous SBA-15 nanoparticles [22] and Quaternary Ammonium-treated clay in water catalyzed [23]synthesis of DHPMs.Drawbacks of these classical methods and catalytic efficacy of environmental benign catalyst gave us a direction to introduce new efficient catalysts for prepration of 4aryl-3,4-dihydropyrimidin-2(1H)-ones with cost effectiveness and mild conditions with high yields.We had earlier communicated our preliminary finding that amino acids can be efficiently used for these reactions [19].Dihydropyrimidinone (DHPM) synthesis was carried out by using benzaldehyde and urea/thiourea.Amino acids are also being reported as efficient catalysts in the Knoevenagel condensations, reduction, oxidation, electrophilic α-fluorination and amination, transamidation, as well as promoter of some of the reactions [24], [25].We are extending this Biginelli, amino acid catalyzed reaction, using some other aryl aldehydes which are now being communicated.

Experimental Work
Most of the chemicals used during the development of this environmentally benign synthesis were of laboratory grade and were used as it as.Progress of the reactions were monitored by using Silica TLC plates and UV light was used as a spot locating agent.IR were recorded on Perkins Elmer FTIR (spectrum RXI) spectrometer.Mass spectra were recorded GC-MS Schimadzu QP2010. 1 H NMR spectra were recorded on and (NMR; Jeol JNM-ECA500).

Synthesis of 4-Aryldihydropyrimidin-2(1H)-ones:
General Method: A reactions mixture containing 40 mmol of aromatic aldehyde, 40 mmol of ethyl acetoacetate, 45 mmol of urea, 0.01 mmol of an amino acid were dissolved in 10 ml of ethanol.The reaction mixture was heated under reflux for two hours.The reaction mixture was work up by allowing to cool down to room temperature and was diluted with ice cold water and the precipitated product was isolated.The product was recrystallized from ethyl acetate o purify.Four aromatic aldehydes were used by using this general procedure to syntheses four different 4-Aryldihydropyrimidin-2(1H)-ones by employing five different amino acids as catalysts.2.1.1By using p-chlrobenzyldehyde (4): 4.5g of p-chlrobenzyldehyde (4) was mixed with 5.2 g of ethyl acetoacetate (1), 4g of urea (2) and .01mmol of glycine in 10 ml of ethanol.The reaction mixture was heated in reflux conditions for 2 hours.The reaction was allowed to stand to room temperature and then crushed ice was added to it, pale yellow crystals of 5-Ethoxycarbonyl-6-methyl-4-pchlorophenyldihydropyrimidin-2-one (4) were collected and recrystallized to purify the product.The product was characterized through its m.p., IR, Mass spectrum and 1 H-NMR.After this the reaction was carried out by employing few other amino acids.These products were identical in their physical and chemical characteristics to the product obtained by using glycine.The proposed reaction is presented in scheme (scheme II) and results are described in (Table 1).

Conclusion
In summary, amino acids were successfully employed as catalyst for the synthesis of various 4aryldihydropyrimidin-2(1H)-ones.Simple and mild reaction conditions, low cost, readily available and biodegradable catalyst are the important features of this protocol.For the present work, only a few representative aromatic aldehydes and urea were used to check the feasibility of amino acids as a catalyst in these reactions.The yields in all these reactions were comparable and the use of these catalysts can be extended to study the utilization of other aldehydes in Biginelli reactions.

Table 4 : Synthesis and characterization of 5-Ethoxycarbonyl-6-methyl-4-hydroxyphenyldihydropyrimidin-2-one (10) Entry Catalyst Yield % m.p o C IR cm -1 MS (m/z) 1 H NMR Lit 227 [27]
The reaction may proceed through the protonation of aromatic aldehyde (A) by the amino acid which provides this proton to catalyze the reaction.Further reaction proceeds via intermediates B and C as depicted in the scheme.