A Green, Expeditious, One-Pot Synthesis of 3, 4-Dihydropyrimidin-2(1H)-ones Using a Mixture of Phosphorus Pentoxide-Methanesulfonic Acid at Ambient Temperature

An expeditious, one-pot method for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones using a mixture of phosphorus pentoxide-methanesulfonic acid (Eaton's reagent) at room temperature under solvent-free conditions is described. The salient features of this method include short reaction time, green aspects, high yields, and simple procedure.


Introduction
The widespread interest in 3,4-dihydropyrimidin-2(1H)ones, Biginelli compounds, has resulted in enormous efforts towards the synthesis of this biologically important moiety. Several methods have been developed for the synthesis of these compounds, but most of these protocols involve expensive reagents, strong acid catalysts, solvents, of prolonged reaction time and even then provide the products in unsatisfactory yields. With the current global awareness of developing environmentally friendly technologies, it is a need to perform a reaction in neat and nonhazardous conditions for providing a green approach towards organic synthesis [1]. Therefore, it was decided to develop an efficient method for the synthesis of Biginelli compounds. In this communication, we report a straightforward and simple procedures for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones using a mixture of phosphorus pentoxide-methanesulfonic acid (Eaton's reagent).
Eaton's reagent (1 : 10 phosphorus pentoxide in methanesulfonic acid) is an inexpensive and commercially available substance synthesized by Eaton in 1973 and found to be a good alternative to polyphosphoric acid which enables the drawbacks of many traditional catalysts to be overcome, because it has a much lower viscosity, it is easier to handle, and no complex separation procedures need to be employed [2]. Many processes that employ a mixture of P 2 O 5 /MeSO 3 H are not only more economical, but also they are more environmentally friendly and offer a number of distinct advantages such as safe in industrial scale, no additional solvent required, chlorine-free, rapid reactions, and high-purity products with excellent yields. The distinctive physical and chemical properties of Eaton's reagent make it a very useful substance in many different reactions with different applications. The mixture of P 2 O 5 /MeSO 3 H is particularly effective for ring closures. McGarry and Detty successfully used this reagent in cycloacylation reactions for producing chromones and flavones [3]; recently, Zewge and coworkers used Eaton's reagent to promote the cyclization of aniline derivatives to produce 4-quinolones [4]. P 2 O 5 /MeSO 3 H offers a simple means of producing poly(benzimidazoles) from ophenylenediamines and aromatic carboxylic acids [5]. Kaboudin and Abedi employed this system for synthesis of aryl mesylates [6].

Result and Discussion
In our recent study about the synthesis of Bis(indolyl)methanes under mild conditions, we found that reagent works extremely well for the coupling reaction. In this paper, herein we employed the reagent in a multicomponent, one-pot reaction for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones at room temperature. Eaton's reagent is a colorless, odorless liquid mixture of nonoxidizing methanesulfonic acid and a powerful dehydrating agent phosphorus pentoxide. The addition of phosphorus pentoxide increases the solubility of organic compounds in methanesulfonic acid; this was introduced by Eaton and has been used enormously in organic synthesis.
In order to standardize the reaction conditions for the condensation reaction, it was decided to synthesize 3,4dihydropyrimidin-2(1H)-one (4a) from benzaldehyde (1a), urea, and ethylacetoacetate using a mixture of P 2 O 5 / MeSO 3 H, and we found that the reaction is fast when compared to other reported methods. The results are compared with the reported methods, and it is clear from Table 1 that the present method is more efficient.
To optimize the reaction condition, the condensation reaction was performed under different conditions (Table 2). In the presence of Eaton's reagent (2 mmol for each operation), initially 4-chlorobenzaldehyde (1k) was used as model for the reaction with ethylacetoacetate and urea. The reaction carried out at room temperature using ethanol as solvent required 2.3 h for completion, and the product (4k) was  obtained in 60% yield (Entry 1). When the reaction was performed by using ethanol under refluxing conditions, it required 2 h and provided the product in 65% yield (Entry 2). When the reaction was performed without any solvent at room temperature using 2 mmol of Eaton's reagent, the reaction was completed in 5 min, and the product (4k) was obtained in 85% yield (Entry 3).
To explore the scope and limitations of this reaction, we extended the procedure to various aromatic aldehydes carrying either electron-releasing or electron-withdrawing substituents in the ortho-, meta-, and para-positions. We have also synthesized the compounds with thiourea and methylacetoacetate, and we found that the reaction proceeds very efficiently with all the cases, and the products are obtained in high yields (Table 3).

Experimental
Eaton's reagent (7.7/92.3% by weight of P 2 O 5 /MeSO 3 H) was purchased from Sigma-Aldrich. All melting points were recorded in open capillaries. The purity of the compounds was checked by TLC on silica gel G (Merck). 1 H NMR spectra were recorded on Varian 300 MHz instrument, in DMSO-d 6 using TMS as the internal standard. IR spectra were obtained using a Nujol for solids on a Perkin-Elmer-1710 spectrophotometer. Mass spectra were recorded on Thermo Finnigan (Model-LCQ Advantage MAX) mass spectrometer. (4a-4u). A mixture of aromatic aldehyde 1 (1 mmol), ethylacetoacetate 2 (1 mmol), and urea 3 (1.5 mmol) was stirred with Eaton's reagent (2 mmol) at room temperature for appropriate time (mentioned in Table  3). After completion of the reaction (monitored by TLC), the reaction mass was transferred to an excess saturated sodium carbonate solution. The solid products separated out, were filtered, and washed with sufficient water and dried. The crude products on recrystallization from ethanol provided 3,4-dihydropyrimidin-2(1H)-ones (4a-4u) in 75-96% yield.

Conclusion
In summary, we have developed an efficient, ecofriendly and solvent-free method for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones (4a-4u). The present method which makes use of commercially available Eaton's reagent offers a very attractive features such as shorter reaction times, simple operations with extremely milder conditions, green aspects avoiding hazardous organic solvents, toxic catalyst, and provides good to excellent yields.