Synthesis of 3,4-Dihydropyrimidin-2(1H)-Ones and Their Corresponding 2(1H)Thiones Using Trichloroacetic Acid as a Catalyst under Solvent-Free Conditions
Trichloroacetic acid was found to be a convenient catalyst for the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones and their corresponding 2(1H)-thiones through a one-pot three-component reaction of aldehydes, alkyl acetoacetate, and urea or thiourea at 70°C under solvent-free conditions. 1. Introduction Biginelli reaction is a useful three-component reaction offering versatile protocol for the production of 3,4-dihydropyrimidin-2(1H)-ones which exhibit widespread biological applications such as antihypertensive, antiviral, antitumor, antibacterial, -1a-antagonism, antioxidant, and anti-inflammatory actions [9, 10]. Although numerous catalysts have been developed in accelerating this reaction [1–8, 11–22], it is still desirable to develop this reaction using newer reagents with greater efficiency, simpler operational procedure, and milder reaction condition, and a higher yield of products coupled with potential bioactivity is important. With the awareness of environmental issues and importance of this reaction and keeping our interest in the development of synthetic routes to heterocyclic compounds [23–27], herein, we report a heterogeneous, solid trichloroacetic acid, as an alternative, cheap, and efficient catalyst for the Biginelli reaction (Scheme 1). Scheme 1 Trichloroacetic acid is a readily available and inexpensive solid reagent and it has been used by our group for the synthesis of dihydropyrano[2,3-c]pyrazoles [23] and tetrahydrobenzo[a]xanthen-11-ones and dibenzo[a,j]xanthenes [24]. 2. Results and Discussion The catalytic activity of trichloroacetic acid was first investigated using three-component reaction of benzaldehyde, ethyl acetoacetate, and urea as a model reaction. After carrying out the reaction at different conditions, the best results have been obtained with 20？mol% trichloroacetic acid at 70°C after 4？min with 85% yield under solvent-free conditions. In the absence of trichloroacetic acid, only 20% yield of the product was obtained even after heating at 70°C for 12？h with recovery of starting material. The reaction was also examined in solvents such as EtOH, H2O, CHCl3, and toluene. In the presence of solvents, reaction was sluggish and the formation of by-products was observed. The reaction temperature was also optimized, below 70°C the reaction proceeded slow giving a relatively low yield and no improvement was observed above 70°C. Having established the reaction conditions, various 3,4-dihydropyrimidin-2(1H)-ones were synthesized in excellent yields through the reaction of different aldehydes, alkyl acetoacetate, and urea. The
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