The Biginelli compounds or 3,4-dihydropyrimidin-2(1H)-ones (DHMPs) and other compounds with the structural similarity constitute an eye-catching class of heterocyclic organic compounds, which exhibit significant biologic and pharmacologic activities and have become the key structural units in many drugs and drug candidates,such as monastrol,L-771688,SNAP-7941, and SQ 32926 ^{[1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11]}. So far,a wide range of biologic effects, including antiviral,antitumor,antifungal,anti-tubercular,antibacterial, antihypertensive,and anti-inflammatory activities,have been described for these compounds ^{[12, 13, 14, 15]}. It was also reported that some of the Biginelli-type analogs such as fused pyrimidinones bearing an arylidene moiety have anticancer properties ^[16]. Consequently,the synthesis of this type of heterocycles is of much current importance for both organic synthesis and medicinal chemistry. These types of heterocyclic pyrimidinones are prepared by the reaction of cycloalkanones with various aldehydes and urea/ thiourea ^{[17, 18, 19, 20, 21, 22, 23]}. In addition,these compounds can also be synthesized from the reaction of the α,α’-bis(arylidene)cycloalkanones with urea/thiourea ^[24]. Typically,processes involved in the synthesis of these compounds are catalyzed by different catalysts. Some of these catalysts include rare earth metal bis(perfluorooctanesulfonyl)imide complexes ^[18],YbCl3 ^[20], Brønsted acidic ionic liquid ^[21],as well as strong Brønsted acid like HCl ^[25]. Strong Brønsted bases such as sodium ethoxide ^{[16, 19]},potassium hydroxide ^[26],sodium butoxide ^{[27, 28]},and potassium tert-butoxide ^[29] have also been used as the catalyst in Biginelli-type reactions. Recently,base-catalyzed Biginelli reactions have gained significance for the reason of the reasonable yields compared to those of the acid-catalyzed reactions ^{[29, 30]}. On the other hand,solvent-free organic processes have gained in popularity in recent years from the viewpoint of green chemistry and ecological importance. The benefits of reactions in the absence of solvent are their simple workup procedures,high efficiency, mild conditions,environmental friendliness,reduction of waste, low cost,and handling ^{[31, 32, 33]}.

In the 1950s when Pines and Eschinazi began studies of the solid basic catalysts,the development of these kinds of catalytic systems utilizing inexpensive,clean,environmentally benign,and commercially available catalysts has been a challenge in organic syntheses ^{[34, 35, 36]}. Potassium phthalimide (PPI) is a stable,mild, green,inexpensive,commercially available,and efficient basic recyclable catalyst. It has been utilized as a reagent in the synthesis of primary amines by the Gabriel method ^{[37, 38]},and the synthesis of phthalimide derivatives ^{[39, 40, 41]}. Also,PPI showed high catalytic activity in the preparation of cyanohydrin trimethylsilyl ethers ^{[42, 43]}. Literature survey shows that there are no reports about the synthesis of pyrimidinone derivatives using PPI as a catalyst. In the present work,we report a solvent-free and solid base PPI-catalyzed synthesis of several derivatives of Biginelli-like compounds via a one-pot,multi-component reaction of aryl aldehydes,cyclopentanone,and urea/thiourea (Scheme 1).

Scheme 1

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Scheme 1.Synthesis of 4-aryl-7-(arylmethylene)-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-2(5H)-ones/thiones catalyzed by PPI.

To a mixture of aryl aldehyde 1 (2 mmol),cyclopentanone 2 (1 mmol),and urea or thiourea 3 (1.3 mmol) was added 15 mol% of PPI. The reaction mixture was heated at 120℃ on a heating mantle for 1.5-6 h. After the completion of the reaction (monitored by TLC analysis),the system was cooled to room temperature. Water (10 mL) was added to the reaction mixture,and the crude product was obtained by filtration followed by washing with ethyl acetate and ethanol. The solid thus obtained was further purified by recrystallization using ethanol. The catalyst was recovered by concentration of the filtrate,and was dried and reused for subsequent reactions. Selected spectral data are listed below.

Compound 4a: IR (KBr,cm^-1): ν 3410,3218,3120,2920,2850, 1670,1468,1445,1355,1070,755; ¹H NMR (400 MHz,DMSO-d₆): d 1.96-2.03 (m,1H),2.49 (m,1H),2.73-2.84 (m,2H),5.16 (s,1H), 6.63 (s,1H),7.19-7.37 (m,11H),8.79 (s,1H); ¹³C NMR (100 MHz, DMSO-d₆): d 29.5,29.8,58.7,117.8,119.6,127.2,127.4,128.6, 129.0,129.5,129.6,137.1,138.8,140.3,144.3,154.4.

Compound 4c: IR (KBr,cm^-1): ν 3385,3215,3115,2955,2850, 1684,1600,1440,1285,1110,895,768; ¹H NMR(400 MHz,DMSOd6): d 1.95-2.06 (m,1H),2.33-2.37 (m,1H),2.67-2.74 (m,2H),3.78 (s,3H),3.79 (s,3H),5.26 (s,1H),6.68 (s,1H),7.32 (s,1H),7.44 (d, 4H,J = 7.6 Hz),7.89 (d,2H,J = 7.6 Hz),7.97 (d,2H,J = 7.2 Hz),8.89 (s,1H); ¹³C NMR (100 MHz,DMSO-d₆): d 28.8,29.1,52.6,57.7, 116.6,120.2,127.1,127.3,128.4,129.3,129.8,130.0,136.7,142.5, 142.9,148.7,155.7,157.9.

Compound 4n: IR (KBr,cm^-1): ν 3388,3205,2923,2850,1668, 1586,1520,1476,1341,1182,1109,856,752; ¹H NMR (400 MHz, DMSO-d₆): d 1.98-2.05 (m,1H),2.37-2.45 (m,1H),2.78-2.91 (m, 2H),5.39 (s,1H),6.89 (s,1H),7.49-7.61 (m,4H),8.18 (d,2H, J = 8.4 Hz),8.29 (d,2H,J = 7.6 Hz),8.80 (s,1H),10.26 (s,1H).

Compound 4o: IR (KBr,cm^-1): ν 3405,3224,3124,2920,2852, 1675,1488,1450,1406,1350,1270,1090,1015,889,828,814, 754; ¹H NMR (400 MHz,DMSO-d₆): d 1.96-2.02 (m,1H),2.36-2.42 (m,1H),2.70-2.79 (m,2H),5.38 (s,1H),6.69 (s,1H),7.26 (s,1H), 7.28-7.33 (m,4H),7.42 (d,2H,J = 8.7 Hz),7.46 (d,2H,J = 12.0 Hz), 8.82 (s,1H); ¹³C NMR (100 MHz,DMSO-d₆): d 28.6,29.2,57.8, 116.6,121.1,121.7,121.9,127.3,128.4,129.1,129.8,131.5,134.9, 138.7,156.5,175.8 3. Results and discussion

In the present study a series of 4-aryl-7-(arylmethylene)-3,4,6,7- tetrahydro-1H-cyclopenta[d]-pyrimidin-2(5H)-ones/thiones (4a-o) were prepared by condensing cyclopentanone (1mmol) with aryl aldehydes (2mmol) and urea/thiourea (1.3mmol) under conventional heating conditions using 15 mol% of PPI as a solid basic catalyst without any solvent (Scheme 1).

At first,in order to optimize the amount of PPI,the cyclocondensation reaction of benzaldehyde (1 mmol),cyclopentanone (1 mmol),and thiourea (1.3 mmol) was carried out under neat conditions at 120℃ in the presence of different quantities of PPI as the catalyst (Table 1).

Table 1

Table 1 Optimization of the amounts of catalyst PPI.a

Table 1 Optimization of the amounts of catalyst PPI.a

As shown in Table 1,in the absence of the catalyst,the formation of product 4l was not observed (Table 1,entry 1). By adding catalyst (2.5 mol%) to the reaction mixture,the product was formed with relatively low yield (Table 1,entry 2). The yield of product 4l was improved as the amount of PPI increased from 2.5 to 5,7.5,10,and 15 mol% (Table 1,entries 2-6). A further increase in mol% of PPI (20 mol%) did not have any significant effect on the yield of the product or reaction time. It was observed that 15 mol% loading of the catalyst provided the best yield. Therefore,15 mol% was chosen as the optimal quantity of PPI. Then,the same reaction was tested under different temperatures including room temperature, 50,80,100,and 120℃. The maximum yield in shorter reaction time was achieved under neat conditions at 120℃. Furthermore,the influence of solvent was also optimized; the model reaction was conducted in various solvents under similar reaction conditions. When the reaction was performed in EtOH, CH₂Cl₂,and CH₃CN,the product 4l was obtained in yields of 60%, 58%,and 50%,respectively.

With the above-mentioned optimized conditions in hand,we then proceeded to probe the substrate diversity of this multicomponent reaction by using readily available starting materials. It was found that the reaction proceeded efficiently and afforded the targeted products (4a-o) in good to high yields. The results are offered in Table 2.

Table 2

Table 2 Synthesis of 4-aryl-7-(arylmethylene)-3,4,6,7-tetrahydro-1H-cyclopenta[d]-pyrimidin-2(5H)-ones/thiones (4a-o) catalyzed by PPI.a

Table 2 Synthesis of 4-aryl-7-(arylmethylene)-3,4,6,7-tetrahydro-1H-cyclopenta[d]-pyrimidin-2(5H)-ones/thiones (4a-o) catalyzed by PPI.a

Based on the results presented in Table 2,it can be seen that the reaction of aryl aldehydes bearing both electron-donating and electron-withdrawing substituents with cyclopentanone and urea or thiourea worked well,and the corresponding 4-aryl-7- (arylmethylene)-3,4,6,7-tetrahydro-1H-cyclopenta[d]-pyrimidin- 2(5H)-ones/thiones were obtained in reasonable yields. The reusability of the catalyst for the synthesis of 4l was also examined. After the completion of the reaction,the solid product was treated with water and filtered off. The catalyst was recovered after the removal of water from the aqueous filtrate and reused for subsequent cycles. It showed nearly the same activity as a fresh catalyst along but with a slight decrease of yield. In four consecutive recycles in which the model reaction was carried out,the desired product was obtained in 82%,78%,75%,and 70% isolated yields,respectively. To compare the effectiveness of PPI with other catalysts in the synthesis of 4-aryl-7-(arylmethylene)- 3,4,6,7-tetrahydro-1H-cyclopenta[d]-pyrimidin-2(5H)-ones/ thiones,results of the reaction of benzaldehyde,cyclopentanone, and urea have been tabulated in Table 3. As shown in Table 3,PPI is comparable to the previously reported methods in terms of reaction time and yields.

Table 3

Table 3 Comparison of the results of the reaction of benzaldehyde,cyclopentanone,and urea using PPI with those obtained by reported catalysts.

Table 3 OComparison of the results of the reaction of benzaldehyde,cyclopentanone,and urea using PPI with those obtained by reported catalysts.

In summary,we have established a simple,efficient,mild,and environmentally benign method for the synthesis of 4-aryl-7- (arylmethylene)-3,4,6,7-tetrahydro-1H-cyclopenta[d]-pyrimidin- 2-(5H)-ones/thiones. This green protocol offers advantages such as good to high yields of the products,green,simple operational procedures,and reusability of the catalyst. Acknowledgment

The authors are thankful to Damghan University Research Council for partial support of this work.