Biginelli reaction catalyzed by PEG400-KHPO under solvent-free conditions

CaoYuqing, Guo Yanxin , Li Yabin
(College of Pharmacy, Hebei University, Baoding 071002, China)

Abstract3,4-Dihydropyrimidin-2(1H)-one and their derivatives were synthesized in good yields (71-93%) by one-pot three-component Biginelli condensation in the presence of KHPO and PEG400 as catalyst under solvent-free conditions. And the reaction time is shortened from 18hr to 1.5-6.5hr. This approach of direct reaction without solvent shows a new direction in green synthesis.

The toxicity and volatile nature of many organic solvents, particularly chlorinated hydrocarbons that are widely used in large amounts for organic reactions have posed as serious threat to the environment [1]. Thus, the design of solventless catalytic reaction has received tremendous attention in recent times in the area of green synthesis [2]
Dihydropyrimidinones (DHPMs) and their derivatives occupy an important place in the realm of natural and synthetic organic chemistry because of their therapeutic and pharmacological properties [3]. They have emerged as integral backbones of several calcium channel blockers, anti-hypertensive agents, R-1a-antagonists and neuropeptide Y (NPY) antagonists [4]. Moreover, several alkaloids containing the dihydropyrimidine core units have been isolated from marine sources, which also exhibit interesting biological properties [5]. Most notable among these are the batzelladine alkaloids, which were found to be potent HIVgp-120-CD4 inhibitors [6]. Thus, the synthesis of this heterocyclic nucleus is of much current importance.
Biginelli reaction, first reported in 1893 [7], is a one-pot three-component condensation using-dicarbonyl compounds with aldehydes and urea or thiourea derivatives in the presence of acid in ethanol furnishing 3,4-Dihydropyrimidin-2(1)-ones. This reaction is carried out by simply heating a mixture of the above three components dissolved in ethanol with catalytic amount of hydrochloric acid at reflux temperature for 18 hours. However, this one-pot, one step protocol provides only low to moderate yields of the desired product (20-50%), in particular when substituted aromatic or aliphatic aldehydes are employed. Therefore, the searching of practical methods for the synthesis of dihydropyrimidin-2 (1H)-ones by the Biginelli reaction continues to attract the attention of researchers. Several improved procedures for the preparation of DHPMs have recently been reported based on Lewis acids [8], solid support [9] or microwave [10] or on reagents like Mn (OAc) [11], I[12], LiBr [13], KHSO[14]. Recently, a number of procedures under solvent-free conditions using Yb (OTf) [15], montmorillonite [16] and ionic liquid [17] as catalysts have been reported. Obviously, many of these methods involve expensive reagents; stoichiometric amounts of catalysts; strongly acidic conditions; long reaction time, unsatisfactory yields and incompatibility with other functional group and the solvent used are not at all acceptable in the context of green synthesis. On the other hand, an inevitable problem exists when Lewis acid used as catalyst, that is a reaction of Lewis acid with water. Therefore, seeking for a new and an inexpensive catalyst for the preparation of dihydropyrimidinones under mild conditions is of prime importance.
Polyethylene glycols (PEG) have been widely used as PTC in many organic reactions owing to their stability, low cost, environment-friendly, and easy availability. It has been proved that PEG incorporating 7-9 units are more effective in catalyzing the reactions in which K+ or Na+ salts participate. PEG400-600 was more suitable for liquid-liquid or solid-liquid phase solvent-free organic reactions. In the continuation of our investigation on the research of using PEG as PTC [18], herein, we report a new study on the Biginelli condensation using KHPO and PEG400 as catalysts under solvent-free conditions (Scheme 1).
Scheme 1

The reaction conditions were studied by carrying out the condensation of benzaldehyde, ethyl acetoacetate, and urea as the reactants. The desired dihydropyrimidinine was obtained with good yield in the presence of a catalytic amount of KHPO at 110. We also examined this reaction in different solvents, but the reaction gave better yield under solvent-free conditions than other tested (such as toluene (71.6%), dichloromethane (38.4%), tetrahydrofuran (62%), acetonitrile (45.8%). Thus, condensation of a mixture of benzaldehyde, ethyl acetoacetate and urea at 110in the presence of 10mol% of KHPO furnished the corresponding dihydropyrimidinone product in 84% yield. The procedure gives the product in good yields and avoids the problems associated with solvent use (cost, handing, safety and pollution). The other reaction product, water, evaporates at the reaction temperature of 110.The efficacy of this procedure was equally high for aromatic aldehyde containing electron withdrawing and electron donating groups. The results are summarized in Table

Table 1. Synthesis of dihydropyrimidinones under solvent-free conditions.

Entry     Time(h) Yield (%) M.p M.p (Lit*)
4a     1.5 84 204-207 202-203[14]
  2.5 86 204-207 202-203[14]
4b 4-OHC     90 228-231 227-229[14]
4c 2-OHC   3.5 83 201-203 202-203[14]
4d 2-NO   4.5 85 207-209 208-210[11]
4e 4-NO     88 207-208 207-208[14]
4f 4-OCH   1.5 90 207-209 205-207[9]
4g 4-ClC     87 214-216 214-215[14]
4h 4-NMe   4.5 84 251-252 257-258[14]
4i 2-ClC   4.5 82 215-217 215-217[14]
4j 3-OHC     85 166-168 167-170[9]
4k 2-OCH     88 258-259 259-260[9]
4l -CH=CH     84 231-233 230-232[9]
4m 3-NO   4.5 81 225-228 227-229[11]
4n 4-OH-3-OMeC   1.5 85 234-237
4o 3,4-(OMe)   1.5 93 175-177 175-177[11]
4p 4-FC     84 182-183 182-184[9]
4q n-C   6.5 71 155-157 154[9]
4r (CHCH     75 174-176 172-174[14]
4s     3.5 82 205-207 209-211[9]
4s’     78 205-207 209-211[9]
4t 3-OHC   4.5 80 183-184 183-184[9]
4u 3-NO   4.5 81 202-204 203-205[9]
4v 4-OMeC     85 152-154 153-155[9]
4w 4-OHC   4.5 89 195-197

Reaction conditions: aldehyde (, 0.1mol), ethyl acetoacetate (, 0.1mol), urea or thiurea (, 0.1mol), KHPO (10%), PEG400 (5%).
Isolated yields. Without PEG400.No catalyst and no solvent.reaction temp 70

From the data in Table , the condensation of a series of aldehydes with ethyl acetoacetate and urea or thiourea leading to 3,4-Dihydropyrimidin-2 (1H)-ones give good yield under solvent-free conditions than that of the classical method. For example, products 4b, 4e, 4f were obtained in 90%, 88%, 89% yields, whereas, in the classical method [7], the yields of 4b, 4e, 4f were 67%, 58%, 61% respectively in 18hr. The reaction was examined without any catalyst and solvent. Based on the results of the comparative experiments (Entry4s, Entry4s),we suggest that the catalyst is important for the reaction. Aromatic aldehydes which carrying either electron-withdrawing or electron-donating substituents obtained good yields of products. This method is effective even witha,b-unsaturated aldehydes which is usually produced with poor yields in the presence of protic or Lewis acids due to their decomposition or polymerization under acidic conditions. From the reaction times in Table , it has been found that the reaction of aldehydes bearingNO groups on the aryl ring can be carried out in relatively longer time than that of the aldehydes bearingOCH on the aryl ring. The probable reason is that the electron-donating groups increase the activity of carbonyl group in the benzaldehydes, while the electron-withdraw ing groups decrease the activity. -substituted aromatic aldehydes needed relatively long reaction times, but low yields were found because of the influence of steric hindrance. Another important feature of this procedure is its efficiency for the good yield synthesis of DHPMS from aliphatic aldehydes.
Thiourea has been used with similar success to provide the corresponding thio-derivatives of dihydropyrimidinones that are also of much interest with respect to their biological activities. Thus, each of benzaldehyde (Entry4s), -methoxy (Entry4v) and -hydroxy (Entry4wreacted efficiently with ethyl acetoacetate and thiourea affording the corresponding S-HPMS in good yields. However, from the data in Table 1, it can be seen that a longer reaction time was necessary for the thiourea to obtain good yield.
In summary, a novel method for Biginelli condensation catalyzed by PEG400 and anhydrous KHPO without solvent was developed. The advantages of this method were safety, high selectivity, environment friendly and ease of work-up.

H-NMR spectra were obtained on a Bruker AVANCE (400MHz) spectrometer using TMS as internal standard and DMSO as solvent. TLC was GF254 thin layer chromatography with petroleum ether/ethyl acetate as eluent. aldehydes, ethyl acetoacetate, urea and thiourea were all commercial products and were used without further purification. All liquid reagents were distilled before use. Melting points were determined on a microscopy apparatus and are uncorrected.

Typical experimental procedure for the preparation ofcompounds(4a-4w):
   A mixture of aromatic aldehydes (, 0.1mol), ethyl aectoacetate (, 0.1mol), urea or thiourea (, 0.1mol), KHPO (1.36g), and PEG400(2g) were taken into a 50ml three-necked, round- bottomed flask. The mixture was vigorously stirred and heated at the 110for a definite time (monitored by TLC). With the progress of reaction the reaction mixture became thick slurry with the solids being deposited. Heating was continued for another 0.5h at that temperature. Then the mixture was washed with cold water and the yellow residue recrystallization from ethanol to give pure products. HNMR spectra data were selectively given.
4e. 5-Ethoxycarbonyl-4- (4-nitroxyphenyl)-6-methyl-3, 4-dihydropyrimidin-2 (1)-2-one
White crystals (EtOH) H-NMR (DMSO- ):=9.36(s, 1H, NH), 7.85 (s, 1H, NH), 8.22-7.45 (m, 4H, Ar), 5.26 (s, 1H, CH), 3.97 (q, =7.0Hz, 2H, OCHCH), 2.25 (s, 3H, CH), 1.08 (t, =7.0Hz, 3H, -OCHCH).
4m. 5-Ethoxycarbonyl-4-(3-nitroxyphenyl)-6-methyl-3, 4-dihydropyrimidin-2 (1)-2-one
White crystals (EtOH) H-NMR (DMSO-):=9.37 (s, 1H, NH), 7.90 (s, 1H, NH)), 8.1-7.63 (m, 1H, Ar), 5.29 (s, 1H, CH) 3.98 (q, =6.9Hz, 2H, -OCHCH), 2.26 (s, 3H, CH), 1.08 (t, =6.9Hz, 3H, -OCHCH).
4n.5-Ethoxycarbonyl-4-(4-hydroxy-3-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1)-2 one
White crystals (EtOH) H-NMR (DMSO-):=9.15 (s, 1H,), 8.93 ( s, 1H,), 7.66 ( s, 1H), 6.80 ( s, 1H), 6.74 (d, =8.4Hz, 1H), 6.61 (d, =8.4Hz, 1H), 5.05 (d, =2.8Hz, 1H), 3.98 (q, =7.2Hz, 2H, -OCHCH), 3.72 (s, 3H, CH), 2.21 (s, 3H, CH), 1.11 (t, =7.2Hz, 3H, -OCHCH).
4w. 5-Ethoxycarbonyl-4-(4-hydroxyphenyl)-6-methyl-3, 4-dihydropyrimidin-2 (1H)-2-thione
White crystals (EtOH) 1H-NMR (DMSO-d6):=9.37 (s, 1H, OH), 10.50 (s,1H, NH), 9.67 (s, 1H, NH), 8.22-7.54 (m, 4H, Ar), 5.27 (s, 1H, CH), 4.00 (q, =7.1Hz, 2H, -OCHCH), 2.34 (s, 3H, CH), 1.24 (t, =7.1Hz, 3H, -OCHCH).