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

Received on June. 7, 2007.

Abstract 3,4-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 KH₂PO₄ 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.
Keywords Biginelli Reaction, PEG400 - KH₂PO₄, Solvent-Free

1. INTRODUCTION
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 b-dicarbonyl compounds with aldehydes and urea or thiourea derivatives in the presence of acid in ethanol furnishing 3,4-Dihydropyrimidin-2(1H)-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) ₃^[11], I₂ ^[12], LiBr ^[13], KHSO₄ ^[14]. Recently, a number of procedures under solvent-free conditions using Yb (OTf) ₃^[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 (PEGs) 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 PEGs 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 PEGs as PTC ^[18], herein, we report a new study on the Biginelli condensation using KH₂PO₄ and PEG400 as catalysts under solvent-free conditions (Scheme. 1).

Scheme 1

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