Solvent effects Biginelli reaction

Biginelli reaction (Figure 2.1)P The 1,3-dicarbonyl compound, aldehyde and urea are heated to around 100 °C for 1 h without any need for solvent or catalyst and yield the dihydropyrimidone in good to excellent yields. Performing the same reaction in refluxing VOCs did not yield any product, indicating a special advantage for a solventless procedure in this case. The reaction has been scaled up successfully to the 1 kg level and the only additional solvents required to work up the product effectively are water and ethanol. 

Madje et al. [107] reported the Biginelli reaction using EAN as a solvent as well as catalyst with high yield of product. Triethylammonium acetate (TEAA) [EtjNH] [CH3COO] IL has been reported for the effective synthesis of 1,5-benzodiazepine (Scheme 4.2). This process benefits from the use of TEAA in organic reaction medium and as a catalyst [108]. 

Liberto and collaborators used cyclodextrin (CAT-33), a cyclic oligosaccharide derived from the enzymatic degradation of starch, as a catalyst for the Biginelli reaction (Table 6) [44]. The authors evaluated the effect of the cavity size of these macrocycles and found that the size of the cavity was not important for the catalytic effects of these compounds [44]. The Biginelli reactions were carried out under solvent-free conditions, fi-Cyclodextrin (CAT-33) was the most efficient catalyst. Aromatic aldehydes showed better yields (>60%) than aliphatic or heteroaromatic aldehydes (<38%). The cyclodextrin was reused at least five times without any loss of efficiency [44]. 

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