The Biginelli Dihydropyrimidine Synthesis

Kappe, C. Oliver; Stadler, Alexander


The cyclocondensation of suitable CH-acidic carbonyl compounds, aldehydes, and urea-type blocks under acidic conditions provides multifunctionalized derivatives. The discovery of this three-component condensation process was made by Biginelli in 1893, therefore this reaction is called the “Biginelli reaction,” “Biginelli condensation,” or the “Biginelli dihydropyrimidine synthesis.” While the early examples of this cyclocondensation process typically involved a beta-ketoester, aromatic aldehyde, and urea, the scope has now been extended considerably by variation of three building blocks, allowing access to a large number of multifunctionalized pyridmidine derivatives. The importance of multicomponent reactions in combinatorial chemistry has generated a renewed interest in the Biginelli reaction and the number of patents and publications on this subject is growing.

In this chapter, all three-component condensations involving suitable CH-acidic carbonyl compounds, aldehydes, and urea-type building blocks following the Biginelli concept are covered. Therefore, reactions involving 1,3-diketones or nitroacetone as building blocks leading to dihydropyrimides that follow the discussed substitution pattern are included in contrast to earlier articles. Patents are only cited if they contain information not otherwise available.