TheBiginelli Dihydropyrimidine Synthesis

Abstract

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.

Ammonia synthons for the multicomponent assembly of complex γ-lactams

“…Only a subset of these involve components that are variable. Typical variable building blocks include amines, aldehydes, ketoesters, isocyanides, etc, as seen in the Hantszch (11), Biginelli (12) and Ugi-type (13) MCRs. It can be argued that these processes and others that meet both of these criteria are the most powerful MCRs because they will generate maximum complexity with minimal effort (14).…”

The application of the CSB to the prediction of single step reactions and reaction pathways

“…Computer modeling experiments were performed on the known three-component Biginelli cycloaddition. The experimental work and computational studies on this reaction were described by Kappe, Falsone et al [14,15,16]. We selected this reaction because it has a high degree of mechanistic complexity, suitable for computer modeling experiments, and because mechanistic alternatives that were proposed by CSB may be verified relating them to the experimentally confirmed reaction mechanism.…”

Synthesis and Biological Properties of Pharmaceutically Important Xanthones and Benzoxanthone Analogs: A Brief Review.

“…MCR also provides a higher overall percentage of yield. Thus these reactions reduces labor by reducing a number of synthetic operations such as extraction, purification, and generates lesser amount of waste as compare to conventional multistep reactions of a complex molecule [4][5][6]. A large number of MCRs are already known, and the searches for new MCRs are still on.…”