The Biginelli reaction is a multiple-component chemical reaction that creates 3,4-dihydropyrimidin-2(1''H'')-ones 4 from ethyl acetoacetate 1, an aryl aldehyde (such as

benzaldehyde Benzaldehyde (C6H5CHO) is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. It is a colorless liquid with a characteristic almond-like odor. ...

2), and urea 3. It is named for the Italian chemist

Pietro Biginelli Pietro Biginelli (25 July 1860 – 15 January 1937) was an Italian chemist, who discovered a three-component reaction between urea, acetoacetic ester and aldehydes (Biginelli reaction). He also studied various aspects of sanitation chemistry a ...

.Kappe, C. Oliver (2005) "The Biginelli Reaction", in: J. Zhu and H. Bienaymé (eds.): ''Multicomponent Reactions'', Wiley-VCH, Weinheim, . This reaction was developed by

in 1891. The reaction can be catalyzed by Brønsted acids and/or by

Lewis acid A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any sp ...

s such as copper(II) trifluoroacetate hydrate and

boron trifluoride Boron trifluoride is the inorganic compound with the formula BF3. This pungent, colourless, and toxic gas forms white fumes in moist air. It is a useful Lewis acid and a versatile building block for other boron compounds. Structure and bondin ...

. Several solid-phase protocols utilizing different linker combinations have been published. Dihydropyrimidinones, the products of the Biginelli reaction, are widely used in the pharmaceutical industry as

calcium channel A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, although there are also ligand-gated calcium channels. Comparison tables The following tables e ...

blockers, antihypertensive agents, and alpha-1-a-antagonists. More recently products of the Biginelli reaction have been investigated as potential selective

Adenosine A2b receptor The adenosine A2B receptor, also known as ADORA2B, is a G-protein coupled adenosine receptor, and also denotes the human adenosine A2b receptor gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to descri ...

antagonists. Including highly selective tricyclic compounds.

Reaction mechanism

The reaction mechanism of the Biginelli reaction is a series of bimolecular reactions leading to the desired dihydropyrimidinone. According to a mechanism proposed by Sweet in 1973 the aldol condensation of ethylacetoacetate 1 and the aryl aldehyde is the rate-limiting step leading to the carbenium ion 2. The nucleophilic addition of urea gives the intermediate 4, which quickly dehydrates to give the desired product 5. This mechanism is superseded by one by Kappe in 1997: Biginelli reaction mechanism

This scheme begins with rate determining nucleophilic addition by the urea to the aldehyde. The ensuing condensation step is catalyzed by the addition of acid, resulting in the imine nitrogen. The β-ketoester then adds to the imine bond and consequently the ring is closed by the nucleophilic attack by the amine onto the carbonyl group. This final step ensues a second condensation and results in the Biginelli compound.

Advances in Biginelli reaction

In 1987, Atwal ''et al.'' reported a modification to the Biginelli reaction that consistently generated higher yields. Atul Kumar has reported first enzymatic synthesis for Biginelli reaction via yeast catalysed protocol in high yields. The reaction has also been reported ''via'' green methodologies.

References

{{DEFAULTSORT:Biginelli Reaction Carbon-carbon bond forming reactions Condensation reactions Multiple component reactions Name reactions Nitrogen heterocycle forming reactions