The Biginelli reaction is a multiple-component

chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...

that creates 3,4-dihydropyrimidin-2(1''H'')-ones 4 from

ethyl acetoacetate The organic compound ethyl acetoacetate (EAA) is the ethyl ester of acetoacetic acid. It is a colorless liquid. It is widely used as a chemical intermediate in the production of a wide variety of compounds. It is used as a flavoring for food. ...

1, an aryl

aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...

(such as benzaldehyde 2), and

urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...

3. It is named for the Italian chemist Pietro Biginelli.Kappe, C. Oliver (2005) "The Biginelli Reaction", in: J. Zhu and H. Bienaymé (eds.): ''Multicomponent Reactions'', Wiley-VCH, Weinheim, . This reaction was developed by Pietro Biginelli in 1891. The reaction can be catalyzed by Brønsted acids and/or by Lewis acids such as copper(II) trifluoroacetate hydrate and boron trifluoride. Several solid-phase protocols utilizing different linker combinations have been published. Dihydropyrimidinones, the products of the Biginelli reaction, are widely used in the

pharmaceutical A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field an ...

industry as calcium channel blockers,

antihypertensive agents Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests that r ...

, 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 An aldol condensation is a condensation reaction in organic chemistry in which two carbonyl moieties (of aldehydes or ketones) react to form a β-hydroxyaldehyde or β-hydroxyketone (an aldol reaction), and this is then followed by dehydration to ...

of ethylacetoacetate 1 and the aryl aldehyde is the

rate-limiting step In chemical kinetics, the overall rate of a reaction is often approximately determined by the slowest step, known as the rate-determining step (RDS or RD-step or r/d step) or rate-limiting step. For a given reaction mechanism, the prediction of th ...

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