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Multicomponent chemical reaction From Wikipedia, the free encyclopedia
The Biginelli reaction is a multiple-component chemical reaction that creates 3,4-dihydropyrimidin-2(1H)-ones 4 from ethyl acetoacetate 1, an aryl aldehyde (such as benzaldehyde 2), and urea 3.[1][2][3][4] It is named for the Italian chemist Pietro Biginelli.[5][6]
| Biginelli reaction | |
|---|---|
| Named after | Pietro Biginelli |
| Reaction type | Ring forming reaction |
| Identifiers | |
| Organic Chemistry Portal | biginelli-reaction |
| RSC ontology ID | RXNO:0000236 |
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[7] and boron trifluoride.[8] Several solid-phase protocols utilizing different linker combinations have been published.[9][10]
Dihydropyrimidinones, the products of the Biginelli reaction, are widely used in the pharmaceutical industry as calcium channel blockers,[11] antihypertensive agents, and alpha-1-a-antagonists.
More recently products of the Biginelli reaction have been investigated as potential selective Adenosine A2b receptor antagonists.[12] Including highly selective tricyclic compounds.[13]
The reaction mechanism of the Biginelli reaction is a series of bimolecular reactions leading to the desired dihydropyrimidinone.[14]
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.[15]
This mechanism is superseded by one by Kappe in 1997:
This scheme begins with rate determining nucleophilic addition by the urea to the aldehyde.[16][17] 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.
In 1987, Atwal et al.[18][19] 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.[20] The reaction has also been reported via green methodologies.[21]
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