Biginelli reaction

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]

This reaction was developed by

More recently products of the Biginelli reaction have been investigated as potential selective Adenosine A2b receptor antagonists.^[12] Including highly selective tricyclic compounds.^[13]

Reaction mechanism

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

This mechanism is superseded by one by Kappe in 1997: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.

Advances in Biginelli reaction

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]

References