Biginelli reaction
The Biginelli reaction is a multicomponent chemical reaction that synthesizes dihydropyrimidinones. It involves an aldehyde, a β-keto ester, and urea or thiourea under acidic conditions[1][7][11]. This reaction was first reported by Italian chemist Pietro Biginelli in 1891[1][8].
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 and an aldehyde forms an intermediate. The nucleophilic addition of urea gives another intermediate, which quickly dehydrates to give the desired product. This mechanism was superseded by one proposed by Kappe in 1997, which begins with rate-determining nucleophilic addition by the urea to the aldehyde.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 addition. This final step ensues a second condensation and results in the Biginelli compound[1].
The Biginelli reaction has been intensively studied in recent decades due to the applications of synthesized dihydropyrimidinone compounds, especially as calcium channel blockers of the nifedipine-type, and then as antitumor, antibacterial, antiviral, anti-inflammatory, analgesic, anti-Alzheimer, or antioxidant compounds[3].
In 1987, Atwal et al. reported a modification to the Biginelli reaction that consistently generated higher yields. The reaction has also been reported via green methodologies and has been used in the development of functional polymers[1][8]. Other catalysts of the Biginelli reaction reported in the literature include co-phthalocyanines, NaHSO4, zeolites, clays, organic polymers, organic–inorganic mesoporous materials, ionic liquids, etc[3].
Despite the advancements, the Biginelli reaction still has a lot of space for further exploration, especially in the field of polymer synthesis[8].
Citations:
[1] https://en.wikipedia.org/wiki/Biginelli_reaction
[2] https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/biginelli-reaction
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8512088/
[4] https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/organic-reaction-toolbox/biginelli-reaction
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755255/
[6] https://www.sciencedirect.com/science/article/pii/S0022328X09003970
[7] https://www.sciencedirect.com/topics/chemistry/biginelli-synthesis
[8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9698737/
[9] https://www.youtube.com/watch?v=ylz1UwSrpAQ
[10] https://pubs.acs.org/doi/10.1021/jo971010u
[11] https://www.name-reaction.com/biginelli-reaction
[12] https://chemistry.illinois.edu/system/files/inline-files/Eric_Woerly_Chem535_FA08_Abstract.pdf