Biginelli reaction

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This mechanism is superseded by one by Kappe in 1997:

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

References

1. Biginelli, P.. (1891). "Ueber Aldehyduramide des Acetessigäthers". [[Chemische Berichte]].
2. Biginelli, P.. (1891). "Ueber Aldehyduramide des Acetessigäthers. II". [[Chemische Berichte]].
3. (1965). "Α-Amidoalkylations at Carbon". [[Org. React.]].
4. Kappe, C. O.. (1993). "100 years of the biginelli dihydropyrimidine synthesis". [[Tetrahedron (journal).
5. Kappe, C. Oliver (2005) "The Biginelli Reaction", in: J. Zhu and H. Bienaymé (eds.): ''Multicomponent Reactions'', Wiley-VCH, Weinheim, {{ISBN. 978-3-527-30806-4.
6. (2004). "The Biginelli Dihydropyrimidine Synthesis". [[Organic Reactions]].
7. (2008). "Copper(II) trifluoroacetate catalyzed synthesis of 3,4- dihydropyrimidin-2(1H)-ones under solvent-free conditions". Reaction Kinetics and Catalysis Letters.
8. (1998). "Unprecedented Catalytic Three Component One-Pot Condensation Reaction: An Efficient Synthesis of 5-Alkoxycarbonyl- 4-aryl-3,4-dihydropyrimidin-2(1H)-ones". [[J. Org. Chem.]].
9. (1995). "A solid phase protocol of the biginelli dihydropyrimidine synthesis suitable for combinatorial chemistry". [[Tetrahedron Lett.]].
10. (1992). "Dihydropyrimidine calcium channel blockers. 4. Basic 3-substituted-4-aryl-1,4-dihydropyrimidine-5-carboxylic acid esters. Potent antihypertensive agents". [[J. Med. Chem.]].
11. (2013-10-03). "Discovery of 3,4-Dihydropyrimidin-2(1H)-ones As a Novel Class of Potent and Selective A2B Adenosine Receptor Antagonists". ACS Medicinal Chemistry Letters.
12. (2016-03-10). "Discovery of Potent and Highly Selective A2B Adenosine Receptor Antagonist Chemotypes". Journal of Medicinal Chemistry.
13. (1933). "Researches on Pyrimidines. CXXXVI. The Mechanism of Formation of Tetrahydropyrimidines by the Biginelli Reaction1". [[J. Am. Chem. Soc.]].
14. (1973). "Synthesis of 3,4-dihydro-2(1H)-pyrimidinones and the mechanism of the Biginelli reaction". [[J. Am. Chem. Soc.]].
15. (1932). "Researches on Pyrimidines. Cxxx. Synthesis of 2-Keto-1,2,3,4-Tetrahydropyrimidines". [[J. Am. Chem. Soc.]].
16. Kappe, C.O.. (1997). "A Reexamination of the Mechanism of the Biginelli Dihydropyrimidine Synthesis. Support for anN-Acyliminium Ion Intermediate1". [[J. Org. Chem.]].
17. (1987). "Synthesis of Substituted 1,2,3,4-Tetrahydro-6-methyl-2-oxo-5-pyrimidinecarboxylic Acid Esters: The Biginelli Condensation Revisited". [[Heterocycles (journal).
18. (1987). "Synthesis of Substituted 1,2,3,4-Tetrahydro-6-methyl-2-thioxo-5-pyrimidinecarboxylic Acid Esters". [[Heterocycles (journal).
19. (2007). "An efficient bakers' yeast catalyzed synthesis of 3,4-dihydropyrimidin-2-(1H)-ones". [[Tetrahedron Letters]].
20. (2012). "Biginelli Reaction: A Green Perspective.". [[Curr. Org. Chem.]].