Biginelli reaction
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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.
This reaction was developed by Pietro Biginelli in 1891. The reaction can be catalyzed by Brønsted acids and/or by Lewis acids such as 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 industry as calcium channel blockers, antihypertensive agents, and alpha-1-a-antagonists.
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[edit] Reaction mechanism
The reaction mechanism of the Biginelli reaction is a series of bimolecular reactions leading to the desired dihydropyrimidinone.
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.
[edit] Variations
[edit] Atwal modification
In 1987, Atwal et al. reported a modification to the Biginelli reaction that consistently generated higher yields.
[edit] References
- ↑ Biginelli, P. Ber. 1891, 24, 1317 & 2962.
- ↑ Biginelli, P. Ber. 1893, 26, 447.
- ↑ Zaugg, H. E.; Martin, W. B. Org. React. 1965, 14, 88. (Review)
- ↑ Kappe, C. O. Tetrahedron 1993, 49, 6937-6963. (Review)
- ↑ Hu, E. H.; Sidler, D. R.; Dolling, U.-H. J. Org. Chem. 1998, 63, 3453-3457.
- ↑ Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36, 7819-7822.
- ↑ Kappe, C. O. Bioorg. Med. Chem. Lett. 2000, 10, 49-51.
- ↑ Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.; Moreland, S.; Gougoutas, J. Z.; O'Reilly, B. C.; Schwartz, J.; Malley, M. F. J. Med. Chem. 1992, 35, 3254-3263.
- ↑ Folkers, K.; Johnson, T. B. J. Am. Chem. Soc. 1933, 55, 3784-3791.
- ↑ Sweet, F.; Fissekis, J. D. J. Am. Chem. Soc. 1973, 95, 7841-8749.
- ↑ O'Reilly, B. C.; Atwal, K. S. Heterocycles 1987, 26, 1185-1188 & 1189-1192.
