Biginelli reaction

The Biginelli reaction is a multiple-component chemical reaction that creates 3,4-dihydropyrimidin-2(1"H")-ones 4 from ethyl acetoacetate 1, an aryl aldehyde (such as benzaldehyde 2), and urea 3. [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)] It is named for the Italian chemist Pietro Biginelli.

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. [Hu, E. H.; Sidler, D. R.; Dolling, U.-H. "J. Org. Chem." 1998, "63", 3453-3457.] Several solid-phase protocols utilizing different linker combinations have been published. [Wipf, P.; Cunningham, A. "Tetrahedron Lett." 1995, "36", 7819-7822.] [Kappe, C. O. "Bioorg. Med. Chem. Lett." 2000, "10", 49-51.]

Dihydropyrimidinones, the products of the Biginelli reaction, are widely used in the pharmaceutical industry as calcium channel blockers [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.] , antihypertensive agents, and alpha-1-a-antagonists.

Reaction mechanism

The reaction mechanism of the Biginelli reaction is a series of bimolecular reactions leading to the desired dihydropyrimidinone. [Folkers, K.; Johnson, T. B. "J. Am. Chem. Soc." 1933, "55", 3784-3791.]

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. [Sweet, F.; Fissekis, J. D. "J. Am. Chem. Soc." 1973, "95", 7841-8749.]

This mechanism is superseded by one by Kappe in 1997:

This scheme begins with rate determining nucleophilic addition by the urea to the aldehyde. [Folkers, K.; Harwood, H. J.; Johnson, T. B. "J. Am. Chem. Soc." 1932, "54", 3751-3758.] [Kappe, C.O. "J. Org. Chem." 1997, "62", 7201-7204.] 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.

Variations

Atwal modification

In 1987, Atwal "et al." [O'Reilly, B. C.; Atwal, K. S. "Heterocycles" 1987, "26", 1185-1188 & 1189-1192.] reported a modification to the Biginelli reaction that consistently generated higher yields.

References