Biginelli reaction

From Wikipedia, the free encyclopedia

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.

The Biginelli Reaction

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.[5] Several solid-phase protocols utilizing different linker combinations have been published.[6][7]

Dihydropyrimidinones, the products of the Biginelli reaction, are widely used in the pharmaceutical industry as calcium channel blockers[8], antihypertensive agents, and alpha-1-a-antagonists.

Contents

[edit] Reaction mechanism

The reaction mechanism of the Biginelli reaction is a series of bimolecular reactions leading to the desired dihydropyrimidinone.[9]


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. [10]

The mechanism of the Biginelli reaction

This mechanism is superseded by one by Kappe in 1997:

This scheme begins with rate determining nucleophilic addition by the urea to the aldehyde.[11] [12] 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.

[edit] Variations

[edit] Atwal modification

In 1987, Atwal et al.[13] reported a modification to the Biginelli reaction that consistently generated higher yields.

[edit] References

  1. ^ Biginelli, P. Ber. 1891, 24, 1317 & 2962.
  2. ^ Biginelli, P. Ber. 1893, 26, 447.
  3. ^ Zaugg, H. E.; Martin, W. B. Org. React. 1965, 14, 88. (Review)
  4. ^ Kappe, C. O. Tetrahedron 1993, 49, 6937-6963. (Review)
  5. ^ Hu, E. H.; Sidler, D. R.; Dolling, U.-H. J. Org. Chem. 1998, 63, 3453-3457.
  6. ^ Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36, 7819-7822.
  7. ^ Kappe, C. O. Bioorg. Med. Chem. Lett. 2000, 10, 49-51.
  8. ^ 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.
  9. ^ Folkers, K.; Johnson, T. B. J. Am. Chem. Soc. 1933, 55, 3784-3791.
  10. ^ Sweet, F.; Fissekis, J. D. J. Am. Chem. Soc. 1973, 95, 7841-8749.
  11. ^ Folkers, K.; Harwood, H. J.; Johnson, T. B. J. Am. Chem. Soc. 1932, 54, 3751-3758.
  12. ^ Kappe, C.O. J. Org. Chem. 1997, 62, 7201-7204.
  13. ^ O'Reilly, B. C.; Atwal, K. S. Heterocycles 1987, 26, 1185-1188 & 1189-1192.
Languages