Anthony crasto presentation of biginelli reaction

3,071 views
2,773 views

Published on

Anthony melvin crasto presentation of Biginelli reaction
amcrasto@gmail.com

Published in: Education, Technology
3 Comments
2 Likes
Statistics
Notes
No Downloads
Views
Total views
3,071
On SlideShare
0
From Embeds
0
Number of Embeds
319
Actions
Shares
0
Downloads
49
Comments
3
Likes
2
Embeds 0
No embeds

No notes for slide

Anthony crasto presentation of biginelli reaction

  1. 1. Biginelli Reaction <ul><li>By Dr Anthony Melvin Crasto, Ph.D </li></ul>
  2. 2. Pietro Biginelli: The Man Behind the Reaction
  3. 3. The Biginelli dihydropyrimidine synthesis is one of the most important and oldest multicomponent reactions and has been extensively investigated in terms of application and mechanism. Surprisingly, little information is available on its discoverer, the Piedmontese chemist Pietro Biginelli (1860—1937). This is, in part, due to the fact that Biginelli dedicated only a few years of his professional life to synthetic organic chemistry. For the most part, he focused on forensic analytical chemistry and commodity science and took on increasing administrative commitments, culminating in his nomination to Director of the Chemical Laboratories of the State Institute of Health (Istituto Superiore di Sanità), Rome, Italy. Pietro Biginelli (1860—1937).
  4. 4. The first Biginelli multicomponent reaction as originally reported by the author in 1891.
  5. 5. Biginelli rxn <ul><li>Cyclocondensation of a beta-ketoester, urea and an aldehyde using an acid catalyst. </li></ul><ul><li>General Scheme &/or Mechanism </li></ul>
  6. 6. Biginelli Reaction This acid-catalyzed, three-component reaction between an aldehyde, a ß -ketoester and urea constitutes a rapid and facile synthesis of dihydropyrimidones, which are interesting compounds with a potential for pharmaceutical application.
  7. 7. Mechanism of the Biginelli Reaction The first step in the mechanism is believed to be the condensation between the aldehyde and urea, with some similarities to the Mannich Condensation. The iminium intermediate generated acts as an electrophile for the nucleophilic addition of the ketoester enol, and the ketone carbonyl of the resulting adduct undergoes condensation with the urea NH 2  to give the cyclized product. Mechanism of the Biginelli Reaction
  8. 8. Mechanism of the Biginelli Reaction
  9. 9. Biginelli  pyrimidone synthesis is the 3 components formation of tetrahydropyrimidinones.
  10. 10. 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 . 
  11. 11. Mechanism of the Biginelli Reaction
  12. 15. Mechanism of the Biginelli Reaction --The Atwal modification
  13. 16. Mechanism of the Biginelli Reaction Biginelli Reaction
  14. 17. Example Reaction The acid catalysed synthesis of substituted 3,4 - dihydro - 2 (1H) - pyrimidinones from, a variety of precursors was studied including the synthesis referred to in the figure. This is the synthesis from the ureide which was obtained in crystalline form when urea and sodium formylacetic ester were treated with conc HCl.
  15. 19. Flourous reaction………
  16. 20. Examples of biologically active DHPMs
  17. 22. BIGINELLI RXN <ul><li>Recent examples of the Biginelli include the following: </li></ul>
  18. 23. First example
  19. 24. Reference:  J org chem 65 (20) 6777-6779 Oct 2000 Second example
  20. 25. Comments:  Use of beta-keto carboxylic acids for the Biginelli cyclocondensation. They used oxalacetic acid and investigated two different sets of rxn conditions. In method A: cat H2SO4, EtOH , heat In method B: cat trifluoroacetic acid, in refluxing dichloroethane Yields were generally higher with method B - conditions are advantageous for the N-acyliminium ion formation, a transient species believed to be a key intermediate in the rxn pathway.
  21. 26. Third example Reference:  J org chem 67 (20) 6979 - 6994 Biginelli Reaction
  22. 27. Biginelli Reaction
  23. 28. Comments:  Here the rxn was studied under different rxn conditions varying the solvent from EtOH to THF, the rxn temp and the cat present from HCL(aq), InCl3. They found the optimum conditions to be using CuCl(l), AcOH and BF3.Et2O in THF at 65degrees for 24hrs. This yielded 65% of product.
  24. 29. N-Substituted Ureas and Thioureas in Biginelli Reaction Promoted by Chlorotrimethylsilane: Convenient Synthesis of  N 1-Alkyl-,  N 1-Aryl-, and  N 1, N 3-Dialkyl-3,4-Dihydropyrimidin-2(1 H )-(thi)ones S. V. Ryabukhin, A. S. Plaskon, E. N. Ostapchuk, D. M. Volochnyuk, A. A. Tolmachev,  Synthesis ,  2007 , 417-427 Biginelli Reaction
  25. 30. Ferric chloride/tetraethyl orthosilicate as an efficient system for synthesis of dihydropyrimidinones by Biginelli reaction I. Cepanec, M. Litvić, A. Bartolinčić, M. Lovrić,  Tetrahedron ,  2005 ,  61 , 4275-4280 Biginelli Reaction
  26. 31. Ruthenium(III) Chloride-Catalyzed One-Pot Synthesis of 3,4-Dihydro­pyrimidin-2-(1 H )-ones under Solvent-Free Conditions J. H. Schauble, E. A. Trauffer, P. P. Deshpande, R. D. Evans,  Synthesis ,  2005 , 1333-1339. Biginelli Reaction
  27. 32. N -Bromosuccinimide as an Almost Neutral Catalyst for Efficient Synthesis of Dihydropyrimidinones Under Microwave Irradiation H. Hazarkhani, B. Karimi,  Synthesis ,  2004 , 1239-1242. Biginelli Reaction
  28. 33. Catalysis of the Biginelli Reaction by Ferric and Nickel Chloride Hexahydrates. One-Pot Synthesis of 3,4-Dihydropyrimidin-2(1 H )-ones J. Lu, Y. Bai,  Synthesis ,  2002 , 466-470. Biginelli Reaction
  29. 34. SQ 3292634 Biginelli Reaction
  30. 35. Biginelli Reaction
  31. 36. Biginelli Reaction
  32. 37. ASSYMETRIC SYN….
  33. 38. Biginelli Reaction
  34. 39. Biginelli Reaction
  35. 40. Example in aq medium
  36. 46. Biginelli Reaction
  37. 47. Biginelli Reaction
  38. 48. References <ul><li>P. Biginelli,  Ber.   24,  1317, 2962 (1891);  26,  447 (1893). </li></ul><ul><li>H. E. Zaugg, W. B. Martin,  Org. React.   14,  88 (1965); </li></ul><ul><li>D. J. Brown,  The Pyrimidines  (Wiley, New York, 1962) p 440;  ibid.,  Suppl. I,  1970,  p 326, </li></ul><ul><li>F. Sweet, Y. Fissekis,  J. Am. Chem. Soc.   95,  8741 (1973). </li></ul><ul><li>Synthetic applications: M. V. Fernandez  et al.,   Heterocycles   27,  2133 (1988); </li></ul><ul><li>K. Singh  et al.,   Tetrahedron   55,  12873 (1999); </li></ul><ul><li>A. S. Franklin  et al.,   J. Org. Chem.   64,  1512 (1999). </li></ul><ul><li>Modified conditions: C. O. Kappe  et al.,   Synthesis   1999,  1799; J. Lu, H. Ma. Synlett   2000,  63. </li></ul><ul><li>Use of cycloalkanones as starting material: Y.-L. Zhu  et al. ,  Eur. J. Org. Chem.   2005 , 2354. </li></ul>
  39. 49. [email_address] DR ANTHONY CRASTO chemistry sites https://sites.google.com/site/anthonycrastoorganicchemistry/sites---my-own-on-the-net
  40. 50. 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) ^  C. Oliver Kampe:  The Biginelli Reaction , in: J. Zhu and H. Bienaymé (Editor): Multicomponent Reactions, Wiley-VCH, Weinheim,  2005 ,  ISBN 978-3-527-30806-4 . ^  Kappe, C. O.; Stadler, A.  Org. React.   2004 ,  63 , 1. (doi:  10.1002/0471264180.or063.01 ) ^  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. ^  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. ^  O'Reilly, B. C.; Atwal, K. S.  Heterocycles   1987 ,  26 , 1185-1188 & 1189-1192. ^   Atul Kumar  and Ram A. Muarya Tetrahedron Letters 48, 2007, 4569-4571  doi : 10.1016/j.tetlet.2007.04.130
  41. 51. Thanks

×