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Biginelli Reaction ,[object Object]
Pietro Biginelli:  The Man Behind the Reaction
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).
The first Biginelli multicomponent reaction as originally reported by the author in 1891.
Biginelli rxn ,[object Object],[object Object]
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.
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
Mechanism of the Biginelli Reaction
Biginelli  pyrimidone synthesis is the 3 components formation of tetrahydropyrimidinones.
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 . 
Mechanism of the Biginelli Reaction
 
 
 
Mechanism of the Biginelli Reaction --The Atwal modification
Mechanism of the Biginelli Reaction Biginelli Reaction
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.
 
Flourous  reaction………
Examples of biologically active DHPMs
 
BIGINELLI RXN ,[object Object]
First example
Reference:  J org chem 65 (20) 6777-6779 Oct 2000 Second example
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.
Third example Reference:  J org chem 67 (20) 6979 - 6994 Biginelli Reaction
Biginelli Reaction
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.
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
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
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
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
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
SQ 3292634 Biginelli Reaction
Biginelli Reaction
Biginelli Reaction
ASSYMETRIC SYN….
Biginelli Reaction
Biginelli Reaction
Example in aq medium
 
 
 
 
 
Biginelli Reaction
Biginelli Reaction
References ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
[email_address] DR ANTHONY CRASTO chemistry sites   https://sites.google.com/site/anthonycrastoorganicchemistry/sites---my-own-on-the-net
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
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Anthony crasto presentation of biginelli reaction

  • 1.
  • 2. Pietro Biginelli: The Man Behind the Reaction
  • 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. The first Biginelli multicomponent reaction as originally reported by the author in 1891.
  • 5.
  • 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. 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. Mechanism of the Biginelli Reaction
  • 9. Biginelli  pyrimidone synthesis is the 3 components formation of tetrahydropyrimidinones.
  • 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. Mechanism of the Biginelli Reaction
  • 12.  
  • 13.  
  • 14.  
  • 15. Mechanism of the Biginelli Reaction --The Atwal modification
  • 16. Mechanism of the Biginelli Reaction Biginelli Reaction
  • 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.
  • 18.  
  • 20. Examples of biologically active DHPMs
  • 21.  
  • 22.
  • 24. Reference:  J org chem 65 (20) 6777-6779 Oct 2000 Second example
  • 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.
  • 26. Third example Reference:  J org chem 67 (20) 6979 - 6994 Biginelli Reaction
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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
  • 40. Example in aq medium
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  • 49. [email_address] DR ANTHONY CRASTO chemistry sites https://sites.google.com/site/anthonycrastoorganicchemistry/sites---my-own-on-the-net
  • 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