Anthony crasto presentation of biginelli reaction

Anthony melvin crasto presentation of Biginelli reaction
[email protected]

1. Biginelli Reaction
•By Dr Anthony Melvin Crasto, Ph.D

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. Biginelli rxn
•Cyclocondensation of a beta-ketoester, urea
and an aldehyde using an acid catalyst.
•General Scheme &/or Mechanism

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

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.

19. Flourous reaction………

20. Examples of biologically active
DHPMs

22. BIGINELLI RXN
•Recent examples of the Biginelli include
the following:

23. First example

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

27. 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 N1-Alkyl-, N1-Aryl-, and N1,N3-Dialkyl-3,4-
Dihydropyrimidin-2(1H)-(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-Dihydro-pyrimidin-2-(1H)-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(1H)-ones
J. Lu, Y. Bai, Synthesis, 2002, 466-470.
Biginelli Reaction

34. SQ 3292634
Biginelli Reaction

35. Biginelli Reaction

36. Biginelli Reaction

37. ASSYMETRIC SYN….

38. Biginelli Reaction

39. Biginelli Reaction

40. Example in aq medium

46. Biginelli Reaction

47. Biginelli Reaction

48. References
•P. Biginelli, Ber. 24, 1317, 2962 (1891); 26, 447 (1893).
•H. E. Zaugg, W. B. Martin, Org. React. 14, 88 (1965);
•D. J. Brown, The Pyrimidines (Wiley, New York, 1962) p
440; ibid., Suppl. I, 1970, p 326,
•F. Sweet, Y. Fissekis, J. Am. Chem. Soc. 95, 8741 (1973).
•Synthetic applications: M. V. Fernandez et al., Heterocycles 27, 2133
(1988);
•K. Singh et al., Tetrahedron 55, 12873 (1999);
•A. S. Franklin et al., J. Org. Chem. 64, 1512 (1999).
•Modified conditions: C. O. Kappe et al., Synthesis 1999, 1799; J. Lu,
H. Ma.Synlett 2000, 63.
•Use of cycloalkanones as starting material: Y.-L. Zhu et al., Eur. J.
Org. Chem. 2005, 2354.

49. [email protected]
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

51. Thanks