Anthony crasto presentation of Biginelli reaction

Views:
 
     
 

Presentation Description

DR Anthony Crasto presentation of Biginelli Reaction

Comments

Presentation Transcript

Biginelli Reaction:

Biginelli Reaction By Dr Anthony Melvin Crasto, Ph.D

PowerPoint Presentation:

Pietro Biginelli: The Man Behind the Reaction

PowerPoint Presentation:

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).

PowerPoint Presentation:

The first Biginelli multicomponent reaction as originally reported by the author in 1891.

Biginelli rxn:

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

PowerPoint Presentation:

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.

PowerPoint Presentation:

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

PowerPoint Presentation:

Mechanism of the Biginelli Reaction

PowerPoint Presentation:

Biginelli pyrimidone synthesis is the 3 components formation of tetrahydropyrimidinones.

PowerPoint Presentation:

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 .

PowerPoint Presentation:

Mechanism of the Biginelli Reaction

PowerPoint Presentation:

Mechanism of the Biginelli Reaction --The Atwal modification

PowerPoint Presentation:

Mechanism of the Biginelli Reaction Biginelli Reaction

PowerPoint Presentation:

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………:

Flourous reaction………

PowerPoint Presentation:

Examples of biologically active DHPMs

BIGINELLI RXN:

BIGINELLI RXN Recent examples of the Biginelli include the following:

First example:

First example

PowerPoint Presentation:

Reference: J org chem 65 (20) 6777-6779 Oct 2000 Second example

PowerPoint Presentation:

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.

PowerPoint Presentation:

Third example Reference: J org chem 67 (20) 6979 - 6994 Biginelli Reaction

PowerPoint Presentation:

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

PowerPoint Presentation:

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

PowerPoint Presentation:

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

PowerPoint Presentation:

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

PowerPoint Presentation:

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:

SQ 3292634 Biginelli Reaction

PowerPoint Presentation:

Biginelli Reaction

PowerPoint Presentation:

Biginelli Reaction

ASSYMETRIC SYN….:

ASSYMETRIC SYN….

PowerPoint Presentation:

Biginelli Reaction

Biginelli Reaction:

Biginelli Reaction

PowerPoint Presentation:

Example in aq medium

PowerPoint Presentation:

Biginelli Reaction

PowerPoint Presentation:

Biginelli Reaction

References:

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.

amcrasto@gmail.com DR ANTHONY CRASTO chemistry sites https://sites.google.com/site/anthonycrastoorganicchemistry/sites---my-own-on-the-net:

amcrasto@gmail.com DR ANTHONY CRASTO chemistry sites https://sites.google.com/site/anthonycrastoorganicchemistry/sites---my-own-on-the-net

PowerPoint Presentation:

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

Thanks:

Thanks

authorStream Live Help