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Biginelli reaction

January 07, 2023

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.[5][6]

Biginelli reaction
Named after Pietro Biginelli
Reaction type Ring forming reaction
Identifiers
Organic Chemistry Portal biginelli-reaction
RSC ontology ID RXNO:0000236

This reaction was developed by Pietro Biginelli in 1891. The reaction can be catalyzed by Brønsted acids and/or by Lewis acids such as copper(II) trifluoroacetate hydrate[7] and boron trifluoride.[8] Several solid-phase protocols utilizing different linker combinations have been published.[9][10]

Dihydropyrimidinones, the products of the Biginelli reaction, are widely used in the pharmaceutical industry as calcium channel blockers,[11] antihypertensive agents, and alpha-1-a-antagonists.

More recently products of the Biginelli reaction have been investigated as potential selective Adenosine A2b receptor antagonists.[12] Including highly selective tricyclic compounds.[13]

Reaction mechanism

The reaction mechanism of the Biginelli reaction is a series of bimolecular reactions leading to the desired dihydropyrimidinone.[14]

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.[15]

 

This mechanism is superseded by one by Kappe in 1997:

 

This scheme begins with rate determining nucleophilic addition by the urea to the aldehyde.[16][17] 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.

Advances in Biginelli reaction

In 1987, Atwal et al.[18][19] reported a modification to the Biginelli reaction that consistently generated higher yields. Atul Kumar has reported first enzymatic synthesis for Biginelli reaction via yeast catalysed protocol in high yields.[20] The reaction has also been reported via green methodologies.[21]

References

  1. ^ Biginelli, P. (1891). "Ueber Aldehyduramide des Acetessigäthers". Chemische Berichte. 24: 1317–1319. doi:10.1002/cber.189102401228.
  2. ^ Biginelli, P. (1891). "Ueber Aldehyduramide des Acetessigäthers. II". Chemische Berichte. 24 (2): 2962–2967. doi:10.1002/cber.189102402126.
  3. ^ Zaugg, H. E.; Martin, W. B. (1965). "Α-Amidoalkylations at Carbon". Org. React. 14: 88. doi:10.1002/0471264180.or014.02. ISBN 0471264180.
  4. ^ Kappe, C. O. (1993). "100 years of the biginelli dihydropyrimidine synthesis". Tetrahedron. 49 (32): 6937–6963. doi:10.1016/S0040-4020(01)87971-0.
  5. ^ Kappe, C. Oliver (2005) "The Biginelli Reaction", in: J. Zhu and H. Bienaymé (eds.): Multicomponent Reactions, Wiley-VCH, Weinheim, ISBN 978-3-527-30806-4.
  6. ^ Kappe, C. O.; Stadler, A. (2004). "The Biginelli Dihydropyrimidine Synthesis". Organic Reactions. 63: 1–116. doi:10.1002/0471264180.or063.01. ISBN 0471264180.
  7. ^ Song, Dailei; Wang, Runxia; Chen, Yongli; Zhang, Shaohua; Liu, Chunsheng; Luo, Genxiang (2008). "Copper(II) trifluoroacetate catalyzed synthesis of 3,4- dihydropyrimidin-2(1H)-ones under solvent-free conditions". Reaction Kinetics and Catalysis Letters. 95 (2): 385. doi:10.1007/s11144-008-5379-2. S2CID 93287161.
  8. ^ Hu, E. H.; Sidler, D. R.; Dolling, U.-H. (1998). "Unprecedented Catalytic Three Component One-Pot Condensation Reaction: An Efficient Synthesis of 5-Alkoxycarbonyl- 4-aryl-3,4-dihydropyrimidin-2(1H)-ones". J. Org. Chem. 63 (10): 3454. doi:10.1021/jo970846u.
  9. ^ Wipf, P.; Cunningham, A. (1995). "A solid phase protocol of the biginelli dihydropyrimidine synthesis suitable for combinatorial chemistry". Tetrahedron Lett. 36 (43): 7819–7822. doi:10.1016/0040-4039(95)01660-A.
  10. ^ Kappe, C. O. (2000). "Highly versatile solid phase synthesis of biofunctional 4-aryl-3,4-dihydropyrimidines using resin-bound isothiourea building blocks and multidirectional resin cleavage". Bioorg. Med. Chem. Lett. 10 (1): 49–51. doi:10.1016/S0960-894X(99)00572-7. PMID 10636241.
  11. ^ 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. (1992). "Dihydropyrimidine calcium channel blockers. 4. Basic 3-substituted-4-aryl-1,4-dihydropyrimidine-5-carboxylic acid esters. Potent antihypertensive agents". J. Med. Chem. 35 (17): 3254–3263. doi:10.1021/jm00095a023. PMID 1387168.
  12. ^ Crespo, Abel; El Maatougui, Abdelaziz; Biagini, Pierfrancesco; Azuaje, Jhonny; Coelho, Alberto; Brea, José; Loza, María Isabel; Cadavid, María Isabel; García-Mera, Xerardo; Gutiérrez-de-Terán, Hugo; Sotelo, Eddy (2013-10-03). "Discovery of 3,4-Dihydropyrimidin-2(1H)-ones As a Novel Class of Potent and Selective A2B Adenosine Receptor Antagonists". ACS Medicinal Chemistry Letters. 4 (11): 1031–1036. doi:10.1021/ml400185v. ISSN 1948-5875. PMC 4027370. PMID 24900602.
  13. ^ El Maatougui, Abdelaziz; Azuaje, Jhonny; González-Gómez, Manuel; Miguez, Gabriel; Crespo, Abel; Carbajales, Carlos; Escalante, Luz; García-Mera, Xerardo; Gutiérrez-de-Terán, Hugo; Sotelo, Eddy (2016-03-10). "Discovery of Potent and Highly Selective A2B Adenosine Receptor Antagonist Chemotypes". Journal of Medicinal Chemistry. 59 (5): 1967–1983. doi:10.1021/acs.jmedchem.5b01586. ISSN 0022-2623. PMID 26824742.
  14. ^ Folkers, K.; Johnson, T. B. (1933). "Researches on Pyrimidines. CXXXVI. The Mechanism of Formation of Tetrahydropyrimidines by the Biginelli Reaction1". J. Am. Chem. Soc. 55 (9): 3784–3791. doi:10.1021/ja01336a054.
  15. ^ Sweet, F.; Fissekis, J. D. (1973). "Synthesis of 3,4-dihydro-2(1H)-pyrimidinones and the mechanism of the Biginelli reaction". J. Am. Chem. Soc. 95 (26): 8741–8749. doi:10.1021/ja00807a040.
  16. ^ Folkers, K.; Harwood, H. J.; Johnson, T. B. (1932). "Researches on Pyrimidines. Cxxx. Synthesis of 2-Keto-1,2,3,4-Tetrahydropyrimidines". J. Am. Chem. Soc. 54 (9): 3751–3758. doi:10.1021/ja01348a040.
  17. ^ Kappe, C.O. (1997). "A Reexamination of the Mechanism of the Biginelli Dihydropyrimidine Synthesis. Support for anN-Acyliminium Ion Intermediate1". J. Org. Chem. 62 (21): 7201–7204. doi:10.1021/jo971010u. PMID 11671828.
  18. ^ O'Reilly, B. C.; Atwal, K. S. (1987). "Synthesis of Substituted 1,2,3,4-Tetrahydro-6-methyl-2-oxo-5-pyrimidinecarboxylic Acid Esters: The Biginelli Condensation Revisited". Heterocycles. 26 (5): 1185–1188. doi:10.3987/R-1987-05-1185.
  19. ^ O'Reilly, B. C.; Atwal, K. S. (1987). "Synthesis of Substituted 1,2,3,4-Tetrahydro-6-methyl-2-thioxo-5-pyrimidinecarboxylic Acid Esters". Heterocycles. 26 (5): 1189–1192. doi:10.3987/R-1987-05-1189.
  20. ^ Kumar, Atul; Maurya, Ram Awatar (2007). "An efficient bakers' yeast catalyzed synthesis of 3,4-dihydropyrimidin-2-(1H)-ones". Tetrahedron Letters. 48 (26): 4569. doi:10.1016/j.tetlet.2007.04.130.
  21. ^ Panda, S.S.; Khanna, P.; Khanna, L. (2012). "Biginelli Reaction: A Green Perspective". Curr. Org. Chem. 16 (4): 507–520. doi:10.2174/138527212799499859.

January 07, 2023
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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 5 6 Biginelli reactionNamed after Pietro BiginelliReaction type Ring forming reactionIdentifiersOrganic Chemistry Portal biginelli reactionRSC ontology ID RXNO 0000236 This reaction was developed by Pietro Biginelli in 1891 The reaction can be catalyzed by Bronsted acids and or by Lewis acids such as copper II trifluoroacetate hydrate 7 and boron trifluoride 8 Several solid phase protocols utilizing different linker combinations have been published 9 10 Dihydropyrimidinones the products of the Biginelli reaction are widely used in the pharmaceutical industry as calcium channel blockers 11 antihypertensive agents and alpha 1 a antagonists More recently products of the Biginelli reaction have been investigated as potential selective Adenosine A2b receptor antagonists 12 Including highly selective tricyclic compounds 13 Reaction mechanism EditThe reaction mechanism of the Biginelli reaction is a series of bimolecular reactions leading to the desired dihydropyrimidinone 14 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 15 This mechanism is superseded by one by Kappe in 1997 This scheme begins with rate determining nucleophilic addition by the urea to the aldehyde 16 17 The ensuing condensation step is catalyzed by the addition of acid resulting in the imine nitrogen The b 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 Advances in Biginelli reaction EditIn 1987 Atwal et al 18 19 reported a modification to the Biginelli reaction that consistently generated higher yields Atul Kumar has reported first enzymatic synthesis for Biginelli reaction via yeast catalysed protocol in high yields 20 The reaction has also been reported via green methodologies 21 References Edit Biginelli P 1891 Ueber Aldehyduramide des Acetessigathers Chemische Berichte 24 1317 1319 doi 10 1002 cber 189102401228 Biginelli P 1891 Ueber Aldehyduramide des Acetessigathers II Chemische Berichte 24 2 2962 2967 doi 10 1002 cber 189102402126 Zaugg H E Martin W B 1965 A Amidoalkylations at Carbon Org React 14 88 doi 10 1002 0471264180 or014 02 ISBN 0471264180 Kappe C O 1993 100 years of the biginelli dihydropyrimidine synthesis Tetrahedron 49 32 6937 6963 doi 10 1016 S0040 4020 01 87971 0 Kappe C Oliver 2005 The Biginelli Reaction in J Zhu and H Bienayme eds Multicomponent Reactions Wiley VCH Weinheim ISBN 978 3 527 30806 4 Kappe C O Stadler A 2004 The Biginelli Dihydropyrimidine Synthesis Organic Reactions 63 1 116 doi 10 1002 0471264180 or063 01 ISBN 0471264180 Song Dailei Wang Runxia Chen Yongli Zhang Shaohua Liu Chunsheng Luo Genxiang 2008 Copper II trifluoroacetate catalyzed synthesis of 3 4 dihydropyrimidin 2 1H ones under solvent free conditions Reaction Kinetics and Catalysis Letters 95 2 385 doi 10 1007 s11144 008 5379 2 S2CID 93287161 Hu E H Sidler D R Dolling U H 1998 Unprecedented Catalytic Three Component One Pot Condensation Reaction An Efficient Synthesis of 5 Alkoxycarbonyl 4 aryl 3 4 dihydropyrimidin 2 1H ones J Org Chem 63 10 3454 doi 10 1021 jo970846u Wipf P Cunningham A 1995 A solid phase protocol of the biginelli dihydropyrimidine synthesis suitable for combinatorial chemistry Tetrahedron Lett 36 43 7819 7822 doi 10 1016 0040 4039 95 01660 A Kappe C O 2000 Highly versatile solid phase synthesis of biofunctional 4 aryl 3 4 dihydropyrimidines using resin bound isothiourea building blocks and multidirectional resin cleavage Bioorg Med Chem Lett 10 1 49 51 doi 10 1016 S0960 894X 99 00572 7 PMID 10636241 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 1992 Dihydropyrimidine calcium channel blockers 4 Basic 3 substituted 4 aryl 1 4 dihydropyrimidine 5 carboxylic acid esters Potent antihypertensive agents J Med Chem 35 17 3254 3263 doi 10 1021 jm00095a023 PMID 1387168 Crespo Abel El Maatougui Abdelaziz Biagini Pierfrancesco Azuaje Jhonny Coelho Alberto Brea Jose Loza Maria Isabel Cadavid Maria Isabel Garcia Mera Xerardo Gutierrez de Teran Hugo Sotelo Eddy 2013 10 03 Discovery of 3 4 Dihydropyrimidin 2 1H ones As a Novel Class of Potent and Selective A2B Adenosine Receptor Antagonists ACS Medicinal Chemistry Letters 4 11 1031 1036 doi 10 1021 ml400185v ISSN 1948 5875 PMC 4027370 PMID 24900602 El Maatougui Abdelaziz Azuaje Jhonny Gonzalez Gomez Manuel Miguez Gabriel Crespo Abel Carbajales Carlos Escalante Luz Garcia Mera Xerardo Gutierrez de Teran Hugo Sotelo Eddy 2016 03 10 Discovery of Potent and Highly Selective A2B Adenosine Receptor Antagonist Chemotypes Journal of Medicinal Chemistry 59 5 1967 1983 doi 10 1021 acs jmedchem 5b01586 ISSN 0022 2623 PMID 26824742 Folkers K Johnson T B 1933 Researches on Pyrimidines CXXXVI The Mechanism of Formation of Tetrahydropyrimidines by the Biginelli Reaction1 J Am Chem Soc 55 9 3784 3791 doi 10 1021 ja01336a054 Sweet F Fissekis J D 1973 Synthesis of 3 4 dihydro 2 1H pyrimidinones and the mechanism of the Biginelli reaction J Am Chem Soc 95 26 8741 8749 doi 10 1021 ja00807a040 Folkers K Harwood H J Johnson T B 1932 Researches on Pyrimidines Cxxx Synthesis of 2 Keto 1 2 3 4 Tetrahydropyrimidines J Am Chem Soc 54 9 3751 3758 doi 10 1021 ja01348a040 Kappe C O 1997 A Reexamination of the Mechanism of the Biginelli Dihydropyrimidine Synthesis Support for anN Acyliminium Ion Intermediate1 J Org Chem 62 21 7201 7204 doi 10 1021 jo971010u PMID 11671828 O Reilly B C Atwal K S 1987 Synthesis of Substituted 1 2 3 4 Tetrahydro 6 methyl 2 oxo 5 pyrimidinecarboxylic Acid Esters The Biginelli Condensation Revisited Heterocycles 26 5 1185 1188 doi 10 3987 R 1987 05 1185 O Reilly B C Atwal K S 1987 Synthesis of Substituted 1 2 3 4 Tetrahydro 6 methyl 2 thioxo 5 pyrimidinecarboxylic Acid Esters Heterocycles 26 5 1189 1192 doi 10 3987 R 1987 05 1189 Kumar Atul Maurya Ram Awatar 2007 An efficient bakers yeast catalyzed synthesis of 3 4 dihydropyrimidin 2 1H ones Tetrahedron Letters 48 26 4569 doi 10 1016 j tetlet 2007 04 130 Panda S S Khanna P Khanna L 2012 Biginelli Reaction A Green Perspective Curr Org Chem 16 4 507 520 doi 10 2174 138527212799499859 Retrieved from https en wikipedia org w index php title Biginelli reaction amp oldid 1097156071, wikipedia, wiki, book, books, library,

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