Multicomponent Reactions in the Last 30 Years: How are we Today?

Lima, Henrique B. de; Neves, Gustavo M. das; Gonçalves, Itamar L.; Merlo, Aloir A.; Eifler-Lima, Vera L.

doi:10.21577/0103-5053.20240075

Henrique B. de Lima

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Henrique Barros holds a bachelor’s degree in Pharmaceutical Sciences from the Federal University of Amapá (UNIFAP). He was a Technology and Innovation scholarship holder (2020-2021) and a CNPq-funded scholarship holder through the Institutional Scientific Initiation Scholarship Program (2021-2022) at the Pharmaceutical and Medicinal Chemistry Laboratory (PharMedChem). He enrolled in a Master’s program (2023) in the Pharmaceutical Sciences Graduate Program at the Universidade Federal do Rio Grande do Sul (UFRGS), where he is currently designing prototypes of antiproliferative drugs at the Medicinal Organic Synthesis Laboratory (LaSOM).

Laboratório de Síntese Orgânica Medicinal (LaSOM®), Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Universidade Federal do Rio Grande do Sul (UFRGS), 90610-000 Porto Alegre-RS, Brazil

https://orcid.org/0000-0002-8973-4902

Gustavo M. das Neves

conceptualization

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Gustavo M. das Neves is Bachelor in Biomedicine from UFCSPA in 2009 and in Pharmacy from UFRGS in 2015. He completed his master’s and PhD in Pharmaceutical Sciences at UFRGS in 2022. He has experience in Medicinal Chemistry with emphasis on computer-aided drug design and drug repositioning using molecular modelling techniques and virtual screening, such as: molecular docking, derivation of pharmacophoric patterns and QSAR. Currently he is a post-doctoral researcher at Medicinal Organic Synthesis Laboratory (LaSOM) supervised by Professor Vera Lucia Eifler-Lima.

Laboratório de Síntese Orgânica Medicinal (LaSOM®), Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Universidade Federal do Rio Grande do Sul (UFRGS), 90610-000 Porto Alegre-RS, Brazil

https://orcid.org/0000-0002-2935-9944

Itamar L. Gonçalves

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Itamar L. Gonçalves earned his Bachelor’s degree in Pharmacy from URI-Erechim in 2015, and later completed his master’s and PhD degrees in Pharmaceutical Sciences (2020) with emphasis on Medicinal Chemistry from the Federal University of Rio Grande do Sul, Brazil. His research is focused on the synthesis of small molecules targeting the cellular proliferation and with application in liquid crystals. In addition, he has developed studies involving the use of planarian (Girardia tigrina) in pharmacological and toxicological assays and investigations involving the chemical and biological properties of yerba-mate extracts. Currently, he acts as a professor in the Pharmacy, Medicine, Biomedicine, and Nutrition courses at URI-Erechim.

Departamento de Ciências da Saúde, Universidade Regional Integrada do Alto Uruguai e das Missões (URI), 99709-910 Erechim-RS, Brazil

https://orcid.org/0000-0001-5952-6291

Aloir A. Merlo

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Aloir A. Merlo is a full professor at Institute of Chemistry, UFRGS, Brazil. He graduated at UFSC in 1993 (Professor Gallardo) and obtained post-doctorate in 2012 at Hull University (Professor Kelly). Teaching activities started very early (1983) and, since 1995, he has been working at the Chemistry Institute. He has been honored with Teaching Awards nine times. Prof Merlo is the author or coauthor of over 70 scientific papers, reviews, books and book chapters. His current research is focused on liquid crystals (LCs) with special emphasis on synthesis of isoxazoline and isoxazole, which has been extensively studied since 2005.

Laboratório de Síntese Orgânica e Materiais Inteligentes (LaSOMI), Instituto de Química, Universidade Federal do Rio Grande do Sul (UFRGS), 91501-970 Porto Alegre-RS, Brazil

https://orcid.org/0000-0002-8071-5297

Vera L. Eifler-Lima ^**e-mail: veraeifler@ufrgs.br

conceptualization

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researcher leader

Vera L. Eifler-Lima studied Pharmacy and got a Master’s degree at UFRGS, and PhD at École Nationale Supérieure de Chimie, Univ. Rennes, under the supervision of Jean Huet and Philippe Uriac. She is Full Professor at FacFar/UFRGS, coordinates projects in Medicinal Chemistry (emphasis in Organic Synthesis), and advises students in pharmacy, chemistry, biomedicine or related areas. Head of the Medicinal Organic Synthesis Laboratory (LaSOM®), Dr Eifler-Lima participated as speaker at the V EVQFM (SPOS: tool for the rational drug design), VI EVQFM (Principles of Combinatorial Chemistry and SPOS) and XXIII EVQFM (Biginelli: a reaction from 1891).

Laboratório de Síntese Orgânica Medicinal (LaSOM®), Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Universidade Federal do Rio Grande do Sul (UFRGS), 90610-000 Porto Alegre-RS, Brazil

https://orcid.org/0000-0002-7656-9477

*e-mail: veraeifler@ufrgs.br

Editor handled this article: Brenno A. D. Neto

This review is part of the special edition of JBCS dedicated to Professor Eliezer Barreiro, founder of the Summer School in Pharmaceutical and Medicinal Chemistry.

Database	Keywords^a a Search by filter Brazil.	Number of publications
PubMed/Scopus/ Web of Science	Reaction AND Biginelli	96
	Reaction AND Hantzsch	43
	Reaction AND Mannich	100
	Reaction AND Passerini	19
	Reaction AND Strecker	11
	Reaction AND Ugi	53
Total		243

Synthesized compound	Number of compounds	Reaction	Biological activities method	Best result	Reference
Ugi and Passerini reaction
4-Aminoquinoline γand δ-lactam	16	Ugi-4C-3CR	enzymatic; cell: P. falciparum T. brucei	compound 1: enzyme: IC₅₀ = 17.62 µM P. falciparum: IC₅₀ = 0.096 µM; compound 2: T. brucei: ED₅₀ = 1.44 µM	⁴⁵45 Musonda, C. C.; Gut, J.; Rosenthal, P. J.; Yardley, V.; de Souza, R. C. C.; Chibale, K.; Bioorg. Med. Chem. 2006, 14, 5605. [Crossref] Crossref...
Bestatin’s derivative	24	Ugi-4CR and Ugi-5C-4CR	enzymatic; cell: P. falciparum	compound 4: enzyme: K_i = 0.4 µM IC₅₀ in cells: Pf3D7 = 18 µM PfFcB1 = 16 µM	⁴⁶46 González-Bacerio, J.; Maluf, S. E. C.; Méndez, Y.; Pascual, I.; Florent, I.; Melo, P. M. S.; Budu, A.; Ferreira, J. C.; Moreno, E.; Carmona, A. K.; Rivera, D. G.; del Rivero, M. A.; Gazarini, M. L.; Bioorg. Med. Chem. 2017, 25, 4628. [Crossref] Crossref...
Isomannide derivative	10	Ugi-4CR	enzymatic	compound 5: IC₅₀ = 4.0 µM (competitive inhibitor) compound 6: IC₅₀ = 12.6 µM	⁴⁷47 Barros, T. G.; Santos, J. A. N.; de Souza, B. E. G.; Sodero, A. C. R.; de Souza, A. M. T.; da Silva, D. P.; Rodrigues, C. R.; Pinheiro, S.; Dias, L. R. S.; Abrahim-Vieira, B.; Puzer, L.; Muri, E. M. F.; Bioorg. Med. Chem. Lett. 2017, 27, 314. [Crossref] Crossref...
Peptoid	13	Ugi-4CR	cell: L. amazonensis promastigotes	compound 7: IC₅₀ = 2.80 µM compound 8: IC₅₀ = 2.61 µM compound 9: IC₅₀ = 7.90 µM	⁴⁸48 Previdi, D.; Rodrigues, S.; Coelho, M. G.; Candido, A. C. B. B.; Magalhães, L. G.; Donate, P. M.; J. Braz. Chem. Soc. 2019, 30, 1334. [Crossref] Crossref...
Epoxy-α‑acyloxycarboxamide	17	Passerini	enzymatic	compound 10: IC₅₀ = 1.33 µM	⁴⁹49 dos Santos, D. A.; Deobald, A. M.; Cornelio, V. E.; Ávila, R. M. D.; Cornea, R. C.; Bernasconi, G. C. R.; Paixão, M. W.; Vieira, P. C.; Corrêa, A. G.; Bioorg. Med. Chem. 2017, 25, 4620. [Crossref] Crossref...
Epoxy-α‑acyloxycarboxamide	5	Passerini + Ugi-4CR	enzymatic	compound 11: K_i = 5.45 µM compound 12: K_i = 9.57 µM	⁵⁰50 Silva, T. L.; dos Santos, D. A.; de Jesus, H. C. R.; Brömme, D.; Fernandes, J. B.; Paixão, M. W.; Corrêa, A. G.; Vieira, P. C.; Bioorg. Med. Chem. 2020, 28, 115597. [Crossref] Crossref...
Biginelli reaction
DHPM	8	Biginelli	in vitro antioxidant capacity	compounds 13, 14 and 15: best results	⁵¹51 Stefani, H. A.; Oliveira, C. B.; Almeida, R. B.; Pereira, C. M. P.; Braga, R. C.; Cella, R.; Borges, V. C.; Savegnago, L.; Nogueira, C. W.; Eur. J. Med. Chem. 2006, 41, 513. [Crossref] Crossref...
DHPM	26	Biginelli	in vitro antioxidant capacity; cell: cytotoxicity in seven cancer cell lines	compounds 16-19: best antioxidant capacity; compound 20 all cancer cells: GI₅₀ < 32.64 µM	⁵²52 da Silva, D. L.; Fernandes, S. A.; Sabino, A. A.; de Fátima, Â.; Tetrahedron Lett. 2011, 52, 6328. [Crossref] Crossref...
DHPM	14	Biginelli	cell: cytotoxicity in seven cancer cell lines	compound 21: IC₅₀ = 5.93-20.60 µM	⁵³53 Russowsky, D.; Canto, R. F. S.; Sanches, S. A. A.; D’Oca, M. G. M.; de Fátima, Â.; Pilli, R. A.; Kohn, L. K.; Antônio, M. A.; de Carvalho, J. E.; Bioorg. Chem. 2006, 34, 173. [Crossref] Crossref...
DHPM	14	Biginelli	cell: cytotoxicity in C6	compounds 22-25: highest activities	⁵⁴54 Canto, R. F. S.; Bernardi, A.; Battastini, A. M. O.; Russowsky, D.; Eifler-Lima, V. L.; J. Braz. Chem. Soc. 2011, 22, 1379. [Crossref] Crossref...
N1-Aryl-substituted DHPM	22	Biginelli	cell: cytotoxicity in C6 and U138; in vivo toxicity: C. elegans	compounds 26 and 27: IC₅₀ = 54.7-142.7 µM; C. elegans: LC₅₀ = 29.80-32.90 µM	⁵⁵55 Gonçalves, I. L.; Rockenbach, L.; das Neves, G. M.; Göethel, G.; Nascimento, F.; Kagami, L. P.; Figueiró, F.; de Azambuja, G. O.; Dias, A. F.; Amaro, A.; de Souza, L. M.; Pitta, I. R.; Avila, D. S.; Kawano, D. F.; Garcia, S. C.; Battastini, A. M. O.; Eifler-Lima, V. L.; MedChemComm 2018, 9, 995. [Crossref] Crossref...
N1-Aryl-substituted DHPM	1	Biginelli	cell: cytotoxicity in T24 in vivo toxicity: C. elegans	compound 28: IC₅₀ = 10.73 µM; C. elegans: decrease of multivulvas number; C. elegans: LC₅₀ > 600 µM	¹⁸18 Kagami, L. P.; Gonçalves, I. L.; da Silva, Á. C.; Silva, A. C.; das Neves, G. M.; Göethel, G.; Spillere, A.; dos Santos, M. R.; Figueiró, F.; Garcia, S. C.; Ávila, D. S.; Battastini, A. M. O.; Eifler-Lima, V. L.; Chem. Biol. Drug Des. 2023, 102, 536. [Crossref] Crossref...
DHPM	10	batch continuous flow Biginelli	cell: cytotoxicity in three cancer cell lines	compounds 29-31: induced death > 50% in 72 h treatment	⁵⁶56 Silva, G. C. O.; Correa, J. R.; Rodrigues, M. O.; Alvim, H. G. O.; Guido, B. C.; Gatto, C. C.; Wanderley, K. A.; Fioramonte, M.; Gozzo, F. C.; de Souza, R. O. M. A.; Neto, B. A. D.; RSC Adv. 2015, 5, 48506. [Crossref] Crossref...
DHPM-fatty acid hybrid (substitution site: C5)	18	Biginelli	cell: cytotoxicity in C6 in 24 h treatment	compound 32 reduced cell viability: 50%	⁵⁷57 Treptow, T. G. M.; Figueiró, F.; Jandrey, E. H. F.; Battastini, A. M. O.; Salbego, C. G.; Hoppe, J. B.; Taborda, P. S.; Rosa, S. B.; Piovesan, L. A.; D’Oca, C. R. M.; Russowsky, D.; D’Oca, M. G. M.; Eur. J. Med. Chem. 2015, 95, 552. [Crossref] Crossref...
DHPM-fatty acid hybrid (substitution site: C6)	6	Biginelli	cell: cytotoxicity in C6 in 48 h treatment	compound 33: IC₅₀ = 5.11 µM; compound 34: C6: IC₅₀ = 5.11 µM	⁵⁸58 de Oliveira, F. S.; de Oliveira, P. M.; Farias, L. M.; Brinkerhoff, R. C.; Sobrinho, R. C. M. A.; Treptow, T. M.; D’Oca, C. R. M.; Marinho, M. A. G.; Hort, M. A.; Horn, A. P.; Russowsky, D.; D’Oca, M. G. M.; MedChemComm 2018, 9, 1282. [Crossref] Crossref...
DHPM-benzazol hybrid	6	Biginelli	cell: cytotoxicity in three cancer cell lines	compounds 35 and 36: IC₅₀ < 40 µM; compound 37: IC₅₀ = 10.7-158.7 µM	⁵⁹59 de Souza, V. P.; Santos, F. S.; Rodembusch, F. S.; Braga, C. B.; Ornelas, C.; Pilli, R. A.; Russowsky, D.; New J. Chem. 2020, 44, 12440. [Crossref] Crossref...
DHPM-cinnamic acids hybrid	6	Biginelli	cell: cytotoxicity in two prostate cancer cell lines	compound 38: IC₅₀ = 11.5-51.7 µM; compounds 39 and 40: best activity against prostate cancer cell lines	⁶⁰60 Barbosa, F. A. R.; Rode, M. P.; Canto, R. F. S.; Silva, A. H.; Creczynski-Pasa, T. B.; Braga, A. L.; ChemistrySelect 2022, 7, e202200274. [Crossref] Crossref...
DHPM	37	ionic liquid catalyzed Biginelli	cell: cytotoxicity	the compounds displayed promising cytotoxic profile	⁶¹61 Ramos, L. M.; Guido, B. C.; Nobrega, C. C.; Corrêa, J. R.; Silva, R. G.; de Oliveira, H. C. B.; Gomes, A. F.; Gozzo, F. C.; Neto, B. A. D.; Chem. - Eur. J. 2013, 19, 4156. [Crossref] Crossref...
DHPM	26	ionic liquid catalyzed Biginelli	enzymatic	compound 41: K_i = 0.96 µM; compound 42: K_i = 0.57 µM	⁶²62 Braga, T. C.; Silva, T. F.; Maciel, T. M. S.; da Silva, E. C. D.; da Silva-Júnior, E. F.; Modolo, L. V.; Figueiredo, I. M.; Santos, J. C. C.; de Aquino, T. M.; de Fátima, A.; New J. Chem. 2019, 43, 15187. [Crossref] Crossref...
DHPM and pyrrolopyrimidinones hybrid	30	Biginelli	cell: chloroquine resistant P. falciparum; cytotoxicity; in vivo: P. berghei parasitemia reduction in rats	compound 43: IC₅₀ = 2.98 µM; compound 44: IC₅₀ = 1.76 µM; compound 45: IC₅₀ = 3.12 µM; compounds 43-45: reduce parasitemia in 33-60% (rats)	⁶³63 Rogerio, K. R.; Carvalho, L. J. M.; Domingues, L. H. P.; Neves, B. J.; Moreira Filho, J. T.; Castro, R. N.; Bianco Júnior, C.; Daniel-Ribeiro, C. T.; Andrade, C. H.; Graebin, C. S.; Mem. Inst. Oswaldo Cruz 2018, 113, e170452. [Crossref] Crossref...
DHPM-quinone hybrid	19	Biginelli	cell: chloroquine resistant P. falciparum	compound 46: IC₅₀ = 1.15 µM compound 47: IC₅₀ = 1.5 µM	⁶⁴64 Rogerio, K. R.; Graebin, C. S.; Domingues, L. H. P.; Oliveira, L. S.; da Silva, V. S. F.; Daniel-Ribeiro, C. T.; Carvalho, L. J. M.; Boechat, N.; Curr. Top. Med. Chem. 2020, 20, 99. [Crossref] Crossref...
Hantzsch reaction
1,4-DHP	14	Hantzsch	in vitro antioxidant capacity cell: cytotoxicity in seven cancer cell lines	compound 48: SC₅₀ = 30.4-217.5 µM compound 49: SC₅₀ = 31.5-181.8 µM	⁶⁵65 Pacheco, S. R.; Braga, T. C.; da Silva, D. L.; Horta, L. P.; Reis, F. S.; Ruiz, A. L. T. G.; de Carvalho, J. E.; Modolo, L. V.; de Fatima, A.; Med. Chem. 2013, 9, 889. [Crossref] Crossref...
1,4-DHP and one 1,3-oxazin-6-one	8	Hantzsch	cell: cytotoxicity in nine cancer cell lines	compound 51: IC₅₀ = 4.63 µM compound 52: IC₅₀ = 4.10 µM	⁶⁶66 Sandjo, L. P.; Kuete, V.; Nana, F.; Kirsch, G.; Efferth, T.; Helv. Chim. Acta 2016, 99, 310. [Crossref] Crossref...
PHQ-fatty acids hybrid	15	Hantzsch-4C	cell: cytotoxicity in C6	compound 53: reduced viability in 40%	⁶⁷67 Cabrera, D. C.; Rosa, S. B.; de Oliveira, F. S.; Marinho, M. A. G.; D’Oca, C. R. M.; Russowsky, D.; Horn, A. P.; D’Oca, M. G. M.; MedChemComm 2016, 7, 2167. [Crossref] Crossref...
Symmetrical and unsymmetrical 1,4-DHP	42	Hantzsch	in vitro antioxidant capacity	compounds 54-56: best activities	⁶⁸68 Cabrera, D. C.; Santa-Helena, E.; Leal, H. P.; de Moura, R. R.; Nery, L. E. M.; Gonçalves, C. A. N.; Russowsky, D.; D’Oca, M. G. M.; Bioorg. Chem. 2019, 84, 1. [Crossref] Crossref...
PHQ-fatty acids hybrid	18	Hantzsch-4C	in vitro antioxidant capacity	compound 57: EC₅₀ = 2.11-4.69 µM	⁶⁹69 Brinkerhoff, R. C.; Santa-Helena, E.; do Amaral, P. C.; Cabrera, D. C.; Ongaratto, R. F.; de Oliveira, P. M.; D’Oca, C. R. M.; Gonçalves, C. A. N.; Nery, L. E. M.; D’Oca, M. G. M.; RSC Adv. 2019, 9, 24688. [Crossref] Crossref...
Hydroquinoline-1,4‑DHPs hybrid	10	microwave assisted modified Hantzsch	photochemistry in vitro: BSA binding	photochemistry: absorption maxima region ca. 350 nm BSA binding: strong interaction	⁷⁰70 da Luz, L. C.; Gündüz, M. G.; Beal, R.; Zanotto, G. M.; Kuhn, E. R.; Netz, P. A.; Şafak, C.; Gonçalves, P. F. B.; Santos, F. S.; Rodembusch, F. S.; J. Photochem. Photobiol., A 2022, 429, 113915. [Crossref] Crossref... ,⁷¹71 Gündüz, M. G.; Albayrak, E.; İşli, F.; Fincan, G. S. Ö.; Yildirim, Ş.; Şimşek, R.; Şafak, C.; Sarioğlu, Y.; Yidirim, S. Ö.; Butcher, R. J.; J. Serb. Chem. Soc. 2016, 81, 729. [Crossref] Crossref...
1,4-DHP	5	Hantzsch	photosystem II fluorescence bioassay	best compounds: 60 and 61 (reduced fluorescence parameters)	72

Condition	Representative molecules	Reference
Biginelli reaction
InBr₃, ethanol, reflux, 7 h	oxo and thio DHPMs	⁴⁴44 Fu, N.-Y.; Yuan, Y.-F.; Cao, Z.; Wang, S.-W.; Wang, J.-T.; Peppe, C.; Tetrahedron 2002, 58, 4801. [Crossref] Crossref...
InBr₃ and InCl₃, ethanol, reflux	oxo and thio DHPMs with ferrocenyl at 4 and 5 positions	¹⁰⁷107 Fu, N.-Y.; Yuan, Y.-F.; Pang, M.-L.; Wang, J.-T.; Peppe, C.; J. Organomet. Chem. 2003, 672, 52. [Crossref] Crossref...
InBr₃, THF, reflux	oxo and thio trichloromethylated tetrahydropyrimidinones	¹¹⁵115 Martins, M. A. P.; Teixeira, M. V. M.; Cunico, W.; Scapin, E.; Mayer, R.; Pereira, C. M. P.; Zanatta, N.; Bonacorso, H. G.; Peppe, C.; Yuan, Y.-F.; Tetrahedron Lett. 2004, 45, 8991. [Crossref] Crossref...
SnCl₂.2H₂O, ethanol and acetonitrile reflux	oxo and thio DHPMs with aromatic aldehydes	¹¹⁶116 Russowsky, D.; Lopes, F. A.; da Silva, V. S. S.; Canto, K. F. S.; D’Oca, M. G. M.; Godoi, M. N.; J. Braz. Chem. Soc. 2004, 15, 165. [Crossref] Crossref...
In(OTf)₃, acetonitrile, reflux	oxo and thio DHPMs with aromatic aldehydes	¹¹⁷117 Godoi, M. N.; Costenaro, H. S.; Kramer, E.; Machado, P. S.; D’Oca, M. G. M.; Russowsky, D.; Quim. Nova 2005, 28, 1010. [Crossref] Crossref...
Cu/silica xerogel composite, etanol, acetonitrile, THF and toluene	oxo DHPMs with aromatic aldehydes	¹¹⁸118 Russowsky, D.; Benvenutti, E. V.; Roxo, G. S.; Grasel, F.; Lett. Org. Chem. 2007, 4, 39. [Crossref] Crossref...
Tetrabutylammonium bromide or ammonium bromide, solvent free 100 ºC	oxo and thio DHPMs with aromatic aldehydes	¹¹⁹119 de Souza, A. L. F.; de Oliveira, M. R. P.; da Silva, E. T.; Fernandeza, T. L.; Antunesa, O. A. C.; Heterocycl. Commun. 2008, 14, 357. [Crossref] Crossref...
p-Sulfonic acid calixarenes organocatalyst, ethanol, reflux	oxo and thio DHPMs with aliphatic and aromatic aldehydes	⁵²52 da Silva, D. L.; Fernandes, S. A.; Sabino, A. A.; de Fátima, Â.; Tetrahedron Lett. 2011, 52, 6328. [Crossref] Crossref...
β-Cyclodextrin, free-solvent, 100 ºC	oxo and thio DHPMs with aliphatic and aromatic aldehydes	¹²⁰120 Liberto, N. A.; Silva, S. P.; de Fátima, Â.; Fernandes, S. A.; Tetrahedron 2013, 69, 8245. [Crossref] Crossref...
Mono or dicarboxylic acids, ethanol, reflux	oxo and thio DHPMs with aromatic aldehydes	¹²¹121 Noreen, S.; Perveen, S.; Khan, M. N.; Nazeer, A.; Khan, M. A.; Munawar, M. A.; Babar, R.; Suhail, F.; Azad, M.; Bernardino, A. M. R.; dos Santos, M. S.; Asian J. Biochem. 2013, 25, 4770. [Crossref] Crossref...
Metal-containing ionic liquids or zeolite β and H₃PW₁₂O₄₀ supported on zeolite β	oxo and thio DHPMs with several aldehydes and hydrogen methylene active compounds	¹⁰²102 Alvim, H. G. O.; de Lima, T. B.; de Oliveira, H. C. B.; Gozzo, F. C.; de Macedo, J. L.; Abdenur, P. V; Silva, W. A.; Neto, B. A. D.; ACS Catal. 2013, 3, 1420. [Crossref] Crossref...
Niobium nanocatalyst (Fe₃O₄@Nb₂O), ethanol, 80 ºC	oxo and thio DHPMs with aromatic and aliphatic aldehydes	¹⁰⁴104 Lima, C. G. S.; Silva, S.; Gonçalves, R. H.; Leite, E. R.; Schwab, R. S.; Corrêa, A. G.; Paixão, M. W.; ChemCatChem 2014, 6, 3455. [Crossref] Crossref...
FeCl₃ and CuCl₂; HCl and CF₃COOH	protocols applied to the monastrol synthesis	¹²²122 Alvim, H. G. O.; Correa, J. R.; Machado, T. R.; Silva, W. A.; Neto, B. A. D.; Quim. Nova 2014, 37, 1713. [Crossref] Crossref...
N-alkylated sulfamic acid, methanol, reflux	oxo and thio DHPMs, with aromatic aldehydes and a long alkyl chain at C5 position	¹⁴14 Hack, C. R. L.; Porciuncula, L.; Weber, A. C. H.; D’Oca, C. R. M.; Russowsky, D.; Moura, J. M.; Pinto, L. A. A.; D’Oca, M. G. M.; J. Braz. Chem. Soc. 2018, 29, 2342. [Crossref] Crossref...
Preyssler heteropoly acid in silica matrix, solvent-free, 80 ºC	oxo DHPMs using aldehydes derivates from furfuraldehyde	¹²³123 Portilla-Zuñiga, O. M.; Sathicq, Á. G.; Martínez, J. J.; Fernandes, S. A.; Rezende, T. R. M.; Romanelli, G. P.; Sustainable Chem. Pharm. 2018, 10, 50. [Crossref] Crossref...
Silica functionalized with p-sulfonic acid calix[4]arene, microwave, 90 ºC	oxo DHPMs using aromatic and aliphatic aldehydes	¹²⁴124 Zacchi, C. H. C.; Vieira, S. S.; Ardisson, J. D.; Araujo, M. H.; de Fátima, Â.; J. Saudi Chem. Soc. 2019, 23, 1060. [Crossref] Crossref...
NbCl₅ in a liquid ionic, 100 ºC	the Biginelli reaction is performed utilizing benzaldehyde, ethyl acetoacetate and urea	¹⁰³103 Santos, M. C.; Uemi, M.; Gonçalves, N. S.; Bizeto, M. A.; Camilo, F. F.; J. Mol. Struct. 2020, 1220, 128653. [Crossref] Crossref...
[Cu(isonicotinate ion)₂(H₂O)₄] complex and Cu(isonicotinate ion)₂, solvent-free	oxo DHPMs using aromatic aldehydes	¹⁰⁵105 Willig, J. C. M.; Granetto, G.; Reginato, D.; Dutra, F. R.; Poruczinski, É. F.; de Oliveira, I. M.; Stefani, H. A.; de Campos, S. D.; de Campos, É. A.; Manarin, F.; Botteselle, G. V.; RSC Adv. 2020, 10, 3407. [Crossref] Crossref...
Chemically and/or thermally treated Nb₂O₅, solvent-free	oxo and thio DHPMs with aromatic aldehydes	¹²⁵125 do Nascimento, L. G.; Dias, I. M.; de Souza, G. B. M.; Dancini Pontes, I.; Fernandes, N. R. C.; de Souza, P. S.; de Oliveira, G. R.; Alonso, C. G.; J. Org. Chem. 2020, 85, 11170. [Crossref] Crossref...
Hantzsch reaction
Proline derivative organocatalysts, methanol, room temperature	1,4-dihydropyridines functionalized with sugars	¹¹¹111 Ducatti, D. R. B.; Massi, A.; Noseda, M. D.; Duarte, M. E. R.; Dondoni, A.; Org. Biomol. Chem. 2009, 7, 1980. [Crossref] Crossref...
In-SiO₂-composite, solvent-free, 100 ºC	symmetrical and non-symmetrical 1,4-dihydropyridines	¹⁰⁹109 Affeldt, R. F.; Benvenutti, E. V.; Russowsky, D.; New J. Chem. 2012, 36, 1502. [Crossref] Crossref...
Ionic liquid bearing an anionic heteropoly acid derivative, 90 ºC	symmetrical 1,4-dihydropyridines	¹⁰⁸108 Alvim, H. G. O.; Bataglion, G. A.; Ramos, L. M.; de Oliveira, A. L.; de Oliveira, H. C. B.; Eberlin, M. N.; de Macedo, J. L.; da Silva, W. A.; Neto, B. A. D.; Tetrahedron 2014, 70, 3306. [Crossref] Crossref...
p-Sulfonic acid calix[6]arene, solvent-free conditions, 25 ºC, under air atmosphere	Hantzsch-like reaction was used for the synthesis of 2-arylpyridines	¹¹²112 Sathicq, Á. G.; Liberto, N. A.; Fernándes, S. A.; Romanelli, G. P.; C. R. Chim. 2015, 18, 374. [Crossref] Crossref...
Zeolite Y, ethanol, 50 ºC, microwave	symmetrical 1,4-dihydropyridines	¹¹⁰110 Alponti, L. H. R.; Picinini, M.; Urquieta-Gonzalez, E. A.; Corrêa, A. G.; J. Mol. Struct. 2021, 1227, 129430. [Crossref] Crossref...
Others MCRs
Ionic liquid bearing an anionic heteropoly acid derivative, 30 ºC	β-amino carbonyl compounds from Mannich reaction with structural variations in the three reagents	¹⁰⁸108 Alvim, H. G. O.; Bataglion, G. A.; Ramos, L. M.; de Oliveira, A. L.; de Oliveira, H. C. B.; Eberlin, M. N.; de Macedo, J. L.; da Silva, W. A.; Neto, B. A. D.; Tetrahedron 2014, 70, 3306. [Crossref] Crossref...
Organocatalyst (diarylprolinolsilylethers), ethanol/water	Passerini adducts bearing epoxides	¹¹⁴114 Deobald, A. M.; Corrêa, A. G.; Rivera, D. G.; Paixão, M. W.; Org. Biomol. Chem. 2012, 10, 7681. [Crossref] Crossref...
Nine Lewis acids. Better results with CeCl₃.7H₂O and SnCl₂.2H₂O, ethanol, reflux	triarylimidazoles	¹⁰¹101 Marques, M. V.; Ruthner, M. M.; Fontoura, L. A. M.; Russowsky, D.; J. Braz. Chem. Soc. 2012, 23, 171. [Crossref] Crossref...
Cu/SiO₂ composite, water, 70 ºC	MCR 1,2,3-triazoles synthesis from benzyl halide, sodium azide and alkines	¹¹³113 Radatz, C. S.; Soares, L. A.; Vieira, E. R.; Alves, D.; Russowsky, D.; Schneider, P. H.; New J. Chem. 2014, 38, 1410. [Crossref] Crossref...

entry	Reaction	Equipment	Reaction conditions	Reference
1	Biginelli	microwave^a a Domestic multi-mode microwave oven;	solvent free	⁷³73 Stefani, H. A.; Gatti, P. M.; Synth. Commun. 2000, 30, 2165. [Crossref] Crossref...
2	Passerini	-	ionic liquids or PEG 400 as greener reaction media	¹⁵⁹159 Andrade, C. K. Z.; Takada, S. C. S.; Suarez, P. A. Z.; Alves, M. B.; Synlett 2006, 1539. [Crossref] Crossref...
3	Biginelli	ultrasound	-	⁵¹51 Stefani, H. A.; Oliveira, C. B.; Almeida, R. B.; Pereira, C. M. P.; Braga, R. C.; Cella, R.; Borges, V. C.; Savegnago, L.; Nogueira, C. W.; Eur. J. Med. Chem. 2006, 41, 513. [Crossref] Crossref...
4	Hantzsch	-	H₂O solvent^b b two-step. PEG400: polyethylene glycol 400; TEOF: triethylorthoformate; DMC: dimethylcarbonate; DEC: diethylcarbonate; USY-zeolite: USY/Ultrastable Y zeolite.	¹⁶⁰160 da Silva, F. M.; Goncalves, M.; Ferre, F. T.; Sena, J. D.; Coelho, R. B.; Jones Junior, J.; Heterocycl. Commun. 2009, 15, 57. [Crossref] Crossref...
5	Ugi	microwave	-	¹⁶¹161 Barreto, A. F. S.; Vercillo, O. E.; Birkett, M. A.; Caulfield, J. C.; Wessjohann, L. A.; Andrade, C. K. Z.; Org. Biomol. Chem. 2011, 9, 5024. [Crossref] Crossref...
6	Passerini	microwave	solvent free	¹⁶²162 Barreto, A. F. S.; Vercillo, O. E.; Andrade, C. K. Z.; J. Braz. Chem. Soc. 2011, 22, 462. [Crossref] Crossref...
7	Biginelli	-	TEOF, associated with citric acid or oxalic acid, solvent free	⁵⁴54 Canto, R. F. S.; Bernardi, A.; Battastini, A. M. O.; Russowsky, D.; Eifler-Lima, V. L.; J. Braz. Chem. Soc. 2011, 22, 1379. [Crossref] Crossref...
8	Biginelli	-	citric acid or tartaric acid as promoter	¹⁶³163 de Vasconcelos, A.; Oliveira, P. S.; Ritter, M.; Freitag, R. A.; Romano, R. L.; Quina, F. H.; Pizzuti, L.; Pereira, C. M. P.; Stefanello, F. M.; Barschak, A. G.; J. Biochem. Mol. Toxicol. 2012, 26, 155. [Crossref] Crossref...
9	Passerini	-	organocatalyst (diarylprolinolsilylethers) /ethanol:water	¹¹⁴114 Deobald, A. M.; Corrêa, A. G.; Rivera, D. G.; Paixão, M. W.; Org. Biomol. Chem. 2012, 10, 7681. [Crossref] Crossref...
10	Hantzch	-	In-SiO₂ composite catalyst/solvent-free	¹⁰⁹109 Affeldt, R. F.; Benvenutti, E. V.; Russowsky, D.; New J. Chem. 2012, 36, 1502. [Crossref] Crossref...
11	Biginelli	-	ionic liquids	¹⁴¹141 Ramos, L. M.; de Leon y Tobio, A. Y. P.; dos Santos, M. R.; de Oliveira, H. C. B.; Gomes, A. F.; Gozzo, F. C.; de Oliveira, A. L.; Neto, B. A. D.; J. Org. Chem. 2012, 77, 10184. [Crossref] Crossref...
12	Hantzsch	-	citric or lactic acid as catalysts	⁶⁵65 Pacheco, S. R.; Braga, T. C.; da Silva, D. L.; Horta, L. P.; Reis, F. S.; Ruiz, A. L. T. G.; de Carvalho, J. E.; Modolo, L. V.; de Fatima, A.; Med. Chem. 2013, 9, 889. [Crossref] Crossref...
13	Biginelli	-	solvent free	¹²⁰120 Liberto, N. A.; Silva, S. P.; de Fátima, Â.; Fernandes, S. A.; Tetrahedron 2013, 69, 8245. [Crossref] Crossref...
14	Biginelli	-	ionic liquid	¹⁰²102 Alvim, H. G. O.; de Lima, T. B.; de Oliveira, H. C. B.; Gozzo, F. C.; de Macedo, J. L.; Abdenur, P. V; Silva, W. A.; Neto, B. A. D.; ACS Catal. 2013, 3, 1420. [Crossref] Crossref...
15	Hantzsch	microflow chemistry	-	¹⁶⁴164 Baraldi, P. T.; Noel, T.; Wang, Q.; Hessel, V.; Tetrahedron Lett. 2014, 55, 2090. [Crossref] Crossref...
16	Ugi	flow chemistry	-	¹⁶⁵165 Salvador, C. E. M.; Pieber, B.; Neu, P. M.; Torvisco, A.; Andrade, C. K. Z.; Kappe, C. O.; J. Org. Chem. 2015, 80, 4590. [Crossref] Crossref...
17	Biginelli	microwave	H₂O solvent	¹⁶⁶166 Gama, F. H. S.; de Souza, R. O. M. A.; Garden, S. J.; RSC Adv. 2015, 5, 70915. [Crossref] Crossref...
18	Biginelli	flow chemistry	coordination polymers	⁵⁶56 Silva, G. C. O.; Correa, J. R.; Rodrigues, M. O.; Alvim, H. G. O.; Guido, B. C.; Gatto, C. C.; Wanderley, K. A.; Fioramonte, M.; Gozzo, F. C.; de Souza, R. O. M. A.; Neto, B. A. D.; RSC Adv. 2015, 5, 48506. [Crossref] Crossref...
19	Hantzsch	-	solvent free	¹⁶⁷167 Facchinetti, V.; Avellar, M. M.; Nery, A. C. S.; Gomes, C. R. B.; Vasconcelos, T. R. A.; de Souza, M. V. N.; Synthesis 2016, 48, 437. [Crossref] Crossref...
20	Bucherer-Bergs reaction	microwave	-	¹⁶⁸168 Monteiro, J. L.; Pieber, B.; Corrêa, A. G.; Kappe, C. O.; Synlett 2016, 27, 83. [Crossref] Crossref...
21	Biginelli	-	propylene carbonate as solvent/I₂ as catalyst	¹⁶⁹169 Cervasio, R. J.; Forero, J. S. B.; Muñoz, J. A. H.; Jones Jr., J.; da Silva, F. M.; Curr. Org. Synth. 2017, 14, 715. [Crossref] Crossref...
22	Hantzsch	microwave	-	¹⁷⁰170 Gündüz, M. G.; da Silva, C. B.; Zanotto, G. M.; Toldo, J. M.; Şimşek, R.; Şafak, C.; Gonçalves, P. F. B.; Rodembusch, F. S.; New J. Chem. 2017, 41, 11686. [Crossref] Crossref...
23	Ugi	flow chemistry	-	¹⁷¹171 Vasconcelos, S. N. S.; Fornari, E.; Caracelli, I.; Stefani, H. A.; Mol. Diversity 2017, 21, 893. [Crossref] Crossref...
24	Passerini	microwave	DMC and DEC as solvent	¹⁷²172 Oliveira, B. R.; Silva, C. C.; Calado, J. C. P.; Batista, W. L.; Siqueira, F. A.; Longo Jr., L. S.; Quim. Nova 2018, 41, 92. [Crossref] Crossref...
25	Ugi	microwave	-	¹⁷³173 Barreto, A. F. S.; Andrade, C. K. Z.; Tetrahedron 2018, 74, 6861. [Crossref] Crossref...
26	Biginelli	-	ionic liquid	¹³¹131 Alvim, H. G. O.; Pinheiro, D. L. J.; Carvalho-Silva, V. H.; Fioramonte, M.; Gozzo, F. C.; da Silva, W. A.; Amarante, G. W.; Neto, B. A. D.; J. Org. Chem. 2018, 83, 12143. [Crossref] Crossref...
27	Passerini	flow chemistry	-	¹⁷⁴174 Salvador, C. E. M.; Andrade, C. K. Z.; Front. Chem. 2019, 7, 531. [Crossref] Crossref...
28	Hantzsch	microwave	USY-zeolite catalyst	¹⁷⁵175 Lima, C. G. S.; Moreira, N. M.; Paixão, M. W.; Corrêa, A. G.; Curr. Opin. Green Sustainable Chem. 2019, 15, 7. [Crossref] Crossref...
29	Biginelli	-	calix[4]arene as catalyst	¹²⁴124 Zacchi, C. H. C.; Vieira, S. S.; Ardisson, J. D.; Araujo, M. H.; de Fátima, Â.; J. Saudi Chem. Soc. 2019, 23, 1060. [Crossref] Crossref...
30	Biginelli	-	ionic liquids	⁶²62 Braga, T. C.; Silva, T. F.; Maciel, T. M. S.; da Silva, E. C. D.; da Silva-Júnior, E. F.; Modolo, L. V.; Figueiredo, I. M.; Santos, J. C. C.; de Aquino, T. M.; de Fátima, A.; New J. Chem. 2019, 43, 15187. [Crossref] Crossref...
31	Biginelli	-	ionic liquids	¹⁴²142 Freitas, E. F.; Souza, R. Y.; Passos, S. T. A.; Dias, J. A.; Dias, S. C. L.; Neto, B. A. D.; RSC Adv. 2019, 9, 27125. [Crossref] Crossref...
32	Passerini	-	solvent mixture (ethanol:water)	¹⁷⁶176 dos Santos, D. A.; da Silva, A. R.; Ellena, J.; da Silva, C. C. P.; Paixão, M. W.; Corrêa, A. G.; Synthesis 2020, 52, 1076. [Crossref] Crossref...
33	Biginelli	-	alumina/perchloric acid (Al₂O₃-HClO₄)/ethanol	¹⁷⁷177 Zanin, L. L.; Porto, A. L. M.; ChemistrySelect 2020, 5, 8604. [Crossref] Crossref...
34	Biginelli	-	solvent ethyl lactate	¹⁷⁸178 Benincá, L. A. D.; Ligiéro, C. B. P.; Santos, J. S.; Jones Junior, J.; da Silva, F. M.; Curr. Org. Synth. 2020, 17, 389. [Crossref] Crossref...
35	Biginelli	mecanochemistry	solvent free	¹⁷⁹179 Gomes, C.; Vinagreiro, C. S.; Damas, L.; Aquino, G.; Quaresma, J.; Chaves, C.; Pimenta, J.; Campos, J.; Pereira, M.; Pineiro, M.; ACS Omega 2020, 5, 10868. [Crossref] Crossref...
36	GBB	microwave	reusable homogeneous Brønsted acidic catalyst	¹⁷17 Anjos, N. S.; Chapina, A. I.; Santos, A. R.; Licence, P.; Longo Jr., L. S.; Eur. J. Org. Chem. 2022, 2022, e202200615. [Crossref] Crossref... ,¹⁸⁰180 Santos, G. F. D.; Anjos, N. S.; Gibeli, M. M.; Silva, G. A.; Fernandes, P. C. S.; Fiorentino, E. S. C.; Longo Jr., L. S.; J. Braz. Chem. Soc. 2020, 31, 1434. [Crossref] Crossref...
37	Hantzsch	microwave	USY-zeolite catalyst	¹¹⁰110 Alponti, L. H. R.; Picinini, M.; Urquieta-Gonzalez, E. A.; Corrêa, A. G.; J. Mol. Struct. 2021, 1227, 129430. [Crossref] Crossref...
38	Biginelli	microwave^a a Domestic multi-mode microwave oven; / parallel synthesis	solvent free/TEOF as promoter	⁹⁹99 Canto, R. F. S.; Gonçalves, I. L.; da Rosa, M. A.; Eifler-Lima, V. L.; Rev. Virtual Quim. 2024, 16, 173. [Crossref] Crossref...

entry	MCR or kind of reaction	Subject	Reference
1	Passerini	eco-friendly approach	¹⁶²162 Barreto, A. F. S.; Vercillo, O. E.; Andrade, C. K. Z.; J. Braz. Chem. Soc. 2011, 22, 462. [Crossref] Crossref...
2	MCR	green approach	¹⁸⁴184 da Silva Jr., E. N.; Res. J. Chem. Environ. 2007, 11, 90. [Crossref] Crossref...
3	MCR	general aspects 2008 and 2011	¹⁸⁵185 Batalha, P. N.; Rev. Virtual Quim. 2012, 4, 13. [Crossref] Crossref...
4	Biginelli	pharmacological properties	¹⁸⁶186 de Fátima, Â.; Braga, T. C.; Neto, L. S.; Terra, B. S.; Oliveira, B. G. F.; da Silva, D. L.; Modolo, L. V.; J. Adv. Res. 2015, 6, 363. [Crossref] Crossref...
5	Biginelli	solvent-free and catalyst-free reaction	¹³⁵135 Alvim, H. G. O.; Lima, T. B.; de Oliveira, A. L.; de Oliveira, H. C. B.; Silva, F. M.; Gozzo, F. C.; Souza, R. Y.; da Silva, W. A.; Neto, B. A. D.; J. Org. Chem. 2014, 79, 3383. [Crossref] Crossref...
6	MCR	synthesis of biologically active molecules	¹⁸⁷187 Rogerio, K. R.; Vitório, F.; Kümmerle, A. E.; Graebin, C. S.; Rev. Virtual Quim. 2016, 8, 1934. [Crossref] Crossref...
7	Mannich	general aspects	¹⁸⁸188 Allochio Filho, J. F.; Lemos, B. C.; de Souza, A. S.; Pinheiro, S.; Greco, S. J.; Tetrahedron 2017, 73, 6977. [Crossref] Crossref...
8	Biginelli	chemistry and biology	¹⁸⁹189 Neto, B. A. D.; Fernandes, T. A.; Correia, M. V.; Targets Heterocycl. Syst. 2018, 22, 356. [Crossref] Crossref...
9	MCR	synthesis of bioactive compounds	¹⁹⁰190 Graebin, C. S.; Ribeiro, F. V.; Rogério, K. R.; Kümmerle, A. E.; Curr. Org. Synth. 2019, 16, 855. [Crossref] Crossref...
10	Ugi	mechanism and the use of fluorescent derivatives	¹⁵²152 Rocha, R. O.; Rodrigues, M. O.; Neto, B. A. D.; ACS Omega 2020, 5, 972. [Crossref] Crossref...
11	MCR	catalytic enantioselective	¹⁹¹191 Nunes, P. S. G.; Vidal, H. D. A.; Corrêa, A. G.; Org. Biomol. Chem. 2020, 18, 7751. [Crossref] Crossref...
12	Biginelli	chemical diversity generation of bioactive derivatives.	¹⁹²192 Gonçalves, I. L.; Neves, G. M.; Kagami, L. P.; Gonçalves, G. A.; Davi, L.; Eifler-Lima, V. L.; Mini-Rev. Med. Chem. 2022, 22, 1545. [Crossref] Crossref...
13	MCR	sustainable and reusable catalyst	¹⁹³193 dos Anjos, N.; Longo Jr., L.; J. Braz. Chem. Soc. 2022, 33, 610. [Crossref] Crossref...
14	MCR	total synthesis of biologically active molecules	¹⁹⁴194 dos Santos, J. A.; Castro, P. P.; Oliveira, K. T.; Brocksom, T. J.; Amarante, G. W.; Curr. Top. Med. Chem. 2023, 23, 990. [Crossref] Crossref...
15	Strecker, Mannich, Passerini and Ugi	synthetic developments of asymmetric	¹⁹⁵195 Carvalho, M.; Amarante, G.; de Castro, P.; J. Braz. Chem. Soc. 2023, 34, 1041. [Crossref] Crossref...

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