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image of Green Ugi-3CR Method for the Synthesis of α-Aminoamides in Water Using SLS

Abstract

Introduction

Quinoline-based α-aminoamides are promising scaffolds in drug discovery due to their enhanced pharmaceutical properties and biological relevance. Developing efficient and environmentally friendly synthetic methods remain a key goal in pharmaceutical chemistry.

Methods

In this study, we developed a green synthetic approach using a Ugi three-component reaction (Ugi-3CR). The reaction involves 2-chloroquinoline-3-carbaldehyde, various aldehydes, and isocyanides in the presence of sodium lauryl sulfate (SLS) as a surfactant in water.

Results

The optimized reaction conditions afforded the desired α-aminoamide products in moderate to good yields (59-79%), depending on the substrate used. The reaction worked well with a broad range of starting materials, showing its versatility and efficiency. The use of SLS in water not only promotes reaction efficiency but also aligns with green chemistry principles.

Discussion

This work highlights how multicomponent reactions like the Ugi-3CR can simplify the synthesis of structurally diverse, biologically relevant molecules. The use of water and SLS also aligns with green chemistry goals, making the process both practical and environmentally conscious.

Conclusion

Our study presents a practical, green, and versatile strategy for the synthesis of quinoline-based α-aminoamides Ugi-3CR, supporting their continued development in medicinal chemistry.

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/content/journals/cos/10.2174/0115701794416357250903073908
2025-09-24
2025-12-22
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References

  1. Shehab W.S. Amer M.M.K. Elsayed D.A. Yadav K.K. Abdellattif M.H. Current progress toward synthetic routes and medicinal significance of quinoline. Med. Chem. Res. 2023 32 12 2443 2457 10.1007/s00044‑023‑03121‑y
    [Google Scholar]
  2. Kumar N. Khanna A. Kaur K. Kaur H. Sharma A. Bedi P.M.S. Quinoline derivatives volunteering against antimicrobial resistance: Rational approaches, design strategies, structure activity relationship and mechanistic insights. Mol. Divers. 2023 27 4 1905 1934 10.1007/s11030‑022‑10537‑y 36197551
    [Google Scholar]
  3. Peron C. Gonçalves R.S.B. Moura S. Advances in the potential of quinoline‐derived metal complexes as antimalarial agents: A review. Appl. Organomet. Chem. 2025 39 3 e70050 10.1002/aoc.70050
    [Google Scholar]
  4. Hamedifar H. Mirfattahi M. Khalili Ghomi M. Azizian H. Iraji A. Noori M. Moazzam A. Dastyafteh N. Nokhbehzaim A. Mehrpour K. Javanshir S. Mojtabavi S. Faramarzi M.A. Larijani B. Hajimiri M.H. Mahdavi M. Aryl-quinoline-4-carbonyl hydrazone bearing different 2-methoxyphenoxyacetamides as potent α-glucosidase inhibitors; molecular dynamics, kinetic and structure–activity relationship studies. Sci. Rep. 2024 14 1 388 10.1038/s41598‑023‑50395‑8 38172167
    [Google Scholar]
  5. Pradhan V. Salahuddin; Kumar, R.; Mazumder, A.; Abdullah, M.M.; Shahar Yar, M.; Ahsan, M.J.; Ullah, Z. Molecular target interactions of quinoline derivatives as anticancer agents: A review. Chem. Biol. Drug Des. 2023 101 4 977 997 10.1111/cbdd.14196 36533867
    [Google Scholar]
  6. Mohasin M. Zafer Alam M. Ullah Q. Ahmad A. Rahaman P.F. Khan S.A. A review on synthesis and biological applications of quinoline derivative as fused aromatic compounds. Polycycl. Aromat. Compd. 2024 44 9 6369 6398 10.1080/10406638.2023.2270118
    [Google Scholar]
  7. Neochoritis C.G. Livadiotou D. Tsiaras V. Zarganes-Tzitzikas T. Samatidou E. The indoleacetic acids in IMCRs: A three-component Ugi reaction involving TosMIC. Tetrahedron 2016 72 33 5149 5156 10.1016/j.tet.2016.07.013
    [Google Scholar]
  8. Duflos M. Courant J. Baut G.L. Grimaud N. Renard P. Manechez D. Caignard D.H. 6-Amino-2,4-lutidine carboxamides: α-aminoamide derivatives as systemic and topical inflammation inhibitors. Eur. J. Med. Chem. 1998 33 7-8 635 645 10.1016/S0223‑5234(98)80022‑6
    [Google Scholar]
  9. Sebastian S. Rohila Y. Meenakshi; Ansari, A.; Sengupta, S.; Kumar, D.; Srivastava, N.; Kumar, L.; Gupta, M.K. Anti-quorum sensing activity of α-amidoamides against Agrobacterium tumefaciensNT1: Insights from molecular docking and dynamic investigations to synergistic approach of metronidazole release from gel formulations. Microb. Pathog. 2024 193 106787 10.1016/j.micpath.2024.106787 38992510
    [Google Scholar]
  10. Al Otaibi A. Deane F.M. Russell C.C. Hizartzidis L. McCluskey S.N. Sakoff J.A. McCluskey A. A methanol and protic ionic liquid Ugi multicomponent reaction path to cytotoxic α-phenylacetamido amides. RSC Advances 2019 9 14 7652 7663 10.1039/C9RA00118B 35521167
    [Google Scholar]
  11. Sun Y. Yang L. Cheng Y. An G. Li G. Pd(I)-catalyzed ring-opening arylation of cyclopropyl-α-aminoamides: Access to α-ketoamide peptidomimetics. Chin. Chem. Lett. 2024 35 6 109250 10.1016/j.cclet.2023.109250
    [Google Scholar]
  12. Morarad R. Uerpairojkit K. Chalermkitpanit P. Sirivat A. Comparative study of iontophoresis-assisted transdermal delivery of bupivacaine and lidocaine as anesthetic drugs. Drug Deliv. Transl. Res. 2025 15 2 688 699 10.1007/s13346‑024‑01627‑5 38782881
    [Google Scholar]
  13. Mizogami M. Tsuchiya H. Harada J. Membrane effects of ropivacaine compared with those of bupivacaine and mepivacaine. Fundam. Clin. Pharmacol. 2002 16 4 325 330 10.1046/j.1472‑8206.2002.00090.x 12570022
    [Google Scholar]
  14. Leuratti C. Sardina M. Ventura P. Assandri A. Müller M. Brunner M. Disposition and metabolism of safinamide, a novel drug for Parkinson’s disease, in healthy male volunteers. Pharmacology 2013 92 3-4 207 216 10.1159/000354805 24136086
    [Google Scholar]
  15. Liang X. Yu G. Su R. Effects of ralfinamide in models of nerve injury and chemotherapy-induced neuropathic pain. Eur. J. Pharmacol. 2018 823 27 34 10.1016/j.ejphar.2018.01.041 29408090
    [Google Scholar]
  16. Carvalho M.H.R. de Castro P.P. de Oliveira K.T. Amarante G.W. Enhancing efficiency and sustainability: unleashing the potential of continuous flow in multicomponent reactions. ChemSusChem 2025 18 4 e202401840 10.1002/cssc.202401840 39392303
    [Google Scholar]
  17. John S.E. Gulati S. Shankaraiah N. Recent advances in multi-component reactions and their mechanistic insights: A triennium review. Org. Chem. Front. 2021 8 15 4237 4287 10.1039/D0QO01480J
    [Google Scholar]
  18. Guan Q. Zhou L.L. Dong Y.B. Construction of covalent organic frameworks via multicomponent reactions. J. Am. Chem. Soc. 2023 145 3 1475 1496 10.1021/jacs.2c11071 36646043
    [Google Scholar]
  19. Nunes P.S.G. Vidal H.D.A. Corrêa A.G. Recent advances in catalytic enantioselective multicomponent reactions. Org. Biomol. Chem. 2020 18 39 7751 7773 10.1039/D0OB01631D 32966520
    [Google Scholar]
  20. Farhid H. Khodkari V. Nazeri M.T. Javanbakht S. Shaabani A. Multicomponent reactions as a potent tool for the synthesis of benzodiazepines. Org. Biomol. Chem. 2021 19 15 3318 3358 10.1039/D0OB02600J 33899847
    [Google Scholar]
  21. Hou W. Zhou X. Yang Z. Xia H. Wang Y. Xu K. Hou S. Zhang S. Cui D. Ma P. Zhou W. Xu H. Multicomponent Reaction Integrating Selenium(II)–Nitrogen Exchange (SeNEx) Chemistry and Copper‐Catalyzed Azide–Alkyne Cycloaddition (CuAAC). Angew. Chem. Int. Ed. 2025 64 16 e202500942 10.1002/anie.202500942 40000436
    [Google Scholar]
  22. Cioc R.C. Ruijter E. Orru R.V.A. Multicomponent reactions: advanced tools for sustainable organic synthesis. Green Chem. 2014 16 6 2958 2975 10.1039/C4GC00013G
    [Google Scholar]
  23. Castro G.A.D. Fernandes S.A. Furans derived from lignocellulosic biomass as renewable substrates in multicomponent reactions. Sustain. Chem. Pharm. 2025 44 101948 10.1016/j.scp.2025.101948
    [Google Scholar]
  24. dos Santos J.A. de Castro P.P. de Oliveira K.T. Brocksom T.J. Amarante G.W. Multicomponent reactions applied to total synthesis of biologically active molecules: A short review. Curr. Top. Med. Chem. 2023 23 11 990 1003 10.2174/1568026623666230403102437 37016527
    [Google Scholar]
  25. Luleburgaz S. Cakmakci E. Durmaz H. Tunca U. Sustainable polymers from renewable resources through click and multicomponent reactions. Eur. Polym. J. 2024 209 112897 10.1016/j.eurpolymj.2024.112897
    [Google Scholar]
  26. Ulaczyk-Lesanko A. Hall D.G. Wanted: new multicomponent reactions for generating libraries of polycyclic natural products. Curr. Opin. Chem. Biol. 2005 9 3 266 276 10.1016/j.cbpa.2005.04.003 15939328
    [Google Scholar]
  27. Li J. Cui J. Guo H. Yang J. Huan W. The road to green efficiency: Exploration of multicomponent reactions from transition metal catalysis to no catalyst conditions. React. Chem. Eng. 2025 10 3 500 510 10.1039/D4RE00522H
    [Google Scholar]
  28. Wang Z.K. Wang L.X. Lin H. Qiu B. Ma Y. Xiao J. An X.D. Visible-light-activated photocatalyst- and additive-free multi-component reaction driven by the cyclopropylamine-based EDA complex in water. Green Chem. 2025 27 17 4565 4572 10.1039/D5GC00265F
    [Google Scholar]
  29. Reguera L. Rivera D.G. Multicomponent reaction toolbox for peptide macrocyclization and stapling. Chem. Rev. 2019 119 17 9836 9860 10.1021/acs.chemrev.8b00744 30990310
    [Google Scholar]
  30. Insuasty D. Castillo J. Becerra D. Rojas H. Abonia R. Synthesis of biologically active molecules through multicomponent reactions. Molecules 2020 25 3 505 10.3390/molecules25030505 31991635
    [Google Scholar]
  31. Hosseininezhad S. Ramazani A. Recent advances in the application of alkynes in multicomponent reactions. RSC Advances 2024 14 1 278 352 10.1039/D3RA07670A 38173570
    [Google Scholar]
  32. Lei J. Meng J.P. Tang D.Y. Frett B. Chen Z.Z. Xu Z.G. Recent advances in the development of polycyclic skeletons via Ugi reaction cascades. Mol. Divers. 2018 22 2 503 516 10.1007/s11030‑017‑9811‑2 29340996
    [Google Scholar]
  33. Mirfattahi M. Yazzaf R. Mahdavi M. Construction of [1,4]oxazepin-2-ones via catalyst-free intramolecular C–O bond formation from Ugi adducts. Tetrahedron Lett. 2024 141 155075 10.1016/j.tetlet.2024.155075
    [Google Scholar]
  34. Fotopoulou E. Anastasiou P.K. Tomza C. Neochoritis C.G. The Ugi reaction as the green alternative towards active pharmaceutical ingredients. Tetrahedron Green Chem. 2024 3 100044 10.1016/j.tgchem.2024.100044
    [Google Scholar]
  35. Kaluđerović G.N. Abbas M. Kautz H.C. Wadaan M.A.M. Lennicke C. Seliger B. Wessjohann L.A. Methionine and seleno-methionine type peptide and peptoid building blocks synthesized by five-component five-center reactions. Chem. Commun. 2017 53 26 3777 3780 10.1039/C7CC00399D 28304024
    [Google Scholar]
  36. Haldar S. Saha S. Mandal S. Jana C.K. C–H functionalization enabled stereoselective Ugi-azide reaction to α-tetrazolyl alicyclic amines. Green Chem. 2018 20 15 3463 3467 10.1039/C8GC01544A
    [Google Scholar]
  37. Chéron N. Ramozzi R. El Kaïm L. Grimaud L. Fleurat-Lessard P. Substituent effects in Ugi-smiles reactions. J. Phys. Chem. A 2013 117 33 8035 8042 10.1021/jp4052227 23885962
    [Google Scholar]
  38. Nazeri M.T. Ghasemi M. Ahmadi M. Shaabani A. Notash B. Using Triazolobenzodiazepine as the Cyclic Imine in Various Types of Joullié–Ugi Reactions. J. Org. Chem. 2023 88 19 13504 13519 10.1021/acs.joc.3c01013 37696794
    [Google Scholar]
  39. Flores-Reyes J.C. Islas-Jácome A. González-Zamora E. The Ugi three-component reaction and its variants. Org. Chem. Front. 2021 8 19 5460 5515 10.1039/D1QO00313E
    [Google Scholar]
  40. Horst B. van Duijnen N. Janssen E. Hansen T. Ruijter E. Modular divergent synthesis of indole alkaloid derivatives by an atypical ugi multicomponent reaction. Chemistry 2024 30 29 e202400477 10.1002/chem.202400477 38498145
    [Google Scholar]
  41. Stiernet P. Lecomte P. De Winter J. Debuigne A. Ugi Three-Component Polymerization Toward Poly(α-amino amide)s. ACS Macro Lett. 2019 8 4 427 434 10.1021/acsmacrolett.9b00182 35651127
    [Google Scholar]
  42. Lesma G. Meneghetti F. Sacchetti A. Stucchi M. Silvani A. Asymmetric Ugi 3CR on isatin-derived ketimine: synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives. Beilstein J. Org. Chem. 2014 10 1 1383 1389 10.3762/bjoc.10.141 24991292
    [Google Scholar]
  43. Kanizsai I. Szakonyi Z. Sillanpää R. Fülöp F. A comparative study of the multicomponent Ugi reactions of an oxabicycloheptene-based β-amino acid in water and in methanol. Tetrahedron Lett. 2006 47 51 9113 9116 10.1016/j.tetlet.2006.10.069
    [Google Scholar]
  44. Nazeri M.T. Nasiriani T. Farhid H. Javanbakht S. Bahri F. Shadi M. Shaabani A. Sustainable synthesis of pseudopeptides via isocyanide-based multicomponent reactions in water. 2022 10 25 8115 8134 10.1021/acssuschemeng.2c01030
    [Google Scholar]
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