Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The use of the Ugi four-component condensation

Nature Protocols volume 2, pages 632–639 (2007)Cite this article

Abstract

This protocol describes a procedure for the Ugi four-component condensation. It describes the general mechanism as well as the effects of the nature of the components on the Ugi reaction. It also describes the effects of the reaction conditions on the reaction, along with special procedures and workup. The experimental procedure is exemplified by a description of the preparation of N-cyclohexyl 2-[N-(2-chloroacetyl)-N-(4-chlorobenzyl)]amino-2-(4-chlorophenyl)acetamide, a typical Ugi product, that is subsequently used for the synthesis of a 2,5-diketopiperazine, an example of an important type of pharmaceutical compound. The experimental procedure is then extended to the synthesis of a 1,5-disubstituted tetrazole via Ugi four-component condensation. The protocol describes the preparation and characterization of the new 1-cyclohexyl-5-(1-phenylamino-2-methyl)propyltetrazole. The total time for the synthesis and isolation of the two example reactions in parallel is 3 d.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

References

  1. Dömling, A. Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem. Rev. 106, 17–89 (2006).

    Article  Google Scholar 

  2. Ngouansavanh, T. & Zhu, J.P. Alcohols in isonitrile-based multicomponent reaction: Passerini reaction of alcohols in the presence of O-iodoxybenzoic acid. Angew. Chem. Int. Ed. Engl. 45, 3495–3497 (2006).

    Article  CAS  Google Scholar 

  3. Ugi, I. & Bodesheim, F. Isonitrile, VIII. Umsetzung von Isonitrilen mit Hydrazonen und Stickstoffwasserstoffsäure. Chem. Ber. 94, 2797–2801 (1961).

    Article  CAS  Google Scholar 

  4. Ugi, I. & Offermann, K. Isonitrile, XVIII. Hydantoin-imide-(4). Chem. Ber. 97, 2276–2281 (1964).

    Article  CAS  Google Scholar 

  5. Ugi, I., Rosendahl, F.K. & Bodesheim, F. Isonitrile, XIII. Kondensation von primären Aminen und Ketonen mit Isonitrilen und Rhodanwasserstoffsäure. Liebigs Ann. Chem. 666, 54–61 (1963).

    Article  CAS  Google Scholar 

  6. Bossio, R., Marcaccini, S. & Pepino, R. Studies on isocyanides and related compounds. A facile synthesis of imidazo[1,5-a]imidazoles. Liebigs Ann. Chem. 1229–1231 (1993).

  7. Ugi, I. & Steinbruckner, C. Über ein neues Kondensations-Prinzip. Angew. Chem. 72, 267–268 (1960).

    Article  CAS  Google Scholar 

  8. Dömling, A. & Illgen, K. 1-Isocyano-2-dimethylamino-alkenes: versatile reagents in diversity-oriented organic synthesis. Synthesis 662–667 (2005).

  9. Bossio, R., Marcaccini, S., Paoli, P., Pepino, R. & Polo, C. Studies on isocyanides and related compounds. Synthesis of benzofuran derivatives. Synthesis 999–1000 (1991).

  10. El Kaïm, L., Grimaud, L. & Oble, J. Phenol Ugi-smiles systems: strategies for the multicomponent N-arylation of primary amines with isocyanides, aldehydes, and phenols. Angew. Chem. Int. Ed. Engl. 44, 7961–7964 (2005).

    Article  Google Scholar 

  11. Ugi, I., Dömling, A. & Hörl, W. Multicomponent reactions in organic chemistry. Endeavour 18, 115–122 (1994).

    Article  CAS  Google Scholar 

  12. Weber, L., Waltbaum, S., Broger, C. & Gubernator, K. Optimization of the biological activity of combinatorial compound libraries by a genetic algorithm. Angew. Chem. Int. Ed. Engl. 34, 2280–2282 (1995).

    Article  CAS  Google Scholar 

  13. Marcaccini, S., Pepino, R., Polo, C. & Pozo, M.C. Studies on isocyanides and related compounds; a facile synthesis of 4-phenyl-1-(2H)phthalazinone-2-alkanoic acid amides. Synthesis 85–88 (2001).

  14. Ugi, I. & Bodesheim, F. Isonitrile, XIV. Umsetzung von Isonitrilen mit Hydrazonen und Carbonsäuren. Liebigs Ann. Chem. 666, 61–64 (1963).

    Article  CAS  Google Scholar 

  15. v. Zychlinski, A. & Ugi, I. MCR IX: a new and easy way for the preparation of piperazine-2-keto-3-carboxamides. Heterocycles 49, 29–32 (1998).

    Article  Google Scholar 

  16. Sañudo, M., Marcaccini, S., Basurto, S. & Torroba, T. Synthesis of 3-hydroxy-6-oxo[1,2,4]triazin-1-yl alaninamides, a new class of cyclic dipeptidyl ureas. J. Org. Chem. 71, 4578–4584 (2006).

    Article  Google Scholar 

  17. Marcos, C.F., Marcaccini, S., Pepino, R., Polo, C. & Torroba, T. Studies on isocyanides and related compounds; a facile synthesis of functionalized 3(2H)-pyridazinones via Ugi four-component condensation. Synthesis 691–694 (2003).

  18. Campian, E., Lou, B. & Saneji, H. Solid-phase synthesis of α-sulfonylamino amide derivatives based on Ugi-type condensation reaction using sulfonamides as amine input. Tetrahedron Lett. 43, 8467–8470 (2002).

    Article  CAS  Google Scholar 

  19. Dömling, A. & Ugi, I. Multicomponent reactions with isocyanides. Angew. Chem. Int. Ed. Engl. 39, 3168–3210 (2000).

    Article  Google Scholar 

  20. Ugi, I. From isocyanides via four-component condensations to antibiotic syntheses. Angew. Chem. Int. Ed. Engl. 21, 810–819 (1982).

    Article  Google Scholar 

  21. Marcaccini, S. & Torroba, T. Post-condensation modifications of the Passerini and Ugi reactions. In Multicomponent Reactions (eds. Zhu, J. & Bienaymé, H.) 33–75 (Wiley-VCH, Weinheim, Germany, 2005).

    Chapter  Google Scholar 

  22. Banfi, L., Basso, A., Guanti, G. & Riva, R. Asymmetric isocyanide-based MCRs. In Multicomponent Reactions (eds. Zhu, J. & Bienaymé, H.) 1–32 (Wiley-VCH, Weinheim, Germany, 2005).

    Google Scholar 

  23. Ugi, I., Werner, B. & Dömling, A. The chemistry of isocyanides, their multicomponent reactions and their libraries. Molecules 8, 53–66 (2003).

    Article  CAS  PubMed Central  Google Scholar 

  24. Ugi, I.K., Ebert, B. & Hörl, W. Formation of 1,1′-iminodicarboxylic acid derivatives, 2,6-diketo-piperazine and dibenzodiazocine-2,6-dione by variations of multicomponent reactions. Chemosphere 43, 75–81 (2001).

    Article  CAS  Google Scholar 

  25. Kaczmarek, K. et al. Tetrazole analogues of cyclolinopeptide A: synthesis, conformation, and biology. Biopolymers 63, 343–357 (2002).

    Article  CAS  Google Scholar 

  26. Ugi, I. & Offermann, K. Isonitrile, XIX. Die Kondensation von Carbonsäuren, Aldehyden und Isonitrilen mit primären aliphatischen Aminen, die einen abspaltbaren alkyl- oder Alkenyl-Rest tragen. Chem. Ber. 97, 2996–3007 (1964).

    Article  CAS  Google Scholar 

  27. Yamada, T., Omote, Y., Yamanaka, Y., Miyazawa, T. & Kuwata, S. Synthesis of tripeptides containing α,α-diphenylglycine by the modified Ugi reaction. Synthesis 991–998 (1998).

  28. Marcaccini, S., Miliciani, M. & Pepino, R. A facile synthesis of 1,4-benzodiazepine derivatives via Ugi four-component condensation. Tetrahedron Lett. 46, 711–713 (2005).

    Article  CAS  Google Scholar 

  29. Bossio, R., Marcaccini, S. & Pepino, R. Studies on isocyanides and related compounds: a novel synthesis of pyrroles via Ugi reaction. Synthesis 765–766 (1994).

  30. Rehn, D. & Ugi, I. Isocyanides as activating reagents for carboxylic acids; ester syntheses under mild conditions. J. Chem. Res. (S) 119(M), 1501–1506 (1977).

    Google Scholar 

  31. Ugi, I. The α-addition of immonium ions and anions to isonitriles accompanied by secondary reactions. Angew. Chem. Int. Ed. 1, 8–21 (1962).

    Article  Google Scholar 

  32. Bossio, R., Marcaccini, S. & Pepino, R. Studies on isocyanides. Synthesis of N-substituted 2-isocyanocarboxamides. Liebigs Ann. Chem. 935–937 (1990).

  33. Goebel, M. & Ugi, I. O-Alkyl-d-glucopyranosylamines and their derivatives. Synthesis 1095–1098 (1991).

  34. Lenhoff, S., Goebel, M., Karl, R.M., Klösel, R. & Ugi, I. Stereoselective syntheses of peptide derivatives with 2-acetamido-3,4,6-tri-O-acetyl-1-amino-2-deoxy-β-d-glucopyranose by four-component condensation. Angew. Chem. Int. Ed. Engl. 34, 1104–1107 (1995).

    Article  Google Scholar 

  35. Cristau, P., Vors, J.P. & Zhu, J. A rapid access to biaryl ether containing macrocycles by pairwise use of Ugi 4CR and intramolecular S(N)Ar-based cycloetherification. Org. Lett. 3, 4079–4082 (2001).

    Article  CAS  Google Scholar 

  36. Constabel, F. & Ugi, I. Repetitive Ugi reactions. Tetrahedron 57, 5785–5789 (2001).

    Article  CAS  Google Scholar 

  37. Jenner, G. Effect of high pressure on sterically congested Passerini reactions. Tetrahedron Lett. 43, 1235–1238 (2002).

    Article  CAS  Google Scholar 

  38. Yamada, T. et al. Four-component condensation (Ugi reaction) at high pressure: novel synthesis of peptides containing very bulky α,α-disubstituted glycines. J. Chem. Soc. Chem. Commun. 1640–1641 (1990).

  39. Ugi, I. & Heck, S. The multicomponent reactions and their libraries for natural and preparative chemistry. Comb. Chem. High Throughput Screen. 4, 1–34 (2001).

    Article  CAS  Google Scholar 

  40. Hoel, H.M.L. & Nielsen, J. Microwave-assisted solid-phase Ugi four-component condensations. Tetrahedron Lett. 40, 3941–3944 (1999).

    Article  CAS  Google Scholar 

  41. Hebach, C. & Kazmaier, U. Via Ugi reactions to conformationally fixed cyclic peptides. Chem. Commun. 596–597 (2003).

  42. Cheng, J.F., Chen, M., Arrhenius, T. & Nazdan, A. A convenient solution and solid-phase synthesis of Δ5-2-oxopiperazines via N-acyliminium ions cyclization. Tetrahedron Lett. 43, 6293–6295 (2002).

    Article  CAS  Google Scholar 

  43. Xu, P., Lin, W. & Zou, X. Synthesis of a peptidomimetic HCMV protease inhibitor library. Synthesis 1017–1026 (2002).

  44. Lee, D., Sello, J.K. & Schreiber, S.L. Pairwise use of complexity-generating reactions in diversity-oriented organic synthesis. Org. Lett. 2, 709–712 (2000).

    Article  CAS  Google Scholar 

  45. Nakamura, M., Inoue, J. & Yamada, T. A two-step, one-pot synthesis of diverse N-pyruvoyl amino acid derivatives using the Ugi reaction. Bioorg. Med. Chem. Lett. 10, 2807–2810 (2000).

    Article  CAS  Google Scholar 

  46. Ross, G.F., Herdtweck, E. & Ugi, I. Stereoselective U-4CRs with 1-amino-5-desoxy-5-thio-2,3,4-O-isobutanoyl-β-d-xylopyranose–an effective and selectively removable chiral auxiliary. Tetrahedron 58, 6127–6133 (2002).

    Article  CAS  Google Scholar 

  47. Zhang, J. et al. Identification of inhibitors of heparin-growth factor interactions from combinatorial libraries of four-component condensation reactions. Bioorg. Med. Chem. 9, 825–836 (2001).

    Article  CAS  Google Scholar 

  48. González-Zamora, E., Fayol, A., Bois-Choussy, M., Chiaroni, A. & Zhu, J. Three component synthesis of oxa-bridged tetracyclic tetrahydroquinolines. Chem. Commun. 1684–1685 (2001).

  49. Ugi, I. & Rosendahl, F.K. Isonitrile, XV. Δ1-Cyclohexenyl-isocyanide. Liebigs Ann. Chem. 666, 65–67 (1963).

    Article  CAS  Google Scholar 

  50. Ignacio, J.M., Macho, S., Marcaccini, S., Pepino, R. & Torroba, T. A facile synthesis of 1,3,5-trisubstituted hydantoins via Ugi four-component condensation. Synlett 3051–3054 (2005).

  51. Faggi, C., García-Valverde, M., Marcaccini, S., Pepino, R. & Pozo, M.C. Studies on isocyanides and related compounds: a facile synthesis of 1,6-dihydro-6-oxopyrazine-2-carboxylic acid derivatives via Ugi four-component condensation. Synthesis 1553–1558 (2003).

  52. Ziegler, T., Kaisers, H.-J., Schlömer, R. & Koch, C. Passerini and Ugi reactions of benzyl and acetyl protected isocyanoglucoses. Tetrahedron 55, 8397–8408 (1999).

    Article  CAS  Google Scholar 

  53. Mironov, M.A., Ivantsova, M.N. & Mokrushin, V.S. Ugi reaction in aqueous solutions: a simple protocol for libraries production. Mol. Divers. 6, 193–197 (2003).

    Article  CAS  Google Scholar 

  54. Pirrung, M.C. & Das Sarma, K. Multicomponent reactions are accelerated in water. J. Am. Chem. Soc. 126, 444–445 (2004).

    Article  CAS  Google Scholar 

  55. Keung, W. et al. Novel a-amino amidine synthesis via scandium(III) triflate mediated 3CC Ugi condensation reaction. Tetrahedron Lett. 45, 733–737 (2004).

    Article  CAS  Google Scholar 

  56. Henkel, B. & Weber, L. A novel four-component synthesis of N-substituted amino acid esters. Synlett 1877–1879 (2002).

  57. Zbinden, K.G. et al. Selective and orally bioavailable phenylglycine tissue factor/factor VIIa inhibitors. Bioorg. Med. Chem. Lett. 15, 5344–5352 (2005).

    Article  CAS  Google Scholar 

  58. Marcaccini, S., Miguel, D., Torroba, T. & García-Valverde, M. 1,4-Thiazepines, 1,4-benzothiazepin-5-ones, and 1,4-benzothioxepin orthoamides via multicomponent reactions of isocyanides. J. Org. Chem. 68, 3315–3318 (2003).

    Article  CAS  Google Scholar 

  59. Bienaymé, H., Hulme, C., Oddon, G. & Schmitt, P. Maximizing synthetic efficiency: multi-component transformations lead the Way. Chem. Eur. J. 6, 3321–3329 (2000).

    Article  Google Scholar 

  60. Chen, J.J., Golebiowski, A., McClenaghan, J., Klopfenstein, S.R. & West, L. Universal Rink–isonitrile resin: application for the traceless synthesis of 3-acylamino imidazo[1,2-a]pyridines. Tetrahedron Lett. 42, 2269–2271 (2001).

    Article  CAS  Google Scholar 

  61. Chen, J.J., Golebiowski, A., Klopfenstein, S.R. & West, L. The universal Rink-isonitrile resin: applications in Ugi reactions. Tetrahedron Lett. 43, 4083–4085 (2002).

    Article  CAS  Google Scholar 

  62. Hulme, C. et al. Novel safety-catch linker and its application with a Ugi/De-BOC/cyclization (UDC) strategy to access carboxylic acids, 1,4-benzodiazepines, diketopiperazines, ketopiperazines and dihydroquinoxalinones. Tetrahedron Lett. 39, 7227–7230 (1998).

    Article  CAS  Google Scholar 

  63. Hulme, C. et al. Novel applications of convertible isonitriles for the synthesis of mono and bicyclic-lactams via a UDC strategy. Tetrahedron Lett. 41, 1883–1887 (2000).

    Article  CAS  Google Scholar 

  64. Kennedy, A.L., Fryer, A.M. & Josey, J.A. A new resin-bound universal isonitrile for the Ugi 4CC reaction: preparation and applications to the synthesis of 2,5-diketopiperazines and 1,4-benzodiazepine-2,5-diones. Org. Lett. 4, 1167–1170 (2002).

    Article  CAS  Google Scholar 

  65. Urban, R. & Ugi, I. Asymmetrically induced four component condensation with extremely high stereoselectivity and multiplication of stereoselectivity. Angew. Chem. Int. Ed. Engl. 14, 61–62 (1975).

    Article  CAS  Google Scholar 

  66. Kunz, H. & Pfrengle, W. Asymmetric synthesis on carbohydrate templates: stereoselective Ugi synthesis of α-amino acid derivatives. J. Am. Chem. Soc. 110, 651–652 (1988).

    Article  CAS  Google Scholar 

  67. Kunz, H., Pfrengle, W., Rück, K. & Sager, W. stereoselective synthesis of l-amino acids via Strecker and Ugi reactions on carbohydrate templates. Synthesis 1039–1042 (1991).

  68. Goebel, M. & Ugi, I. O-Alkyl-d-glucopyranosylamines and their derivatives. Synthesis 1095–1098 (1991).

  69. Lehnhoff, S., Goebel, M., Karl, R.M., Klösel, R. & Ugi, I. Stereoselective syntheses of peptide derivatives with 2-acetamido-3,4,6-tri-O-acetyl-1-amino-2-deoxy-β-d-glucopyranose by four-component condensation. Angew. Chem. Int. Ed. Engl. 34, 1104–1106 (1995).

    Article  CAS  Google Scholar 

  70. Ross, G.F., Herdtweck, E. & Ugi, I. Stereoselectivee U-4CRs with 1-amino-5-desoxy-5-thio-2,3,4-O-isobutanoyl-β-d-xylopyranosean effective and selectively removable chiral auxiliary. Tetrahedron 58, 6127–6133 (2002).

    Article  CAS  Google Scholar 

  71. Marcaccini, S., Pepino, R. & Pozo, M.C. A facile synthesis of 2,5-diketopiperazines based on isocyanide chemistry. Tetrahedron Lett. 42, 2727–2728 (2001).

    Article  CAS  Google Scholar 

  72. Bienaymé, H. & Bouzid, K. Synthesis of rigid hydrophobic tetrazoles using an Ugi multi-component heterocyclic condensation. Tetrahedron Lett. 39, 2735–2738 (1998).

    Article  Google Scholar 

  73. Mayer, J. et al. New cleavable isocyanides for the combinatorial synthesis of á-amino acid analogue tetrazoles. Tetrahedron Lett. 46, 7393–7396 (2005).

    Article  CAS  Google Scholar 

  74. Gokel, G.W., Widera, R.P. & Weber, W.P. Phase-transfer Hofmann carbylamine reaction: tert-butyl isocyanide. Org. Synth. 55, 96–99 (1975).

    Google Scholar 

Download references

Acknowledgements

The authors want to thank Dr. J. Delgado and M. Sañudo for help with NMR recording. This work was supported by the Dirección General de Investigación of Spain (project refs. CTQ2005-07562-C04-02/BQU and CTQ2006-15456-C04-04/BQU) and Junta de Castilla y León, Consejería de Educación y Cultura, y Fondo Social Europeo (project ref. BU013A06).

Author information

Authors and Affiliations

  1. Dipartimento di Chimica Organica “Ugo Schiff”, Università di Firenze, Via della Lastruccia, 13, Sesto Fiorentino, I-50019, Italy

    Stefano Marcaccini

  2. Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Burgos, 09001, Spain

    Tomás Torroba

Authors
  1. Stefano Marcaccini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomás Torroba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tomás Torroba.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Data

Supporting information: the use of the Ugi four-component condensation (PDF 1806 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Marcaccini, S., Torroba, T. The use of the Ugi four-component condensation. Nat Protoc 2, 632–639 (2007). https://doi.org/10.1038/nprot.2007.71

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nprot.2007.71

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing