Multicomponent reactions

Editor: Prof. Thomas J. J. Müller
Heinrich-Heine-Universität Düsseldorf

Chemistry as a central science is facing a steadily increasing demand for new chemical entities. Innovative solutions, in all kinds of disciplines that depend on chemistry, require new molecules with specific properties, and their societal consequences are fundamental and pioneering. However, these molecules not only demand a realistic structural space but also their feasibility poses challenges to synthetic chemists. Nowadays the question of how to perform a synthesis has become most crucial. In particular multicomponent reactions are masterpieces of synthetic efficiency and reaction design. These one-pot processes consist of concatenations of elementary organic reactions under similar conditions.

See also the Thematic Series:
Multicomponent reactions II

Multicomponent reactions

Thomas J. J. Müller

Editorial
Published 13 Jul 2011

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Graphical Abstract

Beilstein J. Org. Chem. 2011, 7, 960–961, doi:10.3762/bjoc.7.107

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A practical two-step procedure for the preparation of enantiopure pyridines: Multicomponent reactions of alkoxyallenes, nitriles and carboxylic acids followed by a cyclocondensation reaction

Christian Eidamshaus,
Roopender Kumar,
Mrinal K. Bera and
Hans-Ulrich Reissig

Full Research Paper
Published 13 Jul 2011

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1. Graphical Abstract
2. Scheme 1: Preparation of β-ketoenamides and subsequent cyclocondensation to 4-hydroxypyridines. a) Et₂O, −40 ...
  
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3. Scheme 2: Mechanistic rational for the formation of β-ketoenamides 16.
  
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4. Scheme 3: Reaction of proline derivative 45 and formation of β-ketoenamide 47 and enolester 48.
  
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5. Figure 1: ¹H NMR spectra of 49 and the mixture of diastereoisomers 49 and 49’.
  
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6. Scheme 4: Synthesis of pyrid-4-yl nonaflate 52.
  
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7. Scheme 5: O-Methylation of pyridine derivatives 22 and 30 followed by desilylation.
  
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8. Scheme 6: Formation of 5-alkoxypyrimidines from β-alkoxy-β-ketoenamides.
  
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Beilstein J. Org. Chem. 2011, 7, 962–975, doi:10.3762/bjoc.7.108

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Long-range diastereoselectivity in Ugi reactions of 2-substituted dihydrobenzoxazepines

Luca Banfi,
Andrea Basso,
Valentina Cerulli,
Valeria Rocca and
Renata Riva

Letter
Published 13 Jul 2011

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1. Graphical Abstract
2. Scheme 1: a) TBAD [(t-BuO₂C−N=)₂], PPh₃, THF, −15 °C → rt, 49% (3a), 62% (3b); b) LiAlH₄, Et₂O–THF, 0 °C, 90%...
  
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3. Figure 1: Model of the expected preferred conformation of imine 5a, as minimized using CSC Chem3D (MOPAC-PM3)....
  
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4. Scheme 2: Possible explanation of diastereoselectivity in Ugi reactions of imines 5.
  
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Beilstein J. Org. Chem. 2011, 7, 976–979, doi:10.3762/bjoc.7.109

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Multicomponent reaction access to complex quinolines via oxidation of the Povarov adducts

Esther Vicente-García,
Rosario Ramón,
Sara Preciado and
Rodolfo Lavilla

Full Research Paper
Published 13 Jul 2011

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1. Graphical Abstract
2. Scheme 1: Povarov oxidation access to substituted quinolines.
  
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3. Scheme 2: Tetrahydroquinoline oxidation.
  
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4. Scheme 3: Synthesis of the Povarov adducts and their oxidation products.
  
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5. Figure 1: Optimization of the reaction conditions for the preparation of quinoline 18.
  
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6. Scheme 4: Oxidation of lactam-fused tetrahydroquinolines 20,20'.
  
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Beilstein J. Org. Chem. 2011, 7, 980–987, doi:10.3762/bjoc.7.110

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A practical route to tertiary diarylmethylamides or -carbamates from imines, organozinc reagents and acyl chlorides or chloroformates

Erwan Le Gall,
Antoine Pignon and
Thierry Martens

Letter
Published 20 Jul 2011

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1. Graphical Abstract
2. Scheme 1: Addition of nucleophiles onto activated imines (A) or iminiums (B).
  
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3. Scheme 2: Activation of the aldimine with MsCl.
  
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Graphical Abstract

Beilstein J. Org. Chem. 2011, 7, 997–1002, doi:10.3762/bjoc.7.112

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Novel synthesis of pseudopeptides bearing a difluoromethyl group by Ugi reaction and desulfanylation

Jingjing Wu,
Hui Li and
Song Cao

Full Research Paper
Published 08 Aug 2011

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1. Graphical Abstract
2. Figure 1: Two examples of bioactive pseudopeptides bearing a CF₂H group.
  
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3. Scheme 1: Synthesis of difluoromethyl-containing pseudopeptides (4a–m) by Ugi reaction and desulfanylation.
  
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4. Scheme 2: The Ugi reaction of aniline, benzaldehyde, (isocyanomethyl)benzene with acetic acid, difluoroacetic...
  
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5. Scheme 3: Synthesis of 2,2-difluoro-2-(phenylthio)acetic acid (2).
  
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Beilstein J. Org. Chem. 2011, 7, 1070–1074, doi:10.3762/bjoc.7.123

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Multicomponent synthesis of artificial nucleases and their RNase and DNase activity

Anton V. Gulevich,
Lyudmila S. Koroleva,
Olga V. Morozova,
Valentina N. Bakhvalova,
Vladimir N. Silnikov and
Valentine G. Nenajdenko

Full Research Paper
Published 19 Aug 2011

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1. Graphical Abstract
2. Figure 1: Novel artificial RNases based on amino acids.
  
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3. Scheme 1: Multicomponent approach to target molecules.
  
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4. Scheme 2: Synthesis of starting diisocyanides 3a–3e.
  
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5. Scheme 3: Synthesis of new aRNAses. Conditions: a. RCHO (3 eqiuv), BnNH₂ (3 equiv), PhP(OH)₂ (1 equiv), r.t.;...
  
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6. Figure 2: Results of RT-qPCR of the TBEV RNA cleavage products in presence of 2.5 mM peptidomimetics 5a–g at ...
  
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7. Figure 3: Results of RT-qPCR of the TBEV RNA cleavage products in the presence of 2.5 mM peptidomimetics afte...
  
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8. Figure 4: Results of electrophoresis in 2% TBE-agarose gel with ethidium bromide of RT-qPCR products from Figure 3. (...
  
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Beilstein J. Org. Chem. 2011, 7, 1135–1140, doi:10.3762/bjoc.7.131

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One-pot four-component synthesis of pyrimidyl and pyrazolyl substituted azulenes by glyoxylation–decarbonylative alkynylation–cyclocondensation sequences

Charlotte F. Gers,
Julia Rosellen,
Eugen Merkul and
Thomas J. J. Müller

Full Research Paper
Published 26 Aug 2011

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1. Graphical Abstract
2. Scheme 1: Selected resonance structures of azulene (1a) and structure of the sesquiterpene guaiazulene (1b).
  
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3. Scheme 2: Synthesis of ynones by glyoxylation–decarbonylative Sonogashira coupling.
  
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4. Scheme 3: Retrosynthetic analysis of N-heterocyclic substituted azulenes by a one-pot four-component approach....
  
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5. Scheme 4: Three-component synthesis of azulenyl- and guaiazulenylynones 3 by glyoxylation–decarbonylative Son...
  
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6. Scheme 5: Four-component synthesis of pyrimidylazulenes 5 by glyoxylation–decarbonylative Sonogashira couplin...
  
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7. Scheme 6: Four-component synthesis of pyrazolylazulenes 7 by glyoxylation–decarbonylative Sonogashira couplin...
  
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Beilstein J. Org. Chem. 2011, 7, 1173–1181, doi:10.3762/bjoc.7.136

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Synthesis of diverse dihydropyrimidine-related scaffolds by fluorous benzaldehyde-based Biginelli reaction and post-condensation modifications

Bruno Piqani and
Wei Zhang

Letter
Published 16 Sep 2011

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1. Graphical Abstract
2. Scheme 1: Synthesis of diverse dihydropyrimidine-related compounds.
  
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Beilstein J. Org. Chem. 2011, 7, 1294–1298, doi:10.3762/bjoc.7.150

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A straightforward approach towards combined α-amino and α-hydroxy acids based on Passerini reactions

Ameer F. Zahoor,
Sarah Thies and
Uli Kazmaier

Full Research Paper
Published 19 Sep 2011

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1. Graphical Abstract
2. Scheme 1: Passerini reactions of α,β-unsaturated aldehyde 5.
  
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3. Scheme 2: Passerini and Ugi reaction of saturated aldehyde 7.
  
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Beilstein J. Org. Chem. 2011, 7, 1299–1303, doi:10.3762/bjoc.7.151

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Ugi post-condensation copper-triggered oxidative cascade towards pyrazoles

Aurélie Dos Santos,
Laurent El Kaim,
Laurence Grimaud and
Caroline Ronsseray

Letter
Published 21 Sep 2011

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1. Graphical Abstract
2. Scheme 1: Copper-catalyzed oxidative cyclization of alkenyl hydrazone.
  
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3. Scheme 2: Pyrazolidinone 3a from Ugi adduct 2a.
  
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4. Scheme 3: Attempted reactions of N-methyl hydrazones.
  
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5. Scheme 4: Proposed mechanism.
  
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Beilstein J. Org. Chem. 2011, 7, 1310–1314, doi:10.3762/bjoc.7.153

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Amines as key building blocks in Pd-assisted multicomponent processes

Didier Bouyssi,
Nuno Monteiro and
Geneviève Balme

Review
Published 10 Oct 2011

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1. Graphical Abstract
2. Scheme 1: Synthesis of substituted amides.
  
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3. Scheme 2: Synthesis of ketocarbamates and imidazolones.
  
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4. Scheme 3: Access to β-lactams.
  
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5. Scheme 4: Access to β-lactams with increased structural diversity.
  
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6. Scheme 5: Synthesis of imidazolinium salts.
  
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7. Scheme 6: Access to the indenamine core.
  
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8. Scheme 7: Synthesis of substituted tetrahydropyridines.
  
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9. Scheme 8: Synthesis of more substituted tetrahydropyridines.
  
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10. Scheme 9: Synthesis of chiral tetrahydropyridines.
  
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11. Scheme 10: Preparation of α-aminonitrile by a catalyzed Strecker reaction.
  
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12. Scheme 11: Synthesis of spiroacetals.
  
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13. Scheme 12: Synthesis of masked 3-aminoindan-1-ones.
  
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14. Scheme 13: Synthesis of homoallylic amines and α-aminoesters.
  
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15. Scheme 14: Preparation of 1,2-dihydroisoquinolin-1-ylphosphonates.
  
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16. Scheme 15: Pyrazole elaboration by cycloaddition of hydrazines with alkynones generated in situ.
  
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17. Scheme 16: An alternative approach to pyrazoles involving hydrazine cycloaddition.
  
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18. Scheme 17: Synthesis of pyrroles by cyclization of propargyl amines.
  
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19. Scheme 18: Isoindolone and phthalazone synthesis by cyclization of acylhydrazides.
  
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20. Scheme 19: Sultam synthesis by cyclization of sulfonamides.
  
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21. Scheme 20: Synthesis of sulfonamides by aminosulfonylation of aryl iodides.
  
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22. Scheme 21: Pyrrolidine synthesis by carbopalladation of allylamines.
  
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23. Scheme 22: Synthesis of indoles through a sequential C–C coupling/desilylation–coupling/cyclization reaction.
  
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24. Scheme 23: Synthesis of indoles by a site selective Pd/C catalyzed cross-coupling approach.
  
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25. Scheme 24: Synthesis of isoindolin-1-one derivatives through a sequential Sonogashira coupling/carbonylation/h...
  
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26. Scheme 25: Synthesis of pyrroles through an allylic amination/Sonogashira coupling/hydroamination reaction.
  
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27. Scheme 26: Synthesis of indoles through a Sonogashira coupling/cyclofunctionalization reaction.
  
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28. Scheme 27: Synthesis of indoles through a one-pot two-step Sonogashira coupling/cyclofunctionalization reactio...
  
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29. Scheme 28: Synthesis of α-alkynylindoles through a Pd-catalyzed Sonogashira/double C–N coupling reaction.
  
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30. Scheme 29: Synthesis of indoles through a Pd-catalyzed sequential alkenyl amination/C-arylation/N-arylation.
  
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31. Scheme 30: Synthesis of N-aryl-2-benzylpyrrolidines through a sequential N-arylation/carboamination reaction.
  
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32. Scheme 31: Synthesis of phenothiazine derivatives through a one-pot palladium-catalyzed double C–N arylation i...
  
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33. Scheme 32: Synthesis of substituted imidazolidinones through a palladium-catalyzed three-component reaction of...
  
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34. Scheme 33: Synthesis of 2,3-diarylated amines through a palladium-catalyzed four-component reaction involving ...
  
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35. Scheme 34: Synthesis of rolipram involving a Pd-catalyzed three-component reaction.
  
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36. Scheme 35: Synthesis of seven-membered ring lactams through a Pd-catalyzed amination/intramolecular cyclocarbo...
  
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Graphical Abstract

Beilstein J. Org. Chem. 2011, 7, 1387–1406, doi:10.3762/bjoc.7.163

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Pseudo five-component synthesis of 2,5-di(hetero)arylthiophenes via a one-pot Sonogashira–Glaser cyclization sequence

Dominik Urselmann,
Dragutin Antovic and
Thomas J. J. Müller

Full Research Paper
Published 04 Nov 2011

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1. Graphical Abstract
2. Scheme 1: Concept of a Sonogashira–Glaser coupling sequence.
  
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3. Scheme 2: Concept of a Sonogashira–Glaser cyclization synthesis of 2,5-di(hetero)arylthiophenes.
  
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4. Scheme 3: Pseudo five-component Sonogashira–Glaser cyclization synthesis of symmetrical 2,5-di(hetero)arylthi...
  
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5. Figure 1: Symmetrical 2,5-di(hetero)arylthiophenes 2 synthesized via the one-pot pseudo five-component Sonoga...
  
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Beilstein J. Org. Chem. 2011, 7, 1499–1503, doi:10.3762/bjoc.7.174

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Synthesis of (−)-julocrotine and a diversity oriented Ugi-approach to analogues and probes

Ricardo A. W. Neves Filho,
Bernhard Westermann and
Ludger A. Wessjohann

Full Research Paper
Published 07 Nov 2011

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1. Graphical Abstract
2. Figure 1: Retrosynthetic scheme for (−)-julocrotine (1).
  
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3. Scheme 1: Reactions and conditions: (a) DCC, NHS, DMF 80 °C, 18 h, 76%. (b) Ph(CH₂)₂Br, K₂CO₃, acetone, r.t.,...
  
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4. Scheme 2: Reactions and conditions: (a) (CH₂O)_n, MeOH, r.t., 2 h then, RCOOH and t-BuNC, r.t., 18 h.
  
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5. Scheme 3: Reactions and conditions: (a) (CH₂O)_n, MeOH, r.t., 2 h then, (S)-2-methylbutanoic acid and 7, r.t. ...
  
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Graphical Abstract

Beilstein J. Org. Chem. 2011, 7, 1504–1507, doi:10.3762/bjoc.7.175

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Regioselectivity in the multicomponent reaction of 5-aminopyrazoles, cyclic 1,3-diketones and dimethylformamide dimethylacetal under controlled microwave heating

Kamal Usef Sadek,
Ramadan Ahmed Mekheimer,
Tahany Mahmoud Mohamed,
Moustafa Sherief Moustafa and
Mohamed Hilmy Elnagdi

Full Research Paper
Published 04 Jan 2012

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1. Graphical Abstract
2. Scheme 1: Microwave-assisted synthesis of 4 and 6.
  
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3. Figure 1: ORTEP diagram of compound 6a.
  
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4. Figure 2: ORTEP diagram of compound 5.
  
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5. Figure 3: ORTEP diagram of compound 6e.
  
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6. Figure 4: ORTEP diagram of compound 6g.
  
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7. Scheme 2: A proposed mechanism to account for the formation of products 6. The factors that determine the nat...
  
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Graphical Abstract

Beilstein J. Org. Chem. 2012, 8, 18–24, doi:10.3762/bjoc.8.3

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