Adventures In Microwave-assisted Organic Synthesis: Contributions From The Kappe Laboratory 2000–2005

Conference paper
Part of the NATO Science Series II: Mathematics, Physics and Chemistry book series (NAII, volume 246)

This review highlights work in the field of microwave-assisted organic synthesis (MAOS) originating from the Kappe research laboratories in Graz, Austria. The focus of the article is on synthetic applications in the area of heterocyclic chemistry, multicomponent reactions, transition metalcatalyzed processes, solid-phase synthesis and combinatorial chemistry.


multicomponent reactions microwave heating homogeneous catalysis solid-phase synthesis 


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  1. 1.
    D. Adam, Microwave chemistry: out of the kitchen, Nature 421, 571–572 (2003).CrossRefGoogle Scholar
  2. 2.
    V. Marx, Riding the microwave, Chem. Eng. News 82 (50), 14–19 (2004).Google Scholar
  3. 3.
    R. Gedye, F. Smith, K. Westaway, H. Ali, L. Baldisera, L. Laberge, and J. Rousell, The use of microwave ovens for rapid organic synthesis, Tetrahedron Lett. 27, 279–282 (1986).CrossRefGoogle Scholar
  4. 4.
    R. J. Gigurere, T. L. Bray, S. M. Duncan, and G. Majetich, Application of commercial microwave ovens to organic synthesis, Tetrahedron Lett. 27, 4945–4948 (1986).CrossRefGoogle Scholar
  5. 5.
    C. O. Kappe, Controlled microwave heating in modern organic synthesis, Angew. Chem. Int. Ed. 43, 6250–6284 (2004), more than 30 review articles published between 1991 and 2004 are cited in this publication.CrossRefGoogle Scholar
  6. 6.
    B. L. Hayes, Recent advances in microwave-assisted synthesis, Aldrichim. Acta 37, 66–77 (2004); A. De La Hoz, A. Diaz-Ortiz, and A. Moreno, Microwaves in organic synthesis. Thermal and non-thermal microwave effects, Chem. Soc. Rev. 34, 164–178 (2005).CrossRefGoogle Scholar
  7. 7.
    Microwaves in Organic Synthesis, ed. A. Loupy (Wiley-VCH, Weinheim, 2002); B. L. Hayes, Microwave Synthesis: Chemistry at the Speed of Light (CEM Publishing, Matthews, NC, 2002); Microwave-Assisted Organic Synthesis, ed. P. Lidsström and J. P. Tierney (Blackwell Publishing, Oxford, 2005).Google Scholar
  8. 8.
    C. O. Kappe and A. Stadler, Microwaves in Organic and Medicinal Chemistry (Wiley-VCH, Weinheim, 2005).CrossRefGoogle Scholar
  9. 9.
    Microwave Assisted Synthesis of Heterocycles, ed. E. Van der Eycken and C. O. Kappe (Springer, Heidelberg, 2006).Google Scholar
  10. 10.
    C. O. Kappe, High-speed combinatorial synthesis utilizing microwave irradiation, Curr. Opin. Chem. Biol. 6, 314–320 (2002); Microwaves in Combinatorial and High-Throughput Synthesis, ed. C. O. Kappe (Kluwer, Dordrecht, 2003), a special issue of Molecular Division.CrossRefGoogle Scholar
  11. 11.
    C. O. Kappe and A. Stadler, in: Microwaves in Organic Synthesis, ed. A. Loupy (Wiley-VCH, Weinheim, 2002), pp. 405–433.CrossRefGoogle Scholar
  12. 12.
    C. O. Kappe and A. Stadler, in: Microwaves in Organic Synthesis, 2nd ed., ed. A. Loupy (Wiley-VCH, Weinheim, 2006), pp. 726–787.Google Scholar
  13. 13.
    C. O. Kappe, in: Comprehensive Medicinal Chemistry II, ed. D. Triggle and J. Taylor (Elsevier, Oxford, 2006), Vol. 3, pp. 79–836.Google Scholar
  14. 14.
    C. O. Kappe and D. Dallinger, The impact of microwave synthesis on drug discovery, Nature Rev. Drug Discov. 5, 51–63 (2006).CrossRefGoogle Scholar
  15. 15.
    C. O. Kappe, Speeding up solid-phase chemistry by microwave irradiation. A new tool for high-throughput synthesis, American Laboratory, 33(10), 13–19; A. Stadler and C. O. Kappe, in: Microwave-Assisted Organic Synthesis, ed P. Lidstöm and J. P. Tierney (Blackwell Publishing, Oxford, 2005), pp. 175–219.Google Scholar
  16. 16.
    B. Desai and C. O. Kappe, in Topics in Current Chemistry, ed A. Kirschning (Springer, Heidelberg, 2004), pp. 177–207.Google Scholar
  17. 17.
    For online resources on microwave-assisted organic synthesis (MAOS), and
  18. 18.
    C. O. Kappe, Biologically active dihydropyrimidones of the Biginelli-type. A literature survey, Eur. J. Med. Chem. 35, 1043–1052 (2000).CrossRefGoogle Scholar
  19. 19.
    For reviews, see: C. O. Kappe, 100 years of the Biginelli dihydropyrimidine synthesis, Tetrahedron, 49, 6937–6963 (1993); C. O. Kappe, 4-Aryldihydropyrimidines via the Biginelli condensation: Aza-analogs of Nifedipine-type calcium channel modulators, Molecules 3, 1–9 (1998); C. O. Kappe, Recent advances in the Biginelli dihydropyrimidine synthesis. New tricks from an old dog, Acc. Chem. Res. 33, 879–888 (2000).Google Scholar
  20. 20.
    C. O. Kappe and A. Stadler, in: Organic Reactions, ed. L. E. Overman (Organic Reactions Inc., 2004), 63, pp 1–117; C. O. Kappe, in: Multicomponent Reactions, ed. J. Zhu and H. Bienaymé (Wiley-VCH, Weinheim, 2005), pp. 95–120.Google Scholar
  21. 21.
    For a discussion of the mechanism of the Biginelli reaction, see: C. O. Kappe, A reexamination of the mechanism of the Biginelli dihydropyrimidine synthesis. Support for an N-acyliminium ion intermediate, J. Org. Chem. 62, 7201–7204 (1997).Google Scholar
  22. 22.
    C. O. Kappe, D. Kumar, and R. S. Varma, Microwave-assisted high-speed parallel synthesis of 4-aryl-3, 4-dihydropyrimidin-2(1H)-ones using a solventless Biginelli condensation protocol, Synthesis 1799–1803 (1999); C. O. Kappe, O. V. Shishkin, G. Uray, and P. Verdino, X-Ray structure, conformational analysis, enantioseparation, and determination of absolute configuration of the mitotic kinesin Eg5 inhibitor monastrol, Tetrahedron 56, 1859–1862 (2000).Google Scholar
  23. 23.
    A. Stadler and C. O. Kappe, Microwave-mediated Biginelli reactions revisited. On the nature of rate and yield enhancements, J. Chem. Soc., Perkin Trans. 2, 1363–1368 (2000).Google Scholar
  24. 24.
    A. Stadler and C. O. Kappe, Automated library generation using sequential microwave-assisted chemistry. Application toward the Biginelli multicomponent condensation, J. Comb. Chem. 3, 624–630 (2001).CrossRefGoogle Scholar
  25. 25.
    C. O. Kappe and A. Stadler, in: Combinatorial Chemistry, ed B. B. Bunin and G. Morales (Elsevier Sciences, 2003), Part B, pp. 197–223.Google Scholar
  26. 26.
    A. Stadler, B. H. Yousefi, D. Dallinger, P. Walla, E. Van der Eycken, N. Kaval, and C. O. Kappe, Scalability of microwave-assisted organic synthesis. From single-mode to multimode parallel batch reactors, Org. Process Res. Dev. 7, 707–716 (2003).CrossRefGoogle Scholar
  27. 27.
    T. N. Glasnov, D. J. Vugts, M. M. Koningstein, B. Desai, W. M. F. Fabian, R. V. A. Orru, and C. O. Kappe, Microwave-assisted Dimroth rearrangement of thiazines to dihydropyrimidinethiones: synthetic and mechanistic aspects, QSAR Comb. Sci. 25, 509–518 (2006).CrossRefGoogle Scholar
  28. 28.
    A. Lengar and C. O. Kappe, Tunable carbon–carbon and carbon–sulfur cross-coupling of boronic acids with 3, 4-dihydropyrimidine-2-thiones, Org. Lett. 6, 771–774 (2004).CrossRefGoogle Scholar
  29. 29.
    J. Wannberg, D. Dallinger, C. O. Kappe, and M. Larhed, Novel microwave-enhanced and metal-catalyzed functionalizations of the 4-aryl-dihydropyrimidone template, J. Comb. Chem. 7, 574–583 (2005).CrossRefGoogle Scholar
  30. 30.
    D. Dallinger, N. Y. Gorobets, and C. O. Kappe, High-throughput synthesis of N3-acylated dihydropyrimidines combining microwave-assisted synthesis and scavenging techniques, Org. Lett. 5, 1205–1208 (2003).CrossRefGoogle Scholar
  31. 31.
    D. Dallinger, N. Y. Gorobets, and C. O. Kappe, Microwave-assisted scavenging of electrophiles utilizing polymer-supported sequestration reagents. Application to the synthesis of N3-acylated dihydropyrimidine libraries, Mol. Diversity 7, 229–245 (2003).CrossRefGoogle Scholar
  32. 32.
    N. Stiasni and C. O. Kappe, A tandem intramolecular Michael-addition/elimination sequence in dihydropyrimidone to quinoline rearrangements, ARKIVOC (8), 71–79 (2002).Google Scholar
  33. 33.
    B. Desai and C. O. Kappe, Heterogeneous hydrogenation reactions using a continuous flow high pressure device, J. Comb. Chem. 7, 641–643 (2005).CrossRefGoogle Scholar
  34. 34.
    B. Desai, D. Dallinger, and C. O. Kappe, Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters, Tetrahedron 62, 4651–4664 (2006).CrossRefGoogle Scholar
  35. 35.
    B. Khanetskyy and D. Dallinger, and C. O. Kappe, Combining Biginelli multicomponent and click chemistry: generation of 6-(1, 2, 3-triazol-1-yl)-dihydropyrimidone libraries, J. Comb. Chem. 6, 884–892 (2004).CrossRefGoogle Scholar
  36. 36.
    R. Pérez, T. Beryozkina, O. I. Zbruyev, W. Haas, and C. O. Kappe, Traceless solid phase synthesis of bicyclic dihydropyrimidones using multidirectional cyclization cleavage, J. Comb. Chem. 4, 501–510 (2002).CrossRefGoogle Scholar
  37. 37.
    G. A. Strohmeier and C. O. Kappe, Rapid parallel synthesis of polymer-bound enones utilizing microwave-assisted solid-phase chemistry, J. Comb. Chem. 4, 154–161 (2002).CrossRefGoogle Scholar
  38. 38.
    N. Yu. Gorobets, B. H. Yousefi, F. Belaj, and C. O. Kappe, Rapid microwave-assisted solution phase synthesis of substituted 2-pyridone libraries, Tetrahedron 60, 8633–8644 (2004).CrossRefGoogle Scholar
  39. 39.
    N. Mont, J. Teixidó, J. I. Borrell, and C. O. Kappe, A three-component synthesis of pyrido[2, 3-d]pyrimidines, Tetrahedron Lett. 44, 5385–5387 (2003).CrossRefGoogle Scholar
  40. 40.
    N. Mont, J. Teixidó, J. I. Borrell, and C. O. Kappe, A one-pot microwave-assisted synthesis of pyrido[2, 3-d]pyrimidines, Mol. Diversity 7, 153–159 (2003).CrossRefGoogle Scholar
  41. 41.
    N. Mont, L. Fernández-Megido, J. Teixidó, C. O. Kappe, and J. I. Borrell, A diversity-oriented, microwave-assisted synthesis of 4-oxo and 4-chloropyrido[2, 3-d]pyrimidin-7(8H)-ones, QSAR Comb. Sci. 23, 836–849 (2004).CrossRefGoogle Scholar
  42. 42.
    O. I. Zbruyev, N. Stiasni, and C. O. Kappe, Rapid preparation of thioamide building blocks via microwave-promoted three-component Kindler reactions, J. Comb. Chem. 5, 145–148 (2003).CrossRefGoogle Scholar
  43. 43.
    A. Stadler, S. Pichler, G. Horeis, and C. O. Kappe, Microwave-assisted reactions under open and closed vessel conditions. A case study, Tetrahedron 58, 3177–3183 (2002).CrossRefGoogle Scholar
  44. 44.
    T. N. Glasnov, W. Stadlbauer, and C. O. Kappe, Microwave-assisted multistep synthesis of functionalized 4-arylquinolin-2(1H)-ones using palladium-catalyzed cross-coupling chemistry, J. Org. Chem. 70, 3864–3870 (2005).CrossRefGoogle Scholar
  45. 45.
    J. J. Vanden Eynde, N. Hecq, O. Kataeva, and C. O. Kappe, Microwave-mediated regioselective synthesis of novel pyrimido[1, 2-a]pyrimidines under solvent-free conditions, Tetrahedron 57, 1785–1791 (2001).CrossRefGoogle Scholar
  46. 46.
    E. Van der Eycken, P. Appukkuttan, W. De Borggraeve, W. Dehaen, D. Dallinger, and C. O. Kappe, High-speed microwave-promoted hetero-Diels–Alder reactions of 2(1H)-pyrazinones in ionic liquid doped solvents, J. Org. Chem. 67, 7904–7907 (2002).CrossRefGoogle Scholar
  47. 47.
    N. Kaval, W. Dehaen, C. O. Kappe, and E. Van der Eycken, The effect of pressure on microwave-enhanced Diels–Alder reactions. A case study, Org. Biomol. Chem. 2, 154–156 (2004).CrossRefGoogle Scholar
  48. 48.
    N. Kaval, E. Van der Eycken, J. Caroen, W. Dehaen, G. A. Strohmeier, C. O. Kappe, and E. Van der Eycken, An exploratory study on microwave-assisted solid-phase Diels–Alder reactions of 2(1H)-pyrazinones: the elaboration of a new tailor-made acid-labile linker, J. Comb. Chem. 5, 560–568 (2003).CrossRefGoogle Scholar
  49. 49.
    N. Kaval, K. Bisztray, W. Dehaen, C. O. Kappe, and E. Van der Eycken, Microwave-enhanced transition metal-catalyzed decoration of 2(1H)-pyrazinone scaffolds, Mol. Diversity 7, 125–133 (2003).CrossRefGoogle Scholar
  50. 50.
    N. Kaval, D. Ermolat’ev, P. Appukkuttan, W. Dehaen, C. O. Kappe, and E. Van der Eycken, The application of “click chemistry” for the decoration of the 2 (1H)-pyrazinone scaffold: generation of new interesting templates, J. Comb. Chem. 7, 490–502 (2005).CrossRefGoogle Scholar
  51. 51.
    A. M. G. Silva, A. C. Tomé, A. M. G. P. M. Neves, J. A. S. Cavaleiro, and C. O. Kappe, Porphyrins in Diels–Alder reactions. Improvements on the synthesis of a barrelene-fused chlorin using controlled microwave irradiation, Tetrahedron Lett. 46, 4723–4726 (2005).CrossRefGoogle Scholar
  52. 52.
    P. Walla and C. O. Kappe, Microwave-assisted Negishi and Kumada cross-coupling reactions of aryl chlorides, Chem. Commun. 564–565 (2004).Google Scholar
  53. 53.
    K. Krascsenicsováa, P. Walla, P. Kasáka, G. Uray, C. O. Kappe, and M. Putala, Stereoconservative Negishi arylation and alkynylation as an efficient approach to enantiopure 2, 2′-diarylated 1, 1′-binaphthyls, Chem. Commun. 2606–2607 (2004).Google Scholar
  54. 54.
    A. Stadler and C. O. Kappe, Rapid formation of triarylphosphines by microwave-assisted transition metal-catalyzed C-P cross-coupling reactions, Org. Lett. 4, 3541–3543 (2002).CrossRefGoogle Scholar
  55. 55.
    S. Garbacia, B. Desai, O. Lavastre, and C. O. Kappe, Microwave-assisted ring-closing metathesis revisited. On the question of the non-thermal microwave effect, J. Org. Chem. 68, 9136–9139 (2003).CrossRefGoogle Scholar
  56. 56.
    A. Steinreiber, A. Stadler, S. F. Mayer, K. Faber, and C. O. Kappe, High-speed microwave-promoted Mitsunobu inversions. application to the deracemization of sulcatol, Tetrahedron Lett. 42, 6283–6286 (2001).CrossRefGoogle Scholar
  57. 57.
    V. A. Chebanov, C. Reidlinger, H. Kanaani, C. Wentrup, C. O. Kappe, and G. Kollenz, Novel macrocyclic systems containing 2, 6, 9-trioxabicyclo[3.3.1]nona-3, 7-dienes as chiral spacer groups. Synthesis, stereochemical features and preliminary complexation properties, Supramol. Chem. 16, 121–127 (2004).CrossRefGoogle Scholar
  58. 58.
    J. M. Kremsner and C. O. Kappe, Microwave-assisted organic synthesis in near-critical water at 300°C. A proof-of-concept study, Eur. J. Org. Chem. 3672–3679 (2005).Google Scholar
  59. 59.
    A. Stadler and C. O. Kappe, High-speed couplings and cleavages in microwave-heated, solid-phase reactions at high temperatures, Eur. J. Org. Chem. 919–925 (2001).Google Scholar
  60. 60.
    A. Stadler and C. O. Kappe, The effect of microwave irradiation on carbodiimide-mediated esterifications on solid-support, Tetrahedron 57, 3915–3920 (2001).CrossRefGoogle Scholar
  61. 61.
    G. A. Strohmeier, W. Haas, and C. O. Kappe, Synthesis of functionalized 1, 3-thiazine libraries combining solid-phase synthesis and post-cleavage modification methods, Chem. Eur. J. 10, 2919–2926 (2004).CrossRefGoogle Scholar
  62. 62.
    See also: G. A. Strohmeier and C. O. Kappe, Combinatorial synthesis of functionalized 1, 3-thiazine libraries using a combined polymer-supported reagent/catch-and-release strategy, Angew. Chem. Int. Ed. 43, 621–624 (2004); G. A. Strohmeier, C. Reidlinger, and C. O. Kappe, Selective polymer-assisted product sequestration for the generation of combinatorial libraries of 1, 3-thiazines, QSAR Comb. Sci. 24, 364–377 (2005).Google Scholar
  63. 63.
    B. Basca, B, Desai, G. Dibo, and C. O. Kappe (submitted for publication).Google Scholar
  64. 64.
    U. Kunz, A. Kirschning, H. L. Wen, W. Solodenko, R. Cecilia, C. O. Kappe, and T. Turek, Monolithic polymer/carrier materials: versatile composites for fine chemical synthesis, Catal. Today 105, 318–324 (2005).CrossRefGoogle Scholar

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© Springer Science + Business Media B.V 2008

Authors and Affiliations

  1. 1.Institute of ChemistryKarl-Franzens University GrazAustria

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