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.
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References
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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.
C. O. Kappe and A. Stadler, in: Microwaves in Organic Synthesis, ed. A. Loupy (Wiley-VCH, Weinheim, 2002), pp. 405–433.
C. O. Kappe and A. Stadler, in: Microwaves in Organic Synthesis, 2nd ed., ed. A. Loupy (Wiley-VCH, Weinheim, 2006), pp. 726–787.
C. O. Kappe, in: Comprehensive Medicinal Chemistry II, ed. D. Triggle and J. Taylor (Elsevier, Oxford, 2006), Vol. 3, pp. 79–836.
C. O. Kappe and D. Dallinger, The impact of microwave synthesis on drug discovery, Nature Rev. Drug Discov. 5, 51–63 (2006).
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.
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For online resources on microwave-assisted organic synthesis (MAOS), see:www.maos.net and www.microwavesynthesis.net.
C. O. Kappe, Biologically active dihydropyrimidones of the Biginelli-type. A literature survey, Eur. J. Med. Chem. 35, 1043–1052 (2000).
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).
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.
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).
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).
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).
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).
C. O. Kappe and A. Stadler, in: Combinatorial Chemistry, ed B. B. Bunin and G. Morales (Elsevier Sciences, 2003), Part B, pp. 197–223.
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).
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).
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).
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).
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).
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).
N. Stiasni and C. O. Kappe, A tandem intramolecular Michael-addition/elimination sequence in dihydropyrimidone to quinoline rearrangements, ARKIVOC (8), 71–79 (2002).
B. Desai and C. O. Kappe, Heterogeneous hydrogenation reactions using a continuous flow high pressure device, J. Comb. Chem. 7, 641–643 (2005).
B. Desai, D. Dallinger, and C. O. Kappe, Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters, Tetrahedron 62, 4651–4664 (2006).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
P. Walla and C. O. Kappe, Microwave-assisted Negishi and Kumada cross-coupling reactions of aryl chlorides, Chem. Commun. 564–565 (2004).
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).
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).
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).
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).
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).
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).
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).
A. Stadler and C. O. Kappe, The effect of microwave irradiation on carbodiimide-mediated esterifications on solid-support, Tetrahedron 57, 3915–3920 (2001).
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).
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).
B. Basca, B, Desai, G. Dibo, and C. O. Kappe (submitted for publication).
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).
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Kappe, C.O. et al. (2008). Adventures In Microwave-assisted Organic Synthesis: Contributions From The Kappe Laboratory 2000–2005. In: Mordini, A., Faigl, F. (eds) New Methodologies and Techniques for a Sustainable Organic Chemistry. NATO Science Series II: Mathematics, Physics and Chemistry, vol 246. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-6793-8_11
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