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Rapid Scaffold Decoration of Dihydropyrimidine Derivatives by Microwave-Assisted Solution Phase Synthesis

Doris Dallinger, Alenka Lengar, Bogdan Khanetskyy, Bimbisar Desai and C. Oliver Kappe, Karl-Franzens-University Graz

Date Posted: Thursday, September 21, 2006

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Abstract
The exploration of privileged structures in drug discovery is a rapidly emerging theme in medicinal chemistry. In the last decade a considerable amount of attention has focused on multicomponent condensation reactions (MCRs) of the Biginelli type.1

The heterocyclic pyrimidine derivatives(DHPMs) derived from the acid-catalyzed condensation of a ß-ketoester, aldehyde and (thio)urea building block (Biginelli condensation) represents a “privileged scaffold” with remarkable pharmacological properties.2  We have previously reported the generation of libraries of DHPMs, employing an automated, sequential microwave-assisted solution phase strategy.3

This presenation describes high-speed microwave scaffold decorations around the DHPM heterocyclic core exploiting the diversity on at least six positions around the scaffold4 of the DHPM heterocycle.

This opens up the preparations of a very large number of highly diverse analogs given the commercial availability of the building blocks that are used in the functionalization process. The use of resin-bound catalysts, reagents, and scavengers in conjunction with microwave heating will also be covered.

1)  Kappe, C. O. "Recent Advances in the Biginelli Dihydropyrimidine Synthesis. New Tricks from an Old Dog", Acc. Chem. Res. 2000, 33, 879. Kappe, C. O. “The Generation of Dihydropyrimidine Libraries Utilizing Biginelli Multicomponent Chemistry“, QSAR Comb. Sci. 2003, 22, 630.
2) Kappe, C. O. “Biologically Active Dihydropyrimidones of the Biginelli-Type. A Literature Survey”, Eur. J. Med. Chem. 2000, 35, 1043.
3)  Stadler, A.; Kappe, C. O. "Automated Library Generation Using Sequential Microwave-Assisted Chemistry. Application Toward the Biginelli Multicomponent Condensation", J. Comb. Chem. 2001, 3, 624.
4) Dallinger, D.; Kappe, C. O. “Selective N 1-Alkylationof 3,4-Dihydropyrimidin-2(1H)-ones Using Mitsunobu-Type Conditions”, Synlett 2002, 1901. Dallinger, D.; Gorobets, N. Yu.; Kappe, C. O. “High-Throughput Synthesis of N3-Acylated Dihydropyrimidines Combining Microwave-Assisted Synthesis and Scavenging Techniques”, Org. Lett. 2003, 5, 1205. A. Lengar, C. O. Kappe, “Tunable Carbon–Carbon and Carbon–Sulfur Cross–Coupling of Boronic Acids with 3,4-Dihydropyrimidine-2-thiones”, Org. Lett. 2004, 6, 771

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