Biginelli compounds

A surprisingly infrequent use of Biginelli compounds to make aromatic pyrimidines has also been reported. Dehydrogenation with ceric ammonium nitrate gave pyrimidinones 23 or pyrimidinediones 24, depending on conditions <06T9726>. 

Kappe CO, Uray G, Roschger P, Lindner W, Kratky C, Keller W (1992) Synthesis and reactions of Biginelli compounds. 5. Facile preparation and resolution of a stable 5-dihy-dropyrimidinecarboxylic acid. Tetrahedron 48 5473-5480... 

As a final example it should be mentioned that precondensed enones, prepared by standard Knoevenagel condensation of the aldehyde with the CH-acidic carbonyl component, when reacted with thioureas provided 1,3-thiazines 37, which are isomeric to thio-Biginelli compounds of the general formula 14 (see Figure 4.5). A published report describes the combinatorial synthesis of a library of 29 derivatives of thiazines 37 utilizing polymer-supported reagents and catalysts [168]. 

Scheme 4.12. Iso-Biginelli compounds (1,3-thiazines) via condensation of thioureas with enones.

The reaction of ethyl acetoacetate, benzaldehyde, and urea leads to ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-phenyl-5-pyrimidinecarboxylate. This reaction (the so called Biginelli reaction) was discovered over 100 years ago [93T6937], Interest in these dihydropyrimidines has increased rapidly mainly due to their close structural relationship to the pharmacologically important dihydropyridine calcium channel blockers of the nifedipine-type [93T6937], The dibromo (51) and monobromo derivatives (55) of the most simple Biginelli compounds mentioned above are readily obtained by bromination [93T6937], and the reactions of these derivatives with sodium azide have been studied recently [90LA505] [91 JCS(P1)1342],... 

Kappe, C. O., Falsone, S. F. Synthesis and reactions of Biginelli compounds. Part 12. Polyphosphate ester-mediated synthesis of dihydropyrimidines. Improved conditions for the Biginelli reaction. Synlett 1998, 718-720. 

Xia, M., Wang, Y.-G. Soluble polymer-supported synthesis of Biginelli compounds. Tetrahedron Lett. 2002, 43, 7703-7705. 

A novel and efficient task-specific ionic liquid synthesis of Biginelli compounds has been developed. Ionic liquid phase-bound acetoacetate reacted with urea or thiourea and various aldehydes in the presence of a cheap catalyst to afford ionic liquid phases supported 3,4-dihydropyrimidine-2-(thi)ones. The desired 3,4-dihydropy-rimidine-2-(thi)ones were easily cleaved from the ionic liquid phase by transesteri-flcation under mild conditions in good yields and high purity. The task-specific ionic liquid technology represents an attractive alternative to the classical solid- and... 

Selective protection of dihydropyrimidinones has been used in a novel approach to improve the synthesis of valuable Biginelli compounds with different substitution patterns [130]. This procedure has been successfully catalyzed by polymer-supported NjN-dimethylaminopyridine (PS-DMAP) (Scheme 16.85). This micro-... 

In the mechanism of the Biginelli synthesis [265], the rate-determining step is the acid-catalyzed formation of an acylimine 35 from aldehyde and urea. By N-protonation (or metal-N-coordination), the imine 35 is activated (as an iminium ion) and intercepted by the P-ketoester (as enol or metal enolate) to give rise to an open-chain ureide 36, which subsequently cyclizes (via the cyclic ureide 37 and its dehydration) to afford the dihydropyrimidinone 33. Biginelli compounds of type 33 have been synthesized independently in multistep sequences [266]. 

Monastrol (Figure 10), the most representative Biginelli adduct in anticancer drug development, showed to be a cell permeable molecule whose mechanism of action on cancer cells involves the selective inhibition of kinesin Eg5 [63]. Kinesin Eg5 is a motor enzyme that is responsible for the formation and maintenance of mitotic spindles. The inhibition of this enzyme activity by monastrol leads to the loss of chromosome alignments and bipolar spindle formation. The resulting "monastral phenotype" inspired scientists to name this specific Biginelli compound as monastrol [63]. Fluorastrol (Figure 10), a monastrol-derived Eg5 inhibitor, showed to be more potent... 

Biginelli compounds can also modulate the protein Hsp 70 [65]. DHPM-peptoid (Figure 10) is one of the most active Biginelli adducts on Hsp 70 [66]. This protein, known to be overexpressed in some cancer cell lines, is responsible for many cellular processes, such as rearrangement and transport of protein complex [66]. 

R) -enantiomers of Biginelli compounds such as 13 and 14 where shown to be more potent than the corresponding... 

D. Russowsky, R.F.S. Canto, S.A.A. Sanches, M.G.M. D Oca, A. de Fatima, R.A. PilU, L.K. Kohn, M.A. Antonio, J.E. de Carvalho, Synthesis and differential antiproliferative activity of Biginelli compounds against cancer cell lines monastrol, oxo-monastrol and oxygenated analogues, Bioorg. Chem. 34 (2006) 173-182. 

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