Knoevenagel condensation inhibitors

Compound (329), a potent inhibitor of dihydrofolate reductase, was synthesized by a Knoevenagel condensation of the ketone (326) with ethyl cyanoacetate to afford (327) in 28-81% yield. Catalytic hydrogenation of (327) over Pd/C gave almost exclusively the undesired endo isomer, whereas with lithium in liquid ammonia and phenol as proton donor the desired exo compound (328) was obtained in 71% yield.222 Knoevenagel condensation of benzaldehydes with malonodinitrile in the presence of a base leads to benzylidenemalonodinitriles. These compounds, especially the 2-chlorobenzylidenemalonodini-trile (CS, 330), are used as riot-control agents (sneeze and tear gas). 2,324... 

Merck described the S5mthesis of PDE4 inhibitor 107 as a potential antiinflammatory drug, the synthesis of which involved a Knoevenagel condensation between aldehyde 105 and benzyl oxadiazole 106 as the key step. The researchers were concerned about the possibility of the formation of olefin isomers in the condensation, due to the similar sterics of the phenyl and ox diazole rings. They found however, that by performing the reaction in isopropanol (in which both the starting aldehyde 105 and product 107 have limited solubility) the initially-formed mixture of olefin isomers equilibrates, and the desired product crystallizes out of the mixture to provide exclusively the desired isomer. 

A new diversification synthetic strategy of phosphinic peptide precursors of metaloprotease inhibitors, via Knoevenagel-type condensation and alkylation of active methylene phosphinic scaffolds, has been described (Scheme 103). ... 

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