Stereoselective Knoevenagel reaction between pyrimidine carbaldehyde bearing an adjacent aryl group and active cyano-containing methylene compounds

The Knoevenagel reaction between cyanoacetic acid and 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-5-pyrimidinecarboxaldehyde (1), which contains an aryl group adjacent to the formyl group in the pyrimidine-5-carbaldehyde moiety, was found to proceed stereoselectively to give an alkene product bearing cyano and phenyl groups in a cis relationship. Similar selective reactions also occurred between 1 and several active methylene compounds bearing a cyano group. An X-ray structure analysis of the alkene products and molecular orbital calculations suggested that the attractive CN/π interaction between the cyano and 4-fluorophenyl groups of 1 plays an important role in the selectivity by stabilizing the carbocation intermediates.