Application of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane derivatives in asymmetric organocatalysis: the Biginelli reaction

This report describes the application of three chiral bicyclic diamines as organocatalysts in the enantioselective Biginelli reaction. The product in this reaction is 3,4-dihydropyrimidin-2(1H)-one (DHPM), a heterocycle of great importance owing to its interesting biological activity. It was found that (1S,4S)-2,5-diazabicyclo[2.2.1] heptane center dot 2HBr (1) and its N-methylated derivative 2 effectively catalyze the reaction between ethyl acetoacetate, representative aromatic aldehydes, and urea to afford the expected DHPMs in good yields and moderate enantioselectivities, 18-37% ee, favoring the (S) enantiomer (like enantioinduction). Better yields (up to 94%) and slightly higher enantiomeric excess (up to 46% ee) of the desired DHPMs were obtained in the presence of 10 mol% of the hydrobromide salt (1S,4S)-2-[(R)-1-phenylethyl]-2,5-diazabicyclo[2.2.1] heptane center dot 2HBr (3).