Organocatalytic direct aldol reaction between acetone and α-substituted β-keto esters

The organocatalytic aldol reaction between acetone and α-substituted β-keto esters is presented. The α-unsubstituted or α-chloro ethyl acetoacetates failed to react with acetone when l-proline was used as catalyst. l-Proline or other optically pure pyrrolidine derivatives catalyzed the direct aldol reaction of acetone and α-fluorinated β-keto esters affording δ-keto-β-hydroxy-α-fluoro esters in high yields. Both the α-fluoro- and α,α-difluoro-β-keto esters functioned as aldol acceptors in these reactions. High ee values, up to 83% coupled with low diastereoselectivities were obtained in the reaction of ethyl 2-fluoroacetoacetate. Our study revealed a novel extension of the scope of the organocatalytic direct aldol reaction catalyzed by chiral organic bases, being the first report in which an asymmetric organocatalytic fluoroketone–ketone aldol addition has been described.

Graphical abstractThe l-proline catalyzed direct aldol addition of acetone on α-fluorinated β-keto esters afforded δ-keto-β-hydroxy-α-fluoro esters in high yields. In the reaction of ethyl 2-fluoroacetoacetate good enantiomeric excesses, up to 83%, coupled with low diastereoselectivities were obtained. Figure optionsDownload full-size imageDownload as PowerPoint slide