Stereoselective continuous-flow alkylation of aldehydes in organocatalytic packed-bed reactors

The development of efficient catalytic enantioselective α-alkylations of carbonyl compounds has been for a long time a challenging task. Among the strategies for performing this reaction, the novel synthetic methodology employing stable carbenium ions catalyzed by MacMillan type chiral organocatalysts has attracted our attention. Given our experience in the synthesis of solid-supported chiral imidazolidinones, we set up a continuous flow system for the enantioselective alkylation of aldehydes. Performing the reaction under continuous flow conditions makes the process extremely attractive because of the several advantages that continuous-flow synthetic methods offer over traditional batch ones: more accurate control of process conditions, shorter reaction times, easier isolation of final products and straightforward scale-up. Silica-supported (A) and Polystyrene-supported (B) catalysts were synthesized and two packed-bed reactors were prepared. The first example of stereoselective continuous-flow α-alkylation of various aldehydes with 1,3-benzodithiolylium tetrafluoroborate was performed in flow reactors at room temperature affording the products with great productivity (higher than those obtained with homogenous catalyst) and excellent enantioselectivity.