Mannich reaction with organozinc reagents in continuous flow: experimental and computational studies

Herein, we report a fully continuous flow version of a Mannich reaction using organozinc reagents. These organometallics were generated in situ in a packed-bed reactor and subsequently introduced in a 1 mL chip to react with an array of substituted aldehydes and primary amines. The highly substituted amine products were obtained in moderate to good yields within 5 minutes and under mild conditions, thereby reducing reaction times. DFT studies suggest the participation of organometallic dimers as nucleophiles, responsible for C-C bond formation through an S_N1 reaction pathway.