Automated generation and reactions of 3-hydroxymethylindoles in continuous-flow microreactors.

An automated sequential approach for the generation and reactions of 3-hydroxymethylindoles in continuous-flow microreactors is described. Consecutive halogen-magnesium exchanges of four 3-iodoindoles followed by addition to three aldehydes provided twelve 3-hydroxymethylindoles in a multi-microreactor setup. The synthetic flow strategy could be coupled with an in line continuous liquid-liquid extraction workup protocol for each reaction. Further elaboration of each of these indoles within the fluidic setup was achieved by acid-catalysed nucleophilic substitutions with allyltrimethylsilane and methanol used as nucleophiles. Overall, a set of four 3-iodoindoles was converted into thirty-six indole derivatives by a range of transformations including iodo-magnesium exchange/electrophile trapping and acid-catalysed nucleophilic substitution in a fully automated sequential fashion.