Verification of preparations of (1H-indol-3-yl)methyl electrophiles and development of their microflow rapid generation and substitution

Although highly reactive (1 H -indol-3-yl)methyl electrophiles such as (1 H -indol-3-yl)methyl halides are potential precursors for the synthesis of various indole derivatives, some researchers have reported difficulties in their preparation due to concomitant undesired dimerization/oligomerization. Nevertheless, there have been some reports on the preparation of (1 H -indol-3-yl)methyl halides. To resolve this contradiction, all the previously reported preparations of (1 H -indol-3-yl)methyl halides were examined. However, we could not reproduce any of these preparations, and we revised several structures of indole derivatives. Here we show the rapid (0.02 s) and mild (25 °C) generation of an (1 H -indol-3-yl)methyl electrophile that enables the rapid (0.1 s) and mild (25 °C) nucleophilic substitution in a microflow reactor. Eighteen unprotected indole analogues can be successfully synthesized using the developed microflow nucleophilic substitution with various nucleophiles. (1 H -indol-3-yl)methyl electrophiles are potential precursors for the synthesis of indole derivatives, however, their preparation remains challenging and only a few syntheses have been reported so far. Here, the authors examine previously reported preparations, clarify inconsistencies within the literature, and develop a highly versatile nucleophilic substitution at the indole 3’-position using microflow technologies.