Microreactor as enabling technology for taming highly reactive metal fluorocarbenoids

Fluorinated compounds have attracted a great deal of interest by scientists involved in many field of science and technology. However, despite their importance, the selective introduction of monofluoromethyl groups (-CH2F) into a small organic molecules is still a challenging task. The selective nucleophilic monofluoromethylation could be accomplished through two main strategies: a) the direct transfer of a “CH2F” moiety into organic molecules; b) the transfer of the fluorinated group linked to a suitable auxiliary which should be removed at the end of the sequence. To date, the limited chemical stability of fluoromethyl carbanions has been efficiently overcome by taking advantage of the stabilizing effect displayed by strong electron-withdrawing functionalities. In striking contrast, the use of a simple M-CH2-F reagent (M = metal) would represent a straightforward method for the direct one-pot functionalization of a given electrophile. Nevertheless, fluorocarbenoid is still considered the "beast" in carbenoid chemistry due to its chemical instability that severely limited its use in synthetic processes. In this communication, we report how the use of engineered PI microreactors and flash chemistry allowed for the generation and use of metal fluorocarbenoids under “external quenching conditions” which seems to be prohibitive under traditional batch conditions.