Continuous Flow Generation of Highly Reactive Lithium-Fluorocarbenoids: A Straighforward Approach for Unprecedented Nucleophilic Fluoroalkylations

Fluorinated molecules find applications in medicinal chemistry, advanced materials sciences, and agrochemistry. Due to the ability of fluorination to dramatically change the physicochemical properties of organic molecules, the installation of fluoroalkyl groups is becoming a routine strategy in drug discovery programs aimed at improving both the pharmacokinetic and pharmacodynamic properties of a drug candidate. Consequently, the introduction of new synthetic tactics to access molecules with fluoroalkyl moieties is highly demanded. In this context, our group recently developed new fluorination strategies exploiting fluorinated lithium carbenoids. Recently, we demonstrated the usefulness of flow microreactor technology in fluoroakylations reporting an external quenching method based on flow microreactors that allow the generation and use of short-lived fluoro-substituted methyllithium species, namely fluoromethyllithium, fluoroiodomethyllithium, and fluoroiodostannylmethyllithium. In this contribution, we further establish the potential of flow microreactor technology in fluoroalkylation chemistry reporting the generation and use of secondary Li/F fluoroalkyllithiums. A careful investigation of the stability and reactivity of these fleeting intermediates will be described.