External Trapping of Halomethyllithium Enabled by Flow Microreactors

Abstract

This work demonstrates that the accurate control of the reaction parameters realized within microreactor systems allowed for a taming of the reactivity of thermally unstable intermediates such as haloalkyllithiums. The first example of effective external trapping of a reactive carbenoid such as the chloromethyllithium is described. By using microreactor systems, a continuous flow synthesis of chloro alcohols and chloro amines could be achieved with high yields. By controlling the residence time the highly reactive chloromethyllithium could be generated and reacted with electrophiles at temperatures much higher than in batch-mode and without internal quenching. The developed continuous-flow process matches the requirements for sustainability.

Flow Technology for the Genesis and Use of (Highly) Reactive Organometallic Reagents

“…Luisi demonstrated that (chloromethyl)lithium could be generated in the absence of the electrophile (i.e. external quenching conditions) using a flow microreactor system . (Chloromethyl)lithium was generated from 8 , with MeLi as lithiating agent, using 0.18 s as residence time, and a reaction temperature of −40 °C, sensibly higher with respect to batch conditions.…”

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

“…In 2014, the first example of effective external trapping of a reactive chloromethyllithium (CML) has been reported [28]. α-Haloalkyllithiums are a useful class of organometallic reagents widely employed in synthetic chemistry.…”

Flow Technology for Organometallic-Mediated Synthesis

“…Luisi and Degennaro reported the first example of external trapping of the highly reactive chloromethyllithium enabled by a flow microreactor system [31]. This kind of halocarbenoids, Scheme 15.…”