Continuous flow synthesis of cyclobutenes via lithium ynolates

Abstract

Batch reactions that involve the generation of highly reactive species require a cryogenic temperature, complicated manipulations by chemists, and higher amounts of reagents, resulting in energy wastage and high costs. In this study, we developed a continuous flow synthesis of functionalised cyclobutenes, where the first step was the flash generation of short-lived lithium ynolates. Lithium ynolates were generated by the reaction of α,α,α-tribromomethyl ketones and n-butyllithium at 30 °C in 2.5 s and transferred to the next reactor before decomposition. The optimal reaction time (2.5 s) and temperature (30 °C) were determined via in-line Raman spectroscopy. The one-flow process involved three steps: the generation of lithium ynolates, the [2 + 2] cycloaddition reaction with α,β-unsaturated esters, and acetylation of the resulting unstable lithium enolates. These reactions were mediated by several reactive chemical species such as lithium ynolates, ketenes, and lithium enolates. Our green, flash flow approach to generating ynolate anions does not require cryogenic conditions and is highly reproducible and scalable, making it suitable for practical applications.