External Flash Generation of Carbenoids Enables Monodeuteration of Dihalomethanes

Abstract

In this study, incorporation of one deuterium atom was achieved by H−D exchange of one of the two identical methylene protons in various dihalomethanes (halogen=Cl, Br, and I) through a rapid‐mixing microflow reaction of lithium diisopropylamide as a strong base and deuterated methanol as a deuteration reagent. Generation of highly unstable carbenoid intermediate and suppression of its decomposition were successfully controlled under high flow‐rate conditions. Monofunctionalization of diiodomethane afforded various building blocks composed of boryl, stannyl, and silyl groups. The monodeuterated diiodomethane, which served as a deuterated C1 source, was subsequently subjected to diverted functionalization methods to afford various products including biologically important molecules bearing isotope labelling at specific positions and homologation products with monodeuteration.

Reaction of Highly Volatile Organic Compounds with Organolithium Species in Flow Microreactor

“…It is well known that the mixing efficiency tends to be better at higher flow velocities, which aligns with our findings. 6 10c 15 Moreover, reducing the amount of methyl formate to 1.5 equiv still gave benzaldehyde 2a in over 80% yield at a total flow rate of higher than 7.9 mL/min. These observations demonstrate the clear impact of mixing efficiency in the flow microreactor system.…”

Flow Chemistry of Metal Carbenoid Species towards Selective Organic Synthesis

“…Nagaki, Okamoto, and co-workers systematically investigated the stability of dihalomethyllithium species (Scheme 7 ). 12a The least stable one, fluoroiodomethane, generates the carbenoid most efficiently at –40 °C with 82 milliseconds (ms) of residence time. 12b Diiodomethyllithium showed the second-highest decomposition rates, with efficient generation of carbenoid species at –40 °C with 0.98 second of residence time.…”

Expanding the Scope of C-Glycoside Synthesis from Unstable Organolithium Reagents Using Flow Microreactors

“…Therefore, we developed a novel synthetic methodology that utilizes a flow microreactor (FMR) system equipped with micrometer-scale mixers and reactors. − The FMR technology enables rapid mixing, efficient heat transfer, and precise control over the reaction time, thereby enhancing the selectivity, substrate scope, and yield of highly reactive organolithium reagents. Therefore, we envisaged that the FMR could overcome the limitations of C -glycoside synthesis.…”