Nitro‐Substituted Aryl Lithium Compounds in Microreactor Synthesis: Switch between Kinetic and Thermodynamic Control

Abstract

Be quick or take your time, depending on your goal: A microflow method for the generation and transformation of o‐, m‐, and p‐nitro‐substituted aryl lithium compounds enabled the selective use of either the kinetically or the thermodynamically preferred intermediate. In the example pictured, a residence time of 0.06 s at −48 °C led to the formation of 1, whereas 2 was obtained exclusively when the residence time was extended to 63 s.

A Catalyst‐Free Amination of Functional Organolithium Reagents by Flow Chemistry

“…[20] By using flow microreactors,the reaction time can be precisely adjusted to milliseconds or less,sothat reactions can either proceed or stop in accordance with the synthetic goal. [21] Herein, we report the design, preparation, and synthetic use of aminating reagents for the flow amination of functionalized organolithiums under mild reaction conditions (Scheme 1). Va rious in situ generated organolithiums were reacted with optimized aminating reagents in flow for C À N bond formation without using any catalysts.Inparticular, the amination of unstable organolithiums was achieved under mild reaction conditions within ashort reaction time by using flow microreactors.…”

Flow Technology for Organometallic-Mediated Synthesis

“…In striking contrast, running the flow microreactor system at higher temperature and for slightly longer residence times, the β-elimination reaction occurs and O-and S-functionalized arylalkynes can be prepared (Scheme 11). Another example on the use of flow microreactor for switching between kinetic and thermodynamic product can be found in the lithiation of nitroaryl bromides [26]. In fact, using an integrated flow microreactor system (Scheme 12) constitutes of two micromixers (M1 and M2) and two residence units (R1 and R2); the Br-Li exchange of 1-bromo-2,5-dimethoxy-3-nitrobenzene 22 led to a selective formation of the corresponding aryllithium using a residence time of 60 ms at −48°C.…”

Microreactor Technology in Lithium Chemistry

“…Moreover, the generation of m-or p-nitro-substituted aryllithium and arylmagnesium compounds has been reported to be impossible in a conventional manner [68]. In contrast, a flow microreactor enables the generation and reactions of o-, m-, and p-nitro-substituted aryllithium compounds without protecting the nitro group by choosing an appropriate temperature (0 or −28 • C) and short residence time (0.01 s) (Figure 17.7) [69]. Moreover, aryllithium compounds bearing highly reactive alkoxycarbonyl groups, such as ethoxycarbonyl or methoxycarbonyl groups and cyano groups, can also be generated and used for reactions with electrophiles [70][71][72].…”