Synthesis of Functionalized Aryl Fluorides Using Organolithium Reagents in Flow Microreactors

Abstract

Flow on: Flow microreactors enable the generation of aryl lithium compounds and subsequent electrophilic fluorination with NFSI and N‐fluorosultam. The reaction can be successfully accomplished to synthesize various aryl fluorides involving an electron‐withdrawing, an electron‐donating, and a sterically hindered functional group in good yields.

Flow microreactor synthesis in organo-fluorine chemistry

“…As an alternative method for aromatic fluorination, Yoshida and Nagaki reported the reactions of aryllithiums with electrophilic fluorinating agents such as NFSI and N -fluorosultam (Scheme 6) [54]. The present flow microreactor method showed a high level of functional group compatibility; a wide repertoire of aryl fluorides possessing electron-withdrawing, electron-donating, and sterically hindered functional groups were obtained in good yields.…”

The continuous flow synthesis of 2,4,5-trifluorobenzoic acid via sequential Grignard exchange and carboxylation reactions using microreactors

“…We used the common EtMgBr as the metalation reagent since this reagent is cheaper and more stable (less reactive) than the common organolithium reagent such as n-BuLi. More importantly, the Grignard exchange reaction could be performed at a modest reaction temperature (e.g., room temperature) avoiding low-temperature regulation, while the halogen-Li exchange process, generally conducted at À40-0°C in microreactors, is still highly energy-consuming from the viewpoint of industrial production [45][46][47][48][49][50]. In addition, the metalation of bromide 2 with organolithium reagents appears troublesome in some case.…”

Managing Hazardous Reactions and Compounds in Process Chemistry

“…Fluorine was used as the fluorinating agent (146). Aryl fluorides can be prepared from other aryl halides, such as iodide, by Grignard formation followed by a fluorinating agent such as N-fluorosultam or N-fluorobenzenesulfonimide (NFSI) (147), DAST, Ruppert's reagent and Selectfluor (148). This seems rather a circuitous route to put in a fluorine but better means are constantly appearing.…”