Selective Continuous Flow Iodination Guided by Direct Spectroscopic Observation of Equilibrating Aryl Lithium Regioisomers

The iodination of 4-fluoro-2-(trifluoromethyl)­benzonitrile via C–H lithiation and subsequent treatment with iodine under continuous flow conditions is described. Screening identified both LDA and PhLi as effective bases, giving the desired 3-iodo regioisomer as the major product. Use of LDA results in varying amounts of the undesired 5-iodo isomer, while PhLi results in more reliable formation of the 3-iodo product. An initial flow process was developed using PhLi that produced 4-fluoro-3-iodo-2-(trifluoromethyl)­benzonitrile in 63% yield on a gram scale. Process modifications to enable pilot-scale operation resulted in a yield decrease to