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 <50%, persistent formation of a byproduct resulting from PhLi addition to the nitrile, and formation of solids during longer runs. As a result, the use of LDA was investigated under continuous flow conditions. In situ NMR and IR spectroscopy allowed observation of the 5-[Li] species and its conversion to the thermodynamically preferred 3-[Li] species. These mechanistic i...