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

• Published in: Organometallics Vol. 38; no. 1; pp. 129 - 137
• Main Authors: Dunn, Anna L, Leitch, David C, Journet, Michel, Martin, Michael, Tabet, Elie A, Curtis, Neil R, Williams, Glynn, Goss, Charles, Shaw, Tony, O’Hare, Bernie, Wade, Charles, Toczko, Matthew A, Liu, Peng
• Format: Journal Article
• Language: English
• Published: American Chemical Society 14-01-2019
• ISSN: 0276-7333; 1520-6041
• DOI: 10.1021/acs.organomet.8b00538

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 insights drove development of a second-generation continuous flow process using LDA that achieves 30:1 regioselectivity and an 84% solution yield of the desired product (67% isolated yield after recrystallization). Furthermore, this process increases throughput by 10-fold, providing a path to manufacturing-scale operation.