Application of Continuous Flow-Flash Chemistry to Scale-up Synthesis of 5‑Cyano-2-formylbenzoic Acid

Efficient scale-up synthesis of 5-cyano-2-formylbenzoic acid or its cyclic isomer 6-cyano-3-hydroxy-2-benzofuran-1­(3H)-one (1) as a key intermediate for various biologically important compounds has been achieved from isopropyl 2-bromo-5-cyanobenzoate (8c) by means of continuous flow-flash chemistry using flow microreactors. It was found that Br/Li exchange reaction of 8c, bearing both a carboisopropoxy group and a cyano group, with BuLi took place within 0.1 s at −50 °C, and the resulting highly reactive aryllithium intermediate underwent formylation with DMF to afford 1, which is extremely difficult to achieve by a conventional batch process. Optimization of the continuous flow-flash reaction conditions and modification of the reaction system brought about the production of 237 g of 1 from 897 g of 8c in 270 min, without purification by column chromatography. The results suggest that phthalaldehydic acid derivatives bearing electrophilic group(s) can be synthesized conveniently from the corresponding 2-bromobenzoic acid esters by means of flow-flash chemistry using flow microreactors.