Efficient alpha-selective chlorination of phenylacetic acid and its para-substituted analogues†

alpha-Chlorophenylacetic acids are synthons with great potential but are limited by the lack of a simple and generalizable method for their preparation from readily available precursors. Therefore, relying on the commercial availability of phenyl acetic acid and a series of para-substituted phenylacetic acids, we explored the practicability of their direct alpha-selective chlorination without the competing electrophilic aromatic chlorination. Indeed, treatment of these substrates with catalytic PCl3 and a slight excess of trichloroisocyanuric acid (TCCA) under solvent-free conditions rapidly provided the desired products in high yields with the only condition being that substituents that strongly activate electrophilic aromatic substitution were absent. An efficient preparative method for alpha-chlorinate phenylacetic acid and its analogues bearing electron-withdrawing or weakly electron-donating para-substituents, such as NO2, CN, CF3, COOMe, halogen, and alkyl, was thus developed, making these synthetic intermediates more accessible and exploitable.