Efficient α-Selective Chlorination of Meta- and Ortho-Substituted Phenylacetic Acids

Treatment with trichloroisocyanuric acid (TCCA) in the presence of catalytic PCl3 under solvent-free conditions is a preparative method, simple and efficient, to selectively α-chlorinate not only phenylacetic acid and its para-substituted analogues, but also meta- and more arduous ortho-substituted phenylacetic acids. With electron-withdrawing or weakly electron-donating substituents, such as NO2, CF3, COOMe, halogen, and methyl, the potentially competing electrophilic aromatic chlorination did not occur and the substrates were univocally chlorinated at the benzylic position. Within our selection of 13 o- and m-substituted phenylacetic acids, the only 2 outliers were m-methylphenylacetic acid, which, unlike the ortho and para regioisomers, gave complex mixtures of products, and o-nitrophenylacetic acid, which was refractory to any chlorination. α-Chlorophenylacetic acids are synthons with a great potential, here exemplified by the preparation of clopidogrel, a very important active pharmaceutical ingredient, from α-chloro-o-chlorophenylacetic acid.