Abstract
Benzo[b]thiophene rings are common synthons for the development of novel drugs and materials, and thus, the discovery of facile ways for their functionalization is of value. In this work, a new method for the C3-chlorination of C2-substituted benzothiophene derivatives is described. The chlorine source is sodium hypochlorite pentahydrate (NaOCl·5H(2)O), and optimal transformations occur in aqueous acetonitrile at 65-75 °C to provide the corresponding C3-halogenated products in variable yields (30-65%). The reaction occurs in the presence of vinyl and alkyl groups, while the presence of alcohols leads to competing oxidation reactions at the heterobenzylic position. The presence of a carbonyl group at the C2-position inhibited the halogenation reaction, while the use of benzofuran led to a highly exothermic reaction, presumably via the formation of a peroxide intermediate. Reactions carried out at lower temperatures led to side reactions associated with competing oxidative processes. To gain a better understanding of the mechanism of the reaction, DFT calculations were carried out, where the heteroatom enables the formation of a hypochlorous acidium ion that serves to generate a C2-C3 chloronium ion intermediate in a step-wise manner, which in turn leads to the formation of an S-stabilized C2-carbocation that undergoes re-aromatization to the corresponding C3-chlorinated products. To probe potential synthetic applications, a model C3-chloro derivative was coupled with phenylboronic acid using standard Suzuki-Miyaura coupling conditions.