Metal and Additive-Free Nondirected Meta-C–S Bond Formation on Anilines: Toward Biologically Relevant <i>S</i> -Aryl Dithiocarbamates

The site-selective C-H functionalization to install meta-C-S bonds on aniline derivatives is highly desirable, due to the preponderance of resulting compounds in numerous medicinally relevant compounds. However, the execution of the same is far from being trivial, due to the intrinsic electronic bias of anilines and concerns associated with the ready availability of an appropriate and odorless sulfur source. Accordingly, we demonstrate a metal- and additive-free, one-pot, multicomponent reaction between <i>p</i>-anisidines/anilines, carbon disulfide, and aliphatic amines to install an otherwise difficult meta-C-S bond on anilines with exclusive regioselectivity, while furnishing an array of biologically relevant anisidine-derived <i>S</i>-aryl dithiocarbamates. The method exhibits broad scope with appreciable functional group tolerance, as demonstrated through late-stage modification of a variety of amino acids, pharmaceuticals, and natural products. Importantly, final <i>S</i>-aryl dithiocarbamates are amenable to further synthetic manipulations, furnishing highly valuable and medicinally relevant sulfur-containing functional moieties, such as thiols, thioethers, and sulfones. Furthermore, in vitro evaluations demonstrate that many of the synthesized dithiocarbamates exhibit promising drug-like properties, demonstrating antiproliferative activity on a nanomolar level for breast cancer cell lines by affecting microtubule dynamics.