A General Amino–(Hetero)arylation of Simple Olefins with (Hetero)aryl Sulfonamides Enabled by an <i>N</i>-Triazinyl Group
Jaxon L. Barney, Andrew J. Wolfram, Rose Litvak, Eric D. Nacsa
Abstract
(Hetero)arylethylamines are privileged substructures in pharmaceuticals, agrochemicals, and other bioactive compounds. In principle, the amino–(hetero)arylation of olefins represents an ideal strategy for the rapid preparation of these pharmacophores, which could accelerate the discovery of valuable new products. Established amino–(hetero)arylation methods, however, do not accommodate several important classes of olefins and (hetero)aromatic structures, which precludes access to an appreciable range of molecular architectures. To address these limitations, we have developed a radical-mediated reaction that adds the amino and (hetero)aryl groups from a simple and stable (hetero)aryl sulfonamide across an alkene. The identification of a readily available triazine as an original N -protecting group was critical to the development of this transformation. The reaction features good regio- and stereoselectivity and succeeds with classes of olefins and medicinally valuable (hetero)aryl groups that are unproductive with alternate protocols. Lastly, we highlighted these advances by synthesizing TMP269, a class IIa histone deacetylase inhibitor that would otherwise be challenging to prepare by olefin amino–arylation.