Barney Jaxon L, Wolfram Andrew J, Litvak Rose, Nacsa Eric D
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
ACS Catal. 2025 Feb 7;15(3):2139-2149. doi: 10.1021/acscatal.5c00157. Epub 2025 Jan 22.
(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 -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.
（杂）芳基乙胺是药物、农用化学品及其他生物活性化合物中的优势亚结构。原则上，烯烃的氨基-（杂）芳基化是快速制备这些药效基团的理想策略，这可以加速有价值新产品的发现。然而，已有的氨基-（杂）芳基化方法并不适用于几类重要的烯烃和（杂）芳族结构，这使得难以获得相当广泛的分子结构。为了解决这些限制，我们开发了一种自由基介导的反应，该反应能将简单稳定的（杂）芳基磺酰胺中的氨基和（杂）芳基基团加成到烯烃上。确定一种易于获得的三嗪作为新型保护基团对该转化反应的开发至关重要。该反应具有良好的区域和立体选择性，并且适用于其他方法无法成功反应的烯烃类别和具有药用价值的（杂）芳基基团。最后，我们通过合成TMP269（一种IIa类组蛋白去乙酰化酶抑制剂）突出了这些进展，否则通过烯烃氨基芳基化制备该抑制剂具有挑战性。
