Hruszkewycz Damian P, Miles Kelsey C, Thiel Oliver R, Stahl Shannon S
Department of Chemistry , University of Wisconsin-Madison , 1101 University Avenue , Madison , Wisconsin 53706 , USA . Email:
Process Development, Drug Substance Technologies , Amgen Inc. , One Amgen Center Drive, Thousand Oaks , California 91320 , USA.
Chem Sci. 2017 Feb 1;8(2):1282-1287. doi: 10.1039/c6sc03831j. Epub 2016 Oct 7.
A simple cobalt(ii)/-hydroxyphthalimide catalyst system has been identified for selective conversion of benzylic methylene groups in pharmaceutically relevant (hetero)arenes to the corresponding (hetero)aryl ketones. The radical reaction pathway tolerates electronically diverse benzylic C-H bonds, contrasting recent oxygenation reactions that are initiated by deprotonation of a benzylic C-H bond. The reactions proceed under practical reaction conditions (1 M substrate in BuOAc or EtOAc solvent, 12 h, 90-100 °C), and they tolerate common heterocycles, such as pyridines and imidazoles. A cobalt-free, electrochemical, NHPI-catalyzed oxygenation method overcomes challenges encountered with chelating substrates that inhibit the chemical reaction. The utility of the aerobic oxidation method is showcased in the multigram synthesis of a key intermediate towards a drug candidate () under process-relevant reaction conditions.
已确定一种简单的钴（II）/羟基邻苯二甲酰亚胺催化剂体系，可将药学相关（杂）芳烃中的苄基亚甲基选择性转化为相应的（杂）芳基酮。该自由基反应途径能够耐受电子性质多样的苄基C-H键，这与最近由苄基C-H键去质子化引发的氧化反应形成对比。反应在实际反应条件下（在醋酸丁酯或醋酸乙酯溶剂中1 M底物，12小时，90 - 100°C）进行，并且能够耐受常见的杂环，如吡啶和咪唑。一种无钴的电化学NHPI催化氧化方法克服了螯合底物抑制化学反应所带来的挑战。该需氧氧化方法的实用性在与工艺相关的反应条件下，用于合成一种药物候选物（）的关键中间体的多克规模合成中得到了展示。
