The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.
Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
J Am Chem Soc. 2022 Oct 5;144(39):18109-18116. doi: 10.1021/jacs.2c08332. Epub 2022 Sep 22.
With the large number of Pd(II)-catalyzed C-H activation reactions of native substrates developed in the past decade, the development of catalysts to enable the use of green oxidants under safe and practical conditions has become an increasingly important challenge. Notably, the compatibility of Pd(II) catalysts with sustainable aqueous HO has been a long-standing challenge in catalysis including Wacker-type oxidations. We report herein a bifunctional bidentate carboxyl-pyridone (CarboxPyridone) ligand that enables room-temperature Pd-catalyzed C-H hydroxylation of a broad range of benzoic and phenylacetic acids with an industry-compatible oxidant, aqueous hydrogen peroxide (35% HO). The scalability of this methodology is demonstrated by a 1000 mmol scale reaction of ibuprofen (206 g) using only a 1 mol % Pd catalyst loading. The utility of this protocol is further illustrated through derivatization of the products and synthesis of polyfluorinated natural product coumestan and pterocarpene from phenol intermediates prepared using this methodology.
在过去十年中，已经开发出了大量用于天然底物的 Pd(II)催化 C-H 活化反应，因此开发能够在安全实用条件下使用绿色氧化剂的催化剂已成为一个日益重要的挑战。值得注意的是，Pd(II)催化剂与可持续水相 HO 的兼容性一直是包括 Wacker 型氧化反应在内的催化领域中的一个长期挑战。我们在此报告了一种双功能的二齿羧基-吡啶酮（CarboxPyridone）配体，它可以使广泛的苯甲酸和苯乙酸在室温下与工业兼容的氧化剂-35%过氧化氢（35%HO）进行 Pd 催化的 C-H 羟化反应。该方法的可扩展性通过使用仅 1 mol%Pd 催化剂负载量对布洛芬（206g）进行 1000mmol 规模的反应得到了证明。该方案的实用性还通过对产物的衍生化以及通过使用该方法制备的酚中间体合成多氟天然产物香豆素和紫檀烷得到了进一步说明。
