The synthetic innovations in generating β-arylethylamines have the potential to propel advancements in drug discovery, as β-arylethylamines are common structural motifs in various bioactive compounds and drugs. Here, we report an efficient Pd (II)-catalyzed method for the selective β-C(sp³)-H arylation of aliphatic amines to construct β-arylethylamine frameworks. With the easy installation and removal of the nitroso directing group on the amine nitrogen, this Pd-catalyzed method enables (hetero)arylation of the β-C(sp³)-H bonds on various aliphatic amine scaffolds to produce β-arylethylamines and tolerates a variety of functional groups on both coupling partners. It offers an approach to direct syntheses of β-arylethylamine drugs from common native amines, thereby overcoming inherent limitations of previously known methods. This identified Pd-catalyst-system features low catalyst loading for C–H functionalization and offers a high reaction rate, originating from the pyridone-amide-ester ligand that increases the activity of the Pd catalyst while protecting all active species from forming inactive Pd complexes. Experimental and computational studies disclose that the valuable ligand effect partially results from the pendant ester group that participates in several steps of the C(sp³)-H activation process and favors the Pd-catalytic cycle.

中文翻译：

---

通过脂肪胺的选择性 C（sp3）-H 芳基化高效构建 β-芳乙胺


生成 β-芳乙胺的合成创新有可能推动药物发现的进步，因为 β-芳乙胺是各种生物活性化合物和药物中的常见结构基序。在这里，我们报道了一种高效的 Pd （II） 催化方法，用于脂肪胺的选择性 β-C（sp³）-H 芳基化以构建 β-芳基乙胺框架。由于在胺氮上易于安装和去除亚硝基导向基团，这种 Pd 催化方法能够在各种脂肪胺支架上实现 β-C（sp³）-H 键的（异）芳基化，以产生β-芳基乙胺，并容忍两个偶联伙伴上的各种官能团。它提供了一种从常见的天然胺直接合成 β-芳乙胺药物的方法，从而克服了以前已知方法的固有局限性。这种已确定的 Pd 催化剂系统具有用于 C-H 官能团化的低催化剂负载量，并提供高反应速率，源自吡啶酮酰胺酯配体，可增加 Pd 催化剂的活性，同时保护所有活性物质不形成非活性 Pd 复合物。实验和计算研究表明，有价值的配体效应部分来自参与 C（sp³）-H 活化过程的几个步骤并支持 Pd 催化循环的悬垂酯基团。