Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, IL 61801, USA.
Science. 2022 Apr 15;376(6590):276-283. doi: 10.1126/science.abn8382. Epub 2022 Apr 14.
Intermolecular cross-coupling of terminal olefins with secondary amines to form complex tertiary amines-a common motif in pharmaceuticals-remains a major challenge in chemical synthesis. Basic amine nucleophiles in nondirected, electrophilic metal-catalyzed aminations tend to bind to and thereby inhibit metal catalysts. We reasoned that an autoregulatory mechanism coupling the release of amine nucleophiles with catalyst turnover could enable functionalization without inhibiting metal-mediated heterolytic carbon-hydrogen cleavage. Here, we report a palladium(II)-catalyzed allylic carbon-hydrogen amination cross-coupling using this strategy, featuring 48 cyclic and acyclic secondary amines (10 pharmaceutically relevant cores) and 34 terminal olefins (bearing electrophilic functionality) to furnish 81 tertiary allylic amines, including 12 drug compounds and 10 complex drug derivatives, with excellent regio- and stereoselectivity (>20:1 linear:branched, >20:1 :).
末端烯烃与仲胺的分子间交叉偶联形成复杂的叔胺——这是药物中的常见结构单元——在化学合成中仍然是一个主要挑战。非定向、亲电的金属催化胺化中的碱性胺亲核试剂往往会与之结合并因此抑制金属催化剂。我们推断，一种将胺亲核试剂的释放与催化剂转化偶联起来的自调节机制可以实现功能化而不会抑制金属介导的异裂碳氢键断裂。在这里，我们报告了一种使用这种策略的钯 (II) 催化烯丙基碳-氢键胺化交叉偶联，使用了 48 个环状和非环状仲胺（10 个具有药物相关核）和 34 个末端烯烃（具有亲电官能团），以提供 81 个叔烯丙基胺，包括 12 个药物化合物和 10 个复杂的药物衍生物，具有极好的区域和立体选择性（>20:1 线性：支化，>20:1 :）。
