Zhang Tianze, Jiang Shan, Qian Meng-Ying, Zhou Qi-Lin, Xiao Li-Jun
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071, China.
J Am Chem Soc. 2024 Feb 7;146(5):3458-3470. doi: 10.1021/jacs.3c13060. Epub 2024 Jan 25.
Ligand modulation of transition-metal catalysts to achieve optimal reactivity and selectivity in alkene hydrofunctionalization is a fundamental challenge in synthetic organic chemistry. Hydroaminoalkylation, an atom-economical approach for alkylating amines using alkenes, is particularly significant for amine synthesis in the pharmaceutical, agrochemical, and fine chemical industries. However, the existing methods usually require specific substrate combinations to achieve precise regio- and stereoselectivity, which limits their practical utility. Protocols allowing for regiodivergent hydroaminoalkylation from the same starting materials, controlling both regiochemical and stereochemical outcomes, are currently absent. Herein, we report a ligand-controlled, regiodivergent nickel-catalyzed hydroaminoalkylation of unactivated alkenes with -sulfonyl amines. The reaction initiates with amine dehydrogenation and involves aza-nickelacycle intermediates. Tri-butylphosphine promotes branched regioselectivity and diastereoselectivity, whereas ethyldiphenylphosphine enables linear selectivity, yielding regioisomers with inverse orientation. Systematic evaluation of diverse monodentate phosphine ligands reveals distinct regioselectivity cliffs, and % (), a ligand steric descriptor, was established as a predictive parameter correlating ligand structure to regioselectivity. Computational investigations supported experimental findings, offering mechanistic insights into the origins of regioselectivity. Our method provides an efficient and predictable route for amine synthesis, demonstrating broad substrate scope, excellent tolerance toward various functional groups, and practical advantages. These include the use of readily available starting materials and cost-effective nickel(II) salts as precatalysts.
在烯烃氢官能化反应中，通过配体调控过渡金属催化剂以实现最佳反应活性和选择性是有机合成化学中的一项基本挑战。氢胺烷基化反应是一种利用烯烃对胺进行烷基化的原子经济性方法，在制药、农用化学品和精细化工行业的胺合成中尤为重要。然而，现有方法通常需要特定的底物组合才能实现精确的区域和立体选择性，这限制了它们的实际应用。目前还缺乏能够从相同起始原料实现区域发散性氢胺烷基化反应，并同时控制区域化学和立体化学结果的方法。在此，我们报道了一种配体控制的、区域发散性的镍催化未活化烯烃与磺酰基胺的氢胺烷基化反应。该反应始于胺的脱氢，并涉及氮杂镍环中间体。三丁基膦促进支链区域选择性和非对映选择性，而乙基二苯基膦则实现线性选择性，生成具有相反取向的区域异构体。对多种单齿膦配体的系统评估揭示了明显的区域选择性悬崖，并且建立了% （），一种配体空间描述符，作为将配体结构与区域选择性相关联的预测参数。计算研究支持了实验结果，为区域选择性的起源提供了机理见解。我们的方法为胺合成提供了一条高效且可预测的途径，展示了广泛的底物范围、对各种官能团的优异耐受性以及实际优势。这些优势包括使用容易获得的起始原料和具有成本效益的镍（II）盐作为预催化剂。
