Department of Chemistry, Zhejiang University, Hangzhou, 310027, China.
Angew Chem Int Ed Engl. 2022 Oct 10;61(41):e202210312. doi: 10.1002/anie.202210312. Epub 2022 Sep 2.
Amides are ubiquitous in physical and life sciences. Given the significant abundance of arenes, dearomative aminocarbonylation of arenes would lead to a large and underexplored chemical space for amide discovery. However, such reactions are challenging due to the high degree of resonance stabilization and selectivity issues. Herein, we disclose an unprecedented dearomative trifluoromethylative aminocarbonylation of arenes via bifunctional coordination to chromium, providing a modular platform for the construction of amides possessing trifluoromethyl (CF ) groups and three-dimensional rings. Its versatility further enabled a switchable difluoromethylation or trifluoromethylation aminocarbonylation of arene C-H bonds. A possible mechanism was proposed based on control experiments. Finally, the synthetic utility was well demonstrated by diverse applications in the total synthesis of CF -functionalized amide-type drugs, including praziquantel, nateglinide, maraviroc and alloyohimbane.
酰胺在物理和生命科学中无处不在。鉴于芳环的大量存在，芳环的去芳构化氨羰基化反应将为酰胺的发现开辟一个广阔但尚未得到充分探索的化学空间。然而，由于芳环具有高度的共振稳定性和选择性问题，此类反应具有挑战性。在此，我们通过双官能团配位到铬原子，首次披露了芳环的前所未有的去芳构化三氟甲基化氨羰基化反应，为构建具有三氟甲基 (CF3) 基团和三维环的酰胺提供了一个模块化平台。其多功能性还进一步实现了芳环 C-H 键的可切换二氟甲基化或三氟甲基化氨羰基化反应。基于控制实验提出了一种可能的反应机制。最后，通过在全合成 CF 功能化酰胺类药物中的多种应用，包括吡喹酮、那格列奈、马拉维若和合金霍姆宾，充分证明了其合成实用性。
