Huang Mengjun, Ma Jiawei, Zou Zhenlei, Li Heyin, Liu Jiyang, Kong Lingyu, Pan Yi, Zhang Weigang, Liang Yong, Wang Yi
State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Collaborative Innovation Center of Advanced Microstructures, School of Chemistry and Chemical Engineering, Nanjing University Nanjing 210023 China
Chem Sci. 2022 Sep 1;13(38):11312-11319. doi: 10.1039/d2sc03989c. eCollection 2022 Oct 5.
The direct functionalization of C(sp)-H bonds is an ultimately ideal synthetic strategy with high atom economy and step efficiency. However, the direct trifluoromethylation of electron-deficient heteroaryl adjacent C(sp)-H bonds remains a formidable challenge. We have described a transient activating strategy involving a Tf-shift process and π-π stacking interaction for catalyst-free direct benzylic C(sp)-H trifluoromethylation of azines, such as pyridine, pyrimidine, quinoline, dihydropyridinone, tetrahydroisoquinoline and tetrahydroquinazoline, with an air-stable crystalline imidazolium sulfonate reagent IMDN-Tf. This bench-stable cationic reagent offers a scalable and practical protocol for the late-stage modification of drug molecules with high site selectivity, which avoids the prefunctionalization and the use of stoichiometric metals and strong oxidants. Furthermore, comprehensive mechanistic studies revealed the determining effect of π-π stacking for the activation of azinylic C(sp)-H bonds.
C(sp)−H键的直接官能团化是一种具有高原子经济性和步骤效率的终极理想合成策略。然而，缺电子杂芳基相邻C(sp)−H键的直接三氟甲基化仍然是一个巨大的挑战。我们描述了一种瞬态活化策略，该策略涉及Tf迁移过程和π-π堆积相互作用，用于在无催化剂的情况下，使用空气稳定的结晶咪唑鎓磺酸盐试剂IMDN-Tf对吡啶、嘧啶、喹啉、二氢吡啶酮、四氢异喹啉和四氢喹唑啉等嗪类化合物进行苄基C(sp)−H键的直接三氟甲基化。这种易于操作的阳离子试剂为药物分子的后期修饰提供了一种可扩展且实用的方案，具有高位点选择性，避免了预官能团化以及化学计量金属和强氧化剂的使用。此外，全面的机理研究揭示了π-π堆积对嗪基C(sp)−H键活化的决定性作用。
