【Angew】董顺喜：镧催化内烯烃区域选择性氢芳基化

化学深耕堂

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长按识别丨直达原文

深耕点评

四川大学董顺喜团队利用阳离子型咪唑啉-2-亚胺基镧配合物催化N-芳基吡唑与内烯烃和端烯烃的区域选择性氢芳基化，实现N-芳基吡唑邻位C–H烷基化。该反应共覆盖94个实例，最高收率99%，区域异构体比（rr）>19:1，并完成克级放大及Hedgehog抑制剂类似物的合成。

深耕亮点：

1）大离子半径的镧中心促进位阻较大的内烯烃迁移插入。在相同配体体系下，催化活性随稀土金属离子半径增大明显提高：Sc和Lu基本不反应，Y、Gd和Ce活性依次增强，La可将模型反应收率提高至99%。较大的La³⁺为位阻较大的内烯烃配位和后续迁移插入提供更开放的配位环境。

2）多类内烯烃及多取代烯烃均可参与区域选择性C–H烷基化。芳基取代内烯烃主要发生2,1-插入，不含配位基团的长链内烯烃、1,1-二取代烯烃、环烯烃以及部分三取代烯烃同样能够反应，进一步拓展了稀土催化C–H烷基化对内烯烃及多取代烯烃的适用范围。

3）烯烃结构可调节插入方向和产物区域选择性。苯乙烯类端烯烃主要经2,1-插入生成直链产物，而脂肪族端烯烃在钪催化条件下倾向1,2-插入生成支链产物，说明烯烃电子性质、金属中心性质及金属–芳环相互作用共同影响迁移插入方向。

4）烯烃迁移插入控制反应速率和2,1-插入选择性。KIE实验表明芳基C(sp²)–H断裂不参与决速步骤，动力学和DFT计算均支持烯烃迁移插入为决速步骤；相比1,2-插入，2,1-插入过渡态具有额外的π–π堆积以及La³⁺与芳环之间的阳离子–π相互作用，因此迁移插入能垒更低。

5）反应具有较好的合成延展性。内烯烃和端烯烃反应均可放大至克级，并可进一步进行Suzuki偶联、酯化、磺酰胺化以及药物类似物合成，所得N-(邻烷基芳基)吡唑可继续作为合成中间体进行衍生化。

Abstract

Catalytic C─H alkylation of pyrazoles with internal alkenes represents an ideal strategy for constructing functionalized pyrazoles. However, such a transformation has remained underexplored to date, likely due to the inherently low reactivity of internal alkenes and the lack of suitable catalysts. In this study, we describe a lanthanum-catalyzed highly regioselective C─H alkylation of N-aryl pyrazoles with internal alkenes. The key to success of this unprecedented transformation is the use of a cationic imidazolin-2-iminato lanthanum catalyst, whose large ionic radius and less steric hindrance provide an open coordination environment that facilitates the coordination of sterically demanding internal alkenes to the metal center and subsequent alkene migratory insertion. Besides internal alkenes, 1,1-disubstituted styrenes and terminal alkenes were amenable to the reaction. This protocol offers a straightforward and atom-efficient route for the synthesis of a new family of N-((ortho-alkyl)aryl) pyrazole derivatives (94 examples, up to 99% yield, >19:1 rr). The scale-up synthesis and further transformation to hedgehog enzyme inhibitor analog highlight the potential application of this method. Combined experimental and computational studies elucidated the reaction mechanism and the influence of metal ion size on the turnover-limiting alkene migratory insertion step.

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