实验海洋生物学重点实验室知识库

吲哚骨架广泛存在于天然产物、活性分子及上市药物中。研究过渡金属催化吲哚C-H键选择性官能团化对于生物活性分子后期修饰具有重要意义。在此，我们主要探索了过渡金属催化吲哚C-H键官能团化策略。本文主要分为三个章节。

第一章：本章，我们报道了通过C-H键活化，以廉价易得的CF₃SO₂Na作为三氟甲基试剂，以3-取代吲哚作为底物，实现了铜催化氧化三氟甲基化反应。该方法可以以良好至优异收率得到产物，并且对于一系列官能团适应性良好。此外，用于睡眠障碍的药物褪黑激素也以68%的收率得到了2位三氟甲基取代产物。对可能的反应途径的研究表明，该反应可能通过自由基途径进行。

第二章：本章，通过在吲哚N上引入易于移除的叔丁氧羰基导向基团，我们实现了铜催化高选择性的吲哚三氟甲基化反应。该策略为各种杂芳烃（吲哚、吡咯、苯并呋喃和乙酰苯胺）的2位选择性三氟甲基取代提供了一种简便快捷的方法。而且，该反应在空气中即可反应，无需外部的配体和添加剂。

第三章：在过去十年，钯催化吲哚苯环的C-H键活化已经实现。但是，钯催化吲哚远程C-H键活化很少报道。在本章中，我们报道了一种基于自由基途径的具有挑战性的钯催化吲哚4位远程膦酰化取代反应。该方法提供了一系列4-膦酰化取代吲哚产物，包括色氨酸和含色氨酸的二肽，由于直接C-H键活化策略对于3位导向基团的严重依赖性，这些底物通常不能通过直接C4-H键活化得到。值得一提的是，通过在4位引入取代基团，我们得到了C6-膦酰化吲哚产物。初步的机理实验表明，该反应可能经过C7-钯环化/远程活化途径进行。基于该策略，我们以BrCF2COOEt为偶联试剂成功实现了吲哚远程C4-H二氟甲基化反应，这表明该策略可能为其他偶联试剂提供了一个通用的蓝图。

综上所述，我们探索了过渡金属催化吲哚吡咯环和苯环C-H键官能团化，实现了吲哚吡咯环三氟甲基取代（2位），吲哚苯环远程膦酯基取代（4位、6位），和吲哚苯环远程二氟甲基取代（4位）。

Indoles represent ubiquitous structural motifs found in natural products, biologically active molecules, and pharmaceutical compounds. In this regard, direct C-H functionalizations of indoles offers an attractive alternative for late-stage diversifications of natural products and pharmaceutical compound. Here, we developed the strategy of transition-metal-catalyzed C-H functionalization of indoles. And the book is divided into three chapters.

Chapter one: Herein, we developed copper-catalyzed oxidative trifluoromethylation of 3-substituted indoles with low-cost CF₃SO₂Na via C-H activation. This reaction proceeds efficiently in good to excellent yields and is tolerance of a broad range of functional groups. Furthermore, melatonin, a medicine for sleep disorders, is converted to its 2-CF3 analogue in 68% yield. Studies of possible reaction pathways suggest that this reaction proceeds through a radical process.

Chapter two: Herein, a highly selective copper-catalyzed trifluoromethylation of indoles is reported with the assistance of a removable tert-butoxycarbonyl directing group. This protocol provides an easy and rapid method to various 2-position-selective trifluoromethylated heteroarenes including indoles, pyrroles, benzofuran, and acetanilide. What is more, the reaction takes place at ambient conditions without any external ligand or additive.

Chapter three：Palladium-catalyzed direct C-H activation of indole benzenoid moiety has been achieved in the past decade. However, palladium-catalyzed remote C-H activation of indoles is rare. Herein, we report a challenging palladiumcatalyzed remote C4-H phosphonylation of indoles by a radical approach. The method provides access to a series of C4-phosphonylated indoles, including tryptophan and tryptophan-containing dipeptides, which are typically inaccessible by direct C4-H activation due to its heavy reliance on C3 directing groups. Notably, unexpected C6-phosphonylated indoles were obtained through blocking of the C4 position. The preliminary mechanistic studies indicated that the reactions may proceed via a C7-palladacycle/remote-activation process. Based on the strategy, examples of remote C4-H difluoromethylation with BrCF2COOEt are also presented, suggesting that the strategy may offer a general blueprint for other cross-couplings.

 In summary, we developed transition-metal-catalyzed C-H functionalizations of indole pyrrole and benzenoid moieties, and realized C2-trifluoromethylation, remote C-H phosphonylation at C4 and C6 positions, and remote C4-trifluoromethylation of indoles.

第1章 绪论... 1

1.1 引言... 1

1.1.1 吲哚衍生物重要性及其在药物中应用... 1

1.1.2 过渡金属催化吲哚C-H键官能团化简介... 2

1.2 吲哚2位C-H键官能团化... 3

1.2.1 永久导向基团... 3

1.2.2 瞬时导向基团... 8

1.3 吲哚苯环C-H键官能团化... 10

1.3.1 吲哚4位C-H键官能团化... 10

1.3.2 吲哚7位C-H键官能团化... 21

1.3.3 吲哚5、6位远程C-H键官能团化... 31

1.4 本章小结... 36

第2章 铜催化吲哚2位三氟甲基化反应研究... 37

2.1 研究背景... 37

2.2 结果与讨论... 41

2.3 实验部分... 48

2.3.1 仪器和试剂... 48

2.3.2 产物通用合成方法... 48

2.3.3 产物表征数据... 49

第3章 叔丁氧羰基导向芳杂环2位三氟甲基取代... 61

3.1 概述... 61

3.2 结果与讨论... 62

3.3 实验部分... 68

3.3.1 仪器和试剂... 68

3.3.2 产物通用合成方法... 68

3.3.3 产物表征数据... 69

第4章 钯催化吲哚远程C4、C6位磷脂化反应... 77

4.1 概述... 77

4.2 结果与讨论... 93

4.3 实验部分... 104

4.3.1 仪器和试剂... 104

4.3.2产物通用合成方法... 105

4.3.3 克级反应... 106

4.3.4 竞争性实验... 106

4.3.6 H/D实验（氘水）... 106

4.3.6 H/D实验（氘代乙酸）... 108

4.3.6 H/D实验... 109

4.3.7 KIE实验... 111

4.3.8 动力学曲线... 111

4.3.9 产物表征数据... 114

第5章 结论与展望... 137

参考文献... 139

附 录... 153

致 谢... 165

作者简历及攻读学位期间发表的学术论文与研究成果... 167