N,O 双齿导向基团在羧酸和氨基酸类化合物碳氢键转化中的应用研究

High selective functionalization of C-H bond has emerged as efficient methodology for constructing carbon-carbon and carbon-heteroatom bond formation. So far, effective approach to realize high site selective C-H transformation is a challenge. Herein, we start this project to solve the site selective problem for carboxylic acids and amines by developing a type of N,O bidentated directing groups. Firstly, one of the N,O bidentate directing group, which could be employed to carboxylic acids， is made from simple amino acid. Primarily the intramolecular amination for phenylpropionic acid derivatives which could lead to synthetic utility products of quinolinone was successfully achieved through a rare seven-membered palladacycle intermediate by employing the new developed N, O bidentate directing group. Inspired by this result, substrates scope will be further expanded to aliphatic carboxylic acid to explore assistance ability of the N,O bidentate directing group in γ and β selectivity. Another N,O bidentate directing group of oxalyl amid which discovered by our group will be employed to aliphatic amines to overcome the unreported γ-C(sp3)-H transformation, such as carbonylation, alkynylation, silication, germaniumation, and one pot synthesis of functionalized quinoline. We also propose a new enantioselective synthesis via our Oxayl amide-directed double C−H functionalization strategy in total synthesis of Pronuciferine. . Finally, we expected to build up an N, O bidentate directing group assisted C-H transformation system, which would be highly valuable in synthetic chemistry and potential application value in industry.

碳氢键直接转化为其它官能团是重要的现代有机合成方法，但有机化合物中的碳氢键数目众多，选择性转化一直是难点与重点。本项目拟发展N,O双齿导向基团，借助于其少见的七元环钯化过渡态，拟实现羧酸和氨基酸/胺类化合物中尚未解决的碳氢键官能团化的难题。首先发展一种以氨基酸为前体的N,O导向基团：解决苯丙酸衍生物分子内碳氮成键问题，实现有应用意义的喹啉酮类化合物地合成；解决羧酸类化合物碳氢键官能团化反应中在 β和γ位选择性的问题。另一方面，利用本课题组最近报道的草酰胺类N,O导向基团，实现未报道的烷基胺/氨基酸类化合物γ位各种官能团化反应：插羰环化、插羰串联、炔基化、硅化反应等；通过两次碳氢键活化，一锅法合成喹啉衍生物；拟研究天然产物前莲碱的合成。. 本项目发展的新型N,O双齿导向体系，将填补羧酸和氨基酸/胺类化合物碳氢键转化的部分空白，属国际学术前沿，而且比其它导向基团更廉价易得，具潜在应用前景。

区域选择性碳氢键官能团化反应一直是有机合成化学中的重点与难点。该项目成功发展了从廉价草酰氯出发，构建的N,O型导向基团，并成功将其应用于苄胺、苯乙胺、和苯丙胺邻位碳氢键活化反应中；另外发展了从甘氨酸出发的N,O型导向基团，实现脂肪酸的顺序碳氢键芳基化反应和分子内碳氮成键反应，合成了各类多取代二氢喹啉酮衍生物。. 远程碳氢键活化反应一直是有机合成化学中的重点与难点。如何调控芳环上邻、间、对位的碳氢键活化反应，是碳氢键活化领域的难点与重点。我们课题组通过发展通过调节底物中配位原子的配位能力，或者催化剂的空间位阻，解决芳环氟官能化反应中无法控制邻、间、对位的难题：（1）首次通过“钝化策略”，即在苯胺类化合物氨基上引入酰基保护基团，降低芳胺的活性，然后利用酰胺中氧原子与钌催化剂弱配位效应，实现苯胺类化合物对位选择性二氟乙酸乙酯化反应（Nat. Commun. 2018, 1189） 和多氟烷基化反应 （Org. Lett. 2019, 6481）；（2）通过对酮羰基不同修饰，调节配位中心原子配位能力，实现钌催化肟醚导向的芳酮类对位二氟乙酸乙酯化反应（Angw. Chem. Int. Ed. 2018, 1277）；（3）利用二价钯为弱路易斯酸特性，将其与芳酮的羰基配位来活化芳环，同时借助钯络合物中三苯基膦位的阻效应，实现芳酮类化合物的对位二氟乙酸乙酯化反应（Angw. Chem. Int. Ed. 2018, 15597）; (4)通过配体空间位阻的调控，实现二芳基吡啶类化合物邻位和间位选择性的碳氢官能团化反应（ACS Catal. 2017, 4138; Org. Chem. Front. 2017, 1867）。. 总之，我们课题组以发展实用性碳氢活化反应为研究目标，实现了多种策略对复杂分子的直接修饰，并提出影响芳环不同位点碳氢键活化的策略，为碳氢键活化反应后续研究打下坚实基础。