Research group of Professor Zhou qianghui of Wuhan University: PD (II) / NBE coordinated catalytic oxidation-reduction neutral "borono catelani" amination reaction

The author: Chen Shuqing and Wang Peng aromatic amines are widely found in active natural products and pharmaceutical products The efficient synthesis of aromatic amines has always been a research hotspot in the field of organic synthesis The synthesis of aromatic amines by transition metal catalysis is one of the most widely used strategies, and a series of substantial progress has been made, such as the famous Buchwald Hartwig amination and Ullmann reaction The in-situ amination products (IPSO amination) of specific functional groups are obtained by this kind of synthesis strategy In 2013 and 2018, Professor Dong guangbin's research group at the University of Chicago in the United States developed a zero valent palladium and norbornene (NBE) synergistic catalytic amination system, successively realized the ortho-c-h bond amination of aryl iodide and aryl bromide, and synthesized a series of meta substituted aromatic amines This strategy is very complementary to Buchwald Hartwig amination, but the reaction needs to add equivalent reductant to regenerate zero valent palladium catalyst Recently, Professor Zhou qianghui from the school of chemistry and molecular science of Wuhan University developed the "borono catelani" reaction in the early stage (angelw Chem Int ed 2018, 57, 7161; org Lett 2019, 21, 3323) on the basis of this, a kind of oxidation-reduction neutral C-H bond amination of arylborate ester catalyzed by palladium and norbornene was creatively developed to realize the efficient synthesis of aromatic amines (Fig 1) According to their research assumption, the whole catalytic cycle of the reaction is started by metal transfer between the divalent palladium catalyst and the arylborate, and the hydrogen ions from the activation and dissociation of the ortho C-H bond in the reaction process are used to carry out the final proton dissociation cycle for the aryl palladium species (IV) formed in the subsequent reaction, while the regenerated divalent palladium catalyst enters the next catalytic cycle Therefore, no additional oxidant is needed for the whole reaction Figure 1 The author of borono catelani amination reaction (source: Chemical Science) which is neutral in oxidation-reduction successfully realized the above research assumption through a large number of reaction conditions screening and optimization Next, they explored the application range of arylborate substrate The experimental results show that the reaction has very good substrate applicability, and most of the substrates can achieve good yields; at the same time, the reaction has good functional group compatibility, such as the common halogen atoms, methoxy, trifluoromethyl, Trifluoromethoxy, nitro and protected amino groups can be well compatible (Figure 2) Figure 2 Substrate development of arylborate (source: Chemical Science) in order to further investigate the universality of this method, the author also investigated the application scope of various amination reagents The amination reagents such as morpholine, piperidine, piperazine, thiomorpholine, tetrahydropyrrole, azacycloheptane and the amination reagents derived from acylbenzylamine can all react smoothly to obtain the corresponding aromatic amines, and the functional groups such as primary alcohol, secondary alcohol, tertiary alcohol, silica ether, ketal, ester and amide are all well compatible Figure 3 Amination reagent substrate development (source: Chemical Science) in order to explore the application potential of the reaction in synthesis, the author has carried out an amplification experiment on the reaction (6 mmol, 30 times magnification), and the reaction can still prepare the target product in G with 72% separation yield (Figure 4a) Secondly, based on the difference in mechanism between the traditional catelani reaction and the traditional catelani reaction, the orthogonal reaction activity of the reaction was investigated The experiment shows that the reaction has very good chemical selectivity, and the compatibility of the reaction with halogen, especially iodine, provides an opportunity for further derivation (Fig 4b) In addition, the intermediate substituted aromatic diamines 3AB and 3aC synthesized by this method can be converted into the core fragment 3,5-bis (1-morpholine) aniline 8 of EphB4 kinase inhibitor by Ullmann Ma amination (Fig 4C) Figure 4 Synthesis application (source: Chemical Science) Finally, in order to explore the proton source of in-situ termination reaction, the author designed a series of deuterium generation control experiments (Figure 5) Through these experiments, the author infers that the proton of the termination step may come from the hydrogen in the ortho position of the arylborate and the residual water in the system Fig 5 Mechanism study (source: Chemical Science) it is worth mentioning that Dong guangbin's research group also independently reported the ortho-h-bond acylation and amination reaction (chem 2019, 5, 929) of the redox neutral boric acid trimer catalyzed by palladium and norbornene Summary: the oxidation-reduction neutral "borono catelani" amination reaction reported by Professor Zhou qianghui's research group has a series of advantages, such as cheap and easy to obtain raw materials, mild reaction conditions, no need to add additional ligands and oxidants, simple operation, wide compatibility of reaction functional groups, and can be enlarged to gram scale This method has good application value, and has been successfully used in the synthesis of the core fragment of EphB4 kinase inhibitor This innovation was highly praised in the peer review and published in chemical science, the flagship journal of Royal Society of chemistry Chen Shuqing, Ph.D., and Wang Peng, M.A., are the co first authors of this paper, and Professor Zhou qianghui is the corresponding author.