Jijianxin research group of Chengdu Institute of biology, Chinese Academy of Sciences and Weiwei research group of Qufu Normal University

The author of the paper: the α - aminophosphonates of Weiwei research group have important biological activities, such as antiviral, antibacterial, antitumor and enzyme inhibitory activities As a result, the synthesis methods are also widely concerned However, the traditional reaction of pudovik and kabachnik fields is limited by the range of reaction substrate and the stability of imine In order to overcome these problems, in recent years, transition metal catalyzed direct phosphorylation of tertiary amines α - C-H has gradually become the most direct way to synthesize α - amino phosphines Although some outstanding achievements have been made in the synthesis of α - aminophosphono, it is necessary to develop a more mild, safe and effective synthesis method Recently, Ji Jianxin research group of Chengdu Institute of biology, Chinese Academy of Sciences and Wei Wei research group of Qufu Normal University developed a tempo catalyzed etheramine phosphorylation reaction by using the three-component reactions of amine, diarylphosphonoxy and ether The reaction conditions of this method are mild, no need of stoichiometric oxidant and metal catalyst, and it has a wide range of substrate applicability Relevant research results were published in org Lett (DOI: 10.1021/acs.orglett.9b01081) Firstly, aniline, diphenylphosphine oxygen and tetrahydrofuran were used as raw materials to optimize the reaction conditions (Table 1) The results showed that when CuBr 2, Febr 3, Cu (OAC) 2 · H 2O, AgNO 3 and agoac were used as catalysts, the reaction yield did not improve significantly When tempo was added into the system, the yield was improved The author further optimized the reaction conditions and found that the best yield could be obtained at 40 ℃ when 10mol% tempo was used (source: org Lett.) next, the author studied the substrate range of the reaction (scheme 2) When the substrates of para substituted aromatic aniline were investigated, the yield of the reaction was good The ortho - or meta substituted aniline can also react well to obtain the target product in good yield What's more interesting is that for amines with more substituents and more complex structures, the corresponding products can also be obtained The author further examined Pyridylamine and aliphatic amines, which can also react smoothly However, this reaction is not suitable for secondary amines Finally, the substituted phosphine oxide was also studied, and the target product can be obtained in medium yield (source: org Lett.) finally, the applicability of various ethers was studied (scheme 3) The results show that this method is also suitable for tetrahydropyran, 2-methyltetrahydrofuran, 1,4-dioxane, and they can obtain the corresponding products of cyclophosphamide acylation In addition to cyclic ethers, the author also found that this method is suitable for benzyl ethers and n-butyl ethers When 2-methyltetrahydrofuran and benzylethyl ether were used as the reaction substrate, only the corresponding target product could be obtained, indicating that the reaction also has high chemical regioselectivity (source: org Lett.) in addition, when 2-furan acetal is used as the reaction substrate, 66% of the product (scheme 4) can be obtained without catalyst By HRMS analysis, the imine intermediates involved in the reaction were detected (source: org Lett.) based on a series of control experiments, the author proposed a possible reaction mechanism (scheme 6): firstly, a hydrogen atom transfer reaction took place between tempo and tetrahydrofuran, producing α - alkoxy radical 6a, and then tempo changed into tempoh In the presence of oxygen, tempoh is oxidized back to tempo itself Then, 6a was further oxidized to form alkoxy cation 7a with electrophilicity The nucleophilic aniline is easy to react with 7a to form unstable acetal amine 8a, and then tautomerism occurs to form imine 9A Finally, 2A reacts with 8A or 9A to produce 4a (source: org Lett.) Summary: the author developed a tempo catalyzed phosphorylation of ether amines, which involves both C-H and C-O bond breaking of ether The reaction conditions are mild and the substrate is widely used A variety of high value-added α - amino phosphines can be effectively prepared by simple starting materials This reaction does not need any metal catalyst and oxidant Compared with the known method, it has more economic and practical value, and has potential application in the synthesis of organophosphorus drugs Relevant research results were published in org Lett (DOI: 10.1021/acs.orglett.9b01081) Huang Qiang, Ph.D student of Chengdu Institute of biology, Chinese Academy of Sciences, is the first author of the article Ji Jianxin, researcher of Chengdu Institute of biology, and Wei Wei, Professor of Qufu Normal University are the co correspondents of the article The related work was supported by the National Natural Science Foundation of China and the natural science foundation of Shandong Province.