JACS: a new type of C-N cross coupling reaction developed by Mapu, Germany

PD or Cu catalyzed cross coupling of aryl (pseudo) halides with nucleophiles is the most commonly used method for the construction of C-N bond (scheme 1) However, this method requires the use of pre functionalized aromatics, and it is very difficult to achieve selective halogenation of aromatics at high sites In the past few years, chemists have developed several methods to directly form aryl C-N bond without pre functionalization, such as C-H amination by amino radical cation, imino radical and pyridinium radical cation However, the direct amination of aromatics is usually limited to a single or a small amount of nitrogen source, and the substrate range and selectivity are also very limited (source: J am Chem SOC.) recently, Professor Tobias Ritter and others from Max Planck Institute of coal research in Germany have demonstrated for the first time that arylthiazolium salt can cross couple with N-nucleophiles This kind of arylthiazolium salt can be obtained by site selective functionalization of aryl C-H bond, which provides a high selectivity that other methods can not match for the introduction of C-N bond in the later stage Based on the basic and nucleophilic properties of nitrogen and the limited tolerance of arylthiaanthracylium salt to strong base, four different C-N coupling reaction conditions, including two palladium catalysis methods and two photo Copper Co catalysis methods, have been developed, which can be applied to different nucleophilic nitrogen reagents and greatly broaden the range of substrate (scheme 2) Relevant research results were published in J am Chem SOC (DOI: 10.1021 / JACS 9b07323) (source: J am Chem SOC.) the author found that two PD catalyzed methods can be well applied to arylthiazolium salt without steric hindrance, in which method a is suitable for cyclic and non cyclic secondary amines, and method B is suitable for aromatic amines, amides, carbamates and ureas (Table 1) The reaction can tolerate ester (2,3), acetal (4) and amide (8a,9), and heteroarene can also be coupled (7) Cu mediated methods c and D are suitable for azoles, imides, pyridones, azides and alkylamines, which are less sensitive to steric hindrances and can tolerate ortho substituents (e.g., 12, 13, 16) Esters (11), alkenes (12) and aryl bromides (13,22) are all tolerable under photocatalytic conditions However, the photocatalysis method can not provide the separated C-N coupling products for the very electron rich aromatics such as catechol derivatives The author thinks that it may be due to the oxidation and subsequent decomposition of the coupling products initially formed (source: J am Chem SOC.) in addition, all methods developed by the authors can be applied to aryl thiazolium salt (TT) and aryl tetrafluorothiazolium salt (TFT) The performance of the two derivatives is similar in the photo oxidation-reduction catalysis, but in the PD catalysis method, the higher yield can be obtained with the arylthiaanthracylium salt as the raw material Methods c and D can be completely converted in all cases But not all aromatics can be converted into thiazolium or tetrafluorothiazolium For example, strychnine cannot be converted to thiazolium salt but can be converted to tetrafluorothiazolium salt On the contrary, indomethacin methyl ester can be converted to thiazolium salt, but not to tetrafluorothiazolium salt Finally, the author shows the application of this method in the later stage of diversification modification (scheme 3) The thiazolium salt (tt-25) derived from flurbiprofen methyl ester can be coupled with different N-nucleophiles by four methods Experiments show that these methods can complement each other, thus providing a feasible way for the later stage diversification of complex small molecules (source: J am Chem SOC.) conclusion: Professor Tobias Ritter of Max Planck Coal Research Institute in Germany and others developed the first C-N cross coupling reaction of arylthiazolium salt A wide range of N-nucleophiles can be cross coupled by four different methods, including alkyl and aryl amines and N-containing heterocycles This method can be applied to the post modification of complex molecules, providing new opportunities for the realization of molecular diversity.