Zhang Fanglin group of Wuhan University of science and technology: palladium catalyzed direct selenidation of benzaldehyde with C (SP2) - H bond as a transient guiding group

The direct selenidation of the ortho-c (SP 2) - H bond of benzaldehyde provides a new way to construct the C-Se bond, which has a high atomic economy Recently, based on the strategy of imine transient orientation, Zhang Fanglin group of Wuhan University of science and technology has realized the direct selenium of benzaldehyde C (SP 2) - H bond catalyzed by palladium The reaction conditions are mild, the substrate range is wide, and two selenium anthracene and one fluorescent probe can be synthesized by one-step derivatization The related work was published in org Lett (DOI: 10.1021 / ACS Orglett 9b0530) Qiao Huihao, a graduate student of the school of chemical engineering, Wuhan University of technology, was the first author Fig 1 palladium catalyzed direct selenidation of benzaldehyde with ortho-c (SP 2) - H bond (source: org Lett.) introduction to Zhang Fanglin's research group Chlorination, bromination, amidation, arylation (j.am Chem SOC 2017, 139, 888), methoxy (org Lett 2019, 21, 3692), alkylation (org Lett 2018, 20, 146), selenidation and C (SP 3) - h-linked arylation (Science 2016351252) derivatization to synthesize polycyclic aromatic hydrocarbons (org Lett 2018, 20, 7620), screw ring structure (Tetrahedron lett 2018, 59, 3554) and other fields have made a lot of progress Zhang Fanglin, associate professor, School of chemistry, chemical engineering and Life Sciences, Wuhan University of technology Graduated from Huazhong University of science and technology in 1999 From 1999 to 2002, he was engaged in the Research Institute of China Lucky Film Group Co., Ltd From 2002 to 2008, he studied for a doctorate in Huazhong University of science and technology From 2008 to 2011, he worked as a postdoctoral researcher in Huazhong University of science and technology Since 2011, he has worked as an associate professor in Wuhan University of Technology From 2014 to 2015, he was a visiting scholar at the Scripps Research Institute in the United States (co tutor Professor Yu Jinquan) He has published more than 20 research papers in science, J am Chem SOC., org Lett., chem Commun., and other famous international chemical journals He presided over the projects of National Natural Science Foundation, Hubei Natural Science Foundation, Wuhan University of science and technology young top talents, etc The main research direction is drug synthesis and total synthesis of compounds with physiological activity Research achievements: biphenylamine, as a transient guiding group, catalyzes the direct selenidation of benzaldehyde with C (SP2) - H bond Organic selenium compounds, especially diaryl selenium compounds, have become the core structure of various photosensitizers and drugs due to their unique photoelectric properties and important biological activities In addition, they also play a key role in catalysis, fluorescent probes and functional organic materials The traditional organic synthesis method is to prepare diaryl selenides by using aryl halides or pseudo halides, which often requires multi-step reaction and complicated operation In order to solve these problems, Zhang Fanglin's group realized the direct selenidation of benzaldehyde C (SP 2) - H bond based on the imine transient guiding strategy The reaction conditions are mild, the substrate range is wide, and two selenium anthracene and one fluorescent probe can be synthesized by one-step derivatization Fig 2 photosensitizers and drug molecules with diaryl selenium structure (source: org Lett.) the authors selected o-methylbenzaldehyde 1a and diphenyl diselenide 2A as template substrates, and initially screened the transient guiding group (TDG) It was found that when benzidine was used as the transient guiding group, the yield could reach the highest 74% (Table 1) On this basis, the author also screened several copper salts and solvents, and found that the best results were obtained by using copper bromide and DMF Finally, the optimal reaction conditions were selected: 10 mol% palladium acetate as catalyst, 30 mol% benzidine as TDG, 1 equivalent copper bromide as oxidant, DMF as solvent, 1a and 2A reacted at 80 ℃ for 48 hours, and the target product 3A could be obtained in 74% yield In Table 1, after the optimal reaction conditions are obtained through the condition screening (source: org Lett.), the author inspected the applicability of the substrate From the results of Fig 3 and Fig 4, it can be seen that the reaction has good substrate universality For benzaldehyde and diaryldiselenide with different substituents, the selenidation can be carried out smoothly, and the corresponding diaryldiselenides can be obtained in a good yield The absolute configuration of product 4A can be confirmed by X-ray single crystal diffraction Fig 3 benzaldehyde substrate expansion (source: org Lett.) Fig 4 diaryldiselenide substrate expansion (source: org Lett.) in order to verify the application of this method, the author has carried out the corresponding gram scale preparation experiment and product derivation Fig 5 shows that the reaction can achieve gram scale preparation under the same conditions, and the target product can be obtained in 58% yield for 3h After treatment with mesitylene in acetic anhydride, it can be converted to 5 in 3 hours, and the yield is 85% Heating for 3 hours in sulfuric acid gives 6 with moderate yield Finally, the fluorescent probe 7 can be easily obtained by one-step reduction condensation with the corresponding primary amines for 3h Fig 5 gram scale experiment and product derivatization (source: org Lett.) next, the author carried out the exploration experiment of experimental mechanism (Fig 6) In the competitive experiment, the equimolar 1a and 1E participate in the reaction to obtain 3:1 3a and 3E, which shows that electron rich benzaldehyde has higher reaction activity The free radical scavengers tempo, BHT and 1,1-stilbene were added to the model reaction of 1a It was found that these three kinds of free radical scavengers had different effects on the conversion: 1-equivalent tempo slowed down the reaction slightly to produce a lower yield, while 5-equivalent tempo significantly inhibited the reaction; in the presence of 1-equivalent BHT, the reaction stopped completely; in the presence of 1,1-equivalent tempo- In the case of stilbene, the treatment with 1 or even 5 equivalent 1,1-stilbene had no significant effect These results show that free radicals do not participate in the catalytic cycle At the same time, the author thinks that tempo and BHT may interact with copper complex and inhibit the selenium process In the presence of D 2O, no deuterium was observed in the product 3l, indicating that the cleavage of C-H bond is irreversible At last, the yield of 3a is 43% by using the reaction of phenylselenole with 1A under standard conditions, which provides experimental support for the proposed mechanism path B Fig 6 control experiment (source: org Lett.) finally, the author proposed the possible reaction mechanism (Fig 7) Firstly, benzaldehyde 1 condensed with T8 to form imine a, which interacted with PD (OAC) 2 to form palladium ring intermediate B through C-H bond activation Then there are three possible ways to complete the catalytic cycle In pathway a, the oxidative addition of B to 2A forms PD (IV) species C substituted by phenyl selenides, which then undergo reduction elimination to produce o-selenided imines D and Pd (II) species E On the one hand, the expected product 3 is released after D hydrolysis and the transient directional group T8 is regenerated for the next catalytic cycle On the other hand, e is treated with acetic acid to obtain phenylselenole F and regenerate PD (OAC) 2 Phenylselenole f can be oxidized back to diphenylselenide 2a by copper salt, or react with B to form five membered palladium ring intermediate g (path B) At the same time, Pd (II) species e can also interact with imine a to produce intermediate g (path C) D and Pd (0) were obtained by reduction of G PD (0) can be oxidized by copper salt to regenerate PD (OAC) 2 This study can not exclude any of the three possible pathways and two key intermediates (C and G) More detailed mechanism research is in progress Fig 7 possible reaction mechanism (source: org Lett.) to sum up, the author successfully developed the first PD catalyzed ortho direct selenium reaction of aromatic aldehydes with benzidine as the transient guiding group The reaction conditions are mild, the functional group compatibility is good, and the reaction can be enlarged to gram scale The product can be transformed into two kinds of selenium anthracene and one kind of fluorescence probe by one step derivatization Finally, a reasonable mechanism is proposed to explain the catalytic cycle This newly developed method represents a practical and effective method for the preparation of organic selenides, which will be widely used in the future The research work was supported by the National Natural Science Foundation of China (21602089) Nowadays, people and scientific research have been paid more and more attention in the economic life China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information website, chembeangoapp, chembeango official micro blog, CBG information wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the representative research groups in China, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.