Professor Huang you research group of Nankai University: organic phosphine catalyzed [3 + 3] cyclization of p-aminobenzoquinone and MBH carbonate: efficient construction of hydroquinoline derivatives

Lead hydroquinoline based heterocyclic compounds are widely used in medicine The development of novel and efficient synthesis methods will provide a new strategy for the synthesis of these compounds Recently, with tricyclohexylphosphine, a commonly used ligand in metal catalytic reactions, as the catalyst, Huang You's research group of Nankai University developed the first case of [3 + 3] cyclization reaction based on formaldehyde MBH Carbonate Catalyzed by organophosphine, realizing the efficient synthesis of hydroquinoline heterocyclic compounds (Fig 1, org Lett DOI: 10.1021 / ACS Orglett 9b00834) Fig 1 [3 + 3] cyclization of p-aminobenzoquinone and MBH Carbonate Catalyzed by organic phosphine (source: org Lett.), brief introduction of Professor Huang You's research group, 10 researchers of Professor Huang You's research group, including 1 Professor, 6 doctoral students and 3 master's students At present, the main research fields of the research group include the domino cyclization reaction catalyzed by organic phosphine, the design and synthesis of new chiral phosphine catalyst and the study of asymmetric catalysis At present, the research group has published more than 80 papers in the international chemical journals such as angew Chem Int ed., acscatal., org Lett., chem Commun., chem EUR J Professor Huang Youjin Hongxing is the first author of this article He was admitted to Huazhong Agricultural University in 2010 and received his Bachelor of Science Degree in 2014 In the same year, he was admitted to Nankai University and studied for master's degree from Professor Huang you In 2016, he became a doctoral student and engaged in the research of organic phosphine catalytic reaction Leading scientific research achievements: organic phosphine catalyzed [3 + 3] cyclization of p-aminobenzoquinone and MBH carbonate: high efficient construction of hydroquinoline derivatives hydroquinoline derivatives is an important kind of drug molecular framework, and most of the existing synthesis methods have certain defects, such as expensive catalyst, heavy metal residues, limited substrate applicability, etc In order to solve these problems, recently, Professor Huang You's research group of Nankai University has realized the highly efficient and selective synthesis of these compounds with p-aminobenzoquinone and MBH carbonate as raw materials and the catalysis of organic phosphine This method has a short reaction time, a wide range of substrates, and can be used for gram level synthesis The research results were published in the Journal of organic chemistry, org Lett., and the first author was Jin Hongxing, Ph.D student, School of chemistry, Nankai University The author selected p-aminobenzoquinone 1D and MBH carbonate 2A as template substrates, and selected several common Lewis base catalysts and reaction solvents (Table 1) The results show that at a lower reaction temperature, only 4 DA can be obtained When the reaction temperature is increased to 100 ℃, 4 DA can be converted into 3 da Finally, the optimum reaction conditions were selected: 20 mol% PCY 3 catalyst, CHCl 3 as solvent, 1 D and 2 a reaction at 100 ℃ for 1.0 h, and the target product 3DA could be obtained with high yield Table 1 After the optimal reaction conditions are obtained by condition screening (source: org Lett.), the author studies the substrate universality of the reaction From the results in Fig 2, it can be seen that the reaction has good substrate compatibility For p-aminobenzoquinone and MBH carbonate with different substituents, the reaction can be carried out well and the corresponding target product can be obtained in high yield The X-ray single crystal diffraction of the product 3ia was studied, and the correctness of the structure of the product was further confirmed Fig 2 substrate development (source: org Lett.) according to the experimental results and the existing literature reports, the author proposed the mechanism process of the reaction (Fig 3) First of all, MBH carbonate 2A can remove carbon dioxide and tert butanol anion under the action of phosphine catalyst, and generate intermediate A The TERT butanol anion produced in the system makes the raw material 1 of p-aminobenzoquinone undergo deprotonation and generate intermediate a ' Subsequently, the intermediate a and a 'undergo the SN2' process and remove the phosphine catalyst to form the separable intermediate C The intermediate ylide D was obtained by the proton transfer process of polarity reversal of C under the action of organic phosphine The intermediate f is formed by intramolecular Michael addition and proton transfer Finally, the target product 3 was obtained by catalyst regeneration There is a reversible process in the reaction, and the whole reaction is realized by the mode of catalyst re catalysis Fig 3 possible reaction mechanism (source: org Lett.) in order to deeply understand the mechanism of the reaction process, the author conducted corresponding mechanism verification experiments (Fig 4) Firstly, the raw material 3VA of methyl protected p-aminobenzoquinone was synthesized, and the raw material 3VA could only be recovered in 70% yield when it was reacted under standard conditions Secondly, the intermediate 4da was synthesized by other methods and reacted under standard conditions The target product 3DA can be obtained in 70% yield and the decomposition product 1D can be obtained in 18% yield The results of control experiments further confirm the correctness of the reaction mechanism proposed by the author Fig 4 mechanism verification experiment (source: org Lett.) then, the author made a gram level synthesis exploration, and the reaction can obtain 1.76 g target product 3AA in 78% yield At the same time, the author also applied the cyclized products to the subsequent functional group transformation experiments, through bromination reaction, reduction reaction, Michael addition reaction and hydrolysis process, other compounds with complex structure can be efficiently synthesized (Fig 5) Figure 5 product derivatization (source: org Lett.) Summary: this method successfully realized the first case of [3 + 3] cyclization based on formaldehyde MBH addition product catalyzed by organophosphorus The reaction has good reactivity and selectivity, which provides a convenient and efficient strategy for the synthesis of hydroquinoline skeleton compounds, and has a good application prospect in the research and development of drug molecules The research was supported by the National Natural Science Foundation of China (21672109, 21871148, 214720797, 21172115, 20972076), Tianjin Natural Science Foundation (15jcybjc20000, 10jcybjc04000, 05yfjmjc00600) and Nankai University A review of previous reports: Professor Huang you, Nankai University Research Group: Domino 1 with continuous catalysis of organic phosphine, Nowadays, more and more attention has been paid to the synthesis of chroman and tetrahydroquinoline with alkynyl substituted quaternary carbon center by 6-addition / cyclization reaction China is ushering 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, chembeangoapp, chembeango official microblog, CBG wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the domestic representative research group, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.