Professor Yang Hua group of Central South University: phosphine mediated MBH type / γ - addition domino reaction: Construction of coumarin skeleton under the guidance of diversification

Lead coumarins and their derivatives are widely found in Rutaceae, Compositae, Leguminosae and other higher plants, as well as in the secondary metabolites of animals and microorganisms Because of its wide range of pharmacological and biological activities, it has been concerned by all kinds of chemists Although the construction of coumarins has made remarkable progress, the synthesis of these important heterocyclic skeletons is still very challenging Recently, Yang Hua, Professor of Central South University and Xiang Fuyue, associate professor, reported that a series of coumarin derivatives were synthesized by the phosphono mediated MBH / γ - addition domino reaction In this work, various 3-substituted coumarins can be synthesized by simple regulation of nucleophiles, which will greatly enrich the coumarin compound library The related results are published in org Lett (DOI: 10.1021 / ACS Orglett 9b04248) Brief introduction of Professor Yang Hua's research group Professor Yang Hua's research group has been committed to the design, synthesis and application of organic small molecular catalysts in asymmetric synthesis since its establishment in the school of chemistry and chemical engineering, Central South University in 2011 Many progresses have been made in visible light catalysis of olefin functionalization, construction of fluorine-containing heterocycles and asymmetric autocatalytic system In recent years, relevant research has been published in international famous journals such as J am Chem SOC., angelw Chem Int ed., org Lett., chem Comm., chem EUR J At present, the research group has 7 doctoral students and 12 graduate students Leading scientific research achievements: phosphono mediated MBH / γ - addition domino reaction: diversified oriented construction of coumarin skeleton phosphono mediated transformation plays an important role in promoting the construction of carbon carbon bond Due to its unique reactivity, activated alkynes have been developed into one of the substrates for phosphine mediated reactions As we all know, as one of the earliest phosphine catalyzed reactions, MBH reaction is one of the most effective methods to construct carbon carbon bond However, the activated alkyne is still a long-term challenge for phosphine catalyzed MBH reaction Based on the previous research of Yanghua research group (org Bio Chem 2019, 17, 2187-2191) and its mechanism, the author designed to connect alkyne ester part to salicylaldehyde substrate to achieve intramolecular MBH type reaction and generate corresponding zwitterion intermediate; the zwitterion intermediate was captured by external nucleophiles and then carried out γ - trans addition reaction, which will successfully build a series of coumarin derivatives with diverse structure Fig 1 research background and project design (source: org Lett.) the author explored the range of different substituted alkyne esters and different types of nucleophiles, including carbon, nitrogen and oxygen centered nucleophiles Finally, the structure of these compounds was clearly confirmed by X-ray crystallography (A1, C1 and D6) Fig 2 study of substrate adaptation range (source: org Lett.) in view of this novel domino reaction can provide a convenient way to rapidly synthesize various coumarins, the author extended the strategy to N - (2-formylphenyl) - 2-butylamide, so as to quickly construct quinolinone scaffold, further proving the diversity of the strategy Fig 3 synthesis of quinolinone by domino reaction (source: org Lett.) in order to understand the reaction pathway, a series of 31 P NMR monitoring experiments and deuterium labeling experiments were carried out (Fig 4) Methyl diphenylphosphine and methyl diphenylphosphine oxide show characteristic peaks at - 27 ppm and 31 ppm respectively When 1A was mixed with methyldiphenylphosphine, three different peaks near 31 ppm, 29 ppm and 18 ppm were observed after 6 hours After mixing 1a and 2a with methyldiphenylphosphine, only 31 ppm characteristic peaks of methyldiphenylphosphine oxide were observed after 6 hours, indicating that phosphine catalyst participated in the formation of intermediates (29 ppm and 18 ppm) In order to verify whether A1 is the precursor of B1, A1 was placed in the reaction conditions of B1 It was found that compound B1 could not be obtained under these conditions Therefore, we speculate that the reductant of this conversion is phosphine catalyst In addition, by adding deuterium water to the reaction, corresponding deuterium products B1-D and f1-d can be detected, which shows that water is the main Proton source in the process Fig 4 phosphorus spectrum and labeling experiment (source: org Lett.) finally, the author proposed the following reaction mechanism (Fig 5): first, the phosphine catalyst is conjugated into alkyne ester, and then the intramolecular nucleophilic attack aldehyde group (MBH type reaction) produces ylide intermediate I Then, ylide I was protonated and dehydrated to obtain phosphonic zwitterionic intermediate II Intermediate II is easily attacked by various nucleophiles, thus forming ylide intermediate Finally, various coumarins are produced by dephosphorization of intermediates in different ways: 1) under anhydrous conditions, intermediate III is easy to directly eliminate phosphine catalyst and obtain conjugated coumarin derivative a; 2) in the presence of excessive water, intermediate III is easy to be attacked by water and Wittig reaction occurs to generate corresponding product B; 3) if The presence of an active carbonyl group in the appropriate position of the nucleophile will further generate the corresponding products D and E by the Wittig reaction in the molecule; 4) in the absence of any additional nucleophile, the intermediate II will be directly attacked by water to generate the corresponding intermediate III, which will further generate the final product F As shown in the figure, the structural characteristics and reaction conditions will significantly affect the later reaction pathway, thus promoting the synthesis of the diversity and guidance of coumarin skeleton Fig 5 reaction mechanism (source: org Lett.) Summary: Based on activated alkyne ketone and various nucleophiles, this method reasonably combines MBH type reaction, γ - trans addition and witting reaction through the design of phosphine mediated domino reaction process The phosphine mediated transformation showed high tolerance to nucleophiles with various structural characteristics, and thus synthesized a variety of coumarins with novel skeleton This work will provide a new way to design an effective reaction pathway to synthesize a challenging heterocyclic framework by more widely using phosphine mediated transformation This achievement was recently published in org Lett (DOI: 10.1021/acs.org lett 9b04248) under the title of "photomediated MBH type / umpolung addition domino sequence: divergent construction of courmarins" The first authors are Deng Zhixiong (Master) and Zheng Yu (Ph.D.), and the communication authors are Professor Yang Hua, Professor Chen Xiaoqing, and associate professor Xiang Fuyue (paper author: Zhi-Xiong Deng, Yu Zheng, Zhen-Zhen Xie,Yue-Heng Gao, Jun-An Xiao,
Si-Qi Xie,Hao-Yue Xiang,*Xiao-Qing Chen,* and Hua Yang* ）。 The research was supported by the National Natural Science Foundation of China (21576296, 21776318, 21676302 and 81703365) 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.