Wu Ge group, Wenzhou Medical University: copper catalyzed sulfation of maleimide with secondary amines and Bunte salts

Lead alkenyl thioether compounds are widely used in drug molecules, pesticides and organic small molecule catalysts, and play an important role in organic synthesis as building blocks So far, transition metal catalyzed C-H of olefins However, these reactions use disulfide, sulfonyl chloride and mercaptan compounds with narrow substrate as sulfurization reagents, which can not be effectively applied to the later modification of drug molecules and reduce the chance of discovery of innovative drug molecules Wu Ge group, School of pharmacy, Wenzhou Medical University, reported for the first time the multicomponent reactions of copper catalysis, S-ALKYL Bunte salt and amine, through C-S bond and C-N The rapid construction of the bond enables the effective synthesis of thiamine maleimide compounds The reaction mechanism confirms that polarity reversal can realize the effective conversion of maleimide electrophilic reagent to nucleophilic reagent, and broaden the application scope of electron deficient olefins The results were published in the recent org Lett (org Lett 2020, DOI: 10.1021 / ACS Orglett 0c00207) Introduction to associate professor Wu Ge, associate professor, master tutor In 2014, he graduated from Fujian Institute of material structure, Chinese Academy of Sciences (Supervisor: researcher Su Weiping), and continued to work as a research assistant in Fujian Institute of material structure for one year From September 2015 to now, he has independently carried out scientific research in the school of pharmacy, Wenzhou Medical University From August 2018 to August 2019, he was engaged in post doctoral research in Kyoto University, Japan (Tutor: Professor Nakao yoshikai) He presided over one project of National Natural Science Foundation of China, one project of Zhejiang Provincial Natural Science Bureau and one project of Wenzhou Municipal Science and Technology Bureau, published 16 SCI papers in international journals such as org Lett., chem comm., green chemistry, organic chemistry frontiers, applied for 23 patents and granted 4 Rights Cutting edge scientific research achievements: in recent years, copper catalyzed sulfation of maleimide with secondary amines and Bunte salts has made innovative research progress in the oxidative coupling of transition metal Bunte salts with carbon nucleophiles For example, Professor Jiang Xuefeng of East China Normal University reported that under the atmosphere of carbon dioxide dioxide reaction, copper catalyzed aromatic boric acid and Bunte Salt sulfurization; palladium catalyzed conversion of aryltriethoxysilane to arylthioether or thioester compounds through ligand regulation strategy; Professor Yi Wenbin of Nanjing University of science and technology reported the decarboxylation sulfurization of alkynic acid catalyzed by copper Up to now, the sulfidation of electron deficient olefins and Bunte salts catalyzed by metals has not been reported The main reason is that they are prone to classic Michael addition reactions (Fig 1a) Recently, the Wuge group of School of pharmacy, Wenzhou Medical University realized the three-component series reaction of copper catalysis, S-ALKYL Bunte salt and amine (Fig 1b) through polarity reversal strategy Through the rapid construction of C-S bond and C-N bond, the sulfation reaction of maleimide compound was realized Figure 1 Copper catalyzed thiamine reaction of maleimide compounds (source: org Lett.) through a large number of screening of reaction conditions, the author found that cuprous iodide can catalyze the series reaction of maleimide, S-ALKYL Bunte salt and secondary amine to synthesize multifunctional maleimide derivatives The reaction process involves the efficient formation of C-S and C-N bonds This method has the advantages of good atomic economy, simple operation, wide substrate range and good functional group compatibility In addition, the method is also applicable to biological activity and later structural modification of drug molecules (Fig 2-fig 5) Fig 2 Secondary amine substrate range inspection (source: org Lett.) Fig 3 Maleimide substrate range inspection (source: org Lett.) Fig 4 S-ALKYL Bunte salt substrate range inspection (source: org Lett.) Fig 5 Drug molecular modification range inspection (source: org Lett.) The simple catalytic system makes the research strategy effectively applied to the later modification of drugs with secondary amine structure Fig 6 Reaction mechanism study (source: org Lett.) in order to explore the reaction mechanism, the author made the following experiments (Fig 6) First of all, tempo, a common free radical inhibitor, was added to the model reaction to confirm that the reaction was not through the free radical reaction process (Fig 61); then, the reaction sequence of multicomponent reaction was determined Under the standard reaction conditions, n-methylmaleimide and morpholine could react to obtain the ketamine product, while s-benzylbunte salt and n- There is no Michael addition or alkenylthioether product in the reaction of methylmaleimide Ketenamine and s-benzylbunte salt can get the target product successfully when morpholine is used as additive It shows that morpholine is not only used as amination reagent to participate in the substrate reaction, but also as activation reagent in the process of copper catalyzed thioamination of maleimide Finally, according to the results of heavy water experiment, 88% of deuterium products show that the C-H bond can be activated under the standard reaction conditions Fig 7 Mechanism prediction (source: org Lett.) the author proposed the possible reaction mechanism Firstly, copper salt as liwes acid activated maleimide was added to n-micahel to obtain the addition product (a), then it was oxidized and dehydrogenated to obtain the intermediate (b) of ketenamine in oxygen atmosphere, and then copper salt and ketenamine passed through C-H The bond is activated to form alkenyl copper intermediate (c), and ligand exchange (d) is carried out with S-ALKYL Bunte salt The high valence copper intermediate (E) is obtained by disproportionation or oxygen oxidation to remove sulfur trioxide (f) and reduce to eliminate the target compound The research results were published in org Lett (org Lett 2020, DOI: 10.1021 / ACS Orglett 0c00207) The research work was supported by NSFC, NSFC of Zhejiang Province and Wenzhou Medical University 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.