Research group of Professor Xu Huadong, Changzhou University: intramolecular imino ene reaction of 2h-azacyclopropene with olefin

According to statistics, 59% of small molecule drugs contain nitrogen heterocyclic compounds As the smallest nitrogen heterocycle, aziridine (aziridine) has unique structure and properties Many anticancer drugs and bioactive molecules contain this structure, but its synthesis method is very limited Recently, the research group of Professor Xu Huadong of the school of pharmacy and life sciences of Changzhou University has made a breakthrough in the synthesis of spiropropyridine For the first time, an ene reaction between 2h-azacyclopropene and olefin has been discovered, which has realized the efficient preparation of spiropropyridine This method enables pharmacochemists to rapidly obtain spiro-nh-aziridine with various structures for drug development (org Lett 2018, 20, 1643-1646; doi: 10.1021/acs.orglett 8b00821) Introduction to Professor Xu Huadong's research group Xu Huadong's research group was founded in July 2012 At present, there are 1 Professor, 1 associate professor, 7 master students in the research group, relying on the school of pharmacy and life sciences of Changzhou University The research group is mainly engaged in the research of "new synthesis methods and biological activities of nitrogen heterocycles" Using the chemical reactivity of organic azides, a variety of efficient synthesis methods of nitrogen heterocycles with unique structure have been developed At present, more than 20 research results have been published in international famous journals such as angelw Chem Int ed., organic lett Prof Xu Huadong, Professor of Changzhou University, master tutor Jiangsu Province "Blue Project" and "six talent peak" training object He served as the young editorial board member of China Chemical express Professor Xu received his bachelor's degree from Lanzhou University in 1998, his master's degree from East China University of science and technology in 2000, his research assistant from Shanghai Institute of organic chemistry, Chinese Academy of Sciences in 2000-2003, his doctoral degree in organic chemistry from UIC in 2007 and University of Wisconsin in 2007-2009- Madison is engaged in postdoctoral research After returning to China, he first served in Shanghai Hongbo Zhiyuan Pharmaceutical Research Co., Ltd for a short time, then worked as an associate researcher in East China Normal University from 2010 to 2012, joined Changzhou University in 2012, served as a distinguished professor, and was promoted to a professor in 2016 Leading scientific research achievements: the reaction of 2h-aziridine with olefin intramolecular imino-ene - the rapid construction of spiro-nh-aziridine from vinyl azide Professor Xu Huadong's research group focused on the application of organic azide in the synthesis of nitrogen heterocycles, and made a series of achievements （1） The research team innovatively found the series reaction pathway of [3 + 2] cyclization / imine formation / intramolecular cyclization / [3,3] rearrangement of copper catalyzed sulfonylazide and n-allylamine (Fig 1, path B) (angel Chem Int ed 2014, 53, 9284-9288; org Lett 2015, 17, 5598-5601; ORG Lett 2015, 17, 3654-3657; Org Lett 2016 , 18 , 889-891; Org.Biomol Chem 2016 , 14 , 1272 -1276 ）。 Fig 1 Tandem reaction pathway (source: angelw Chem Int.ed 2014, 53, 9284-9288) (II) the research team first used nitrogen atom as the connecting atom, connected sulfonyltriazole and carbene receptor, and then used metal catalyst to crack triazole The metal carbene C and carbene acceptor produced intramolecular cyclization to form nitrogen heterocycle D (Fig 2) This strategy combines high reactivity of nitrogen atom, high activity of carbene and high stability of triazole Using this strategy, the research team has successfully developed a variety of efficient methods to prepare alkaloids (Asian J org Chem 2014, 3, 1154-1158; tetrahedron 2015, 71, 5124-5129; org Lett 2015, 17, 66-69; synthesis 2015, 47, 641-646; org BIOMOL Chem 2015, 13, 4851-4854; tetrahedron lett 2015, 56, 6734-6737) Fig 2 The intramolecular cyclization of C and carbene receptor generates D (III) The research team first realized the intramolecular [4 + 2] cycloaddition reaction of 2 h-acridine and 1,3-diene by using alkenylazide to generate 2 h-acridine, and efficiently constructed the heterocyclic acridine framework (angel Chem Int ed 2016, 55, 2540 – 2544) In addition, the team realized the intramolecular Schmidt rearrangement of alkenylazide and CYCLOKETONE for the first time (org Lett 2018, 20, 1643-1646) Fig 3 Construction of the framework of heterocyclic aziridine (source: angelw Chem Int ed 2016, 55, 2540 – 2544) (IV) based on the above study, the team realized that the C = n double bond in 2h-azacyclic propene was activated by cyclic tension, and the compound was a good receptor for ene reaction Based on this, the project of ene reaction between 2 h-aza-propylene and olefin was put forward Firstly, the reaction of alkenylazide 1 with several alkenes 2 was studied It was found that the intermolecular reaction could not take place, only 2 H - azacyclopropene 3 was separated Figure 4 Intermolecular reactions between alkenylazido 1 and several alkenes 2 (source: org Lett 2018, 20, 1643-1646; doi: 10.1021/acs.orglett.8b00821) The author has further studied the intramolecular reactions, hoping that the advantages of the intramolecular reactions in dynamics and thermodynamics can overcome the energy barrier of this ene reaction Under heating conditions, benzyl protected alkenylazide 5A can be converted into product 7a, and the reaction selectivity is very good In most cases, cis isomers are obtained Figure 5 Conversion of alkenylazide 5A to 7a (source: org Lett 2018, 20, 1643-1646; doi: 10.1021/acs.orglett.8b00821) Then, the author carried out an extended study on the substrate (Table 1) The results show that the reaction substrate range is relatively wide, and more complex polycyclic compounds such as spiropropyridine can also be constructed rapidly by this method (Table 2) A reaction conditions: 5 (0.3 mmol), toluene (1ml), 100 o C, 8 h B isolatedyield C NMR ratio D weight ratio Table 1 Substrate Development Research (source: org Lett 2018, 20, 1643-1646; doi: 10.1021/acs.orglett.8b00821) a reaction conditions: 9 (0.3 mmol), toluene (1ml), 100 o C, 10 h B isolatedyield Table 2 The structure of the product of the construction of more complex polycyclic compounds (source: org Lett 2018, 20, 1643-1646; doi: 10.1021/acs.orglett.8b00821) was determined by NMR and MS, and the relative configuration was analyzed by single crystal diffraction of typical products or their derivatives, as shown in the following figure Figure 6 Single crystal diffraction analysis of the product (source: org Lett 2018, 20, 1643-1646; doi: 10.1021/acs.orglett.8b00821) The results of this study were published in org Lett (org Lett 2018, 20, 1643-1646; doi: 10.1021/acs.orglett.8b00821) Another co-author of this study is Shen Meihua, associate professor of Changzhou University Zhou Hao, a graduate student of Changzhou University, completed the preliminary study Liu Taishang, a graduate student, improved the conditions and expanded the substrate 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, 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.