Professor Wang Qingmin, Nankai University Research Group: silver copper synergistic catalytic intramolecular cyclization / de sulfonamide / dehydrogenation reaction for efficient synthesis of substituted carbazole

Lead nitrogen heterocycles are one of the basic frameworks of natural products and drug molecules According to research statistics, 59% of small molecule drugs contain nitrogen heterocycles It is of great significance to develop a new methodology for efficient construction of N-heterocyclic framework and to study its biological activity Recently, Professor Wang Qingmin's research group of School of chemistry, Nankai University has developed the intramolecular cyclization / desulfonamide / dehydrogenation reaction catalyzed by silver and copper, and realized the efficient synthesis of substituted carbazole (DOI: 10.1039 / c8cc03600d) Professor Wang Qingmin's research group focuses on the separation, identification, total synthesis and structural transformation of natural pesticides; design, synthesis, biological activity and structure-activity relationship of new and efficient green chemical pesticides; total synthesis of natural products and efficient construction of heterocyclic molecular framework Prof Wang Qingmin, Ph.D., Professor, doctoral supervisor Born in March 1970, obtained bachelor's degree from Lanzhou University in 1994, master's degree in organic chemistry and doctor's degree in agricultural pharmacy from Nankai University in 1997 and 2000 respectively In June 2000, he received a doctorate degree and stayed in school He was promoted to associate professor in December 2000, professor in December 2004 and doctoral supervisor in 2005 In 2004, it was selected into the "new century talent support plan" of the Ministry of education Mainly engaged in the research and development of natural pesticide, green chemical pesticide and drug Since 2000, he has worked independently as a correspondent in J agric Food chem., pestmanag SCI., angew Chem Int ed., Arts & Rheumatism, org Lett., adv synth Catalyst., chem EUR J., an international authoritative journal, J Org Chem Et al Published more than 180 papers included in SCI; applied for more than 70 Chinese invention patents and 12 PCT patents; applied for one American patent and one European patent, and authorized more than 40 Chinese invention patents; published 3 works (seal) The invention patent "new clean production method of pyrethroid series products of bionic pesticide such as fenpropathrin and cypermethrin" has been successfully applied to industrial production and has produced huge economic benefits A number of super efficient plant virus disease control agents and green acaricide candidate varieties have been created, which are now in different stages of industrial development; the national class I new drugs "anti rheumatoid arthritis chiral drugs" and "new drugs targeting HIV integrase" have been created, which are under pre clinical research It has undertaken a number of scientific research projects, such as the national special fund for outstanding doctoral dissertation authors, the National Natural Science Foundation, the national science and technology support plan, 973 project, the key project of the Ministry of education, the key project of Tianjin applied basic and cutting-edge technology research plan, and the special scientific research fund for doctoral discipline points in Colleges and universities Brief introduction to Dr Song Hongjian, doctor Born in April 1985, he received his bachelor's degree from Qufu Normal University in 2008, and his master's degree and doctor's degree in organic chemistry from Nankai University in 2011 and 2014 respectively During his doctoral period, he was awarded the excellent doctoral dissertation cultivation fund of Nankai University in 2013 In June 2014, he worked in the university after receiving a doctor's degree Mainly engaged in the research and development of natural pesticide As the first author or corresponding author in the international authoritative journal j.agricultural Food chem., org Lett., adv synth Catalyst., chem EUR J, Chem Comm et al Published more than 20 papers included in SCI; applied for 11 Chinese invention patents, 4 PCT patents, 1 U.S patent and 1 European patent respectively, and authorized 3 Chinese invention patents; participated in the creation of a number of super efficient candidate varieties of plant virus disease control agents, which are now in the stage of industrial development He presided over 1 youth project of NSFC, 1 general project of NSFC, 2 special scientific research funds for doctoral discipline of institutions of higher learning, and participated in many international cooperation projects such as Syngenta Leading scientific research achievements: silver copper coordinated intramolecular cyclization / de sulfonamide / dehydrogenation reaction is used for the efficient synthesis of substituted carbazole, and the development of new methods for the efficient construction of heterocyclic nitrogen skeleton and the exploration of its biological activity has always been a research hotspot Wang Qingmin, Professor of School of chemistry, Nankai University, has developed novel tandem reactions for efficient construction of various nitrogen-containing heterocycles (org Lett., 2013, 15, 3274-3277; org Lett., 2014, 16, 3240 − 3243; chem EUR J., 2015, 21, 5337-5340; SCI Rep., 2015, 5, 13516; org Chem Front., 2017, 4, 1731-1735; org Lett., 2017 , 19 , 6056−6059; Chem Eur J.,
2018 , 24 , 2065–2069; Adv Synth Catal , 2018 , 360 , 1077–1081）。
Carbazole is a kind of important nitrogen heterocyclic compounds, which widely exists in medicine, natural products and organic materials In recent years, the synthesis of carbazole skeleton has attracted the attention of many synthetic chemists Catalytic series reaction has been widely used in the construction of many complex molecules because of its advantages of high efficiency, high atom economy and environmental friendliness Recently, Professor Wang Qingmin's research group has developed a series reaction of intramolecular cyclization, desulfonamide and dehydrogenation catalyzed by silver and copper, which has realized the "one pot method" and high yield synthesis of a variety of substituted carbazole products The reaction has good functional group tolerance and a wide range of substrate applications The N-sulfonyl protected tert butyl sulfimide 1A was selected as the template substrate to optimize the reaction conditions (Table 1) Under the action of 1 equivalent agsbf 6, the target product 2A (entry 1) can be obtained with 88% separation yield of the substrate; when the catalyst is 1 equivalent Cu (OAC) 2, the by-product 2A '(entry 2) can be obtained with only 20% separation yield of the substrate In the silver copper CO catalytic reaction, the amount of catalyst agsbf 6 and Cu (OAC) 2 has little effect on the reaction (entries 3 − 8) The results of silver catalyst showed that agsbf 6 had the best catalytic effect (entries 9 − 13); the results of solvent investigation showed that 1,2-dichloroethane (DCE) was the most suitable solvent (entries 14 − 17) Table 1 Optimization of reaction conditions a (source: chem Comm.) with the optimal conditions, the author inspected the application scope of the substrate (Figure 1) The target product (2a − 2L) can be obtained in good yield by the substrates containing different substituents on the aromatic ring The electrical properties of substituents on the aromatic ring have a certain influence on the reaction The yield of the substituent (1b − 1D, 1J, 1L) with electron absorption group is higher than that with electron supply group (1E, 1F) The steric hindrance (1g − 1I) and position (1C, 1K) of substituents have little effect on the reaction The reaction is also applicable to the substrate (1b − 1D) containing halogen substituents on the aromatic ring The chirality of n-ts has no effect on the reaction The target product can be obtained with the same separation yield no matter the R or s configuration Fig 1 The effect of substituents on the reaction a (source: chem Comm.) later, the author investigated the sulfonyl protecting group on the nitrogen atom of aniline (Fig 2) The target product (2m − 2V) can be obtained by 60 − 83% separation yield of all substrates The electrical properties of substituents on the benzene ring have little effect on the reaction (1n − 1s); the substrate containing halogen (1n − 1P) on the benzene ring also has good compatibility; when the benzene sulfonyl group is replaced with thiophene-2-sulfonyl (1t), methylsulfonyl (1U) or cyclopropylsulfonyl (1V), the reaction can proceed smoothly The structure of the target product 2S was verified by X-ray crystallography Fig 2 Effect of sulfonyl protecting group on aniline nitrogen atom on the reaction a (source: chem Comm.) in order to better understand the reaction mechanism, the author conducted some control experiments (Fig 3) First of all, without the addition of Tetrachlorobenzoquinone, the intramolecular cyclization product a can be obtained in 80% yield, and 2A can be obtained in 90% yield under standard conditions (Fig 3a), which indicates that a may be the intermediate of the reaction The product 2A 'can be obtained in 20% yield without adding agsbf 6 After adding agsbf 6, the target product 2A can be obtained in 90% yield (Fig 3b), which indicates that 2A' may also be the intermediate of the reaction When Cu (OAC) 2 is not added, the target product 2A can be obtained in 34% yield (Fig 3C) When Tetrachlorobenzoquinone is not added, the mixture of 2a and 2A 'is obtained, and the structure of 2A' is verified by 1H NMR After Tetrachlorobenzoquinone is added, 2A 'can be transformed into 2A (Fig 3D) Based on the control experiments, the author speculated on the possible mechanism of the reaction (Fig 3e): the catalyst silver or copper, as Lewis acid, activated alkyne, generated intramolecular cyclization, proton migration and hydrogen metallization to produce intermediate 2A '; indole 3 of 2A' attacked imine to generate intramolecular nucleophilic attack under the catalysis of silver, and obtained intermediate a of 4-amino-tetrahydrocarbazole The product 2a was formed by desulfonamide and dehydrogenation Figure 3 Control experiment and possible reaction mechanism (source: chem Comm.) The research results were published in Chem Comm (DOI: 10.1039 / c8cc03600d) Huang Yuanqiong, doctoral candidate of Nankai University, was the first author, Professor Wang Qingmin, and song Hongjian, Ph.D., was the corresponding author The research work was supported by National Natural Science Foundation of China (21602117, 21732002, 21672117) and Tianjin Natural Science Foundation (16jczdjc32400) 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.