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    Home > Wu Anxin, Professor of central China Normal University Research Group: iodine promoted multi-component double cyclization and ring opening: Construction of benzo [e] [1,4] diazo-3-one reaction by breaking double C-O bond

    Wu Anxin, Professor of central China Normal University Research Group: iodine promoted multi-component double cyclization and ring opening: Construction of benzo [e] [1,4] diazo-3-one reaction by breaking double C-O bond

    • Last Update: 2019-10-16
    • Source: Internet
    • Author: User
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    Lead 1,4-benzodiazepine skeleton was found in the 1960s, which showed good biological activity Therefore, it plays an important role in the field of pharmaceutical chemistry In the past few decades, a variety of new drug molecules containing 1,4-benzodiazepine skeleton have been designed and synthesized For example, diazepam tablet is one of the most effective drugs for the treatment of central nervous system; bromethanil is part of the agonist of GABAA receptor; flumazenil is a high affinity gabaa-bz site antagonist; divaricept is a cholecystokinin (CCK) antagonist The framework shows good drug value, which provides guidance for the design of drug molecules Therefore, the design and synthesis of new molecules containing 1,4-benzodiazepine skeleton is a challenging and meaningful subject Recently, the research group of Professor Wu Anxin of central China Normal University has made a new breakthrough in the new molecular design of 1,4-benzodiazepine skeleton (DOI: 10.1021/acs.orglett.9b02789) Prof Wu Anxin's research group has been engaged in the research of supramolecular chemistry and organic methodology since its establishment The research focus is to explore the internal law of small molecule self-organized synthesis of complex structure based on the self classification principle of molecular cluster, so as to generate novel synthesis design strategy and explore new synthesis methodology, and thus to explore a new high-efficiency and simple synthesis method of drug molecules, so as to realize the direct total synthesis of active natural products; the developed I 2 / DMSO The reaction system based on in-situ capture of methyl ketone to construct heterocycles mediated by combined reagents has been widely used as a tool reaction The research group has published more than 100 papers in internationally renowned academic journals, including J am Chem SOC., angel Chem Int ed., org Lett., chem Commun., J org Chem., adv synth Catalyst., chem EUR J and other internationally renowned journals At present, the research group has 5 doctors and 6 masters Introduction to Professor Wu Anxin, Professor of central China Normal University, doctoral supervisor, expert on government special allowance under the State Council, young and middle-aged experts with outstanding contributions in Hubei Province, and excellent science and technology workers in Wuhan city He received his bachelor's degree in chemistry from Lanzhou University in 1985 In 1988, he obtained a master of science from Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences From 1988 to 1994, he taught in the Department of pharmacy, medical college, Lanzhou University In 1997, he received his Ph.D in science from Lanzhou University, under the guidance of Professor Pan Xinfu From September 1997 to March 2001, he worked as a postdoctoral researcher in the Department of chemistry, Hong Kong University of science and technology, under the guidance of Professor Dai Weimin From April 2001 to July 2003, he worked as a postdoctoral researcher in the Department of chemistry and biochemistry, University of Maryland, and studied under Professor Lyle Isaac Since July 2003, he has worked in Central China Normal University Presided over 9 funds including the key points of NSFC Frontier research achievements: iodine promoted multi-component double cyclization and ring opening: Construction of benzo [e] [1,4] diazo-3-one reaction by breaking double C-O bond; ortho substituted aniline derivatives are a kind of small organic molecular fragments with simple and good reactivity These compounds play an important role in the synthesis of nitrogen-containing heterocyclic compounds 2-aminobenzyl alcohol, as one of the most commonly used ortho substituted aniline derivatives, has been widely used in the construction of nitrogen-containing heterocyclic compounds It has been reported that 2-aminobenzyl alcohol is often used as a quaternary and pentameric synthon to construct heterocyclic compounds containing N and O / N through [5 + 1], [4 + 1] or [4 + 2] cycloaddition However, these works mainly focus on the reaction of two components, which limits the complexity and novelty of the product to a certain extent It is important to note that some progress has been made in recent years in multicomponent reactions involving 2-aminobenzyl alcohol For example, Wu Huayue group reported a novel copper catalyzed three-component reaction to construct 2-substituted quinazoline In addition, Yu Yongping's group reported an efficient method to construct fused heterocycles by three-component cascade cyclization with ketal hydrate, 2-aminobenzyl alcohol and KSCN as substrates under the catalysis of acid Recently, Wu Anxin's group has realized a novel acid catalyzed four component cascade polycyclic reaction Unfortunately, only one isomer can be separated Although these works are very important and meaningful, they mainly focus on the construction of six membered heterocyclic compounds The use of 2-aminobenzyl alcohol in multicomponent reactions to construct medium-sized rings has not been reported Therefore, it is a significant and challenging task to further develop the reaction diversity of 2-aminobenzyl alcohol Recently, Wu Anxin's research group reported a method for the construction of benzo [e] [1,4] diazo-3-ketones by iodine promoted multi-component double ring opening reaction Fig 1 a multicomponent reaction (source: Organic letters) in which 2-aminobenzyl alcohol is involved Firstly, acetophenone and 2-aminobenzyl alcohol are used as reaction substrates to react in I 2 / DMSO The target compound 3AA can be obtained in 52% yield with a small amount of byproduct 4AA After that, a lot of conditions were selected Under the optimal conditions, the target compound can be obtained in 73% yield After the optimal reaction conditions are obtained, the substrate has been expanded The side of acetophenone is replaced by electron donor, halogen, naphthalene ring, electron acceptor and heterocycle, and the corresponding target product can be obtained in medium to excellent yield The structure of product 3AA is confirmed Fig 2 study on the application scope of substrate (source: Organic letters) for 2-aminobenzyl alcohol side, both 4-substituted and 5-substituted 2-aminobenzyl alcohol have good functional compatibility When 3-methyl-2-aminobenzyl alcohol is used, the target compound can be obtained in 70% yield It should be noted that there are two distinct peaks in both hydrogen and carbon spectra due to the effect of rotational isomerism Four groups of cross experiments were also carried out, and the target products could be obtained with high yield Figure 3 Study on the application scope of substrate (source: Organic letters) Then, the author studied the practicability of the reaction When the reaction is expanded to gram scale, the target compound can also be obtained in medium yield, and the target compound 3AA can be oxidized by m-CPBA to obtain the target product 6A Fig 4 practical study of the reaction (source: Organic letters) Finally, in order to study the mechanism of the reaction, the author conducted a lot of control experiments First, under standard conditions, ketal and its hydrate can be obtained in almost quantitative yield Secondly, the target product 3AA can be obtained in medium yield by the reaction of ketoaldehyde hydrate 1Ac instead of acetophenone under standard conditions Considering that the system is a strong oxidizing system, 2-aminobenzyl alcohol may be oxidized to 2-aminobenzaldehyde However, when 2-aminobenzaldehyde is used to react with acetophenone, the target compound 3AA cannot be obtained, which indicates that 2-aminobenzaldehyde is not an intermediate The target compound 3AA can be obtained in 59% yield when the prepared substrate a and 1.0 equivalent 2-aminobenzyl alcohol are placed under standard conditions In addition, when deuterized DMSO is used for control experiment, the target product of thiomethyl almost completely deuterized can be obtained In order to further explain the specific process of DMS participating in the reaction, the author put the byproduct 4AA and DMS under standard conditions and found that 4AA could not react This experiment showed that the main product 3AA did not go through 4AA Therefore, the author speculates that the formation of byproduct 4AA may be through the competitive reaction between water and DMS Finally, under the standard conditions, 4.0 equivalent heavy water can take part in the reaction to obtain 4AA, a byproduct with oxygen 18 tag, in 33% yield Figure 5 mechanism research experiment (source: organizational letters) Finally, based on the above control experiments and the related work reported before, the author proposed the following possible mechanisms Firstly, acetophenone was oxidated by iodation and Kornblum to form ketal intermediate, then dehydrated and condensed with 1.0 equivalent 2-aminobenzyl alcohol to form intermediate a Next, another 1.0 equivalent 2-aminobenzyl alcohol is dehydrated and condensed with intermediate a to form intermediate B Then, benzyl alcohol is protonated and nucleophilic substitution occurs to form intermediate C C is further protonated to form intermediate D The nucleophilic attack of D and DMS occurred at the same time, and then they were further oxidized to intermediate E Finally, the final product 3AA was obtained by the elimination of iodomethane by E Fig 6 possible mechanism (source: Organic letters) in summary, the author reported a method of constructing benzo [e] [1,4] diazo-3-one and its derivatives by iodine promoted multicomponent reaction This method is an efficient and novel method for the construction of heptacrolactam In this study, 2-aminobenzyl alcohol was used for the first time in the construction of seven membered nitrogen heterocycle, which further enriched the reactivity of 2-aminobenzyl alcohol The results of mechanism study show that the reaction may go through a series of multi-component double ring opening process This achievement was recently published on organizational letters (DOI: 10.1021 / ACS Orglett 9b02789) The corresponding authors of this paper are Professor Wu Anxin and Mr Wu Yandong The full text is written by Xiao Geng, can Wang, Chun Huang, Pengzhao, you Zhou, Yan Dong Wu *, and an Xin Wu * The above research work was supported by the National Natural Science Foundation of China (grants 21602070, 21472056 and 21772051) and the special funds for basic scientific research of Central Universities (ccnu15zx002 and ccnu18qn011) Previous reports: Professor Wu Anxin research group of central China Normal University: building 3,4-dihydrobenzo [b] [1,7] naphthidine reaction through continuous decarboxylation / ring opening / bicyclization strategy 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.
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