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    Home > Professor Wu Anxin's research group of central China Normal University: using tosmic as the "binary synthon" of c1n1, imidazole derivatives are synthesized through the strategy of ortho assisted synthesis

    Professor Wu Anxin's research group of central China Normal University: using tosmic as the "binary synthon" of c1n1, imidazole derivatives are synthesized through the strategy of ortho assisted synthesis

    • Last Update: 2020-01-03
    • Source: Internet
    • Author: User
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    Introduction imidazole compounds are important heterocyclic structures They are not only the histidine component in organism, but also the purine component in ribonucleic acid and deoxyribonucleic acid With the development of society, it is also widely used in the fields of medicine, chemical industry and materials Because of its structural superiority, physiological activity and other excellent properties, the synthesis and application of imidazole derivatives have been studied continuously for more than one hundred years, and many famous reactions for the synthesis of imidazole compounds have been reported successively Among them, as one of the most simple and efficient synthesis methods of imidazole, the van Terson imidazole synthesis method has been widely used and developed However, these works are mainly based on the use of the van der son reagent (tosmic) as a c2n1 ternary synthon to participate in the construction of imidazole However, it has never been reported that tosmic was used as a binary synthon of c1n1 to participate in imidazole synthesis Recently, Professor Wu Anxin's research group of central China Normal University has made a new breakthrough in this field (DOI: 10.1021 / ACS Orglett 9b04060) This work not only unlocked a new strategy of imidazole synthesis, but also broadened the reactivity of tosmic Introduction to Professor Wu Anxin's research group the 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 new efficient and concise synthesis methods 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 Cutting edge scientific research achievements: using tosmic as the "binary synthon" of c1n1, synthesis of imidazole derivatives (source: org Lett.) van Terson reagent (tosmic) by ortho assisted strategy is an important heterocyclic construction module, which is widely used in organic synthesis Its nucleophilic methylene carbon, highly active isonitrile group and easily leaving p-methylbenzenesulfonic acid group are the main sites of the reaction Among them, the use of tosmic as a ternary synthon has made important progress in the construction of five membered nitrogen heterocycles, especially in the synthesis of imidazole derivatives, later known as van Terson imidazole synthesis The traditional Vanterson imidazole synthesis method mainly uses imine or in-situ generated imine and TosMIC to generate [3+2] cycloaddition between molecules under alkaline conditions (Fig 1, a) In 2014, Xiao research group reported a case of in-situ formation of imine intermediate by photocatalytic air oxidation of secondary amines, followed by intermolecular [3 + 2] cycloaddition reaction with tosmic under alkaline conditions (Fig 1, b) This novel method of imine formation provides a development opportunity to enrich the synthesis of van terseimizole However, this method is still limited to the application of tosmic as c2n1 "ternary synthon" in the reaction It has never been reported that tosmic was used as c1n1 "binary synthon" to construct imidazole derivatives The key to realize this assumption is to complete the fracture of C (SP 3) - N or C ≡ n Fig 1 synthesis of imidazole (source: org Lett.) with the help of tosmic Inspired by previous work, isonitrile can be converted into corresponding amines after hydrolysis Therefore, it is assumed that tosmic can be hydrolyzed to Tsch 2nh 2 in acid condition, and then dehydrated with c-acylimide in situ to form intermediate g, and then cyclized and aromatized to form 1,4-disubstituted imidazole compounds (Fig 2, a) However, when acetophenone, p-toluidine and tosmic were used as substrates to react under the designed conditions, they could not get the expected products, but formed a kind of unexpected radziszewski type reaction products After careful analysis, it is found that the reason may be that the I 2 / DMSO reaction system is an acid system, and the electrophilicity of protonated imines is stronger than that of carbonyls under this acid condition Therefore, the author tried to introduce a ortho group to block the formation of imines, and successfully constructed another kind of active intermediates This kind of intermediate is likely to undergo cyclization reaction with Tsch 2nh 2 formed in situ to realize the synthesis of imidazole (Fig 2, b) Fortunately, a novel van Terson type imidazole synthesis was realized by using acetophenone, 2-aminobenzyl alcohol and tosmic reagent It is reported that this is the first case in which tosmic is used as the "binary synthon" of c1n1, and imidazole compounds are successfully synthesized by combining the strategy of ortho assistance Fig 2 Synthesis of imidazole compounds (source: org Lett.) the author first used acetophenone, 2-aminobenzyl alcohol, tosmic and iodine as raw materials, and carried out one pot two-step reaction in DMSO The target compound can be obtained in 51% yield After that, a lot of conditions were selected, and the target compound could be obtained in 74% yield under the optimal conditions After the optimal reaction conditions are obtained, the substrate has been expanded The target product can be obtained by substituting one side of arylacetophenone with electron donor, halogen, electron acceptor and heterocycle in medium to excellent yield, and the product 4BA has been confirmed by crystal In addition, some arylacetones with larger conjugated structures, such as 2-acetylphenanthrene, 2-acetylfluorene and 2-acetylnaphthalene, are also well compatible with the system However, 1-acetylnaphthalene, 9-acetylanthracene and benzylidene acetone are not well compatible (Fig 3) Fig 3 study on the application scope of substrate (source: org Lett.) for the side of 2-aminobenzyl alcohol, it has good functional group compatibility whether it is electron substituted or halogenated 2-aminobenzyl alcohol It is gratifying that the substituent of benzyl alcohol at α position substituted by phenyl can also be well compatible Some cross substrates have also been made, and the target product can be obtained in medium to excellent yield (Fig 4) Figure 4 Study on the application scope of substrate (source: org Lett.) later, 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 (Fig 5, a) The ortho benzyl alcohol group is easy to be further derivatized Therefore, the target product 10A was obtained by esterification with EDC and DMAP as catalyst and CH2Cl2 as solvent in 91% yield using dehydrocholic acid and 4AA as substrate (Fig 5, b) Fig 5 practical research (source: org Lett.) finally, in order to study the mechanism of the reaction, the author conducted a large number of control experiments Firstly, the target product can be obtained with high yield by the reaction of ketoaldehyde hydrate 1Ac instead of acetophenone under standard conditions (Fig 6, a) When the prepared substrate a and tosmic are placed under standard conditions, the target compound can be obtained in high yield However, the target product could not be obtained without adding iodine (Fig 6, b) The results show that a is a possible intermediate and iodine plays a decisive role in the formation of target products According to the literature, tosmic can be easily transformed into 6a and 8A Therefore, we can't get the target compound (Fig 6, C, d) by using 6a and 8A instead of tosmic under standard conditions This control experiment denies the possibility that 6a and 8A are intermediates Fortunately, without the addition of 2-aminobenzyl alcohol, 9A compound can be obtained in medium yield (Fig 6, e) This control experiment further proves that TsCH 2 NH 2 is a possible intermediate Fig 6 mechanism study (source: org Lett.) finally, based on the above control experiments and related work previously reported, the author proposed the following possible mechanisms Firstly, acetophenone is oxidated by iodation and Kornblum to form ketal intermediate, then dehydrated, condensed and cyclized with 2-aminobenzyl alcohol to form intermediate a At the same time, the hydrolysis of tosmic was promoted by acid to produce Tsch 2nh 2 Intermediate Then, two active intermediates a and Tsch 2nh 2 undergo intermolecular dehydration and condensation to obtain intermediate B or its resonance structure B ' Then, B or B 'undergoes intramolecular cyclization to form intermediate C The intermediate D was obtained by desalting TSH from C, and then the intermediate e was obtained by ring opening under acidic condition Finally, the target product 4AA was obtained by e oxidation aromatization (Fig 7) Fig 7 possible mechanism (source: org Lett.) in summary, the author reported a case of synthesis of imidazole derivatives using tosmic as c1n1 "binary synthon" The ortho group (- CH2OH) plays an auxiliary role This work not only unlocked a new strategy of imidazole synthesis, but also broadened the reactivity of tosmic This achievement was recently published on organizational letters (DOI: 10.1021 / ACS Org lett 9b04060) The authors of this paper are xiaogeng, can Wang, Chun Huang, Yang Bao, Peng Zhao, you Zhou, Yan Dong Wu, Ling Ling Ling Feng *, and an Xin Wu * The above research work was supported by the National Natural Science Foundation of China and the special fund for basic scientific research of central universities 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.
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