Xuanjun research group of Anhui University: Silver monovalent and alkali promoted [3 + 3] cycloaddition reaction of azoxyallylic cations with yilide

Prof Xuan Jun is a Humboldt scholar and a distinguished professor of the school of chemistry and chemical engineering, Anhui University In June 2015, he obtained his doctor's degree from central China Normal University, and then he was funded by the Humboldt Foundation of Germany, and engaged in post doctoral research in the Institute of organic chemistry, University of Minster, Germany Worked in Anhui University since July 2017 Professor Xuan Jun's research interests are mainly focused on heterocyclic synthesis chemistry, free radical chemistry and asymmetric catalysis The related research work was published in Chem SOC Rev.; angel Chem Int ed.; org Lett.; chem Commun.; chem EUR J.; adv synth Catalyst And other well-known chemical academic journals by the first author or corresponding author, and the papers were cited for more than 1400 times, among which the highest citation for a single article was more than 750 times Some of the work was highlighted by review journals such as synfacts, organizational chemistryhighlights or academic websites Professor Xuan Jun (source: School of chemistry and chemical engineering, Anhui University) the [3 + 3] cycloaddition reaction of azoxyallylic cation with azomethine ylide promoted by monovalent silver and alkali is widely found in a variety of natural products, active drug molecules and many fine chemicals Among these heterocyclic compounds, 1,2,4-Triazine and isoquinoline are particularly important because of their abundant physiological and pharmacological activities As shown in Figure 1, Lamictal and azaribine are commonly used anticonvulsant and antiviral drugs, while BMS 690514 is a tyrosine kinase inhibitor PD 102807 is a highly effective selective muscarinic receptor antagonist for isoquinoline containing molecules, while the natural alkaloid lamellarin I shows potential antitumor activity Therefore, the development of efficient synthesis methods of these two heterocyclic skeletons has attracted the attention of synthetic workers Although there are many studies on the synthesis of 1,2,4-Triazine and isoquinoline, there are few reports on the efficient construction of isoquinoline-triazine skeleton Figure 1 Active biomolecules (source: Organic letters) containing 1,2,4-Triazine and isoquinoline skeletons Recently, Professor Xuan Jun's research group of Anhui University started from simple and easily available raw materials and successfully constructed isoquinoline and triazine skeletons through [3 + 3] cycloaddition reaction of two active intermediates produced in situ (Figure 2) Specifically, the author used silver as catalyst to convert substrate 1 into intermediate of imine ylide; meanwhile, in the presence of alkali, substrate 2 in situ removed a molecule of hydrogen halide to produce a cationic intermediate of azaallyl The final isoquinolinotriazine heterocyclic compounds were obtained by selective [3 + 3] cycloaddition reaction of two in-situ active intermediates This strategy can not only provide a new idea for the synthesis of a series of isoquinolinotriazine compounds, but also realize the cycloaddition reaction between the in-situ generated azoallyl cation intermediate and the in-situ generated active species of another component for the first time Fig 2 The [3 + 3] cycloaddition of [3 + 3] methylimide ylide with azaallyl cations (source: Organic letters) was studied It was found that the [3 + 3] cycloaddition could be carried out smoothly and efficiently when 10 mol% agotf was used as catalyst, potassium carbonate as base and acetonitrile as solvent As shown in Fig 3, for substrate 1, the reaction can be carried out smoothly no matter the methyl group introduced to the electron or the fluorine, chlorine, cyano and nitro group absorbed to the electron on the aromatic ring of the protecting group In addition, when methyl is introduced into the ortho position of aromatic ring, 96% separation yield can be obtained However, with the increase of steric hindrance, the reaction did not take place when 2,4,6-trimethyl substituent was used for 1H It is worth mentioning that the substrates 1I protected by 2-Naphthalenesulfonyl, 1J protected by thiophenesulfonyl, 1K protected by methanesulfonyl, 1L protected by benzoyl and 1m protected by tert butoxycarbonyl are all compatible with the reaction, and the corresponding heterocyclic compounds can be obtained in medium to excellent yields In addition to aryl substitution, the alkynyl segments in substrate 1 can be well compatible with all kinds of alkyl substituted substrates and even terminal alkyne substrates For azoallyl cationic precursor 2, benzyloxy segments can be successfully replaced by methoxy, ethoxy and tert butoxy However, when the alkoxy segment is replaced by benzyl, the expected product cannot be obtained The possible reason is that benzyl group can not stabilize the in-situ production of azoallyl cation intermediates Moreover, it should be noted that the mono methyl substituted substrate is not compatible with the reaction, and the formation of product 3V has not been detected in the reaction system Fig 3 Application scope of reaction substrate (source: Organic letters) This achievement was published on organic letters The first author of this paper is Cheng Xiao, master's degree candidate, School of chemistry and chemical engineering, Anhui University The research was supported by the National Natural Science Foundation of China (No 21702001) and the start-up fund for high-level talent research of Anhui University Original link: http://pubs.acs.org/doi/10.1021/acs.orglett.7b03344 Professor Xuan Jun information: http://chem.ahu.edu.cn/nshow/? 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