Professor Wu Anxin research team of central China Normal University and Dr. Jia Fengcheng of Wuhan University of Engineering: a new method of selective synthesis of 4-quinolones by alkali regulation

Nitrogen-containing heterocycles are important small organic molecules, which play an indispensable role in medicine, materials, life and other fields Therefore, the development of efficient synthesis methods of nitrogen-containing heterocycles has been widely concerned Recently, Professor Wu Anxin's research team of central China Normal University and Dr Jia Fengcheng of Wuhan University of engineering developed a new type of tandem reaction under the condition of no metal, and realized the efficient construction of two different 4-quinolones through alkali regulation (DOI: 10.1021 / ACS Orglett 8b01645) 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 taught in the school of chemistry of central China Normal University, and published more than 160 research papers in J am Chem SOC., angel Chem Int ed., org Lett, chem Commun J org Chem Adv.synth Catalyst Chem EUR J Presided over 7 funds including the key points of NSFC 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 high-efficiency and simple synthesis methods of drug molecules, so as to realize the direct total synthesis of active natural products; at the same time, on the basis of the research of complex system molecular cluster behavior In order to be used in the functional research of crystal engineering, molecular machines, signal sensing and molecular probes, new molecular aggregates are obtained Brief introduction to Dr Jia Fengcheng, Dr Jia Fengcheng, lecturer of Wuhan University of engineering Graduated from Wuhan University of Engineering in 2011 with a bachelor's degree in engineering In 2017, he received his doctorate from central China Normal University, under the guidance of Professor Wu Anxin Since September 2017, he has taught in the school of chemistry and environmental engineering, Wuhan University of engineering So far, as the first author or corresponding author in org.lett, chem Commun., J org Chem, Adv synth Catalyst And other journals published more than 10 research papers, presided over one natural fund and one youth project of Hubei Provincial Science and Technology Department, respectively At present, research work is mainly focused on organic synthesis methodology, including two aspects: one is the series reaction research based on new active intermediates; the other is the design, synthesis and reaction research of new reagents Frontier research achievements: a new method of selective synthesis of 4-quinolones by alkali regulation 4-quinolones are a kind of very important nitrogen-containing heterocyclic framework, widely exist in a variety of biological activities and drug molecules For example, lvacafto R, a drug for cystic fibrosis, evitegravir, nedopromil, an anti asthma drug, levofloxacin, norfloxacin ciprofloxacin and other antibiotics all contain 4-quinolones (Figure 1) Figure 1 Examples of 4-quinoline derivatives with pharmacological activities (source: organicletters) through literature research, the main methods for the synthesis of 4-quinolones can be summarized into three categories (Figure 2) One of the most common reactions is classical cyclocondensation, such as Niementowski, Conrad limpet and camps However, these reactions usually have some disadvantages, such as harsh conditions, low yield, narrow substrate range and so on The other is the cyclization reaction of ortho modified alkyne ketone prepared by complex prefabrication In order to make up for the shortcomings of the above methods in the synthesis of 4-quinolones, many new methods based on simple amines and alkynes have been gradually explored For example, in 2015, larhed et al Developed palladium catalyzed series reactions for the synthesis of 4-quinolones with o-iodoaniline, hexacarbonyl molybdenum and alkyne as substrates In 2017, Zhang Xu and others realized the copper (II) / acid system to catalyze the preparation of 4-quinolone derivatives from secondary aromatic amines and alkynate derivatives In 2018, Lee et al Developed a copper catalyzed epoxidation reaction with o-aminobenzoate and α, β - unsaturated ketone as substrates to construct a 4-quinolone derivative Indigo is a unique structure with γ - lactam and carbonyl groups Since its discovery in the early 19th century, it has been used as a star molecular reagent to construct a series of bioactive compounds The reaction of indirubin is mainly focused on the spiro cyclization of carbonyl at C-3 and nucleophile with double sites In addition, some scholars have developed a series reaction for the construction of complex and Novel Nitrogen-containing fused rings, focusing on the carbonyl group at C-3 position of indigo and the masked amino group Recently, the author has developed the selective oxidation of indirubin in situ to produce indirubin anhydride intermediates under TBHP / alkali system, and the subsequent cyclization of the intermediates with amidine salt, indigo red and o-haloisothiocyanate, respectively, to achieve the efficient synthesis of quinozolinone, tryptamine, quinozolinone benzothiazole and other heterocycles (org.lett 2016, 18, 2942; chem Commun., 2017, 53 , 1056 ）。 As a continuation of the methodology of oxidation and cyclization of indigo, Professor Wu Anxin's research team of central China Normal University and Dr Jia Fengcheng of Wuhan University of Engineering published a paper entitled "switchable access to 3 carboxylate-4-quinolones and 1 ‑ vinyl-3-carboxylate-4-quinolones via oxidative cyclization of isatins and alkynes" on organic letters The method uses Indigo and alkyne ester were used as substrates, which were oxidized and cyclized under the synergistic action of TBHP / alkali Two different 4-quinolones were synthesized selectively Fig 2 The construction method of 4-quinolones (source: organicletters) firstly, the author takes indigo and methyl benzoalkynate as template substrates, with reference to the previous reaction system, under the conditions of 1 equivalent TBHP, 2 equivalent CS 2CO3, DMSO as solvent, 100 OC for 12 hours, 75% of them can be achieved The yield of 4-quinolones was expected to contain N-H bond In addition, 4-quinolones were obtained by n-alkenylation in 6% yield In order to realize the selectivity of the reaction, the author further investigated the types of bases, equivalents, oxidants, solvents and temperatures Finally, the author found that under the reaction conditions of 1 equivalent TBHP, 2 equivalent CS 2CO 3, DMSO and 100oC, the best selectivity and yield of 4-quinolones with N-H bond can be obtained, while under the condition of 1 equivalent TBHP, 2 equivalent CS 2CO 3, DMSO, 4-quinolones with N-H bond can be obtained TBHP, 2 equivalent K 3PO 4, DMSO as solvent, 100 o C as reaction conditions, n-alkenylated 4-quinolones can be obtained (Table 1) a Reactionsconditions: 1a (0.5 mmol), 2a (0.5 mmol), Base (1 mmol) and oxidant (0.5 mmol) were heated in 3 ml solution in a sealed vessel for 12 h As shown in Table 2, for indigo with different electric groups and various substituted methyl phenylpropargylic acid on the aromatic ring, the corresponding 4-quinolones containing N-H can be obtained in good yield And for the butyrate, various substituted indigo can also show better reactivity In addition, the cyano substituted 4-quinolones can also be obtained by the reaction of indigo with phenylpropargylidene nitrile under standard conditions Table 2 The range of substrates for the reaction of indirubin with alkyne monomolecular esters (source: organicletters) is closely followed by an expansion of the range of substrates for the reaction of indirubin with alkyne bimolecular esters As shown in Table 3, for indigo with different electric groups and various substituted methyl phenylpropanoate on the aromatic ring, the corresponding n-alkenylated 4-quinolones can be obtained in good yield In addition, the cyano modified n-alkenyl 4-quinolones can be obtained by the reaction of indigo with phenylpropargylidene nitriles under standard conditions However, for diacetyl butyrate, the reaction remains in a single molecular stage The author speculates that the existence of ester group may affect the activity of ortho NH Table 3 The range of substrates (source: organicletters) for the reaction of indirubin with bimolecular alkyne ester Considering that the product has rich groups, the author modified the product to synthesize some novel nitrogen-containing heterocycles For example, compound 3AB can react with hydrazine hydrate to convert into a novel fused ring compound 2,3-dihydropyridazino [4,5-b] quinoline-1,4,10 (5H) - trione in high yield; compound 3AA can decarboxylate to compound 2-phenylquinolin-4 (1H) - one under the action of polyphosphate The practicability of the reaction was also investigated The experimental results show that the reaction is suitable for amplification synthesis (Fig 3) Fig 3 Post modification and amplification experiments of the product (source: Organic letters) In order to find out the mechanism of the reaction, the author carried out four groups of control experiments (Fig 4) Control experiment (a) without adding alkyne ester, indigo anhydride can be obtained under standard conditions Control experiment (b) the target product 3AA can be obtained by the reaction of indigo anhydride and alkyne ester The above two groups of experiments show that indirubic anhydride is a possible intermediate The control experiment (c) shows that the reaction of N-methyl substituted indigo anhydride with phenylpropargyl ester can not be realized under standard conditions, which shows that the presence of NH is very important for the initiation of cyclization The control experiment (d) showed that 3AA could undergo nucleophilic addition to n-alkenyl-4-quinolones in the presence of K3PO4 Figure 4 Control experiments (source: organizational letters) Based on the above control experiments and the previous work of the research group, the author proposed the possible reaction mechanism In the synergism of alkali and TBHP, the addition reaction of indigo to produce negative ion B, followed by 1, The intermediate C was obtained by the addition reaction of NH and alkyne ester Then, the nucleophilic attack was carried out to remove CO 2 to obtain the intermediate D, and further proton transfer was carried out to obtain the target product 3AA Under the further induction of alkali, NH can nucleophilic add another alkyne ester to obtain n-alkenylated 4-quinolone (Fig 5) Figure 5 Possible reaction mechanisms (source: organicletters) Summary: the team developed a mild TBHP / alkali synergistic oxidation system that can induce