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    Home > Wang Tao, associate professor, Shaanxi Normal University: general synthesis method of 3 - (isoquinoline-4-chromonenone and 4-quinolonone in metal free condition

    Wang Tao, associate professor, Shaanxi Normal University: general synthesis method of 3 - (isoquinoline-4-chromonenone and 4-quinolonone in metal free condition

    • Last Update: 2019-12-25
    • Source: Internet
    • Author: User
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    4-chromone and 4-quinolone are the common core skeletons in natural products and drug molecules

    For example, the 4-chromone derivatives of ipriflavone and flavone piperate are anti asthma drugs and anti spasm drugs, respectively

    4-quinolones are the core framework of norfloxacin, ofloxacin, ciprofloxacin and sparfloxacin

    In addition, 4-quinolone derivatives can also be used as anticancer, antitumor and anti HIV drugs

    On the other hand, quinoline and isoquinoline structures are important structural parent nuclei of many bioactive natural products and drug molecules

    Recent studies have shown that 3-quinolino-4-quinolones, which combine 4-quinolones with quinoline units, exhibit excellent antibacterial activity

    However, the biological activity of these compounds has not been systematically studied, because the classical strategy for the synthesis of these compounds is to use Suzuki miyuara coupling (Figure 1, a), which requires the use of expensive (isoquinoline boric acid) and transition metal catalysts that may lead to heavy metal residues

    However, there are few reports on the simple synthesis of 3 - (isoquinolino) 4-chromones

    Recently, the research group of Wang Tao, associate professor of Shaanxi Normal University, reported the general synthesis method of 3 - (isoquinoline-4-chromone) and 3 - (isoquinoline-4-quinolone under the condition of no metal

    This method uses cheap and easy to get (isoquinoline) nitrogen oxide as the substrate, has high atomic economy and universality of the substrate, and has synthesized a series of derivatives very efficiently, which provides the material basis for further biological activity test

    Relevant research results were recently published in org

    Lett

    (DOI: 10.1021/acs.orglett.9b03921)

    Figure 1

    Transition metal catalyzed synthesis of 3-quinolinyl4-quinolones and our hypothesis (source: org

    Lett.) according to the research of Wang Tao's research group in recent years, the author found that the reaction of (isoquinoline-n-oxide) and alkyne ketone compound can generate α - (isoquinoline-β-diketone intermediate under the condition of no metal Through further transformation, various nitrogen-containing heterocycles can be constructed

    Therefore, the author assumes that alkynone 1 can react with (isoquinoline) nitrogen oxide to form α - (isoquinoline - β - diketone intermediate a, and then the intermediate undergoes intramolecular dehydration under the promotion of Bronsted acid, which can be used not only to synthesize 3 - (isoquinoline-4-chromonenone, but also to synthesize 3 - (isoquinoline-4-quinolone (Figure 1

    B, taking quinoline nitrogen oxide as an example)

    At the beginning of the study, the authors used alkynone 1a and isoquinoline nitrogen oxide 2A as model substrates to test their hypothesis (Table 1)

    At 140 ℃, 1a and 2a and 0.5 equivalent HCl (12 mol · L-1 HCl solution) were reacted in 0.5ml DMF for 2 hours

    3-isoquinolino-4-chromone 3A was obtained with 88% separation yield and 6% by-product 4A was obtained

    Changing other conditions such as concentration (Table 1, entries 2-3), equivalence ratio of hydrochloric acid (Table 1, entries 4-5), equivalence ratio of 2A (Table 1, entry 6), type of acid (Table 1, entries 7-8) and different solvents (Table 1, entries 9-12) can not further improve the yield

    Table 1

    Optimization of the reaction conditions

    A (source: org

    Lett.) after determining the optimal reaction conditions, the author first investigated the substrate range for the synthesis of 3 - (isoquinolino) 4-chromenone (Table 2)

    When R2 represents substituted phenyl, a good yield (3a-3h, 70-88%) was obtained, and the single crystal structure of 3A was obtained

    When R2 represents thiophene, 76% yield is obtained

    When R2 is n-butyl and cyclopropyl, the yield is also moderate to good

    Interestingly, when 1L and 2A react under standard conditions, TMS will leave and 3L will be obtained, with a yield of 84%

    In addition, isoquinoline nitrogen oxides and quinoline nitrogen oxides with substituents can obtain corresponding products (3n-3s) in good yield

    However, the yield of quinoxaline nitrogen oxide is low (3T) due to its low activity

    However, the activity of pyridine nitrogen oxides is low, and only 4a is obtained

    In addition, 3 - (isoquinoline-4-thiochromone) was not obtained due to the decomposition of raw materials

    Next, the author extended the method to the synthesis of 3 - (isoquinoline-4-quinolone (Table 3)

    Similar to 3 - (isoquinoline-4-chromonenone, the starting material with substituted benzene ring at the end of alkyne can obtain the target product with good to excellent yield (6a-6f, 70-90%)

    The product with thiophene group (6G, 92%) was obtained in high yield

    6h and 6I with aliphatic substituents were obtained in 54% and 74% yields, respectively

    When the raw material with TMS group was put into standard condition, the corresponding product without TMS was obtained (6J, 37%)

    The substituted isoquinoline N-oxide and quinoline N-oxide can also react to obtain the corresponding product (6k-6m)

    T able 3

    Substrate scope for the formation of 3 - (ISO) quinolinyl 4-quinolones a (source: org

    Lett.) when no HCl is involved, the main product of 1a and 2A is 4a, only 20% of the target product 3a is obtained, while 35% of 7 (EQ 1) is separated

    Due to the tautomerism of imine enamine and ketone enol, the four tautomers of 7 (7a-7d) are in equilibrium

    Under the standard condition, 7 can all be converted to 3A (EQ 2)

    This shows that 7 is a reasonable intermediate for the reaction

    (source: org

    Lett.) based on the experimental results and previous studies, the author proposed a possible mechanism for the synthesis of 3 - (isoquinoline-4-chromonenone and 3 - (isoquinoline-4-quinolones (Figure 2, taking the reaction of 1A with isoquinoline-n-oxide 2A as an example)

    The intermediate I was formed by [3 + 2] cycloaddition between 1a and 2A

    The intermediate was unstable, and stable intermediate 7 was obtained by rapid ring opening

    In the presence of Bronsted acid, intermediate 7 undergoes intramolecular dehydration to obtain final product 3a

    Figure 2

    Proposed mechanism (source: org

    Lett.) conclusion: the author developed a general method for the synthesis of 3 - (isoquinoline-4-chromenone) and 3 - (isoquinoline-4-quinolone from easily available raw materials without the participation of metals

    This method is easy to operate and has a wide range of substrates

    It provides an effective method for the preparation of a series of derivatives.
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