阅读说明：本技术 电化学合成c5、c7二卤化喹啉酰胺衍生物的方法 (Method for electrochemically synthesizing C5 and C7 dihalogenated quinoline amide derivatives ) 是由 谢媛媛 侯加浩 王凯 魏婷婷 于 2020-06-17 设计创作，主要内容包括：一种电化学合成式(I)所示C5、C7二卤化喹啉酰胺衍生物的方法,所述方法为：将式(II)所示喹啉酰胺、卤化试剂、电解质溶于溶剂中,插入电极,在25-80℃下以5-15mA恒流搅拌反应5-60min,之后反应液经后处理,得到式(I)所示产物；本发明采用电化学的方法合成C5、C7二卤化喹啉酰胺化合物,不使用大量氧化剂和金属催化剂,产物收率高,反应条件更温和,底物适用性广,符合绿色化学的要求；<Image he="167" wi="700" file="DDA0002543279860000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(A method for electrochemically synthesizing a C5, C7 dihalogenated quinoline amide derivative shown as a formula (I) comprises the following steps: dissolving quinoline amide shown in a formula (II), a halogenating reagent and electrolyte in a solvent, inserting an electrode, stirring and reacting at a constant current of 5-15mA for 5-60min at 25-80 ℃, and then carrying out post-treatment on reaction liquid to obtain a product shown in a formula (I); the method adopts an electrochemical method to synthesize the C5 and C7 dihalogenated quinoline amide compound, does not use a large amount of oxidant and metal catalyst, has high product yield, milder reaction conditions and wide substrate applicability, and meets the requirement of green chemistry;)

1. A method for electrochemically synthesizing a C5, C7 dihalogenated quinoline amide derivative shown as a formula (I), which is characterized by comprising the following steps:

dissolving quinoline amide shown in a formula (II), a halogenating reagent and electrolyte in a solvent, inserting an electrode, stirring and reacting at a constant current of 5-15mA for 5-60min at 25-80 ℃, and then carrying out post-treatment on reaction liquid to obtain a product shown in a formula (I);

the mass ratio of the quinoline amide represented by the formula (II) to the halogenating agent is 1: 4; the halogenating reagent is sodium halide, dihalo dimethyl hydantoin or N-halogenated succinimide;

the mass ratio of the quinoline amide represented by the formula (II) to the electrolyte is 3: 1; the electrolyte is tetrabutylammonium bromide or tetrabutylammonium fluoroborate;

in the formula (I) or (II),

R₁is phenyl, naphthyl, substituted phenyl or heterocycle, the substituted phenyl is phenyl which is mono-substituted by 1 substituent, and the substituent is C1-C4 alkyl, C1-C4 alkoxy or halogen;

R₂is H, C1-C4 alkyl or C1-C4 alkoxy on the quinoline skeleton;

and X is Cl or Br.

2. The method for electrochemically synthesizing the quinoline amide derivative represented by the formula (I) represented by C5 or C7 as defined in claim 1, wherein the reaction conditions are as follows: the reaction was stirred at 50 ℃ for 15min at a constant current of 15 mA.

3. The method for electrochemically synthesizing the quinoline amide derivative represented by formula (I) C5, C7 as defined in claim 1, wherein the halogenating agent is N-halosuccinimide.

4. The method for the electrochemical synthesis of the quinoline amide derivative represented by formula (I) C5, C7 as defined in claim 1, wherein the electrolyte is tetrabutylammonium fluoroborate.

5. The method for electrochemically synthesizing the quinoline amide derivative represented by the formula (I) and having 5 and 7 dihalides in terms of volume as set forth in claim 1, wherein the solvent is used in an amount of 2 to 10mL/mmol, based on the amount of the substance of the quinoline amide represented by the formula (II).

6. The method for electrochemically synthesizing the quinoline amide derivative represented by formula (I) C5 or C7 according to claim 1, wherein the solvent is one or a mixture of two or more of 1, 2-dichloroethane, dichloromethane, acetonitrile, acetone, ethyl acetate, dioxane and tetrahydrofuran in any ratio.

7. The method for electrochemically synthesizing the quinoline amide derivative of formula (I) C5 or C7 as defined in claim 1, wherein the electrode is C (+) -Pt (-), C (+) -C (-), or Pt (+) -Pt (-).

8. The method for electrochemically synthesizing the quinoline amide derivative represented by the formula (I) C5, C7 as defined in claim 1, wherein the post-treatment method comprises: after the reaction, the reaction solution was concentrated under reduced pressure, and the reaction solution was concentrated under reduced pressure using petroleum ether: the volume ratio of ethyl acetate is 20: the mixed solution of 1 is used as developing agent, and the product shown in the formula (I) is obtained by column chromatography separation.

Technical Field

The invention relates to a novel method for electrochemically synthesizing C5 and C7 halogenated quinoline amide, belonging to the field of organic synthesis.

Background

The halogenated quinoline compound has wide biological activity, has the structure in a plurality of medicaments, has wide biological activity, is a key component for constructing a plurality of medicaments and active intermediates, such as chloroquine, is used for treating malaria initially, has gradually expanded application later, and has certain effect for treating chloroquine rheumatoid arthritis. Meanwhile, halogenated quinoline derivatives are also key intermediates for constructing medicaments or active substances. Therefore, how to rapidly and effectively synthesize the halogenated quinoline amide compound is a focus of attention of researchers.

In modern organic synthesis, C-H functionalization is widely concerned by organic chemists because of the characteristics of no need of pre-functionalization of substrates, high atomic effect and the like. Therefore, the method for directly carrying out C-halogen functionalization is an effective synthetic method. Zhang et al used iodobenzene diacetic acid as an oxidant and copper acetate as a metal catalyst to carry out C5 and C7 dibromination reactions on quinoline amide; the dichlorination reaction of quinoline amide C5 and C7 is realized by adopting hydrochloric acid and potassium peroxymonosulfonate (Oxone). However, these methods either use toxic and harmful reagents, large amounts of oxidizing agents and metal catalysts, and do not meet the requirements of green chemistry.

Therefore, it is necessary to develop a method for synthesizing selective C5, C7 dihaloquinoline amide compound which does not use metal catalyst and oxidant and is green and environment-friendly. Compared with the previously reported methods, the method does not use a large amount of oxidant and metal catalyst, has high yield and milder reaction conditions.

Disclosure of Invention

The invention aims to provide a novel method for synthesizing C5 and C7 dihalogenated quinoline amide derivatives, which is green, friendly, simple, convenient and efficient.

The technical scheme of the invention is as follows:

a method for electrochemically synthesizing a C5, C7 dihalogenated quinoline amide derivative shown as a formula (I) comprises the following steps:

dissolving quinoline amide shown in a formula (II), a halogenating reagent and electrolyte in a solvent, inserting an electrode, stirring and reacting at a constant current of 5-15mA (preferably 15mA) for 5-60min (preferably 15min) at 25-80 ℃ (preferably 50 ℃), and then carrying out aftertreatment on a reaction solution to obtain a product shown in a formula (I);

the mass ratio of the quinoline amide represented by the formula (II) to the halogenating agent is 1: 4; the halogenating agent is sodium halide, dihalo dimethyl hydantoin or N-halogen succinimide, preferably N-halogen succinimide;

the mass ratio of the quinoline amide represented by the formula (II) to the electrolyte is 3: 1; the electrolyte is tetrabutylammonium bromide or tetrabutylammonium fluoroborate, preferably tetrabutylammonium fluoroborate;

the volume usage amount of the solvent is 2-10 mL/mmol, preferably 5mL/mmol, based on the amount of the substance of the quinoline amide shown in the formula (II); the solvent is one or a mixed solvent of more than two of 1, 2-dichloroethane, dichloromethane, acetonitrile, acetone, ethyl acetate, dioxane and tetrahydrofuran in any proportion, preferably acetonitrile;

the electrode is C (+) -Pt (-), C (+) -C (-), or Pt (+) -Pt (-), preferably C (+) -Pt (-);

the post-treatment method comprises the following steps: after the reaction, the reaction solution was concentrated under reduced pressure, and the reaction solution was concentrated under reduced pressure using petroleum ether: the volume ratio of ethyl acetate is 20: 1 as developing agent, and obtaining the product shown in the formula (I) through column chromatography separation;

in the formula (I) or (II),

R₁is phenyl, naphthyl, substituted phenyl, which is phenyl monosubstituted with 1 substituent, which is C1-C4 alkyl, C1-C4 alkoxy or halogen, or a heterocycle, which is, for example, thiophene;

R₂is H, C1-C4 alkyl or C1-C4 alkoxy on the quinoline skeleton;

and X is Cl or Br.

The structure of the compound (I) obtained by the invention¹H NMR、¹³C NMR, MS, HRMS and the like. In the past research, the brominated quinoline amide compound realizes the C5 site cyanation of quinoline amide, and further utilizes Suzuki to functionalize a quinoline ring, so that the brominated quinoline amide compound is applied to the chemical industry. The dibrominated products obtained according to the invention can be used for the synthesis of herbicides by further reaction (example 18).

The invention has the beneficial effects that: in the prior art, toxic and harmful reagents, a large amount of oxidants and metal catalysts are adopted, so that the requirements of green chemistry are not met. The method adopts an electrochemical method to synthesize the C5 and C7 dihalogenated quinoline amide compound, does not use a large amount of oxidant and metal catalyst, has high product yield, milder reaction conditions and wide substrate applicability, and meets the requirement of green chemistry.

Detailed Description

The technical solution of the present invention is further described below by specific examples, but the scope of the present invention is not limited thereto.