A method for synthesizing furanquinoline derivatives with the participation of carbon dioxide

Abstract

The invention provides a method for synthesizing furanquinoline derivatives under the participation of carbon dioxide, and belongs to the technical field of organic synthesis. The synthesis method provided by the invention uses green and safe carbon dioxide and easily prepared o-arylamine alkenyl cycloalkane as raw materials, and in the presence of a base, a Lewis acid and a solvent, a target product furanquinoline derivative is prepared by a one-step method. The yield of the target product obtained by the method of the invention is high, and it has atom economy. The raw material carbon dioxide used is convenient and easy to obtain, which meets the requirements of the green sustainable development strategy. In addition, the method also has the advantages of simple operation, mild conditions, wide application range of substrates, good regional selectivity, etc., and is very suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing furanquinoline derivatives with the participation of oxygen dioxide. Background Art

[0002] Furanoquinoline derivatives are a very important class of nitrogen- and oxygen-containing heterocyclic compounds, which are widely present in the structural units of natural products, drugs and organic materials. There are only a few reports on the synthesis methods of such compounds. For example, Shi Min's research group at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences (Chem. Commun., 2016, 52: 2701-2704.) first proposed a one-step method using triphosgene as a raw material to obtain the relevant target compound in a high yield. The reaction is efficient, novel and highly practical. However, since triphosgene is used as a raw material in this type of reaction, the atomic utilization rate of the reaction itself is low, and triphosgene may release highly toxic phosgene during heating, which poses a great safety hazard and brings inconvenience to the synthesis. Therefore, the selection of a suitable triphosgene substitute has become the key to the further development of this type of reaction.

[0003] Patent document CN 110642866 B provides a method for synthesizing a class of dihydrofuranoquinoline derivatives, which are prepared by reacting N-(2-chloromethyl)phenyl-4-methylbenzenesulfonamide derivatives and furan derivatives as raw materials in an alkaline substance and an organic solvent in the presence of oxygen. Although this synthesis method has the advantages of being simple, easy to control and having a short cycle, its reaction raw materials are difficult to obtain and the cost is relatively high.

[0004] Patent document CN 106397449 A provides a method for preparing a furanoisoquinoline derivative, which is to add the prepared N-methyl-N-isobutyrylbenzamide to the reaction solvent, and then add the oxidant TBHP, the mixed solution reacts at a certain temperature for 12 hours, quench with water, extract with ethyl acetate, and wash once with saturated brine. The crude product is decompressed and dried to dry the solvent, and the intermediate product containing the alcohol of 1,3-isoquinolinedione skeleton is obtained by column chromatography. Then the obtained intermediate product is dissolved in tetrahydrofuran, and lithium aluminum hydride is added in batches, and the reaction is carried out at room temperature for 12 hours. After the reaction is completed, it is quenched with dilute hydrochloric acid, extracted with dichloromethane, washed once with saturated brine, and the crude product is decompressed and dried to dry the solvent, and the target product furanoisoquinoline derivative is obtained by column chromatography. The preparation method has a long reaction time and a relatively complicated post-processing.

[0005] Carbon dioxide is a gas that is closely related to people's lives and survival. It is a greenhouse gas. In recent years, with the large-scale emission of greenhouse gases, the capture and utilization of CO2 has attracted widespread attention. From the perspective of organic synthesis, CO2 is an important and ideal single carbon (C1) source. Due to its non-toxicity, abundance, availability and recyclability, it shows great potential in organic synthesis. From an economic perspective, the study of organic synthesis methodology for efficiently converting carbon dioxide into some high-value-added chemicals has become one of the most important research directions.

[0006] Considering the economic and environmental characteristics of CO2, if we can develop a method to synthesize furanquinoline derivatives using easily available CO2 as raw material through simple operation steps, it will not only have important theoretical significance but also have important application value.

[0007] Therefore, how to develop a method for synthesizing furanquinoline derivatives using CO2 as a reaction raw material has become a technical problem that needs to be solved urgently. Summary of the invention

[0008] The present invention aims to provide a new method for synthesizing furanquinoline derivatives in view of the shortcomings and disadvantages of the existing synthesis methods. Therefore, the technical purpose of the present invention is to solve the problems that the existing methods for synthesizing furanquinoline derivatives have uneconomical reaction raw materials, difficult to obtain raw materials, low atomic utilization rate of the reaction, large safety hazards in the reaction system, and complex preparation process and high post-processing cost.

[0009] In order to achieve the above technical objectives, the technical solution adopted by the present invention is as follows:

[0010] A method for synthesizing furan quinoline derivatives in the presence of carbon dioxide, wherein carbon dioxide and o-arylamine alkenyl cycloalkane are used as raw materials, reacted at 30-160° C. for 4-48 hours in the presence of a base, a Lewis acid and a solvent, and a target compound furan quinoline derivative is prepared;

[0011] The structural formula of the o-arylamine alkenyl cycloalkane is shown in the following formula <Ⅰ>;

[0012]

[0013] The structural formula of the furan quinoline derivative is shown in the following formula <Ⅱ>:

[0014]

[0015] Wherein, the R is The R1 and R2 are both selected from at least one of hydrogen, hydrocarbon or fluorine-containing hydrocarbon, alkoxy, alkylthio, halogen, ester, amide, acyl, carbonyl, nitrile, carboxyl, hydroxyl, thiol, nitro, amine, phosphino or phosphinooxy, silicon or boron-containing groups; the number of R1 and R2 is 1, 2 or 3, and R1 and R2 are located at the 1st, 2nd, 3rd, 4th or 5th position of the benzene ring;

[0016] Alternatively, R is any one of hydrogen, hydrocarbon, fluorine-containing hydrocarbon, alkoxy, alkylthio, halogen, ester, amide, acyl, carbonyl, nitrile, carboxyl, hydroxyl, thiol, nitro, amine, phosphino, phosphinooxy, silicon or boron-containing groups;

[0017] The n is a natural number ranging from 1 to 10.

[0018] The above-mentioned synthesis method provided by the present invention uses green and safe CO2 and o-arylamine alkenyl cycloalkane to generate isocyanate compounds in situ, and then a cyclization reaction occurs under heat induction, and the target compound furanquinoline is obtained in a one-step method with a high yield. The synthesis method uses CO2 as a raw material, avoids the disadvantage of using toxic and harmful triphosgene as a raw material, has the advantages of convenient and easy raw materials, simple operation, mild conditions, wide substrate application range, good regional selectivity, etc., and has good application prospects in actual production and research.

[0019] It is worth noting that the CO2 of the present invention avoids the use of toxic CO, phosgene or triphosgene, and CO2 participates in the synthesis of heterocycles, which is green, safe and non-toxic. The raw material o-arylamine alkenyl cycloalkane compounds are cheap and easy to synthesize, so the use of the above two raw materials makes the synthesis method green, safe, clean, simple and atom-economical.

[0020] Furthermore, the hydrocarbon group includes methyl, ethyl, tert-butyl, alkenyl or alkynyl; and the alkoxy group includes methoxy or ethoxy.

[0021] Furthermore, the halogen includes fluorine, chlorine, bromine or iodine.

[0022] Furthermore, the silicon group includes a silicon hydrogen group, a silicon oxygen group or a silicon halide group.

[0023] Furthermore, the boron-containing group includes a boric acid group or a boric ester group.

[0024] Furthermore, the base includes an inorganic base or an organic base, the inorganic base includes at least one of an alkali metal or alkaline earth metal alkoxide, cesium fluoride, potassium fluoride, sodium fluoride, potassium hydroxide, sodium hydroxide or lithium hydroxide; the organic base includes at least one of an amine compound, 1,8-diazabicycloundec-7-ene or 1,5,7-triazabicyclo[4.4.0]-5-decene.

[0025] Furthermore, the alkali metal or alkaline earth metal alkoxide includes at least one of potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, potassium hydrogen phosphate, sodium acetate, cesium acetate, butyl lithium, phenyl lithium, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide or magnesium tert-butoxide.

[0026] Furthermore, the Lewis acid includes at least one of iron, iron salt, ferrous salt, zinc salt, magnesium, magnesium salt, aluminum salt, nickel salt, tin chloride, boron trifluoride or boron trifluoride ether solution.

[0027] Furthermore, the iron salt includes at least one of ferric bromide, ferric fluoride, ferric chloride, ferric sulfate, ferric nitrate, iron tetrafluoroborate hexahydrate, ferric chloride hexahydrate, ferrocene, ferric triacetylacetonate or anhydrous ferric acetate; the ferrous salt includes at least one of ferrous bromide, ferrous fluoride, ferrous chloride, ferrous iodide, ferrous sulfate, ferrous acetate, ferrous nitrate nonahydrate, ferrous sulfate heptahydrate or iron (II) fluoride tetrahydrate; the zinc salt includes at least one of zinc chloride, zinc bromide, zinc iodide, zinc fluoride tetrahydrate, zinc sulfate, zinc nitrate, zinc trifluoromethanesulfonate, zinc cyanide or zinc acetate; the magnesium salt includes at least one of magnesium chloride, magnesium bromide, magnesium iodide or magnesium fluoride; the aluminum salt includes aluminum chloride and aluminum bromide; the nickel salt includes at least one of nickel iodide, nickel bromide, nickel chloride or nickel trichloride.

[0028] Furthermore, the solvent includes at least one of water, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, benzene, tetrahydrofuran, cyclohexane, decalin, xylene, chlorobenzene, trimethylbenzene, 1,2-dioxane, 1,2-dichloroethane, 1,2-dimethoxyethane, dimethoxyfuran, 2-methyltetrahydrofuran, 2,2,2-trifluoroethanol, acetonitrile, N-methylpyrrolidone or diethylene glycol dimethyl ether.

[0029] Furthermore, the amount of the Lewis acid used in the method of the present invention is 0.005-2 times the molar equivalent of the reaction raw material o-arylamine alkenyl cycloalkane; the amount of the base used is 1-6 times the molar equivalent of the reaction raw material o-arylamine alkenyl cycloalkane.

[0030] The present invention uses carbon dioxide and o-arylamine alkenyl cycloalkane as raw materials, and the reaction conditions are: base, Lewis acid, solvent, and a certain reaction time (4-48h) and reaction temperature (30-160°C) to prepare a furanquinoline compound in the next step. It is a new method for industrially synthesizing furanquinoline derivatives with cheap raw materials, simple operation, and a wide range of substrate applications.

[0031] The present invention provides a method for synthesizing furanquinoline derivatives, wherein the specific reaction formula is:

[0032]

[0033] The beneficial effects of the present invention are as follows:

[0034] (1) The present invention uses green and economical CO2 as raw material. CO2 is easy to obtain and environmentally friendly. It is non-toxic, abundant, available and recyclable, and has great potential to turn waste into treasure, which meets the requirements of green chemistry and sustainable development strategies;

[0035] (2) The synthesis method of the present invention has few experimental steps, simple operation and high safety;

[0036] (3) The reaction raw materials of the present invention are easily available, the reaction cost is low, and the economic efficiency is good; at the same time, the safety problems caused by the triphosgene method are well avoided;

[0037] (4) The synthetic method of the present invention has good functional group tolerance, a wide substrate range, high yield, and high atom economy.

[0038] (5) The present invention can obtain a variety of derivative products and can also be used to synthesize high-value compounds such as material molecules and drug molecules. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 Schematic diagram of the synthetic reaction mechanism of the present invention. DETAILED DESCRIPTION

[0040] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is described in detail below in conjunction with the embodiments. It is necessary to point out that the following embodiments are only used to explain and illustrate the present invention and are not used to limit the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above invention content still belong to the protection scope of the present invention.

[0041] Example 1

[0042] This embodiment mainly introduces the synthesis method of the present invention, and the raw materials in the synthesis are exemplified as follows:

[0043] The compound furanquinoline is prepared in one step under heating conditions using carbon dioxide and o-arylamine alkenyl cycloalkane as raw materials, lithium tert-butoxide as a base, ferric chloride as a Lewis acid, and a mixed solution of N,N-dimethylformamide and o-xylene as a solvent.

[0044] The specific reaction formula involved in the above reaction is as follows:

[0045]

[0046] in:

[0047] R 1 , R represents different substituent groups (for details, please refer to the specification);

[0048] A is the raw material of the reaction, o-arylamine alkenyl cycloalkane, and the amount used in the reaction is 1.0 equivalent;

[0049] B is the base in the reaction (lithium tert-butoxide), and the amount used in the reaction is 4.5 equivalents;

[0050] C is the acid in the reaction (ferric chloride), and the amount used in the reaction is 0.1 equivalent;

[0051] D is the reaction solvent in the reaction (a mixed solution of N,N-dimethylformamide and o-xylene), and the volume ratio of the two is 1:1.

[0052] The specific preparation method is as follows:

[0053] First, select a suitable reactor and dry the reactor with a high-temperature heating gun until it is free of water and oxygen. Weigh raw material A, 4.5 equivalents of lithium tert-butoxide, and 0.1 equivalent of ferric chloride in a glove box. After taking them out of the glove box, replace the inert gas in the reaction tube with carbon dioxide. Add a 1:1 mixed solution of N,N-dimethylformamide and o-xylene under a carbon dioxide atmosphere. After closing the reaction tube, mix well and place it at 110°C for stirring and reaction for 24 hours.

[0054] The post-treatment method of the product is as follows: after the reaction product is cooled, it is extracted three times with ethyl acetate, anhydrous sodium sulfate is added to dry it, and then the solvent is removed in a vacuum and then separated and purified by column chromatography to obtain the product.

[0055] Example 2

[0056] Based on the synthesis method of Example 1, R is a benzene ring as a template reaction to examine the yield of the product. The reaction formula involved in the template reaction is as follows:

[0057]

[0058] The specific synthesis method is as follows:

[0059] A 2.0 ml Schlenk sealed tube reactor was dried with a high temperature heating gun until it was free of water and oxygen. Raw material A (0.0443 g, 0.2 mmol), lithium tert-butoxide (0.072 g, 0.9 mmol), and ferric chloride (0.0033 g, 0.02 mmol) were weighed in a glove box. After taking them out of the glove box, the inert gas in the reaction tube was replaced with carbon dioxide. A mixed solution of N,N-dimethylformamide and o-xylene (1:1, 1 ml+1 ml) was added under a carbon dioxide atmosphere. After the reaction tube was tightly closed, the mixture was mixed evenly and stirred at 110°C for reaction for 24 hours.

[0060] The post-treatment of the product is as follows: after the reaction product is cooled, it is extracted with ethyl acetate three times, and then anhydrous sodium sulfate is added to dry it. Then, the solvent is removed in a vacuum and then separated and purified by column chromatography. The TCL developing solvent is petroleum ether: ethyl acetate = 4:1, and the Rf value is 0.37. The eluent of the column chromatography is petroleum ether: ethyl acetate, and the ratio is: 15:1 (64 ml); 13:1 (56 ml); 10:1 (110 ml); 9:1 (100 ml); 8:1, until the product is completely produced. The obtained product is white crystals with a yield of 80%.

[0061] Example 3

[0062] Based on the synthesis method of Example 1, the reaction conditions of different substituents were investigated. The specific raw materials involved are as follows. Different reaction substrates were reacted according to the method of Example 1. The yields of the obtained target products are as follows:

[0063]

[0064] It can be seen from the above results that the reaction provided by the present invention has a good reaction efficiency for various substrates, and the yield of the obtained product is higher than 50%, which can be well used for industrial production.

[0065] The reaction mechanism of the synthesis method provided by the present invention is as follows:

[0066] like Figure 1 As shown, aniline compounds can react with carbon dioxide under alkaline conditions to generate aromatic isocyanate esters. Therefore, using carbon dioxide as a raw material, under alkaline conditions, o-arylamine alkenyl cycloalkanes react with carbon dioxide to generate isocyanate ester compounds in situ. Such compounds undergo rapid ring closure and rearrangement reactions under heating conditions to obtain the target product in one step.

Claims

1. A method for synthesizing furanquinoline derivatives in the presence of carbon dioxide, characterized in that: The method uses carbon dioxide and o-arylamine alkenyl cycloalkane as raw materials, reacts at 30-160° C. for 4-48 hours in the presence of a base, a Lewis acid and a solvent, and prepares a target compound, a furan quinoline derivative; The structural formula of the o-arylamine alkenyl cycloalkane is shown in the following formula <Ⅰ>; The structural formula of the furan quinoline derivative is shown in the following formula <Ⅱ>: Wherein, the R is The R1 and R2 are both selected from any one of hydrogen, methyl, ethyl, methoxy, ethoxy, and halogen; the number of the R1 and R2 is 1, 2, or 3; Alternatively, said R is hydrogen, methyl or ethyl; The base is selected from at least one of potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, potassium hydrogen phosphate, sodium acetate, cesium acetate, butyl lithium, phenyl lithium, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide or magnesium tert-butoxide; The Lewis acid is an iron salt, and the iron salt is selected from at least one of ferric bromide, ferric fluoride, ferric chloride, ferric sulfate, ferric nitrate, ferric tetrafluoroborate hexahydrate, ferric chloride hexahydrate, ferrocene, ferric triacetylacetonate or anhydrous ferric acetate.

2. The method according to claim 1, characterized in that The solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, benzene, tetrahydrofuran, cyclohexane, decalin, xylene, chlorobenzene, trimethylbenzene, 1,2-dioxane, 1,2-dichloroethane, 1,2-dimethoxyethane, dimethoxyfuran, 2-methyltetrahydrofuran, 2,2,2-trifluoroethanol, acetonitrile, N-methylpyrrolidone or diethylene glycol dimethyl ether.

3. The method according to claim 1 or 2, characterized in that: The amount of the Lewis acid used is 0.005-2 times the molar equivalent of the o-arylamine alkenyl cycloalkane.

4. The method according to claim 1 or 2, characterized in that: The amount of the base used is 1-6 times the molar equivalent of the o-arylamine alkenyl cycloalkane.

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