CN112410809B

CN112410809B - Method for synthesizing fluorine-containing quinolinone compound by electrocatalysis of indole using electrochemical microchannel reaction device

Info

Publication number: CN112410809B
Application number: CN202011260052.4A
Authority: CN
Inventors: 郭凯; 孙蕲; 袁鑫; 邱江凯; 覃龙洲; 段秀; 庄恺强; 崔玉声; 陈琳
Original assignee: Nanjing Tech University
Current assignee: Nanjing Tech University
Priority date: 2020-11-12
Filing date: 2020-11-12
Publication date: 2022-10-11
Anticipated expiration: 2040-11-12
Also published as: CN112410809A

Abstract

The invention discloses a method for synthesizing a fluorine-containing quinolinone compound by electrocatalysis of indole by utilizing an electrochemical microchannel reaction device, which is characterized in that a first solution containing N-substituted 2-aryl indole compound shown as a formula I and a second solution containing a fluorine source and an electrolyte are respectively and simultaneously pumped into the electrochemical microchannel reaction device for reaction to obtain a reaction solution containing the fluorine-containing quinolinone compound shown as a formula II. The invention uses the microchannel reaction device to prepare the fluorine-containing quinolinone compound, can effectively control the reaction rate, shorten the reaction time, realize continuous production, has high diastereoselectivity, reduces the generation of byproducts, has the highest yield of 98.7 percent, ensures that the refining process is simpler, and improves the product quality; basically has no amplification effect, and is beneficial to industrial amplification.

Description

Method for synthesizing fluorine-containing quinolinone compound by electrocatalysis of indole using electrochemical microchannel reaction device

Technical Field

The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing a fluorine-containing quinolinone compound by electrocatalysis of indole fluorination, cyclization and cracking through an electrochemical microchannel reaction device.

Background

Due to its synthetic use and unique biological activity, organofluorine compounds are of great significance in organic synthesis, pharmaceutical and agrochemical applications. Thus, methods of installing fluoroalkyl groups into drugs or bioactive molecules continue to be strongly desired, as the addition of such groups can significantly alter their metabolic stability, lipophilicity, and bioactivity. Among the existing processes, free radical-initiated fluoroalkylation/cyclization of unactivated olefins is one of the most promising strategies for the synthesis of complex fluorochemicals, requiring the selection of an appropriate source of fluoroalkyl group and the specific design of fluoroalkyl-initiated transformations. In fact, this conversion of olefins is well documented and generally requires stoichiometric amounts of oxidant and transition metal catalyst to generate the fluoroethyl group, resulting in undesirable free radical decomposition and other side reactions. Photooxidation-reduction catalysis is superior to the traditional free radical fluoroalkylation reaction to a certain extent. However, the development of Ir or Ru based photo-redox catalysts is also limited by their high price. Recently, organic electrosynthesis has been considered as an effective and mild alternative to the traditional chemical methods of performing redox transformations, in which the redox process proceeds smoothly under extremely mild conditions (room temperature, without the need for hazardous reagents). In particular, the use of the Langerlu reagent (CF) ₃ SO ₂ Na) has been widely adopted, and it is still highly desirable to develop a general fluoromethylation/cyclization process of an unactivated olefin under mild conditions using readily available reagents. However, selective oxidative cleavage of heterocyclic C = C bonds is one of the most efficient routes for organic transformations. In particular, oxidative cleavage of the indole C (2) = C (3) double bond has attracted extensive attention in the construction of N-formylated products. In 1951, witkop reported catalytic oxidation of the C (2) = C (3) double bond of indole by catalysis (Pt/O) ₂ ) And a first chemical oxidative cleavage from autoxidation, after which this reaction has progressed significantly to the Witkop-WinterFeldt oxidation. For the preparation of the 2-aminoarylcarbonyl substrate, each of the different reagents was usedMethods such as peroxy acids, periodic acid, chromic acid, and ozone have attracted attention in the industry and academia. For the preparation of 2-aminoarylcarbonyl substrates, different methods are used, such as peroxyacids, periodic acid, chromic acid and ozone. Recently, several groups have developed visible light-induced processes with oxygen radical C = C bond cleavage and indole oxidation. Electrochemical organic synthesis, a powerful, sustainable synthetic tool, has been little explored in the oxidative cleavage of indoles to carbonyl and amide fragments, compared to most traditional methods, which are limited by the requirements of chemical oxidants and reductants.

Disclosure of Invention

The invention aims to: the technical problem to be solved by the invention is to provide a method for synthesizing fluorine-containing quinolinone compounds by electrocatalysis of indole by utilizing an electrochemical microchannel reaction device, so as to solve the problems of long reaction time and limited amplification potential in the process of continuously preparing the fluorine-containing quinolinone compounds by fluorinating, cyclizing and cracking N-substituted 2-aryl indoles in the prior art.

In order to solve the technical problem, the invention discloses a method for synthesizing a fluorine-containing quinolinone compound by electrocatalysis of indole by utilizing an electrochemical microchannel reaction device, as shown in figure 1, a first solution containing N-substituted 2-aryl indole compound shown in formula I and a second solution containing a fluorine source and electrolyte are respectively pumped into the electrochemical microchannel reaction device at the same time, and fluorination/cyclization/indole oxidative cracking reaction is carried out under constant current to obtain a reaction solution containing the fluorine-containing quinolinone compound shown in formula II;

wherein R is ₁ And R ₃ Independently in the ortho, meta or para position; r ₁ And R ₃ Each independently selected from hydrogen, alkyl, halogen, methoxy or cyano; r is ₂ Selected from hydrogen, alkyl or phenyl; r ₄ Selected from hydrogen or methyl。

Wherein, in the first solution, the concentration of the N-substituted 2-aryl indole compounds is 0.01-0.2 mol/L, preferably 0.2mol/3L.

Wherein the fluorine source is CF ₃ SO ₂ Na (sodium triflate) or CF ₂ HSO ₂ Na (sodium difluoromethylsulfinate).

Wherein the electrolyte is Et ₄ NClO ₄ (tetraethylammonium perchlorate), nBu ₄ NBF ₄ (tetrabutylammonium tetrafluoroborate), nBu ₄ NBF ₆ (tetrabutylammonium hexafluoroborate), nBu ₄ NClO ₄ (tetrabutylammonium perchlorate) and Et ₄ NPF ₆ Any one or a combination of more than one of (tetraethyl ammonium hexafluorophosphate).

Wherein, the concentration of the fluorine source in the second solution is 0.02-0.4 mol/L, preferably 0.4mol/3L.

Wherein, the concentration of the electrolyte in the second solution is 0.02-0.4 mol/L, preferably 0.4mol/3L.

Wherein the molar ratio of the fluorine source to the N-substituted 2-aryl indole compound is 1; the molar ratio of the electrolyte to the N-substituted 2-arylindole compound is 1.

Wherein, the solvents of the first solution and the second solution are respectively and independently selected from water or a mixed solution of water and acetonitrile.

Wherein, the volume ratio of water to acetonitrile in the mixed solution of water and acetonitrile is 1-20, preferably 1.

Preferably, the first solvent is the same as the second solvent; more preferably, the first solvent and the second solvent are both mixed solution of water and acetonitrile.

The electrochemical microchannel reaction device comprises a first feeding pump, a second feeding pump, a microreactor, a cathode sheet, an anode sheet and a receiver; wherein the first feed pump and the second feed pump are connected in parallel to the microreactor through connecting pipes, and the microreactor and the receiver are connected in series through a conduit; wherein, the inside of the micro reactor is provided with an electrode consisting of a cathode sheet and an anode sheet; preferably, a micro mixer is arranged inside the micro reactor, and after mixing, the micro mixer reacts.

Among them, graphite, platinum sheet and RVC may be used as a cathode and an anode; preferably, the anode is a carbon electrode and the cathode is a platinum electrode.

Wherein, the micro-channel in the micro-reactor has the size inner diameter of 0.5-5 mm and the length of 0.5-40 m.

Wherein the pumping rates of the first solution and the second solution are controlled so that the volume ratio of the first solution to the second solution is 1.

Preferably, the rates of the first solution and the second solution are each 0.1 to 5mL/min, and more preferably 0.2mL/min.

Wherein the reaction temperature is 15-50 ℃, and room temperature is preferred; the current for the reaction is 1 to 30mA, preferably 5mA.

Wherein the residence time of the reaction is 0.5 to 60min, preferably 15min.

After the reaction is finished, quenching the reaction solution, adding an organic solvent for extraction, collecting an organic phase, drying, concentrating and recrystallizing to obtain the fluorine-containing quinolinone compound.

Has the advantages that: compared with the prior art, the invention has the following advantages:

(1) The fluorine-containing quinolinone compound is prepared by using the microchannel reaction device, so that the reaction rate can be effectively controlled, the reaction time is shortened, the continuous production is realized, the diastereoselectivity is high, the generation of byproducts is reduced, the yield can reach 98.7 percent at most, the refining process is simpler, and the product quality is improved; basically has no amplification effect, and is beneficial to industrial amplification.

(2) The reaction conditions are mild (room temperature and weak current), in addition, a powerful green strategy shows a wide substrate range and a wide functional tolerance, and under the mild electrooxidation conditions, reports of one-step combination of three free radical fluoralkylation, tandem cyclization and indole oxidative cleavage reactions are not reported.

(3) The electrocatalytic N-substituted 2-aryl indole compound does not need expensive metal catalysts and oxidants in the processes of fluorination, cyclization and cracking.

(4) The fluorine source is a Langlois reagent which is easy to store and use, readily available in raw materials and inexpensive.

Drawings

The foregoing and/or other advantages of the invention will become further apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings.

FIG. 1 is a schematic reaction scheme.

FIG. 2 is an electrocatalytic microchannel reactor device.

FIG. 3 is an electrocatalytic microchannel reaction module.

FIG. 4 is a 1H NMR chart (400Hz, CDCl3) of the product of example 1.

FIG. 5 is a 3C NMR chart of the product of example 1 (100Hz, CDCl3).

FIG. 6 is a 19FNMR map (376Hz, CDCl3) of the product of example 1.

FIG. 7 is a 1H NMR chart of the product of example 10 (400Hz, CDCl3).

FIG. 8 is a 3C NMR chart of the product of example 10 (100Hz, CDCl3).

FIG. 9 is a 19FNMR map (376Hz, CDCl3) of the product of example 10.

FIG. 10 is a 1H NMR chart of the product of example 11 (400Hz, CDCl3).

FIG. 11 is a 3C NMR chart of the product of example 11 (100Hz, CDCl3).

FIG. 12 is a graph of 19FNMR of the product of example 11 (376Hz, CDCl3).

FIG. 13 is a 1H NMR chart of the product of example 12 (400Hz, CDCl3).

FIG. 14 is a 3C NMR chart of the product of example 12 (100Hz, CDCl3).

FIG. 15 is a 19FNMR map (376Hz, CDCl3) of the product of example 12.

FIG. 16 is a 1H NMR chart of the product of example 13 (400Hz, CDCl3).

FIG. 17 is a 3C NMR chart (100Hz, CDCl3) of the product of example 13.

FIG. 18 is a graph of 19FNMR of the product of example 13 (376Hz, CDCl3).

FIG. 19 is a 1H NMR chart of the product of example 14 (400Hz, CDCl3).

FIG. 20 is a 3C NMR chart of the product of example 14 (100Hz, CDCl3).

FIG. 21 is a graph of 19FNMR of the product of example 14 (376Hz, CDCl3).

FIG. 22 is a 1H NMR chart of the product of example 15 (400Hz, CDCl3).

FIG. 23 is a 3C NMR chart of the product of example 15 (100Hz, CDCl3).

FIG. 24 is a 19FNMR map (376Hz, CDCl3) of the product of example 15.

FIG. 25 is a 1H NMR chart of the product of example 16 (400Hz, CDCl3).

FIG. 26 is a 3C NMR chart of the product of example 16 (100Hz, CDCl3).

FIG. 27 is a 19FNMR map (376Hz, CDCl3) of the product of example 16.

FIG. 28 is a 1H NMR chart of the product of example 17 (400Hz, CDCl3).

FIG. 29 is a 3C NMR chart of the product of example 17 (100Hz, CDCl3).

FIG. 30 is a 19FNMR map (376Hz, CDCl3) of the product of example 17.

FIG. 31 is a 1H NMR chart of the product of example 18 (400Hz, CDCl3).

FIG. 32 is a 3C NMR chart of the product of example 18 (100Hz, CDCl3).

FIG. 33 is a 19FNMR map (376Hz, CDCl3) of the product of example 18.

Detailed Description

The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.

Example 1

The microchannel reaction apparatus is shown in FIG. 2, wherein the reactants are as described above, and R is taken ₁ Is p methyl, R ₂ Is methyl, R ₃ Is hydrogen, R ₄ N-substituted 2-arylindole reactant 0.058g (0.2mmol, 1.0 equiv) as methyl group was dissolved in 3mL of a mixed solvent (H) ₂ O: meOH = 1) to give a first solution, and weighing the trifluoromethyl source CF ₃ SO ₂ Na 0.062g (0.4mmol, 2.0equiv), electrolyte Et ₄ NClO ₄ 0.092g (0.4mmol, 2.0equiv) of a mixed solvent (H) of 3mL ₂ O: meCN = 1) to obtain a second solution, which is loaded into the syringe after complete dissolution. Simultaneously pumping the first solution and the second solution into a reactor with a coil pipe inner diameter of 0.5mm for mixing, wherein the volume is 6mL, the flow rate of the first solution and the flow rate of the second solution are both 0.2mL/min, pumping into an electrochemical microreactor, reacting at a constant current of 5mA and at a temperature of 25 ℃ for 15min, wherein the anode is a carbon electrode and the cathode is a platinum electrode. After the reaction, TLC detection was performed, and the final product 76.812mg was obtained by EA: PE =1 silica gel column chromatography, with a yield of 98.7%, and nuclear magnetic resonance as shown in fig. 4 to 6.

Example 2

The procedure is as in example 1, except that the electrolyte is changed to Et ₄ NPF ₆ 0.11g (0.4mmol, 2.0equiv), TLC detection after the reaction was completed, and column chromatography on silica gel by EA: PE =1 10 gave 70.82mg of the final product in 91% yield.

Example 3

The procedure is as in example 1, except that the electrolyte is changed to nBu ₄ NClO ₄ 0.11g (0.4mmol, 2.0equiv), and TLC detection after the completion of the reaction, and column chromatography on silica gel by EA: PE =1 to obtain 69.5mg of a final product in 89.3% yield.

Example 4

The method is the same as example 1, except that the mixed solvent of the first material and the second material is changed into (H) ₂ O: meCN = 1), TLC detection after the reaction is finished, and silica gel column chromatography by EA: PE = 1.

Example 5

Example 6

The method is the same as example 1, except that the mixed solvent of the first material and the second material is changed into H ₂ And O, performing TLC detection after the reaction is finished, and performing silica gel column chromatography by using EA: PE = 1.

Example 7

The method is the same as example 1, except that the electrode is changed to: and (3) taking a carbon electrode as an anode and a carbon electrode as a cathode, carrying out TLC detection after the reaction is finished, and carrying out silica gel column chromatography by EA: PE = 1.

Example 8

The procedure is as in example 1 except that TLC detection is carried out at a constant current of 8mA after the reaction is finished and the final product is obtained in 75.96mg with a yield of 97.6% by chromatography on EA: PE = 1.

Example 9

The procedure is as in example 1 except that TLC detection is carried out at a constant current of 12mA after the reaction is completed and the final product is obtained in 71.44mg with a yield of 91.8% by EA: PE = 1.

Example 10

The procedure is as in example 1, except that R of the N-substituted 2-arylindole reactant is ₁ p-Cl was modified and loaded separately into syringes after complete dissolution as indicated above. After the reaction, TLC detection was performed, and the final product was 77.314mg, 94.5% yield by EA: PE =1 silica gel column chromatography, nuclear magnetic resonance was as shown in fig. 7 to 9.

Example 11

The procedure is as in example 1, except that R on the N-substituted 2-arylindole reactant is ₁ Modification of m-Me, as indicated above, after complete dissolution, was loaded separatelyIn a syringe. After the reaction, TLC detection was performed, and the final product 73.31mg, yield 94.2%, and nuclear magnetic resonance data are shown in fig. 10 to 12 were obtained by EA: PE = 1.

Example 12

The procedure is as in example 1, except that R of the N-substituted 2-arylindole reactant is ₃ The P-Me was modified as indicated above and loaded separately into the syringe after complete dissolution. After the reaction, TLC detection was performed, and the final product was obtained in 75.63mg, 93.8% yield by EA: PE =1 silica gel column chromatography, nuclear magnetic resonance being shown in fig. 13 to 15.

Example 13

The procedure is as in example 1, except that R of the N-substituted 2-arylindole reactant is ₁ 、R ₃ Modification of H, R ₂ Modified to phenyl as shown in the above figure. After the reaction, TLC detection was performed, and the final product was obtained 81.48mg in 93.2% yield by EA: PE =1 silica gel column chromatography, nuclear magnetic resonance being shown in fig. 16 to 18.

Example 14

The procedure is as in example 1, except that the fluorine source is changed to CF ₂ HSO ₂ Na, as indicated above, after the reaction was completed, TLC detection was performed, and the final product was 70.66mg, yield 95.2%, and nuclear magnetic resonance was shown in fig. 19 to 21 by EA: PE = 1.

Example 15

The procedure is as in example 14, except that R on the N-substituted 2-arylindole reactant is ₁ p-Cl was changed as described above, and the resulting solutions were completely dissolved and loaded into syringes, and after completion of the reaction, TLC detection was performed, and the final product was obtained in 73.91mg, 94.5% yield by EA: PE = 1.

Example 16

The procedure is as in example 14, except that R on the N-substituted 2-arylindole reactant is ₃ The m-Me was changed as described above, TLC detection was performed after the reaction was completed, and the final product was 71.41mg, 92.7% yield by EA: PE =1, silica gel column chromatography, and nuclear magnetic resonance was as shown in fig. 25 to 27.

Example 17

The procedure is as in example 14, except that R on the N-substituted 2-arylindole reactant is ₁ 、R ₃ Modification of H, R ₂ The reaction was changed to phenyl, and TLC detection was performed after completion of the reaction as described above, and the final product was 76.95mg, yield 91.8%, and nuclear magnetic resonance was shown in fig. 28 to 30 by EA: PE = 1.

Example 18

The procedure is as in example 1, except that R of the N-substituted 2-arylindole reactant is ₃ After the reaction was completed, TLC was performed as shown in the above figure to obtain 79.257mg of a final product by EA: PE =1 through silica gel column chromatography, with 98.3% yield and nuclear magnetic resonances as shown in fig. 31 to 33.

Comparative example 1

The reactants are as indicated above, R is taken ₁ Is p methyl, R ₂ Is methyl, R ₃ Is hydrogen, R ₄ N-substituted 2-arylindole reactant which is methyl 0.058g (0.2mmol, 1.0equiv), trifluoromethyl Source CF ₃ SO ₂ Na 0.062g (0.4mmol, 2.0equiv), electrolyte Et ₄ NClO ₄ 0.092g (0.4mmol, 2.0equiv) of a 6mL mixed solvent (H) ₂ O: meCN = 1) to obtain a reaction solution, putting the reaction solution into a common electrochemical reactor after the reaction solution is completely dissolved, wherein the anode is a carbon electrode, the cathode is a platinum electrode, and reacting at 25 ℃ under the condition that the constant current is 5mA for 20 hours. After the reaction was completed, TLC detection was performed by EA: PE = 1.

Comparative example 2

The method is the same as example 1, except that the mixed solvent of the first material and the second material is changed into (H) ₂ O: etOH =1 = 3), loaded in syringes respectively after complete dissolution. Simultaneously pumping the first solution and the second solution into a reactor with a coil pipe inner diameter of 0.5mm for mixing, wherein the volume is 6mL, the flow rate of the first solution and the flow rate of the second solution are both 0.2mL/min, pumping into an electrochemical microreactor, reacting at a constant current of 5mA and at a temperature of 25 ℃ for 15min, wherein the anode is a carbon electrode and the cathode is a platinum electrode. After the reaction was completed, TLC detection was performed, and column chromatography was performed by EA: PE = 1.

Comparative example 3

The procedure of example 1 was followed except that the solvent mixture of the first and second materials was changed to MeCN, and the materials were completely dissolved and then loaded into syringes, respectively. After the reaction was completed, TLC detection was carried out, and no significant product was found.

The invention provides a thought and a method for synthesizing quinolinone compounds by electrocatalytic indole fluorination, cyclization and cracking through an electrochemical microchannel reaction device, and a plurality of methods and ways for realizing the technical scheme are provided. All the components not specified in this embodiment can be implemented by the prior art.

Claims

1. A method for synthesizing a fluorine-containing quinolinone compound by electrocatalysis of indole by utilizing an electrochemical microchannel reaction device is characterized in that a first solution containing N-substituted 2-aryl indole compound shown as a formula I and a second solution containing a fluorine source and an electrolyte are respectively and simultaneously pumped into the electrochemical microchannel reaction device for reaction to obtain a reaction solution containing the fluorine-containing quinolinone compound shown as a formula II;

wherein R is ₁ And R ₃ Each independently selected from hydrogen, alkyl, halogen, methoxy or cyano; r ₂ Selected from hydrogen, alkyl or phenyl; r ₄ Selected from hydrogen or methyl;

wherein, in the first solution, the concentration of the N-substituted 2-aryl indole compound is 0.01-0.2 mol/L;

wherein the fluorine source is CF ₃ SO ₂ Na or CF ₂ HSO ₂ Na；

Wherein the electrolyte is Et ₄ NClO ₄ 、nBu ₄ NBF ₄ 、nBu ₄ NBF ₆ 、nBu ₄ NClO ₄ And Et ₄ NPF ₆ Any one or a combination of several of them;

2. The method of claim 1, wherein the concentration of the fluorine source in the second solution is 0.02 to 0.4mol/L.

3. The method of claim 1, wherein the concentration of the electrolyte in the second solution is 0.02 to 0.4mol/L.

4. The method according to claim 1, wherein the pumping rates of the first solution and the second solution are controlled such that the volume ratio of the first solution to the second solution is 1.

5. The method according to claim 1, wherein the temperature of the reaction is 15 to 50 ℃ and the current of the reaction is 1 to 30mA.

6. The process according to claim 1, wherein the residence time of the reaction is between 0.5 and 60min.