CN113549939A - Method for continuously electrically synthesizing isoindolinone by using micro-reaction device - Google Patents
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Abstract
The invention discloses a new method for continuously electrochemically synthesizing isoindolinone, which comprises the steps of taking N-methoxy-2-vinylbenzamide I and sodium trifluoromethanesulfonate II as reaction raw materials, carrying out continuous electrolytic reaction in a microchannel reaction device in the presence of electrolyte and solvent, and obtaining trifluoromethyl functionalized isoindolinone III through intramolecular free radical cascade reaction; the reaction process is shown as a reaction formula. Compared with the prior art, the invention provides a novel preparation method of isoindolinone, and the preparation method has the advantages of green, safe and efficient process operation and mild reaction conditions.
Description
Technical Field
The invention belongs to the field of organic electro-synthesis, and particularly relates to a method for continuously electro-synthesizing isoindolinone by using a micro-reaction device.
Background
Isoindolinones are a class of key structural motifs often found in many natural products, pharmacologically active compounds and materials. Have attracted considerable interest for their excellent biological activity and for a variety of synthetic applications in the preparation of complex molecular frameworks. The most efficient method for preparing functionalized isoindolinone compounds is provided by a series of free radical mediated reactions.
At present, the method for constructing the skeleton of the trifluoromethyl functionalized isoindolinone compound comprises the following steps: (1) copper catalyzed intramolecular aminotrifluoromethylation of olefins to prepare trifluoromethyl functionalized isoindolinones, see reference (org. chem. front.,2016,3, 222-); (2) trifluoromethyl functionalized isoindolinones were prepared by copper-promoted intramolecular aminotrifluoromethylation of olefins using Langlois reagent as the source of trifluoromethyl, as described in the reference (Synlett 2017; 28(08): 962-. Although the above methods have been reported, these methods still have some significant drawbacks: the reaction conditions are harsh, and an oxidant and an excessive amount of a metal catalyst are required for the reaction. These drawbacks not only present safety and environmental concerns, but also make industrial scale-up difficult.
Disclosure of Invention
The purpose of the invention is as follows: the technical problem to be solved by the invention is to develop a novel isoindolinone electric synthesis method, and overcome the problems of harsh reaction conditions, and the need of an oxidant and metal of the traditional system.
The technical scheme is as follows: in order to solve the technical problems, the technical scheme adopted by the invention is a method for continuously and electrically synthesizing isoindolinone by using a microchannel reaction device, which comprises the following steps:
(1) dissolving N-methoxy-2-vinylbenzamide, sodium trifluoromethanesulfonate and electrolyte in a solvent to prepare a homogeneous solution A;
(2) pumping the homogeneous solution A into a microchannel reaction device provided with an electrode for electrolytic reaction, and collecting effluent liquid, namely the solution containing the isoindolinone shown in the formula III;
the reaction equation for continuously and electrically synthesizing isoindolinone by using the microchannel reaction device is as follows:
as a preferable scheme:
in the step (1), the electrolyte is one or a combination of more of tetrabutylammonium acetate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium iodide, tetraethylammonium perchlorate and sodium iodide, and tetrabutylammonium acetate is preferred.
In the step (1), the solvent is any one or a combination of more of acetonitrile, water, dichloroethane and methanol, preferably a combination of acetonitrile and water; more preferably the volume ratio of acetonitrile to water is 4: 1.
In the step (1), the concentration of the N-methoxy-2-vinylbenzamide is 0.02-0.1 mmol/mL; the concentration of the sodium trifluoromethanesulfonate is 0.05-0.2 mmol/mL; the concentration of the electrolyte is 0.05-0.3 mmol/mL; preferably, the concentration of the N-methoxy-2-vinylbenzamide is 0.05 mmol/mL; the concentration of the sodium trifluoromethanesulfonate is 0.15 mmol/mL; the concentration of the electrolyte was 0.1 mmol/mL.
In the step (2), the microchannel reaction device provided with the electrode comprises an injection pump, a microchannel reactor, a cathode sheet, an anode sheet and a receiver; wherein, both sides of the microchannel reactor are respectively provided with a cathode sheet and an anode sheet; the injector, the microchannel reactor and the receiver are connected in series; the connection is a pipeline connection.
Wherein the reaction volume of the microchannel reactor is 200-250 muL, preferably 225 muL.
Wherein, the cathode sheet is a platinum sheet; the anode sheet is a graphite plate.
In the step (2), the current intensity of the electrolytic reaction is 5-20 mA, preferably any one of 5mA, 10mA, 15mA and 20 mA; more preferably 10 mA.
In the step (2), the flow rate of the homogeneous phase solution A pumped into the microchannel reactor is 22.5-450 mu L/min, preferably 225 mu L/min; the temperature of the electrolytic reaction is room temperature; the residence time of the reaction is 0.5-10 min, preferably 1 min.
The microchannel reactor technology has gradually become a research hotspot in the technical field of international fine chemical engineering. A microchannel reactor is a three-dimensional structural element that can be used for chemical reactions, fabricated with a fixed matrix by means of special microfabrication techniques. Microchannel reactors typically contain very small channel sizes (equivalent diameters less than 500 μm) and channel diversity in which fluids flow, mix, and react. And therefore have a very large specific surface area (surface area/volume) in such a micro-structured chemical device. The advantages brought by this are the great mass and heat transfer efficiency, i.e. the precise control of the reaction temperature and the instantaneous mixing of the reaction mass in a precise ratio can be realized. These are all key to improving yield, selectivity, safety, and product quality.
The microchannel reactor used in the invention is a microchannel reactor with small channel diameter and high mass transfer efficiency. The isoindolinone is quickly synthesized by using the microchannel reactor, so that the amplification reaction is facilitated, and the reaction process is safe, efficient and green.
Has the advantages that: compared with the prior art, the invention has the following advantages:
(1) the invention reports the preparation of isoindolinones by electrochemical oxidation for the first time;
(2) the microchannel reaction device is combined with the electrochemical device, the distance between a positive electrode and a negative electrode is short, energy conversion is effectively realized, an electric level hot spot effect is avoided, mass and heat transfer are efficient, the reaction is efficient and rapid, the decomposition of a product is avoided, and the reaction efficiency is obviously improved;
(3) the method does not need alkali, oxidant and metal catalyst, is simple and convenient to operate, and is green and efficient;
(4) the invention continuously reacts through the injection pump and the microchannel reaction device, the preparation process is easy to operate and control, the reaction condition is mild, and the invention has better industrial amplification potential.
Drawings
FIG. 1 is a schematic view of a microchannel electrosynthesis reaction apparatus of the present invention.
FIG. 2 is a schematic view of a microchannel electrosynthesis reaction apparatus according to the present invention.
Detailed Description
The invention will be better understood from the following examples. However, those skilled in the art will readily appreciate that the description of the embodiments is only for illustrating the present invention and should not be taken as limiting the invention as detailed in the claims.
Using the apparatus (name: the Asia Flux module, Model: Model No.2200554, manufacturer: Syrris Ltd) illustrated in FIGS. 1 and 2, the following steps were followed: (1) adding the solution A prepared in proportion into an injection pump a; (2) injecting the mixture into a microchannel reaction device by an injection pump according to a certain proportion for mixing and reacting; (3) adjusting the required current; (4) collecting the effluent reaction liquid, and calculating the product yield by an HPLC method; and measuring the product yield by a high performance liquid chromatography, and separating by column chromatography to obtain the target product.
Example 1 synthesis of compound iii:
0.5mmol (0.0886g) of compound I, 1.5mmol (0.234g) of sodium trifluoromethanesulfonate II and 1mmol (0.302g) of tetrabutylammonium acetate are dissolved in acetonitrile/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A, which is added to syringe pump a; the injection flow rate of the injection pump a is 225 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 1 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 84% by an HPLC method, and obtaining a product III after column chromatography separation.1H NMR(400MHz,Chloroform-d)δ7.74(d,J＝7.5Hz,1H),7.53(d,J＝7.6Hz,1H),7.44–7.37(m,2H),4.86(dd,J＝6.7,4.0Hz,1H),3.88(s,3H),2.97–2.78(m,1H),2.55–2.40(m,1H).13C NMR(101MHz,Chloroform-d)δ164.7,140.7,132.6,129.3,129.2,125.2(q,J＝276.0Hz,1C),123.9,122.7(q,J＝2.0Hz,1C),63.8,53.9(q,J＝3.2Hz,1C),35.2(q,J＝28.6Hz,1C).HRMS(TOF)m/z[M+H]+Calcd for C11H11F3NO2 246.0736found 246.0731.
Example 2 synthesis of compound iii:
0.5mmol (0.0886g) of compound I, 1.5mmol (0.234g) of sodium trifluoromethanesulfonate II and 1mmol (0.387g) of tetrabutylammonium hexafluorophosphate were dissolved in acetonitrile/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A, which was added to syringe pump a; the injection flow rate of the injection pump a is 225 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 1 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 77% by an HPLC method, and obtaining a product III after column chromatography separation.
Example 3 synthesis of compound iii:
0.5mmol (0.0886g) of Compound I, 1.5mmol (0.234g) of sodium trifluoromethanesulfonate II and 1mmol (0.329g) of ammonium tetrabutyltetrafluoroborate in acetonitrile/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A, which is added to syringe pump a; the injection flow rate of the injection pump a is 225 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 1 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 74% by an HPLC method, and obtaining a product III after column chromatography separation.
Example 4 synthesis of compound iii:
0.5mmol (0.0886g) of Compound I, 1.5mmol (0.234g) of sodium trifluoromethanesulfonate II and 1mmol (0.229g) of tetraethylammonium perchlorate are dissolved in acetonitrile/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A which is added to syringe pump a; the injection flow rate of the injection pump a is 225 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 1 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 80% by an HPLC method, and obtaining a product III after column chromatography separation.
Example 5 synthesis of compound iii:
0.5mmol (0.0886g) of Compound I, 0.5mmol (0.234g) of sodium trifluoromethanesulfonate II and 1mmol (0.302g) of tetrabutylammonium acetate were dissolved in dichloroethane/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A, which was added to syringe pump a; the injection flow rate of the injection pump a is 225 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 1 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 69% by an HPLC method, and obtaining a product III after column chromatography separation.
Example 6 synthesis of compound iii:
0.5mmol (0.0886g) of compound I, 1.5mmol (0.234g) of sodium trifluoromethanesulfonate II and 1mmol (0.302g) of tetrabutylammonium acetate are dissolved in methanol/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A, which is added to syringe pump a; the injection flow rate of the injection pump a is 225 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 1 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 65% by an HPLC method, and obtaining a product III after column chromatography separation.
Example 7 synthesis of compound iii:
0.5mmol (0.0886g) of Compound I, 0.5mmol (0.078g) of sodium trifluoromethanesulfonate II and 1mmol (0.302g) of tetrabutylammonium acetate are dissolved in acetonitrile/water (10mL, volume ratio 4/1, the same applies hereinafter) to give a homogeneous solution A, which is added to syringe pump a; the injection flow rate of the injection pump a is 225 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 1 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 60% by an HPLC method, and obtaining a product III after column chromatography separation.
Example 8 synthesis of compound iii:
0.5mmol (0.0886g) of compound I, 1.0mmol (0.156g) of sodium trifluoromethanesulfonate II and 1mmol (0.302g) of tetrabutylammonium acetate are dissolved in acetonitrile/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A, which is added to syringe pump a; the injection flow rate of the injection pump a is 225 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 1 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 71% by an HPLC method, and obtaining a product III after column chromatography separation.
Example 9 synthesis of compound iii:
0.5mmol (0.0886g) of compound I, 2mmol (0.312g) of sodium trifluoromethanesulfonate II and 1mmol (0.302g) of tetrabutylammonium acetate are dissolved in acetonitrile/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A, which is added to syringe pump a; the injection flow rate of the injection pump a is 225 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 1 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 81% by an HPLC method, and obtaining a product III after column chromatography separation.
Example 10 synthesis of compound iii:
0.5mmol (0.0886g) of Compound I, 1.5mmol (0.234g) of sodium trifluoromethanesulfonate II and 0.5mmol (0.151g) of tetrabutylammonium acetate are dissolved in acetonitrile/water (10mL, volume ratio 4/1, the same applies hereinafter) to give a homogeneous solution A, which is added to syringe pump a; the injection flow rate of the injection pump a is 225 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 1 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 70% by an HPLC method, and obtaining a product III after column chromatography separation.
Example 11 synthesis of compound iii:
0.5mmol (0.0886g) of compound I, 1.5mmol (0.234g) of sodium trifluoromethanesulfonate II and 2mmol (0.604g) of tetrabutylammonium acetate are dissolved in acetonitrile/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A, which is added to syringe pump a; the injection flow rate of the injection pump a is 225 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 1 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 77% by an HPLC method, and obtaining a product III after column chromatography separation.
Example 12 synthesis of compound iii:
0.5mmol (0.0886g) of Compound I, 1.5mmol (0.234g) of sodium trifluoromethanesulfonate II and 3mmol (0.906g) of tetrabutylammonium acetate are dissolved in acetonitrile/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A, which is added to syringe pump a; the injection flow rate of the injection pump a is 225 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 1 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 76% by an HPLC method, and obtaining a product III after column chromatography separation.
Example 13 synthesis of compound iii:
0.5mmol (0.0886g) of compound I, 1.5mmol (0.234g) of sodium trifluoromethanesulfonate II and 1mmol (0.302g) of tetrabutylammonium acetate are dissolved in acetonitrile/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A, which is added to syringe pump a; the injection flow rate of the injection pump a is 225 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 200 mu L, and the reaction time is 0.89 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 80% by an HPLC method, and obtaining a product III after column chromatography separation.
Example 14 synthesis of compound iii:
0.5mmol (0.0886g) of compound I, 1.5mmol (0.234g) of sodium trifluoromethanesulfonate II and 1mmol (0.302g) of tetrabutylammonium acetate are dissolved in acetonitrile/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A, which is added to syringe pump a; the injection flow rate of the injection pump a is 225 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 250 mu L, and the reaction time is 1.11 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 82% by an HPLC method, and obtaining a product III after column chromatography separation.
Example 15 synthesis of compound iii:
0.5mmol (0.0886g) of compound I, 1.5mmol (0.234g) of sodium trifluoromethanesulfonate II and 1mmol (0.302g) of tetrabutylammonium acetate are dissolved in acetonitrile/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A, which is added to syringe pump a; the injection flow rate of the injection pump a is 225 mu L/min; the applied current was 5 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 1 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 67% by using an HPLC method, and obtaining a product III after column chromatography separation.
Example 16 synthesis of compound iii:
0.5mmol (0.0886g) of compound I, 1.5mmol (0.234g) of sodium trifluoromethanesulfonate II and 1mmol (0.302g) of tetrabutylammonium acetate are dissolved in acetonitrile/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A, which is added to syringe pump a; the injection flow rate of the injection pump a is 225 mu L/min; the applied current was 20 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 1 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 70% by an HPLC method, and obtaining a product III after column chromatography separation.
Example 17 synthesis of compound iii:
0.5mmol (0.0886g) of compound I, 1.5mmol (0.234g) of sodium trifluoromethanesulfonate II and 1mmol (0.302g) of tetrabutylammonium acetate are dissolved in acetonitrile/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A, which is added to syringe pump a; the injection flow rate of the injection pump a is 450 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 0.5 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 72% by an HPLC method, and obtaining a product III after column chromatography separation.
Example 18 synthesis of compound iii:
0.5mmol (0.0886g) of compound I, 1.5mmol (0.234g) of sodium trifluoromethanesulfonate II and 1mmol (0.302g) of tetrabutylammonium acetate are dissolved in acetonitrile/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A, which is added to syringe pump a; the injection flow rate of the injection pump a is 45 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 5 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 65% by an HPLC method, and obtaining a product III after column chromatography separation.
Example 19 synthesis of compound iii:
0.5mmol (0.0886g) of compound I, 1.5mmol (0.234g) of sodium trifluoromethanesulfonate II and 1mmol (0.302g) of tetrabutylammonium acetate are dissolved in acetonitrile/water (10mL, volume ratio 4/1, the same applies below) to give a homogeneous solution A, which is added to syringe pump a; the injection flow rate of the injection pump a is 22.5 mu L/min; the applied current was 10 mA; the reaction volume V of the microchannel reactor is 225 mu L, and the reaction time is 10 min; after one period of reaction in the microchannel reactor, collecting reaction liquid, calculating the product yield to be 62% by an HPLC method, and obtaining a product III after column chromatography separation.
While the invention has been described with respect to a number of specific embodiments and methods, it will be appreciated by those skilled in the art that various modifications, additions and substitutions can be made without departing from the scope and spirit of the invention. All the components not specified in the present embodiment can be realized by the prior art.
Claims (10)
1. A method for continuously and electrically synthesizing isoindolinone by using a microchannel reaction device is characterized by comprising the following steps:
(1) dissolving N-methoxy-2-vinylbenzamide, sodium trifluoromethanesulfonate and electrolyte in a solvent to prepare a homogeneous solution A;
(2) pumping the homogeneous solution A into a microchannel reaction device provided with an electrode for electrolytic reaction, and collecting effluent liquid, namely the solution containing the isoindolinone shown in the formula III;
2. the method for continuously electrosynthesis of isoindolinone using microchannel reactor device according to claim 1, wherein in step (1), the electrolyte is one or more selected from tetrabutylammonium acetate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium iodide, tetraethylammonium perchlorate and sodium iodide.
3. The method for continuously electrosynthesis of isoindolinone with microchannel reaction device according to claim 1, wherein in step (1), the solvent is any one or combination of acetonitrile, water, dichloroethane and methanol.
4. The method for continuously electrosynthesis of isoindolinone with microchannel reaction device according to claim 1, wherein in step (1), the concentration of N-methoxy-2-vinylbenzamide in the homogeneous solution A is 0.02-0.1 mmol/mL; the concentration of the sodium trifluoromethanesulfonate is 0.05-0.2 mmol/mL; the concentration of the electrolyte is 0.05-0.3 mmol/mL. The mol ratio of the N-methoxy-2-vinylbenzamide to the sodium trifluoromethanesulfonate to the electrolyte is 1: (1-4): (1-6).
5. The method for continuously electrosynthesis of isoindolinone with the microchannel reaction device according to claim 1, wherein in step (2), the microchannel reaction device provided with the electrode comprises a syringe pump, a microchannel reactor, a cathode sheet, an anode sheet and a receiver; wherein, both sides of the microchannel reactor are respectively provided with a cathode sheet and an anode sheet; the injection pump, the microchannel reactor and the receiver are connected in series; the connection is a pipeline connection.
6. The method for continuously and electrically synthesizing isoindolinone according to claim 5, wherein the cathode sheet is a platinum sheet; the anode sheet is a graphite plate.
7. The method for continuously electrosynthesis of isoindolinone with a microchannel reactor device according to claim 1, wherein the microchannel reactor has a reaction volume of 200-250 μ L.
8. The method for continuously electrosynthesis of isoindolinone with a microchannel reactor as set forth in claim 1, wherein the current intensity of the electrolysis reaction in step (2) is 5-20 mA.
9. The method for continuously electrosynthesis of isoindolinone using microchannel reactor as set forth in claim 1, wherein in the step (2), the temperature of the electrolysis reaction is room temperature; the residence time of the reaction is 0.5-10 min.
10. The method for continuously electrosynthesis of isoindolinone with the use of microchannel reactor device according to claim 1, wherein in step (2), the flow rate of the homogeneous solution A pumped into the microchannel reactor is 22.5-450 μ L/min.
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