CN110627823A - A kind of method for catalyzing arylamine deamination boronation or halogenation - Google Patents

Abstract

The invention belongs to the technical field of organic synthesis, and specifically discloses a method for catalyzing the deamination, boronization or halogenation of arylamines. pre-reacted; then add the raw materials that can provide the functionalized group A, the catalytic amount of the reaction accelerator, and carry out the deamination functionalization reaction under light irradiation at a temperature of 10 to 50 ° C to obtain the amino group in the arylamine. The product of position modification functional group A. Through the coordinated control of the substrate, the reaction solvent, the mixing method, the temperature, the reaction accelerator and the addition amount, the present invention can realize the effective treatment of the arylamine, especially the electron-donating substituted arylamine which is difficult to be effectively handled by the technical solutions in the industry. Boronated or halogenated.

Description

A kind of method for catalyzing arylamine deamination boronation or halogenation

technical field

The invention relates to a method for catalyzing the deamination of arylamines. It belongs to the field of organic chemical synthesis.

Background technique

Amines widely exist in the biological world and have extremely important physiological and biological activities. For example, proteins, nucleic acids, many hormones, antibiotics and alkaloids are complex derivatives of amines. Most of the drugs used clinically are also amines or amines. Derivatives. Arylamine compounds also exist in a large number in nature and industry. Due to their low cost and high activity, arylamine compounds are widely used as substrates in the field of organic synthesis. is of practical significance.

For example, for the functionalization reaction of arylamine boronate esters, precious metal catalysts are mostly used in the prior art, and the processing cost is high, and it is difficult to be practically applied in industry. In terms of halogenation, the Stack team reported in 2017 that using aniline and trichlorobromomethane or diiodomethane as raw materials, sodium nitrite as diazotization reagent, acetic acid as acid, and dichloromethane as solvent, the deamination and halogenation reaction was completed at room temperature (Derek A. Leas, Yuxiang Dong, Jonathan L. Vennerstrom, and Douglas E. Stack Org. Lett. 2017, 19, 2518-2521), although this method can bring certain effects, it requires expensive and strong selective halogenation reagents For example, bromination requires BrCCl3 reagent, and the preparation effect of weakly selective CBr4 bromination reagent is poor. In addition, this preparation method has better effect on strongly electron-withdrawing substrates, but the preparation effect of electron-donating substituted substrates poor. And some products can only be brominated, but not iodized, and the method is not versatile enough. And there is no essential difference from the traditional diazonium salt reaction.

SUMMARY OF THE INVENTION

Aiming at the lack of general technology in the prior art that aryl amines are deaminated by light to generate different functionalized products, the purpose of the present invention is to provide a general method for deamination of aryl amines and different functional groups. Arylamines and different functionalization reagents, using diacetyl as the photoreaction accelerator, mildly boronic esterification and halogenation of aryl groups by photoirradiation.

A method for catalyzing the deamination, boronization or halogenation of an arylamine, the arylamine having the formula 1 and the compound having the formula 2 are placed in a mixed solvent, and pre-reacted at 0 to 5°C; then adding It can provide the raw material of the functionalized group A and a catalytic amount of the reaction accelerator, and carry out the deamination functionalization reaction under light irradiation at a temperature of 10-50 ° C, and modify the functional group A at the amino position of formula 1 to obtain product of formula 3;

Described reaction accelerator is diacetyl;

The mixed solvent is a mixed solvent comprising water and a hydrophobic organic solvent;

Formula 1

Formula 2

Formula 3

R1-R3 are independently H, C1-C6 alkyl, C1-C6 alkoxy, phenoxy, benzyloxy, nitro, halogen, cyano, ester, trifluoromethyl, C1-C4 alkylthio, sulfonyl or allyloxy;

R4 is H or F;

Described R5 is C1～C6 alkyl or metal sodium ion;

The A is I or Br.

The present invention innovatively provides a method for photocatalyzed deamination of arylamine, boronation esterification and halogenation functionalization. By controlling the substrate, reaction solvent, material mixing method, butanedione reaction accelerator and dosage, the inventors can unexpectedly realize the highly selective boronation or halogenation of arylamines.

In the technical scheme of the present invention, in order to realize the efficient boronation and halogenation of the arylamine, it is necessary to strictly control the ortho position of the substrate of formula 1, not only that, but also to control the water and the hydrophobic organic solvent. The mixed solvent, the mixing sequence of materials and the method of pre-reaction, the innovative use of butanedione and the control of the addition amount of butanedione, and the synergistic control of various parameters, can realize the boronization under light promotion. and halogenated functionalization.

According to the research of the present invention, at least one ortho position of the amino group of the substrate of formula 1 is H, and the other ortho position can be H or F, so that the yield of the product can be unexpectedly improved,

In the present invention, it is found through further research that the control of the substituent group and the substitution position of the arylamine is helpful to further improve the yield of the target product.

Preferably, R1, R3 and R4 are hydrogen.

R2 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, methylthio, nitro, trifluoromethyl, benzyloxy, allyloxy, fluorine, bromine, chlorine atom or cyano group.

The present invention also finds that when the R2 is an electron donor, for example, a C1-C6 alkyl group or a C1-C6 alkoxy group, the photopromoting yield can be better than that of the existing method. The method of the invention can solve the defects of the existing electron-donating substituent group boronization and unsatisfactory halogenation effect, and can realize the efficient functionalization of the electron-donating arylamine.

The electron donating group is, for example, a C1-C6 alkyl group or a C1-C6 alkoxy group.

The C1-C6 alkyl group is, for example, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or isopropoxy.

In the present invention, described R5 is C1～C6 alkyl or metal sodium ion,

Preferably, the R5 is a tert-butyl group, a p-amyl group or a metal sodium ion.

Different R5 groups will lead to different applicability to different functionalization reactions. This group can be adjusted to obtain good applicability to functionalization reactions. For example, when R5 is tert-butyl, boronation, bromination or iodination all have very good yields.

Preferably, the order of adding the reactants is as follows: first add the arylamine, then add the mixed solvent, drop the compound of formula 2 at 0 to 5°C, and after the reaction for 10 min, add the raw material that can provide the functionalized group A and promote the reaction agent, and then reacted by light and temperature. The problem of low yield of electron-donating arylamine can be solved unexpectedly through the addition sequence, the control of the substrate, the reaction system and the temperature.

Further preferably, the molar ratio of the arylamine and the nitrous acid compound of formula 2 is 1:1.1-2. Under this preferred molar ratio, the removal of the amino group is facilitated, thereby helping to further improve the yield of the functionalized product. The dosage of nitrous acid compounds is higher than 2 equivalents, which is not conducive to the next step of functionalization.

In the present invention, the mixed solvent needs to be a two-phase solution of the water and the hydrophobic solvent. In this way, the yield of the desired functionalized product of arylamines, especially electron donating arylamines, can be surprisingly improved.

Preferably, in the mixed solvent, the hydrophobic organic solvent is at least one of ethyl acetate, dichloromethane and diethyl ether.

In the mixed solvent, the volume ratio of water and hydrophobic organic solvent is 1:0.5-1.5.

In the reaction starting solution, the concentration of the arylamine is 0.05-0.5 mol/L.

The raw material that can provide the functionalized group A of the present invention is a material that can modify the functionalized group A at the amino position in the reaction system of the present invention.

Preferably, the raw material that can provide functionalized group A is biboronic acid pinacol ester Sodium iodide or carbon tetrabromide. The halogenated raw materials of the present invention are inorganic salts of iodine and carbon tetrabromide. In the prior art, the yield of such halogenated raw materials is generally unsatisfactory. However, in the technical solution of the present invention, a high yield can be obtained through the joint control of the system.

In the present invention, when the raw material that can provide the functionalized group A is biboronic acid pinacol ester, the synthesized product of formula 3 is the compound of formula 3-A; when the raw material that can provide the functionalized group A is Sodium iodide or carbon tetrabromide, the product of which is a compound of formula 3-B (X is Br or I).

Further preferably, the raw material that can provide the functionalized group A is based on the functional group A, and the molar ratio of the arylamine to the raw material that can provide the functionalized group A is 1:2-4. Under the preferred molar ratio, the formation of the corresponding functionalized product can be facilitated, and the formation of acyl by-products can be effectively inhibited at the same time. The addition of equivalents of functionalization reagents higher than 4 is not conducive to the electron transfer of the reaction accelerator.

The invention innovatively utilizes butanedione as a reaction accelerator, studies the reaction, and the use of a catalytic amount of butanedione can significantly improve the product yield, especially can significantly improve the deamination functionalization of the electron-donating substituent arylamine yield. The research found that the amount of the reaction accelerator has a great influence on the reaction yield, and the larger dosage will seriously affect the selectivity of deamination functionalization, and reduce the functionalization yield of boronization and halogenation.

Preferably, the molar ratio of the arylamine and the reaction accelerator is 1:0.05-0.2, which is the catalytic amount. Under this preferred molar ratio, butanedione can excellently complete the photoelectric conversion, assist the deamination of arylamines, and form benzene radicals. When the dosage of butanedione is higher than 0.2, a large amount of acetylated by-products will be generated, which is not conducive to the generation of functionalized products.

In the present invention, after the pre-reaction, the functionalized raw material and the reaction accelerator are added, and then the temperature is raised to 15-35° C. for the reaction.

The light is preferably white light, such as 36w white light.

The photoreaction time is preferably 12-24 hours.

After the reaction, it is extracted with a hydrophobic solvent, and the organic phase obtained by concentrating the extraction is obtained by chromatographic purification.

In the technical scheme of the present invention, after the reaction is completed, the reaction mixture is extracted with dichloromethane and rotary-evaporated under reduced pressure to obtain a crude product; the crude product is then separated and purified by a chromatographic column to obtain the final product. The eluent used in the chromatographic column is petroleum ether, and the product with higher polarity uses a mixed eluent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether and ethyl acetate is 99:1 to 1:1.

The reaction mechanism of the present invention is shown in reaction formula 1 (in formula 1, R1/R3/R4 is H, R4 is methoxy group as an example):

Reaction 1

Beneficial technology:

1. The technical solution of the present invention provides a general method for deamination of arylamines for boronization and halogenation. Through the coordinated control of the substrate, the reaction solvent, the mixing method, the temperature and the reaction accelerator, the present invention can realize the efficient deamination of arylamines, especially the electron-donating substituted arylamines that are difficult to be effectively handled by technical solutions in the industry. Acidified or halogenated.

2. The technical solution of the present invention adopts a one-pot reaction, with mild process conditions, short process flow, simple steps, wide substrate applicability, and meets industrial production requirements;

The technical scheme of the present invention produces different functionalized products from arylamine substrates, and the yield is high. ; The study found that the yield of the product can be as high as 80%.

Description of drawings

FIG. 1 is a ¹ HNMR spectrum of the product obtained in Example 1. FIG.

FIG. 2 is a ¹³ CNMR spectrum of the product obtained in Example 1. FIG.

3 is a ¹ HNMR spectrum of the product obtained in Example 5. FIG.

4 is a ¹³ CNMR spectrum of the product obtained in Example 5. FIG.

FIG. 5 is a ¹ HNMR spectrum of the product obtained in Example 10. FIG.

FIG. 6 is a ¹³ CNMR spectrum of the product obtained in Example 11. FIG.

Detailed ways:

The following examples are intended to illustrate the content of the present invention, rather than to further limit the protection scope of the claims of the present invention.

In the following examples and comparative examples, unless otherwise stated, the illumination refers to white light; for example, there is a 36W white light irradiation reaction.

In the following cases, the room temperature is 15-35°C.

Example 1

Synthesis, separation and purification of 4-methoxyphenylboronic acid pinacol ester: 4-methoxyaniline (see Table 1 for structural formula: 1 mmol, 1.0 eq) was added to a 20 mL glass bottle, 5 mL of water, and 5 mL of dichloromethane. The reaction flask was placed in an ice bath at 0° C., stirred for 5 minutes, and tert-butyl nitrite (0.24 mL, 2 mmol, 2.0 eq) was slowly added dropwise to the reaction flask with a syringe. After the dropwise addition was completed, stir for another 10 minutes, add butanedione (8.7 μL, 0.1 mmol, 0.1 eq) to the reaction flask with a micro syringe, and then add biboronic acid pinacol ester (761.8 mg, 3 mmol, 3 eq), room temperature Light reaction for 16 hours. After the reaction was completed, it was quenched with water, and the reaction solution was extracted twice with 20 mL of dichloromethane, and then the obtained organic phase was dried with anhydrous sodium sulfate, filtered, and rotary-evaporated under reduced pressure to obtain a crude product with a small amount of solvent. Then the crude product was separated by silica gel chromatography, and the eluent was a mixture of petroleum ether:ethyl acetate=20:1 to obtain the final product: 4-methoxyphenylboronic acid pinacol ester was a white solid, and the yield was was 51%.

¹ H NMR (400MHz, CDCl3)δ=7.75(d,J=8.3Hz,2H),6.90(d,J=8.3Hz,2H),3.83(s,3H),1.33(s,12H) ^.13C NMR (101MHz, CDCl3)δ=162.15, 136.52, 113.32, 83.57, 55.11, 24.87.

Example 2

Synthesis, separation and purification of 4-methylphenylboronic acid pinacol ester: 4-methylaniline (see Table 1 for structural formula: 1 mmol, 1.0 eq) was added to a 20 mL glass bottle, 5 mL of water, and 5 mL of dichloromethane. The reaction flask was placed in an ice bath at 0° C., stirred for 5 minutes, and tert-butyl nitrite (0.24 mL, 2 mmol, 2.0 eq) was slowly added dropwise to the reaction flask with a syringe. After the dropwise addition was completed, stir for another 10 minutes, add butanedione (8.7 μL, 0.1 mmol, 0.1 eq) to the reaction flask with a micro syringe, and then add biboronic acid pinacol ester (761.8 mg, 3 mmol, 3 eq), room temperature Light reaction for 16 hours. After the reaction was completed, it was quenched with water, and the reaction solution was extracted twice with 20 mL of dichloromethane, and then the obtained organic phase was dried with anhydrous sodium sulfate, filtered, and rotary-evaporated under reduced pressure to obtain a crude product with a small amount of solvent. Then the crude product was separated by silica gel chromatography, and the eluent was a mixture of petroleum ether:ethyl acetate=20:1 to obtain the final product: 4-methylphenylboronic acid pinacol ester as a white solid, and the yield was 54%.

¹ H NMR (400MHz, CDCl3)δ=7.70(d, J=7.7, 2H), 7.19(d, J=7.6, 2H), 2.36(s, 3H), 1.34(s, 12H). ¹³ C NMR( 101MHz, CDCl3)δ=141.43, 134.82, 128.54, 83.64, 24.87, 21.74.

Example 3

Synthesis, separation and purification of 4-chlorophenylboronic acid pinacol ester: 4-chloroaniline (see Table 1 for structural formula: 1 mmol, 1.0 eq) was added to a 20 mL glass bottle, 5 mL of water, and 5 mL of dichloromethane. The reaction flask was placed in an ice bath at 0° C., stirred for 5 minutes, and tert-butyl nitrite (0.24 mL, 2 mmol, 2.0 eq) was slowly added dropwise to the reaction flask with a syringe. After the dropwise addition was completed, stir for another 10 minutes, add butanedione (8.7 μL, 0.1 mmol, 0.1 eq) to the reaction flask with a micro syringe, and then add biboronic acid pinacol ester (761.8 mg, 3 mmol, 3 eq), room temperature Light reaction for 16 hours. After the reaction was completed, it was quenched with water, and the reaction solution was extracted twice with 20 mL of dichloromethane, and then the obtained organic phase was dried with anhydrous sodium sulfate, filtered, and rotary-evaporated under reduced pressure to obtain a crude product with a small amount of solvent. Then the crude product was separated by silica gel chromatography, and the eluent was a mixture of petroleum ether:ethyl acetate=50:1 to obtain the final product: 4-chlorophenylboronic acid pinacol ester as a white solid with a yield of 39 %.

¹ H NMR(400MHz, CDCl3)δ=7.75(d,J=8.2,2H),7.36(d,J=8.3,2H),1.36(s,12H) ^.13C NMR(101MHz,CDCl3)δ=137.54 ,136.83,128.02,84.03,24.87.

Example 4

Synthesis, separation and purification of 4-fluorophenylboronic acid pinacol ester: 4-fluoroaniline (see Table 1 for structural formula: 1 mmol, 1.0 eq) was added to a 20 mL glass bottle, 5 mL of water, and 5 mL of dichloromethane. The reaction flask was placed in an ice bath at 0° C., stirred for 5 minutes, and tert-butyl nitrite (0.24 mL, 2 mmol, 2.0 eq) was slowly added dropwise to the reaction flask with a syringe. After the dropwise addition was completed, stir for another 10 minutes, add butanedione (8.7 μL, 0.1 mmol, 0.1 eq) to the reaction flask with a micro syringe, and then add biboronic acid pinacol ester (761.8 mg, 3 mmol, 3 eq), room temperature Light reaction for 16 hours. After the reaction was completed, it was quenched with water, and the reaction solution was extracted twice with 20 mL of dichloromethane, and then the obtained organic phase was dried with anhydrous sodium sulfate, filtered, and rotary-evaporated under reduced pressure to obtain a crude product with a small amount of solvent. Then the crude product was separated by silica gel chromatography, and the eluent was a mixture of petroleum ether:ethyl acetate=50:1 to obtain the final product: 4-fluorophenylboronic acid pinacol ester was a colorless and transparent liquid, and the yield was was 41%.

¹ H NMR (400MHz, CDCl3) δ=7.80 (dd, J=8.4, 6.4, 2H), 7.05 (t, J=8.9, 2H), 1.34 (s, 12H). ¹³ C NMR (101 MHz, CDCl3) δ =166.35,163.86,137.03,136.95,114.96,114.76,83.92,24.87.

Example 5

Synthesis, separation and purification of 4-methanesulfonyl iodobenzene: 4-methanesulfonylaniline (see Table 1 for structural formula: 1 mmol, 1.0 eq) was added to a 20 mL glass bottle, 5 mL of water, and 5 mL of dichloromethane. The reaction flask was placed in an ice bath at 0° C., stirred for 5 minutes, and tert-butyl nitrite (0.24 mL, 2 mmol, 2.0 eq) was slowly added dropwise to the reaction flask with a syringe. After the dropwise addition was completed, stir for another 10 minutes, add butanedione (8.7 μL, 0.1 mmol, 0.1 eq) to the reaction flask with a micro syringe, and then add sodium iodide (449.7 mg, 3 mmol, 3 eq), and react with light at room temperature for 16 Hours. After the reaction was completed, it was quenched with water, and the reaction solution was extracted twice with 20 mL of dichloromethane, and then the obtained organic phase was dried with anhydrous sodium sulfate, filtered, and rotary-evaporated under reduced pressure to obtain a crude product with a small amount of solvent. Then the crude product was separated by silica gel chromatography, and the eluent was a mixture of petroleum ether:ethyl acetate=9:1 to obtain the final product: 4-methanesulfonyl iodobenzene was a yellow transparent liquid with a yield of 78% .

¹ H NMR(400MHz, CDCl3)δ=7.93(d,J=8.3,2H),7.64(d,J=8.4,2H),3.04(s,3H) ^.13C NMR(101MHz,CDCl3)δ=140.15 ,138.68,128.79,101.65,44.47.

Example 6

Synthesis, separation and purification of 4-chloroiodobenzene: add 4-chloroaniline (see Table 1 for structural formula: 1 mmol, 1.0 eq) into a 20 mL glass bottle, 5 mL of water, and 5 mL of dichloromethane. The reaction flask was placed in an ice bath at 0° C., stirred for 5 minutes, and tert-butyl nitrite (0.24 mL, 2 mmol, 2.0 eq) was slowly added dropwise to the reaction flask with a syringe. After the dropwise addition was completed, stir for another 10 minutes, add butanedione (8.7 μL, 0.1 mmol, 0.1 eq) to the reaction flask with a micro syringe, and then add sodium iodide (449.7 mg, 3 mmol, 3 eq), and react with light at room temperature for 16 Hours. After the reaction was completed, it was quenched with water, and the reaction solution was extracted twice with 20 mL of dichloromethane, and then the obtained organic phase was dried with anhydrous sodium sulfate, filtered, and rotary-evaporated under reduced pressure to obtain a crude product with a small amount of solvent. Then the crude product was separated by silica gel chromatography, and the eluent was a mixture of petroleum ether:ethyl acetate=20:1 to obtain the final product: 4-chloroiodobenzene as a yellow transparent liquid with a yield of 71%.

¹ H NMR (400MHz, CDCl3) δ=7.60 (d, J=8.6, 2H), 7.08 (d, J=8.6, 2H). ¹³ C NMR (101 MHz, CDCl3) δ=138.75, 134.24, 130.56, 91.21.

Example 7

Synthesis, separation and purification of 4-fluoroiodobenzene: 4-fluoroaniline (see Table 1 for structural formula: 1 mmol, 1.0 eq) was added to a 20 mL glass bottle, 5 mL of water, and 5 mL of dichloromethane. The reaction flask was placed in an ice bath at 0° C., stirred for 5 minutes, and tert-butyl nitrite (0.24 mL, 2 mmol, 2.0 eq) was slowly added dropwise to the reaction flask with a syringe. After the dropwise addition was completed, stir for another 10 minutes, add butanedione (8.7 μL, 0.1 mmol, 0.1 eq) to the reaction flask with a micro syringe, and then add sodium iodide (449.7 mg, 3 mmol, 3 eq), and react with light at room temperature for 16 Hours. After the reaction was completed, it was quenched with water, and the reaction solution was extracted twice with 20 mL of dichloromethane, and then the obtained organic phase was dried with anhydrous sodium sulfate, filtered, and rotary-evaporated under reduced pressure to obtain a crude product with a small amount of solvent. Then the crude product was separated by silica gel chromatography, and the eluent was a mixture of petroleum ether:ethyl acetate=20:1 to obtain the final product: 4-fluoroiodobenzene as a pale yellow transparent liquid with a yield of 69%.

¹ H NMR (400MHz, CDCl3) δ=7.56(m, 2H), 6.77(t, J=8.7, 2H). ¹³ C NMR (101 MHz, CDCl3) δ=163.96, 161.50, 139.01, 138.93, 117.91, 117.69, 86.96, 86.93.

Example 8

Synthesis, separation and purification of 4-iodophenylacetonitrile: add 4-aminophenylacetonitrile (see Table 1 for structural formula: 1 mmol, 1.0 eq) into a 20 mL glass bottle, 5 mL of water, and 5 mL of dichloromethane. The reaction flask was placed in an ice bath at 0° C., stirred for 5 minutes, and tert-butyl nitrite (0.24 mL, 2 mmol, 2.0 eq) was slowly added dropwise to the reaction flask with a syringe. After the dropwise addition was completed, stir for another 10 minutes, add butanedione (8.7 μL, 0.1 mmol, 0.1 eq) to the reaction flask with a micro syringe, and then add sodium iodide (449.7 mg, 3 mmol, 3 eq), and react with light at room temperature for 16 Hours. After the reaction was completed, it was quenched with water, and the reaction solution was extracted twice with 20 mL of dichloromethane, and then the obtained organic phase was dried with anhydrous sodium sulfate, filtered, and rotary-evaporated under reduced pressure to obtain a crude product with a small amount of solvent. Then the crude product was separated by silica gel chromatography, and the eluent was a mixture of petroleum ether:ethyl acetate=9:1 to obtain the final product: 4-iodobenzeneacetonitrile as a pale yellow transparent liquid with a yield of 80%.

¹ H NMR (400MHz, CDCl3) δ=7.84 (d, J=8.4, 2H), 7.36 (d, J=8.4, 2H). ¹³ C NMR (101 MHz, CDCl3) δ=138.53, 133.20, 118.25, 111.76, 100.36.

Example 9

Synthesis, separation and purification of 4-methoxyiodobenzene: 4-methoxyaniline (see Table 1 for structural formula: 1 mmol, 1.0 eq) was added to a 20 mL glass bottle, 5 mL of water, and 5 mL of dichloromethane. The reaction flask was placed in an ice bath at 0° C., stirred for 5 minutes, and tert-butyl nitrite (0.24 mL, 2 mmol, 2.0 eq) was slowly added dropwise to the reaction flask with a syringe. After the dropwise addition was completed, stir for another 10 minutes, add butanedione (8.7 μL, 0.1 mmol, 0.1 eq) to the reaction flask with a micro syringe, and then add sodium iodide (449.7 mg, 3 mmol, 3 eq), and react with light at room temperature for 16 Hours. After the reaction was completed, it was quenched with water, and the reaction solution was extracted twice with 20 mL of dichloromethane, and then the obtained organic phase was dried with anhydrous sodium sulfate, filtered, and rotary-evaporated under reduced pressure to obtain a crude product with a small amount of solvent. Then the crude product was separated by silica gel chromatography, and the eluent was a mixture of petroleum ether:ethyl acetate=20:1 to obtain the final product: 4-methoxyiodobenzene was a pale yellow transparent liquid with a yield of 86 %.

¹ H NMR (400 MHz, CDCl ₃ ) δ=7.55(d, J=9.0, 2H), 6.68 (d, J=9.0, 2H), 3.77 (s, 3H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ = 159.49, 138.21, 116.38, 82.69, 55.33.

Example 10

Synthesis, separation and purification of 4-methoxybromobenzene: 4-methoxyaniline (see Table 1 for structural formula: 1 mmol, 1.0 eq) was added to a 20 mL glass bottle, 5 mL of water, and 5 mL of dichloromethane. The reaction flask was placed in an ice bath at 0° C., stirred for 5 minutes, and tert-butyl nitrite (0.24 mL, 2 mmol, 2.0 eq) was slowly added dropwise to the reaction flask with a syringe. After the dropwise addition was completed, stir for another 10 minutes, add butanedione (8.7 μL, 0.1 mmol, 0.1 eq) to the reaction flask with a micro-syringe, and then add carbon tetrabromide (994.9 mg, 3 mmol, 3 eq), and react with light at room temperature. 16 hours. After the reaction was completed, it was quenched with water, and the reaction solution was extracted twice with 20 mL of dichloromethane, and then the obtained organic phase was dried with anhydrous sodium sulfate, filtered, and rotary-evaporated under reduced pressure to obtain a crude product with a small amount of solvent. Then the crude product was separated by silica gel chromatography, and the eluent was a mixture of petroleum ether:ethyl acetate=99:1 to obtain the final product: 4-methoxybromobenzene was a yellow transparent liquid with a yield of 78% .

¹ H NMR(400MHz, CDCl3)δ=7.38(d,J=8.8,2H),6.79(d,J=8.8,2H),3.78(s,3H) ^.13C NMR(101MHz,CDCl3)δ=158.70 ,132.25,115.74,112.82,55.45.

Example 11

Synthesis, separation and purification of 4-ethoxybromobenzene: 4-ethoxyaniline (see Table 1 for structural formula: 1 mmol, 1.0 eq) was added to a 20 mL glass bottle, 5 mL of water, and 5 mL of dichloromethane. The reaction flask was placed in an ice bath at 0° C., stirred for 5 minutes, and tert-butyl nitrite (0.24 mL, 2 mmol, 2.0 eq) was slowly added dropwise to the reaction flask with a syringe. After the dropwise addition was completed, stir for another 10 minutes, add butanedione (8.7 μL, 0.1 mmol, 0.1 eq) to the reaction flask with a micro-syringe, and then add carbon tetrabromide (994.9 mg, 3 mmol, 3 eq), and react with light at room temperature. 16 hours. After the reaction was completed, it was quenched with water, and the reaction solution was extracted twice with 20 mL of dichloromethane, and then the obtained organic phase was dried with anhydrous sodium sulfate, filtered, and rotary-evaporated under reduced pressure to obtain a crude product with a small amount of solvent. Then the crude product was separated by silica gel chromatography, and the eluent was a mixture of petroleum ether:ethyl acetate=99:1 to obtain the final product: 4-ethoxybromobenzene was a colorless and transparent liquid, and the yield was 76 %.

¹ H NMR (400MHz, CDCl3) δ=7.24 (d, J=9.0, 2H), 6.65 (d, J=9.0, 2H), 3.86 (q, J=7.0, 2H), 1.29 (t, J=7.0 , 3H). ¹³ C NMR (101MHz, CDCl3) δ=158.10, 132.23, 116.32, 112.65, 63.70, 14.78.

Example 12

Synthesis, separation and purification of p-dibromobenzene: 4-bromoaniline (see Table 1 for structural formula: 1 mmol, 1.0 eq) was added to a 20 mL glass bottle, 5 mL of water, and 5 mL of dichloromethane. The reaction flask was placed in an ice bath at 0° C., stirred for 5 minutes, and tert-butyl nitrite (0.24 mL, 2 mmol, 2.0 eq) was slowly added dropwise to the reaction flask with a syringe. After the dropwise addition was completed, stir for another 10 minutes, add butanedione (8.7 μL, 0.1 mmol, 0.1 eq) to the reaction flask with a micro-syringe, and then add carbon tetrabromide (994.9 mg, 3 mmol, 3 eq), and react with light at room temperature. 16 hours. After the reaction was completed, it was quenched with water, and the reaction solution was extracted twice with 20 mL of dichloromethane, and then the obtained organic phase was dried with anhydrous sodium sulfate, filtered, and rotary-evaporated under reduced pressure to obtain a crude product with a small amount of solvent. Then, the crude product was separated by silica gel chromatography, and the eluent was a mixture of petroleum ether:ethyl acetate=99:1 to obtain the final product: p-dibromobenzene was a colorless and transparent liquid with a yield of 78%.

¹ H NMR (400 MHz, CDCl 3 ) δ=7.36 (s, 4H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ=133.16, 121.08.

The substrates, products and yields of Examples 1 to 12 are shown in Table 1:

Table 1

From the data in Table 1, it can be seen that the technical solution of the present invention can still obtain good product yields without noble metal catalysts, especially the electron-donating substrates can still achieve a yield of about 80%.

Comparative Example 1

Compared with Example 10, the main difference is that no nitrous acid compound is added, and the specific operations are as follows:

Synthesis, separation and purification of 4-methoxybromobenzene: 4-methoxyaniline (1 mmol, 1.0 eq) was added to a 20 mL glass bottle, 5 mL of water, and 5 mL of dichloromethane. The reaction flask was placed in an ice bath at 0°C and stirred for 15 minutes. Butanedione (8.7 μL, 0.1 mmol, 0.1 eq) was added to the reaction flask with a micro syringe, followed by carbon tetrabromide (994.9 mg, 3 mmol, 3 eq) ), reacted under room temperature light for 16 hours. After the reaction is completed, the product is not obtained by processing according to the post-processing method of the present invention. This comparative example shows that nitrous acid compounds have a major effect on the deamination functionalization of arylamines.

Comparative Example 2

Compared with Example 10, the main difference is that the solvent used is a single water or methylene chloride, and a mixed solvent is not used, and the specific operations are as follows:

Synthesis, separation and purification of 4-methoxybromobenzene: 4-methoxyaniline (1 mmol, 1.0 eq) was added to a 20 mL glass bottle, 10 mL of water or dichloromethane. The reaction flask was placed in an ice bath at 0° C., stirred for 5 minutes, and tert-butyl nitrite (0.24 mL, 2 mmol, 2.0 eq) was slowly added dropwise to the reaction flask with a syringe. After the dropwise addition was completed, stir for another 10 minutes, add butanedione (8.7 μL, 0.1 mmol, 0.1 eq) to the reaction flask with a micro-syringe, and then add carbon tetrabromide (994.9 mg, 3 mmol, 3 eq), and react with light at room temperature. 16 hours. After the reaction, the post-processing method of the present invention is carried out. When water is the solvent, the product yield is 23%; when DCM is the solvent, the product yield is less than 10%, while the yield of Example 9 is as high as 78%. This comparative example shows that the yield of the mixed solvent of dichloromethane and water is higher.

Comparative Example 3

Compared with Example 10, the main difference is that it does not react under illumination, and the specific operations are as follows:

Synthesis, separation and purification of 4-methoxybromobenzene: 4-methoxyaniline (1 mmol, 1.0 eq) was added to a 20 mL glass bottle, 5 mL of water, and 5 mL of dichloromethane. The reaction flask was placed in an ice bath at 0° C., stirred for 5 minutes, and tert-butyl nitrite (0.24 mL, 2 mmol, 2.0 eq) was slowly added dropwise to the reaction flask with a syringe. After the dropwise addition was completed, stir for another 10 minutes, add diacetyl (8.7 μL, 0.1 mmol, 0.1 eq) to the reaction flask with a micro syringe, and then add carbon tetrabromide (994.9 mg, 3 mmol, 3 eq), and protect from light at room temperature The reaction was carried out for 16 hours. After the reaction, the post-treatment method of the present invention is carried out to obtain a product with a yield of 7%. Compared with Example 9, without light treatment, the yield of the product decreased significantly.

Comparative Example 4

Compared with Example 10, the main difference is that the addition order of the functionalization reagent is different, and the specific operations are as follows:

Synthesis, separation and purification of 4-methoxybromobenzene: add 4-methoxyaniline (1mmol, 1.0eq), carbon tetrabromide (994.9mg, 3mmol, 3eq) into a 20mL glass bottle, 5mL water, 5mL Dichloromethane. The reaction flask was placed in an ice bath at 0° C., stirred for 5 minutes, and tert-butyl nitrite (0.24 mL, 2 mmol, 2.0 eq) was slowly added dropwise to the reaction flask with a syringe. After the dropwise addition was completed, the mixture was stirred for another 10 minutes, and diacetyl (8.7 μL, 0.1 mmol, 0.1 eq) was added to the reaction flask with a microsyringe, and the reaction was performed under light at room temperature for 16 hours. After the reaction is completed, the treatment is carried out according to the post-treatment method of the present invention to obtain a product with a yield of 35%.

Comparative Example 5

Compared with Example 10, the difference mainly lies in the addition of diacetyl equivalent (the mol ratio of diacetyl and 4-methoxyaniline), and the specific operations are as follows:

Synthesis, separation and purification of 4-methoxybromobenzene: 4-methoxyaniline (1 mmol, 1.0 eq) was added to a 20 mL glass bottle, 5 mL of water, and 5 mL of dichloromethane. The reaction flask was placed in an ice bath at 0° C., stirred for 5 minutes, and tert-butyl nitrite (0.24 mL, 2 mmol, 2.0 eq) was slowly added dropwise to the reaction flask with a syringe. After the dropwise addition was completed, stir for another 10 minutes, add diacetyl (1.0eq, 2eq, 4eq, respectively) to the reaction flask with a syringe, and then add carbon tetrabromide (994.9mg, 3mmol, 3eq), and react with light at room temperature for 16 Hours. After the reaction is completed, the post-processing method of the present invention is carried out to obtain a product with a yield of less than 20%, and a partial acetylation product is produced. Compared with Example 9, the excess of butanedione leads to an increase in side reactions and a decrease in the reaction yield.

Comparative Example 6

Compared with Example 10, the difference is that 4-methoxyaniline is replaced with an ortho-methoxy-substituted substrate (2-methoxyaniline). It was found that the yield of the product was less than 10%. It was found that the yield of the ortho-containing group of the amino group decreased significantly.

Comparative Example 7

Compared with Example 10, the difference is that butanedione is replaced with Hantzsh ester or eosin Y disodium salt. It was found that the yield of Hantzsh ester product was 30%, while the yield of eosin Y disodium salt was less than 10%. It was found that other photocatalysts could affect the yield of this reaction.

Comparative Example 8

Compared with Example 10, the difference is that acetonitrile is used to replace dichloromethane to form a mixed solvent of acetonitrile and water. It was found that the product yield was 33%, which was much lower than that of Example 10. It was found that hydrophilic solvents would reduce the yield of the reaction.

In summary, the deamination can be completed by the arylamine of formula 1, the nitrous acid compound of formula 3, pinacol biboronic acid ester or sodium iodide or carbon tetrabromide under the catalysis of butanedione and light irradiation. functionalization. The study also found that through the joint control of the described substrate, reaction solvent, mixing sequence, temperature, diacetyl and dosage, arylamines, especially the electron-donating substituted substrates that are difficult to handle by technical solutions in the industry, can be improved. The effect of deamination boronation and halogenation.

Claims (10)

1. a kind of method that catalyzes arylamine generation deamination boronate esterification or halogenation, it is characterized in that, the arylamine with formula 1, the compound with formula 2 structural formula are placed in mixed solvent, at 0～5 ℃ pre-reacted; then add the raw materials that can provide the functionalized group A, the catalytic amount of the reaction accelerator, and carry out the deamination functionalization reaction under light irradiation at a temperature of 10 to 50 ° C, and modify the functional group at the amino position of formula 1. Group A, to obtain the structural product of formula 3; Described reaction accelerator is butanedione; The mixed solvent is a mixed solvent comprising water and a hydrophobic organic solvent; R1-R3 are independently H, C1-C6 alkyl, C1-C6 alkoxy, phenoxy, benzyloxy, nitro, halogen, cyano, ester, trifluoromethyl, C1-C4 alkylthio, sulfonyl or allyloxy; R4 is H or F; Described R5 is C1～C6 alkyl or metal sodium ion; The A is I or Br. 2. The method of claim 1, wherein R1, R3, R4 are hydrogen; R2 is hydrogen, methyl, methoxy, methylthio, nitro, trifluoromethyl, benzyloxy, allyloxy, fluorine, bromine, chlorine atom or cyano. 3. The method of claim 1, wherein R5 is tert-butyl group, p-amyl group or metal sodium ion. 4. The method of claim 1, wherein the molar ratio of the arylamine and the compound of formula 2 is 1:1.1-2. 5. The method of claim 1, wherein, in the mixed solvent, the hydrophobic organic solvent is at least one of ethyl acetate, toluene, dichloromethane, and ether; In the mixed solvent, the volume ratio of water and hydrophobic organic solvent is 1:0.5-1.5. 6. The method according to claim 1, wherein the order of adding the reactants is: first add arylamine, then add mixed solvent, drop the compound of formula 2 at 0～5°C, react for 10min, add The raw materials and reaction accelerators of the functionalized group A can be provided, and then the reaction is performed by light and temperature. 7. The method of claim 1, wherein the raw material that can provide the functionalized group A is biboronic acid pinacol ester, sodium iodide or carbon tetrabromide. 8. The method according to claim 1, wherein the raw material that can provide functionalized group A is calculated as functional group A, and the molar ratio of the arylamine to the raw material that can provide functionalized group A is 1 : 2-4. 9. The method of claim 1, wherein the molar ratio of the arylamine and the reaction accelerator is 1:0.05-0.2. 10. The method of claim 1, wherein the light is white light; The photoreaction time is preferably 12-24 hours.