Dehalogenation method for reducing N heteroaryl halide by using hydrogen-containing silane

Abstract

The invention relates to the technical field of organic chemistry, in particular to a dehalogenation method for reducing N heteroaryl halide by using hydrogen-containing silane. The method comprises the following steps: adding N heteroaryl halide into a palladium carbon / base catalysis system, removing air in the system, injecting hydrogen-containing silane into the system, and placing the system at a certain temperature for full reaction; the new dehalogenation method is used for removing N ortho-halogen atoms such as quinoline, pyridine and pyrimidine, provides a new dehalogenation thought for (hetero) aryl halides, and has special significance for reducing environmental pollution.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemistry, and in particular to a dehalogenation method for reducing N-heteroaryl halides by utilizing hydrosilane. Background Art

[0002] As an organic synthesis method, heterogeneous catalytic hydrogenation dehalogenation can convert highly toxic or environmentally polluting halogenated hydrocarbons that are difficult to handle by conventional methods into low-toxic, easy-to-handle or non-toxic recyclable compounds; for example, chlorine atoms of organic chlorinated compounds such as chlorinated alkanes, chlorobenzenes, and polychlorinated biphenyls can be removed by catalytic hydrogenation dechlorination, and chlorinated organic pollutants can be converted into corresponding alkanes, benzene and biphenyls. The usual catalytic hydrogenation reaction uses a Group VIII metal or complex as a hydrogenation catalyst and an alcohol, organic acid or hydrogen as a hydrogen source. European patent (1990, EP 352,164) uses Pd(OAc)2 as a catalyst. In the presence of PPh3 and Net3, chlorobenzene and hydrogen undergo a hydrodehalogenation reaction to produce benzene, and the conversion rate is only 41%; US patent (1986, US 4,618,686) uses Pd / C as a catalyst and adds phosphate to dechlorinate polychlorinated biphenyls; US patent (1994, US 9407828) uses Pt, Pd, Ru or Ir supported catalysts to treat wastewater containing organochlorine pesticides at 220°C, and the dechlorination and detoxification effect is good.

[0003] At present, there are several research methods for removing heteroaryl chloride:

[0004] (1) Using lithium wire to sonochemically dehalogenate chloroquinoline in tetrahydrofuran solution, this method uses ultrasound to promote organic reactions and can obtain dehalogenated products in medium to high yields, which has considerable application prospects. However, the high activity, flammability and high price of lithium also limit its application in the field of organic synthesis.

[0005] (2) Using PdCl2 as a catalyst, halogenated heteroaromatic aldehydes were dehalogenated in a H2 atmosphere. The dehalogenation of quinoline and N-alkylimidazole halides also gave high yields of products. This method is simple and reliable, and has brought a new idea to the field of organic chemistry. However, since H2 requires a specific pressure, the complexity and operability of the reaction are increased, resulting in an increase in the cost of the reaction.

[0006] (3) Using methanol and magnesium as reaction conditions, dehalogenation of chlorine-containing heteroaryl compounds was achieved at room temperature for 6 to 12 hours. However, magnesium as an active metal has certain limitations in participating in the reaction.

[0007] (4) Using palladium complexes or palladium catalytic systems, halogenated compounds can be hydrodehalogenated under mild reaction conditions and can be highly chemoselective in the presence of different functional groups, with good yields in the regioselective reduction of a variety of polyhalogenated substrates. Summary of the invention

[0008] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a dehalogenation method for reducing N-heteroaryl halides using hydrosilane.

[0009] In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is:

[0010] Provided is a dehalogenation method for reducing N-heteroaryl halides by using hydrosilane, which comprises the following steps: putting N-heteroaryl halides into a palladium carbon / base catalytic system, removing air from the system, injecting hydrosilane into the system, and placing the system at a certain temperature for full reaction.

[0011] Further, the hydrogen-containing silane includes trimethylsilane, triisopropylsilane, tributylsilane, tri(fluoroisopropyl)silane, tri(chloromethyl)silane, tri(trifluoromethyl)silane, tri(trimethylsiloxy)silane, bis(trimethylsiloxy)ethylsilane, bis(chloromethyl)bis(trimethylsiloxy)silane.

[0012] Further, the heteroaryl halide includes 2-chloroquinoline-5-carboxylic acid, 2-chloro-4-methylquinoline, 6-bromo-2-chloroquinoline, 2-4-dichloropyrimidine, 5-bromo-2,4-dichloropyrimidine, 2,4,5-trichloropyrimidine, 2-amino-4,6-dichloropyrimidine, 2,4-diamino-6-chloropyrimidine, 4-amino-6-chloropyrimidine, 4-amino-2,6-dichloropyrimidine, 2,3,5-trichloropyridine, 2-amino-6-chloropyridine, 3-amino-2-chloropyridine, 2-bromo-5-chloropyridine, 3-bromo-2-chloropyridine, 5-bromo-2-chloropyridine, 6-fluoro-2-chloropyridine, 5-aminomethyl-2-chloropyridine, and 6-chloropyridine-2-carboxylic acid.

[0013] Further, the base includes K2CO3, triethylamine, KOH.

[0014] Furthermore, the solvent includes methanol, acetonitrile, DMF, toluene, tetrahydrofuran, dichloromethane, ethyl acetate, and water.

[0015] Furthermore, the reaction temperature is 20-50° C., and the reaction time is 4-24 h.

[0016] Furthermore, the molar ratio of the N-heteroaryl halide to the hydrosilane is 1:1-5.

[0017] Furthermore, the mass ratio of the N-heteroaryl halide to the catalyst is 1:0.04-0.08.

[0018] Furthermore, the molar ratio of the N-heteroaryl halide to the base is 1:0.5-2.

[0019] The beneficial effects of the present invention are:

[0020] 1. High selectivity: The present invention utilizes hydrogen-containing silane to react only with the halogen at the N-ortho position to remove it, and usually has little effect on the carbon-carbon bond. Therefore, it has high selectivity and can retain other structures of the compound.

[0021] 2. Environmental protection: Compared with traditional halogen elimination methods (such as acid-base method or oxidation method), the dehalogenation of hydrogen-containing silane usually produces fewer by-products, is more convenient and efficient in post-processing, and the silane and hydrogen generated during the reaction can be recycled, reducing waste and environmental pollution.

[0022] 3. Mild reaction conditions: The present invention utilizes hydrosilane dehalogenation at room temperature and normal pressure, and the reaction conditions are mild, which is beneficial to protecting the structure of the target compound.

[0023] 4. Wide application scope: The present invention can be used for the dehalogenation of various N-heteroaryl halides such as quinoline, pyridine, pyrimidine, etc. with 2-halogen substituted, and has a wide range of application prospects.

[0024] 5. Economical: Although the cost of using hydrogen-containing silane in the present invention may be higher, in the long run, due to its high selectivity and less by-products, the production cost can be reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1a The hydrogen NMR spectrum of quinoline prepared in Example 1 of the present invention;

[0026] Figure 1b The NMR carbon spectrum of quinoline prepared in Example 1 of the present invention;

[0027] Figure 2a This is the H NMR spectrum of 4-methylquinoline prepared in Example 2 of the present invention;

[0028] Figure 2b The NMR carbon spectrum of 4-methylquinoline prepared in Example 2 of the present invention;

[0029] Figure 3a This is the H NMR spectrum of 2-aminopyrimidine prepared in Example 3 of the present invention;

[0030] Figure 3b This is the carbon NMR spectrum of 2-aminopyrimidine prepared in Example 3 of the present invention;

[0031] Figure 4a This is the H NMR spectrum of 4-aminopyrimidine prepared in Example 4 of the present invention;

[0032] Figure 4b This is the NMR carbon spectrum of 4-aminopyrimidine prepared in Example 4 of the present invention;

[0033] Figure 5a This is the H NMR spectrum of 4-aminopyridine prepared in Example 5 of the present invention;

[0034] Figure 5b This is the NMR carbon spectrum of 4-aminopyridine prepared in Example 5 of the present invention;

[0035] Figure 6a This is the H NMR spectrum of 2-aminopyridine prepared in Example 6 of the present invention;

[0036] Figure 6b This is the carbon NMR spectrum of 2-aminopyridine prepared in Example 6 of the present invention. DETAILED DESCRIPTION

[0037] The specific implementation modes of the present invention are described below so that those skilled in the art can understand the present invention. However, it should be clear that the present invention is not limited to the scope of the specific implementation modes. For those of ordinary skill in the art, as long as various changes are within the spirit and scope of the present invention as defined and determined by the attached claims, these changes are obvious, and all inventions and creations utilizing the concept of the present invention are protected.

[0038] Example 1 Dehalogenation of 2-chloroquinoline

[0039] Weigh 0.324g (2mmol) of 2-chloroquinoline, add it to a 25ml reaction bottle, add 15mg (5%) of Pd / C catalyst and 0.4g (3mmol) of anhydrous potassium carbonate, add 5ml of methanol solution; then plug the reaction bottle with a rubber stopper, place it in an ice water bath, use an oil pump and a syringe to extract the gas in the reaction bottle; then weigh 0.481g (4mmol) of triethylsilane, slowly inject it into the reaction bottle, seal it well, and stir it with a magnetic stirrer to allow the reactants to fully react for 12h. Finally, use chromatography to separate and purify the product, and the calculated yield is 80.65%.

[0040] Example 2 Dehalogenation of 2-chloro-4-methylquinoline

[0041] Weigh 0.354g (2mmol) 2-chloro-4-methylquinoline, add it to a 25ml reaction bottle, add 15mg (5%) Pd / C catalyst and 0.4g (3mmol) anhydrous potassium carbonate, add 5ml methanol solution; then plug the reaction bottle with a rubber stopper, place it in an ice water bath, use an oil pump and a syringe to extract the gas in the reaction bottle; then weigh 0.465g (4mmol) triethylsilane, slowly inject it into the reaction bottle, seal it well, and stir it with a magnetic stirrer to allow the reactants to fully react for 24h. Finally, use chromatography to separate and purify the product, and the calculated yield is 47.63%.

[0042] Example 3 Dehalogenation of 2-amino-4,6-dichloropyrimidine

[0043] Weigh 0.323g (2mmol) 2-amino-4,6-dichloropyrimidine, add it to a 25ml reaction bottle, add 15mg (5%) Pd / C catalyst and 0.4g (3mmol) anhydrous potassium carbonate, add 5ml methanol solution; then plug the reaction bottle with a rubber stopper, place it in an ice water bath, use an oil pump and a syringe to extract the gas in the reaction bottle; then weigh 1.16g (5mmol) triethylsilane, slowly inject it into the reaction bottle, seal it well, and stir it with a magnetic stirrer to allow the reactants to fully react for 8h. Finally, use chromatography to separate and purify the product, and the calculated yield is 53.67%.

[0044] Example 4 Dehalogenation of 4-amino-6-chloropyrimidine

[0045] Weigh 0.26g (2mmol) 4-amino-6-chloropyridine, add it to a 25ml reaction bottle, add 10mg (4%) Pd / C catalyst and 0.4g (3mmol) anhydrous potassium carbonate, add 5ml methanol solution; then plug the reaction bottle with a rubber stopper, place it in an ice water bath, use an oil pump and a syringe to extract the gas in the reaction bottle; then weigh 1.16g (5mmol) triethylsilane, slowly inject it into the reaction bottle, seal it well, and stir the reactants under a magnetic stirrer to fully react for 8h. Finally, use chromatography to separate and purify the product, and the calculated yield is 85.08%.

[0046] Example 5 Dehalogenation of 4-amino-2-chloropyridine

[0047] Weigh 0.27g (2mmol) 4-amino-2-chloropyridine, add it to a 25ml reaction bottle, add 20mg (8%) Pd / C catalyst and 0.4g (3mmol) anhydrous potassium carbonate, add 5ml methanol solution; then plug the reaction bottle with a rubber stopper, place it in an ice water bath, use an oil pump and a syringe to extract the gas in the reaction bottle; then weigh 1.16g (5mmol) triethylsilane, slowly inject it into the reaction bottle, seal it well, and stir it with a magnetic stirrer to allow the reactants to fully react for 8h. Finally, use chromatography to separate and purify the product, and the calculated yield is 64.83%.

[0048] Example 6 Dehalogenation of 2-amino-6-chloropyridine

[0049] Weigh 0.272g (2mmol) 2-amino-6-chloropyridine, add it to a 25ml reaction bottle, add 20mg (8%) Pd / C catalyst and 0.4g (3mmol) anhydrous potassium carbonate, add 5ml methanol solution; then plug the reaction bottle with a rubber stopper, place it in an ice water bath, use an oil pump and a syringe to extract the gas in the reaction bottle; then weigh 1.16g (5mmol) triethylsilane, slowly inject it into the reaction bottle, seal it well, and stir it with a magnetic stirrer to allow the reactants to fully react for 8h. Finally, use chromatography to separate and purify the product, and the calculated yield is 72.01%.

[0050] Product detection: The products prepared in Examples 1-6 were subjected to hydrogen spectrum analysis and carbon spectrum analysis, respectively. The product structures are as follows:

[0051] Example 1 Product Quinoline:

[0052]

[0053] Quinoline (Example 1). 1H-NMR: δ8.89 (dd, J = 4.3, 1.8 Hz, 1H), 8.16-8.03 (m, 2H), 7.77 (d, J = 8.2 Hz, 1H), 7.68 (ddd, J = 8.3, 6.7, 1.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.34 (dd, J = 8.3, 4.3 Hz, 1H). 13C-NMR: δ150.32, 148.18, 136.09, 129.47, 129.34, 128.27, 127.78, 126.54, 121.05.

[0054] according to Figure 1a Proton spectrum and Figure 1b Carbon spectrum analysis can confirm that the hydrogen atoms and carbon atoms in the product obtained in Example 1 are the same as those of quinoline.

[0055] Example 2 Product 4-methylquinoline:

[0056]

[0057] 4-Methylquinoline (Example 2). 1H-NMR: δ8.76 (d, J = 4.4 Hz, 1H), 8.11 (dd, J = 8.5, 1.3 Hz, 1H), 7.97 (dd, J = 8.4, 1.4 Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.55 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.21 (dd, J = 4.4, 1.0 Hz, 1H), 2.68 (d, J = 1.0 Hz, 3H). 13C-NMR: δ150.08, 147.85, 144.43, 129.89, 129.16, 128.28, 126.32, 123.83, 121.87, 18.67.

[0058] according to Figure 2a Proton spectrum and Figure 2b Carbon spectrum analysis can confirm that the hydrogen atoms and carbon atoms in the product obtained in Example 2 are the same as those of 4-methylquinoline.

[0059] Example 3 Product 2-aminopyrimidine:

[0060]

[0061] 2-aminopyrimidine (Example 3). 1H-NMR: δ8.21 (d, J = 4.8 Hz, 2H), 6.54 (dd, J = 10.0, 5.2 Hz, 3H). 13C-NMR: δ164.06, 158.47, 110.55.

[0062] according to Figure 3a Proton spectrum and Figure 3b Carbon spectrum analysis can confirm that the hydrogen atoms and carbon atoms in the product obtained in Example 3 are the same as those of 2-aminopyrimidine.

[0063] Example 4 Product 4-aminopyrimidine:

[0064]

[0065] 4-aminopyrimidine (Example 4). 1H-NMR: δ8.33 (s, 1H), 8.03 (d, J = 5.9 Hz, 1H), 6.81 (s, 2H), 6.41 (d, J = 5.8 Hz, 1H). 13C-NMR: δ163.72, 158.82, 155.19, 105.49.

[0066] according to Figure 4a Proton spectrum and Figure 4bCarbon spectrum analysis can confirm that the hydrogen atoms and carbon atoms in the product obtained in Example 4 are the same as those of 4-aminopyrimidine.

[0067] Example 5 Product 4-aminopyridine:

[0068]

[0069] 4-Aminopyridine (Example 5). 1H-NMR: δ7.96 (d, J = 5.4 Hz, 2H), 6.49-6.39 (m, 2H), 5.99 (s, 2H). 13-C-NMR: δ153.70, 148.64, 108.22.

[0070] according to Figure 5a Proton spectrum and Figure 5b Carbon spectrum analysis can confirm that the hydrogen atoms and carbon atoms in the product obtained in Example 5 are the same as those of 4-aminopyridine.

[0071] Example 6 Product 2-aminopyridine:

[0072]

[0073] 2-Aminopyridine (Example 6). 1H-NMR: δ7.89 (dd, J=5.0, 2.1 Hz, 1H), 7.34 (ddd, J=8.7, 7.1, 2.0 Hz, 1H), 6.49-6.41 (m, 2H), 5.83 (s, 2H). 13C-NMR: δ160.20, 148.14, 137.37, 112.26, 108.41.

[0074] according to Figure 6a The hydrogen spectrum and carbon spectrum analysis of 6b confirmed that the hydrogen atoms and carbon atoms in the product obtained in Example 6 were the same as those of 2-aminopyridine.

[0075] In summary, the present invention adopts a new dehalogenation method for removing N-ortho halogen atoms such as quinoline, pyridine, and pyrimidine, provides a new dehalogenation idea for (hetero)aryl halides, and has a special significance for reducing environmental pollution.

[0076] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

[0077] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A dehalogenation method using hydrosilane to reduce N-heteroaryl halides, characterized in that: The following steps are involved: The N-heteroaryl halide is put into a palladium carbon / base catalytic system, the air in the system is removed, the hydrosilane is injected into the system, and the system is placed at a certain temperature for a full reaction.

2. The dehalogenation method of N-heteroaryl halides by reducing them with hydrosilane according to claim 1, characterized in that: Hydrogen-containing silanes include trimethylsilane, triisopropylsilane, tributylsilane, tri(fluoroisopropyl)silane, tri(chloromethyl)silane, tri(trifluoromethyl)silane, tri(trimethylsiloxy)silane, bis(trimethylsiloxy)ethylsilane, bis(chloromethyl)bis(trimethylsiloxy)silane.

3. The dehalogenation method of N-heteroaryl halides by reducing them with hydrosilane according to claim 1, characterized in that: Heteroaryl halides include 2-chloroquinoline-5-carboxylic acid, 2-chloro-4-methylquinoline, 6-bromo-2-chloroquinoline, 2-4-dichloropyrimidine, 5-bromo-2,4-dichloropyrimidine, 2,4,5-trichloropyrimidine, 2-amino-4,6-dichloropyrimidine, 2,4-diamino-6-chloropyrimidine, 4-amino-6-chloropyrimidine, 4-amino-2,6-dichloropyrimidine, 2,3,5-trichloropyridine, 2-amino-6-chloropyridine, 3-amino-2-chloropyridine, 2-bromo-5-chloropyridine, 3-bromo-2-chloropyridine, 5-bromo-2-chloropyridine, 6-fluoro-2-chloropyridine, 5-aminomethyl-2-chloropyridine, and 6-chloropyridine-2-carboxylic acid.

4. The dehalogenation method of N-heteroaryl halides by reducing them with hydrosilane according to claim 1, characterized in that: Bases include K2CO3, triethylamine, KOH.

5. The dehalogenation method of N-heteroaryl halides by reducing them with hydrosilane according to claim 1, characterized in that: Solvents include methanol, acetonitrile, DMF, toluene, tetrahydrofuran, dichloromethane, ethyl acetate, water.

6. The dehalogenation method of N-heteroaryl halides by reducing them with hydrosilane according to claim 1, characterized in that: The reaction temperature is 20-50°C, and the reaction time is 4-24h.

7. The dehalogenation method of N-heteroaryl halides by reducing them with hydrosilane according to claim 1, characterized in that: The molar ratio of the N-heteroaryl halide to the hydrosilane is 1:1-5.

8. The dehalogenation method of N-heteroaryl halides by reducing them with hydrosilane according to claim 1, characterized in that: The mass ratio of N-heteroaryl halide to catalyst is 1:0.04-0.

08.

9. The dehalogenation method of N-heteroaryl halides by reducing them with hydrosilane according to claim 1, characterized in that: The molar ratio of the N-heteroaryl halide to the base is 1:0.5-2.

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