Process for the preparation of aryl halides starting from aryl amines

Abstract

The application provides a method for preparing aryl halide from arylamine, which comprises the following steps: adding concentrated nitric acid solution dropwise into a mixed system comprising an organic base and an arylamine compound, and then adding a halogenating reagent into the reaction system after the dropwise addition is completed to perform halogenation reaction to obtain the aryl halide. The method for preparing aryl halide provided by the application has the advantages of safety and high efficiency, mild conditions, environmental friendliness, high atom economy and wide substrate application range.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology and relates to a method for preparing aryl halides from aromatic amines. Background Technology

[0002] Aryl halide skeletons are widely found in many bioactive natural products and have broad applications in the pharmaceutical and pesticide fields. Aryl halides are also important intermediates in organic synthesis, significantly improving the efficiency of organic synthesis. Therefore, developing synthetic methods for aryl halides is of great significance in the field of organic synthesis.

[0003] Using aromatic amines as raw materials, the conversion of aromatic amines to diazonium salts via diazotization, followed by nucleophilic substitution reactions with the corresponding copper halide salts to obtain aryl halides, is a classic synthetic method for aryl halides. However, the diazotization method has many drawbacks. Specifically, diazonium salts are unstable and easily decompose under light or heat. Some diazonium salts can rapidly decompose and explode under heat or vibration in a dry state. Furthermore, the diazotization reaction needs to be carried out at low temperatures, and the resulting diazonium salt solution must be used immediately and is not suitable for storage or drying. The reaction conditions are extremely demanding. Additionally, side reactions such as decomposition, hydrolysis, and coupling are prone to occur during the reaction, generating large amounts of acidic wastewater and waste gas, causing environmental pollution.

[0004] In summary, how to prepare aryl halides from aromatic amines in a milder, safer, and more environmentally friendly manner remains a pressing technical problem to be solved in this field. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a method for preparing aryl halides from aromatic amines. This method uses aromatic amines as raw materials and prepares aryl halides in a one-pot process under the action of an organic base / nitric acid / halogenated reagent. This method has the advantages of being safe and efficient, having mild conditions, being environmentally friendly, having high atom economy, and having a wide range of applicable substrates.

[0006] This invention provides a method for preparing aryl halides from aromatic amines, comprising the following steps:

[0007] Concentrated nitric acid solution is added dropwise to a mixed system comprising an organic base and an aromatic amine compound. After the addition is complete, a halogenating reagent is added to the reaction system to carry out a halogenation reaction, thereby obtaining the aryl halide.

[0008] Compared to the traditional method of first converting aromatic amines into diazonium salt intermediates and then halogenating them to obtain aryl halides, the method provided by this invention eliminates the need for diazonium salt intermediates. Using aromatic amines as raw materials, aryl halides can be prepared in a one-pot process under the action of an organic base / nitric acid / halogenating reagent. This method offers advantages such as safety, high efficiency, mild conditions, environmental friendliness, high atom economy, and a wide range of applicable substrates.

[0009] The inventors speculate that in the above preparation method, the aromatic amine compound undergoes the following reaction process: First, concentrated nitric acid solution is added dropwise to a mixed system including an organic base and an aromatic amine compound to promote the formation of ammonium nitrate salt. Then, a halogenating reagent is added to the reaction system to cause the ammonium nitrate salt to lose one molecule of water to form a nitramide intermediate. The lost one molecule of water can be consumed by the halogenating reagent to promote the formation of the intermediate. In addition, the halide ions in the halogenating reagent carry out nucleophilic attack on the carbon atom where the nitramide group is located, and the nitramide group leaves as a leaving group, thereby obtaining the aryl halide.

[0010] It is understandable that the reaction will release a lot of heat when the concentrated nitric acid solution is added dropwise. The temperature should be controlled so that the system temperature during the dropwise process is not too high to avoid the occurrence of spraying and side reactions. It is preferable to control the temperature during the dropwise process to not exceed 30°C. After the concentrated nitric acid solution is added, in order to ensure that the concentrated nitric acid solution, organic base and aromatic amine mixture are fully mixed, the halogenation reagent can be added after thorough stirring at room temperature to carry out the halogenation reaction.

[0011] The method described above, wherein the aromatic amine compound has the general formula structure shown in Formula 1:

[0012] Ar-NH2 Formula 1

[0013] In Formula 1, Ar represents aryl or substituted aryl;

[0014] The aryl group is selected from 6-10 aryl groups or 5-10 heteroaryl groups;

[0015] The substituents in the substituted aryl group are selected from one or more of the following: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, ester, trialkylsilyl, halogen, trifluoromethyl, cyano, hydroxyl, phenyl, phenoxy, benzyloxy, nitro, thiocyanate, and Bpin.

[0016] As is known in the art, an aryl group refers to an aromatic ring composed of carbon and hydrogen atoms, which can be a single aromatic ring or multiple aromatic rings fused together; a heteroaryl group refers to an aromatic ring in which at least one carbon atom is replaced by a heteroatom (such as O, N, S). 6-10 membered aryl groups refer to aryl groups with 6 to 10 atoms, and 5-10 membered heteroaryl groups refer to heteroaryl groups with 5 to 10 atoms.

[0017] For example, a heteroaryl group can be a five-membered heteroaryl group containing 1 to 4 heteroatoms or a six-membered heteroaryl group containing 1 to 5 heteroatoms. Specifically, a five-membered heteroaryl group containing 1 heteroatom includes, but is not limited to, one of pyrroleyl, furanyl, or thiopheneyl; a five-membered heteroaryl group containing 2 heteroatoms includes, but is not limited to, one of imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl; a five-membered heteroaryl group containing 3 heteroatoms includes, but is not limited to, one of triazolyl, oxadiazolyl, or thiadiazolyl; a five-membered heteroaryl ring containing 4 heteroatoms includes, but is not limited to, tetrazolyl; a six-membered heteroaryl group containing 1 heteroatom includes, but is not limited to, pyridinyl or pyranyl; a six-membered heteroaryl group containing 2 heteroatoms includes, but is not limited to, pyridazinyl, pyrazinyl; a six-membered heteroaryl group containing 3 heteroatoms includes, but is not limited to, triazinyl; and a six-membered heteroaryl group containing 4 heteroatoms includes, but is not limited to, tetraazinyl.

[0018] The fused aryl group is not limited to fusion between benzene rings; it can also be fusion between a benzene ring and a heteroaromatic ring, or between two heteroaromatic rings. Fused aryl groups obtained by fusion of benzene rings are naphthyl groups. Fused aryl groups obtained by fusion of benzene rings and heteroaromatic rings include, but are not limited to, one of indole, quinoline, isoquinoline, benzofuran, benzothiazole, and benzimidazole. Fused aryl groups obtained by fusion of heteroaromatic rings include, but are not limited to, purines and pteridines.

[0019] In this invention, substituted aryl refers to an aryl group further connected with substituents, wherein the substituents on the aryl group are selected from one or more of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, ester, trialkylsilyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, phenyl, phenoxy, benzyloxy, nitro, thiocyanate, and Bpin.

[0020] Alkyl refers to a saturated aliphatic hydrocarbon group. C1 to C6 alkyl refers to straight-chain alkyl and branched alkyl with 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, etc.

[0021] Alkenyl refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond. C2 to C6 alkenyl refers to straight-chain alkenyl or branched alkenyl containing 2 to 6 carbon atoms, including but not limited to vinyl, 1-propenyl, 2-propenyl, etc.

[0022] Alkynyl refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. C2 to C6 alkynyl refers to straight-chain or branched alkynyl groups containing 2 to 6 carbon atoms, including but not limited to ethynyl, 1-propynyl, 2-propynyl, etc.

[0023] Alkoxy refers to a group composed of an alkyl group and an oxygen atom. C1 to C6 alkoxy refers to a straight-chain alkoxy or branched-chain alkoxy with 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0024] An ester group refers to a group with a -COOR1 structure, where R1 is selected from C1 to C3 alkyl groups.

[0025] Trialkylsilyl groups refer to groups in which three hydrogen atoms in a silane are replaced by alkyl groups, including but not limited to trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), triisobutylsilyl (TIBS), etc.

[0026] Halogens refer to fluorine, chlorine, bromine, or iodine.

[0027] Bpin refers to pinacol boronic ester group, and its structural formula is:

[0028] This invention does not limit the number of the above-mentioned substituents contained in the aryl group or the position of the substituents. It is understood that the aryl group is connected to an amino group to form the aromatic amine compound of this invention, and the above-mentioned substituents can be present in one or more at the ortho, para or meta position of the amino group.

[0029] The inventors discovered that when the aryl group is selected from one of the following groups, aryl halides can be obtained smoothly in high yield.

[0030]

[0031] in, This indicates that an amino group is attached to the aryl group at this position, thereby forming an aromatic amine compound. The present invention does not limit the specific position of the amino group in the above-mentioned aryl group. Taking pyridinyl as an example, the amino group can be located at the 2-position, 3-position, or 4-position of the pyridine nitrogen atom.

[0032] Furthermore, the aromatic amine compound is selected from one of the following compounds:

[0033]

[0034]

[0035]

[0036] It should be noted that the linkage between the aromatic ring and the amino group in the above compounds... It is a regular single bond, used only to highlight the position of the amino group compared to other single bonds.

[0037] The aromatic amine compound is the herbicide fluroxypyr 1-methylheptyl ester. The present invention has found that the amino group in this substrate can also undergo halogenation reaction efficiently through the method of the present invention, with a product yield of over 80%, showing excellent selectivity.

[0038] The vast majority of the above-mentioned aromatic amine compounds can be halogenated to obtain aryl halides in yields of more than 50%, indicating that the method of the present invention has a wide range of applicable substrates and good universality.

[0039] The present invention does not impose any particular limitation on the type of organic base, as long as it can catalyze the reaction. Preferably, the organic base is selected from one or more of N,N-dimethylaminopyridine (DMAP), triethylamine, pyridine, and diisopropylethylamine; more preferably, the organic base is selected from N,N-dimethylaminopyridine.

[0040] In a preferred embodiment, in the above preparation method, the molar ratio of the aromatic amine compound, the nitric acid in the concentrated nitric acid solution, the organic base, and the halogenated reagent is 1:(1.0-3.0):(0.1-3.0):(1.0-3.0).

[0041] The present invention does not impose a particular limitation on the concentration of the concentrated nitric acid solution, which can be selected from commercially available concentrated nitric acid solutions with a mass fraction of 65% to 68%.

[0042] In a preferred embodiment, in the above preparation method, the halogenated reagent is selected from chlorinated reagents or brominated reagents.

[0043] This invention does not specifically limit the type of chlorinated or brominated reagent, and can be selected from chlorinated or brominated reagents with water-absorbing function that are commonly used in the field of organic synthesis.

[0044] Preferably, the chlorination reagent is selected from one of thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, sulfonyl chloride, N-chlorosuccinimide, and dichlorohydantoin;

[0045] And / or, the brominating reagent is selected from one of dibromo sulfoxide, bromine, phosphorus tribromide, phosphorus tribromooxyphosphine, dibromohydantoin, and N-bromosuccinimide.

[0046] In a preferred embodiment, the halogenation reaction temperature in the above preparation method is 40–90°C, more preferably 70–80°C.

[0047] Furthermore, the above preparation process is carried out in a solvent system, and the mixed system also includes an organic solvent. The present invention does not specifically limit the type of organic solvent, which is preferably a polar aprotic solvent, including but not limited to one or more of dichloroethane, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, ethylbenzene, xylene, and chlorobenzene.

[0048] The above preparation process can be monitored using conventional reaction monitoring methods in the field, such as HPLC or TLC, with the complete conversion of the aromatic amine compound considered as the reaction endpoint.

[0049] After the halogenation reaction is completed, a post-treatment process is included to obtain pure aryl halides. In one specific embodiment, the post-treatment process includes: subjecting the reaction solution to quenching, separation, and washing with saturated brine in sequence; drying and concentrating the separated organic phase; and then purifying it using conventional purification methods such as column chromatography, recrystallization, and distillation to obtain the target product.

[0050] The implementation of this invention has at least the following beneficial effects:

[0051] Compared to existing technologies that first convert aniline compounds into diazonium salts and then perform halogenation reactions to prepare aryl halides, the preparation method provided by this invention achieves a one-pot, efficient process for preparing aryl halides from aniline, and has the advantages of mild reaction conditions, safe operation, high atom economy, and wide substrate applicability. Detailed Implementation

[0052] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions in the embodiments of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Obviously, the described embodiments are only some embodiments of this invention, not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0053] The method for preparing aryl halides from aromatic amines according to the present invention will be described in detail below with reference to specific embodiments.

[0054] In the following embodiments, unless otherwise specified, all raw materials can be prepared by commercially available or literature-described conventional methods. Experimental methods without specific conditions shall be performed in accordance with conventional methods and conditions in the art, or according to the product instructions.

[0055] Example 1-1

[0056] Preparation of 2-chloro-5-bromopyridine

[0057]

[0058] The specific steps include: dissolving 10 g of 3-bromo-4-aminopyridine (1.0 equivalent) and 17.63 g of 4-dimethylaminopyridine (2.5 equivalent) in 100 mL of dichloroethane, then adding concentrated nitric acid solution (6.62 g, 1.2 equivalent, mass fraction 65%–68%) dropwise, controlling the temperature at 10–20 °C during the dropwise addition. During the dropwise addition, solids precipitate out, and the system changes from colorless and transparent to milky white. After the addition is complete, stirring is continued at room temperature for 10 min, and then thionyl chloride (17.2 g, 2.5 equivalent) is added dropwise to the reaction system. During the dropwise addition, the reaction system shows obvious exothermic temperature rise and gas generation. The color of the reaction system changes from milky white to pale yellow and then to dark yellow. The temperature is controlled at around 30 °C using an ice bath. After the dropwise addition is completed in about 15 min, the temperature is raised to 70 °C and the reaction continues for 1 h. After the reaction is complete as monitored by HPLC, 50 mL of water is added to quench the reaction.

[0059] After the reaction solution was allowed to stand and separate into layers, the organic phase was separated. The organic phase was washed with 50g of saturated brine, allowed to stand and separate into layers again, and then dried and concentrated. 3-Bromo-4-chloropyridine was obtained by column chromatography (PE:EtOAc = 10:1 (volume ratio)) with a yield of 55%.

[0060] To the product 1 H NMR and 13 C NMR characterization, the characterization results are as follows:

[0061] 1 H NMR (400MHz, CDCl3) δ8.44 (d, J = 2.3Hz, 1H), 7.75 (dd, J = 8.4, 2.5Hz, 1H), 7.22 (d, J = 8.4Hz, 1H).

[0062] 13 C NMR (100MHz, CDCl3) δ150.79,150.18,141.35,125.75,119.23.

[0063] Examples 1-2 to 1-16 are all for the preparation of 2-chloro-5-bromopyridine and serve as screening experiments for reaction conditions. The specific differences from Example 1-1 are as follows:

[0064] Examples 1-2: The molar ratio of 3-bromo-4-aminopyridine, 4-dimethylaminopyridine, nitric acid, and thionyl chloride was 1.0:1.5:1.0:2.5; the yield of 3-bromo-4-chloropyridine was 42%.

[0065] Examples 1-3: The molar ratio of 3-bromo-4-aminopyridine, 4-dimethylaminopyridine, nitric acid, and thionyl chloride was 1.0:2.0:1.5:2.5; the yield of 3-bromo-4-chloropyridine was 51%.

[0066] Examples 1-4: The molar ratio of 3-bromo-4-aminopyridine, 4-dimethylaminopyridine, nitric acid, and thionyl chloride was 1.0:3.0:1.2:2.5; the yield of 3-bromo-4-chloropyridine was 53%.

[0067] Examples 1-5: The halogenation reaction was carried out at 55°C; the yield of 3-bromo-4-chloropyridine was 31%.

[0068] Examples 1-6: The halogenation reaction was carried out at a temperature of 85°C; the yield of 3-bromo-4-chloropyridine was 53%.

[0069] Examples 1-7: The reaction solvent was tetrahydrofuran; the yield of 3-bromo-4-chloropyridine was 18%.

[0070] Examples 1-8: The reaction solvent was 1,4-dioxane; the yield of 3-bromo-4-chloropyridine was 25%.

[0071] Examples 1-9: The reaction solvent was dichloromethane; the yield of 3-bromo-4-chloropyridine was 40%.

[0072] Examples 1-10: The chlorinating agent was phosphorus oxychloride; the yield of 3-bromo-4-chloropyridine was 45%.

[0073] Examples 1-11: The chlorinating agent was phosphorus pentachloride; the yield of 3-bromo-4-chloropyridine was 49%.

[0074] Examples 1-12: DMAP was replaced with triethylamine; the yield of 3-bromo-4-chloropyridine was 26%.

[0075] Examples 1-13: DMAP was replaced with pyridine; the yield of 3-bromo-4-chloropyridine was 35%.

[0076] Examples 1-14: DMAP was replaced with diisopropylethylamine; the yield of 3-bromo-4-chloropyridine was 28%.

[0077] Examples 2 to 39 are substrate expansion experiments.

[0078] The reaction conditions for Examples 2 to 31 are the same as those for Examples 1-1. The difference lies in the use of different aromatic amine substrates compared to Examples 1-1. The specific substrates, product structures, product yields, and product characterization data are as follows:

[0079] Example 2: Preparation of 3-chloro-5-bromopyridine

[0080]

[0081] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 3-amino-5-bromopyridine and the product yield is 55%.

[0082] 1 H NMR (400MHz, CDCl3) δ8.56 (d, J = 1.5Hz, 1H), 8.50 (d, J = 1.7Hz, 1H), 7.88-7.83 (m, 1H).

[0083] 13 C NMR (100MHz, CDCl3) δ148.93,147.15,138.42,132.54,120.64.

[0084] Example 3: Preparation of 4-chloro-3-bromopyridine

[0085]

[0086] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 3-bromo-4-aminopyridine and the product yield is 53%.

[0087] 1 H NMR (400MHz, CDCl3) δ8.74 (s, 1H), 8.41 (d, J = 5.1Hz, 1H), 7.40 (d, J = 5.2Hz, 1H).

[0088] 13 C NMR (100MHz, CDCl3) δ152.95,148.89,144.09,125.49,121.46.

[0089] Example 4: Preparation of 2,5-dichloropyrazine

[0090]

[0091] The specific preparation steps are basically the same as those in Examples 1-1, except that the aromatic amine substrate is 2-amino-5-chloropyrazine and the product yield is 67%.

[0092] 1 H NMR (400MHz, CDCl3) δ8.39 (s, 2H).

[0093] 13 C NMR (100MHz, CDCl3) δ147.70,143.92.

[0094] Example 5: Preparation of methyl 2-chlorobenzoate

[0095]

[0096] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is methyl 2-aminobenzoate and the product yield is 68%.

[0097] 1 H NMR (400MHz, CDCl3) δ7.82 (dd, J = 7.8, 1.4Hz, 1H), 7.48–7.38 (m, 2H), 7.34–7.27 (m, 1H), 3.93 (s, 3H).

[0098] 13 C NMR (100MHz, CDCl3) δ166.30,133.81,132.67,131.50,131.19,130.19,126.68,52.56.

[0099] Example 6: Preparation of 2-chloro-3-bromopyridine

[0100]

[0101] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 2-amino-3-bromopyridine and the product yield is 78%.

[0102] 1 H NMR (400MHz, CDCl3) δ8.34 (dd, J=4.6, 1.4Hz, 1H), 7.93 (dd, J=7.9, 1.5Hz, 1H), 7.12 (dd, J=7.9, 4.7Hz, 1H).

[0103] 13 C NMR (100MHz, CDCl3) δ150.99,148.06,142.37,123.45,120.53.

[0104] Example 7: Preparation of 2-chloro-3-nitropyridine

[0105]

[0106] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 2-amino-3-nitropyridine and the product yield is 80%.

[0107] 1H NMR (400MHz, CDCl3) δ8.63 (dd, J=4.7, 1.7Hz, 1H), 8.23 ​​(dd, J=8.0, 1.7Hz, 1H), 7.48 (dd, J=8.0, 4.7Hz, 1H).

[0108] 13 C NMR (100MHz, CDCl3) δ152.53,145.00,143.62,134.32,123.08.

[0109] Example 8: Preparation of 2-chloro-3-trifluoromethylpyridine

[0110]

[0111] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 2-amino-3-trifluoromethylpyridine, and the product yield is 78%.

[0112] 1 H NMR (400MHz, CDCl3) δ8.57(d,J=4.8Hz,1H),8.02(d,J=7.8Hz,1H),7.41–7.37(m,1H).

[0113] 13 C NMR (100MHz, CDCl3) δ152.53,145.00,143.62,134.32,123.08.

[0114] 19 F NMR (376MHz, CDCl3) δ -63.82.

[0115] Example 9: Preparation of 2-chloro-3-benzyloxypyridine

[0116]

[0117] The specific preparation steps are basically the same as those in Examples 1-1, except that the aromatic amine substrate is 2-amino-3-benzyloxypyridine and the product yield is 76%.

[0118] 1 H NMR (400MHz, CDCl3) δ7.99 (dd, J=4.6, 1.3Hz, 1H), 7.45 (d, J=7.3Hz, 2H), 7.40 (t, J=7.3 Hz,2H),7.37–7.31(m,1H),7.22(dd,J=8.1,1.3Hz,1H),7.17–7.12(m,1H),5.17(s,2H).

[0119] 13 C NMR (100MHz, CDCl3) δ150.82,141.35,140.87,135.59,128.82,128.39,127.16,123.15,121.04,70.89.

[0120] HRMS(ESI)m / z:[M+H] + Calcd for C 12 H 11 ClNO 220.0524; Found: 220.0524.

[0121] Example 10: Preparation of 2-chloro-3-((trimethylsilyl)ethynyl)-5-bromopyridine

[0122]

[0123] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 2-amino-3-benzyloxypyridine and the product yield is 68%.

[0124] 1 H NMR (400MHz, CDCl3) δ8.35 (d, J = 2.4Hz, 1H), 7.90 (d, J = 2.4Hz, 1H), 0.27 (s, 9H).

[0125] 13 C NMR (100MHz, CDCl3) δ151.17,149.33,143.69,121.84,118.19,105.18,97.97,-0.30.

[0126] HRMS(ESI)m / z:[M+H] + Calcd for C 10 H 12 BrClNSi 287.9605; Found:287.9601.

[0127] Example 11: Preparation of 2-chloro-3-cyano-5-bromopyridine

[0128]

[0129] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 2-amino-3-cyano-5-bromopyridine, and the product yield is 75%.

[0130] 1H NMR (400MHz, CDCl3) δ8.66 (d, J = 2.4Hz, 1H), 8.12 (d, J = 2.4Hz, 1H).

[0131] 13 C NMR (100MHz, CDCl3) δ154.13,151.45,144.49,118.77,113.50,112.21.

[0132] HRMS(ESI)m / z:[M+H] + Calcd for C6H3BrClN2 216.9163; Found:216.9156.

[0133] Example 12: Preparation of 2-chloro-6-methoxypyridine

[0134]

[0135] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 2-amino-6-methoxypyridine and the product yield is 50%.

[0136] 1 H NMR (400MHz, CDCl3) δ7.53–7.46(m,1H),6.88(d,J=7.5Hz,1H),6.63(d,J=8.2Hz,1H),3.90(s,3H).

[0137] Example 13: Preparation of 2-chloro-5-phenylpyridine

[0138]

[0139] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 2-amino-5-phenylpyridine and the product yield is 77%.

[0140] 1 H NMR (400MHz, CDCl3) δ8.60(d,J=2.3Hz,1H),7.83(dd,J=8.3,2.5Hz,1H),7.54(d,J=7.4Hz,2H),7.48(t,J=7.4Hz,2H),7.44–7.36(m,2H).

[0141] 13 C NMR (100MHz, CDCl3) δ150.39,148.04,137.22,136.53,135.69,129.27,128.53,127.10,124.27.

[0142] Example 14: (E)-3-(6-chloropyridin-3-yl)ethyl acrylate

[0143]

[0144] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is (E)-3-(6-aminopyridin-3-yl)ethyl acrylate, and the product yield is 55%.

[0145] 1 H NMR (400MHz, CDCl3) δ8.49(d,J=2.4Hz,1H),7.79(dd,J=8.3,2.5Hz,1H),7.61(d,J=16.1Hz,1H ),7.35(d,J=8.3Hz,1H),6.47(d,J=16.1Hz,1H),4.26(q,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H).

[0146] 13 C NMR (100MHz, CDCl3) δ166.15,152.72,149.63,139.39,136.71,129.27,124.69,121.12,61.03,14.37.

[0147] Example 15: Preparation of 2-chloropyridine-5-boronic acid pinacol ester

[0148]

[0149] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 2-aminopyridine-5-boronic acid pinacol ester, and the product yield is 69%.

[0150] 1 H NMR (400MHz, CDCl3) δ8.65(d,J=1.9Hz,1H),7.95(dd,J=7.9,1.9Hz,1H),7.29(d,J=7.9Hz,1H),1.30(s,12H).

[0151] Example 16: Preparation of 2-chloro-4-methyl-5-bromopyridine

[0152]

[0153] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 2-amino-4-methyl-5-bromopyridine, and the product yield is 74%.

[0154] 1H NMR (400MHz, CDCl3) δ8.39(s,1H),7.20(s,1H),2.37(s,3H).

[0155] 13 C NMR (100MHz, CDCl3) δ150.88,150.21,150.08,126.07,122.08,22.33.

[0156] Example 17: Preparation of 2-chloro-4,6-dimethyl-5-bromopyridine

[0157]

[0158] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 2-amino-4,6-dimethyl-5-bromopyridine, and the product yield is 77%.

[0159] 1 H NMR (400MHz, CDCl3) δ7.01(s,1H),2.61(s,3H),2.35(s,3H).

[0160] 13 C NMR (100MHz, CDCl3) δ158.10,150.42,148.58,123.40,122.75,25.44,23.29.

[0161] Example 18: Preparation of 2-chloro-3,5-dibromo-6-methylpyridine

[0162]

[0163] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 2-amino-4,6-dimethyl-5-bromopyridine, and the product yield is 72%.

[0164] 1 H NMR (400MHz, CDCl3) δ8.01 (s, 1H), 2.57 (s, 3H).

[0165] 13 C NMR (100MHz, CDCl3) δ156.77,148.43,144.65,119.55,117.26,24.26.

[0166] HRMS(ESI)m / z:[M+H] + Calcd for C6H5Br2ClN 283.8372; Found:283.8469.

[0167] Example 19: Preparation of 3,6-dichloropyridazine

[0168]

[0169] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 3-amino-6-chloropyridazine and the product yield is 70%.

[0170] 1 H NMR (400MHz, CDCl3) δ7.51 (s, 2H).

[0171] 13 C NMR (100MHz, CDCl3) δ156.15,130.50

[0172] Example 20: Preparation of 4,6-dichloropyrimidine

[0173]

[0174] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 3-amino-6-chloropyrimidine and the product yield is 61%.

[0175] 1 H NMR (400MHz, CDCl3) δ8.81(s,1H),7.44(s,1H).

[0176] 13 C NMR (100MHz, CDCl3) δ162.18, 158.90, 122.09.

[0177] Example 21: Preparation of 2-chloro-4-trifluoromethylpyrimidine

[0178]

[0179] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 2-amino-4-trifluoromethylpyrimidine, and the product yield is 78%.

[0180] 1 H NMR (400MHz, CDCl3) δ8.90 (d, J = 4.9 Hz, 1H), 7.61 (d, J = 4.9 Hz, 1H).

[0181] 19 F NMR (376MHz, CDCl3) δ -69.94.

[0182] Example 22: Preparation of methyl 3-chloro-4-methylthiophene-2-carboxylate

[0183]

[0184] The specific preparation steps are basically the same as those in Examples 1-1, except that the aromatic amine substrate is methyl 3-amino-4-methylthiophene-2-carboxylate, and the product yield is 43%.

[0185] 1 H NMR (400MHz, CDCl3) δ7.18(s,1H),3.88(s,3H),2.23(s,3H).

[0186] 13 C NMR (100MHz, CDCl3) δ161.37,138.05,132.41,126.33,125.46,52.24,14.86.

[0187] HRMS(ESI)m / z:[M+H] + Calcd for C7H8ClO2S190.9928; Found:190.9924.

[0188] Example 23: Preparation of 2-chloro-5-nitrothiazole

[0189]

[0190] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 2-amino-5-nitrothiazole and the product yield is 36%.

[0191] 1 H NMR (400MHz, CDCl3) δ8.32 (s, 1H).

[0192] 13 C NMR (100MHz, CDCl3) δ157.17,141.78.

[0193] HRMS(ESI)m / z:[M+H] + Calcd for C3H2ClN2O2S164.9520; Found:164.9519.

[0194] Example 24: Preparation of 2-chloro-5-methyl-1,3,4-thiadiazole

[0195]

[0196] The specific preparation steps are basically the same as those in Examples 1-1, except that the aromatic amine substrate is 2-amino-5-methyl-1,3,4-thiadiazole, and the product yield is 80%.

[0197] 1 H NMR (400MHz, CDCl3) δ2.74 (s, 3H).

[0198] HRMS(ESI)m / z:[M+H] + Calcd for C3H4ClN2S134.9778; Found:134.9775.

[0199] Example 25: Preparation of 5-chloro-1-phenylpyrazole-4-onitrile

[0200]

[0201] The specific preparation steps are basically the same as those in Examples 1-1, except that the aromatic amine substrate is 5-amino-1-phenylpyrazole-4-nitrile, and the product yield is 80%.

[0202] 1 H NMR (400MHz, CDCl3) δ7.95 (s, 1H), 7.56–7.47 (m, 5H).

[0203] 13 C NMR (100MHz, CDCl3) δ142.56,136.91,133.27,129.74,129.46,125.03,111.51,94.33.

[0204] Example 26: Preparation of 3-chloro-5-nitrobenzisothiazole

[0205]

[0206] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 3-amino-5-nitrobenzisothiazole and the product yield is 60%.

[0207] 1 H NMR (400MHz, CDCl3) δ8.72 (d, J = 1.9 Hz, 1H), 8.24 (dd, J = 9.7, 2.2 Hz, 1H), 7.86 (d, J = 9.7 Hz, 1H).

[0208] 13 C NMR (100MHz, CDCl3) δ161.51,155.94,145.49,130.95,123.87,122.99,118.04.

[0209] HRMS(ESI)m / z:[M+H] +Calcd for C7H4ClN2O2S214.9677; Found:214.9672.

[0210] Example 27: Preparation of 2-chlorobenzothiazole

[0211]

[0212] The specific preparation steps are basically the same as those in Examples 1-1, except that the aromatic amine substrate is 3-amino-5-nitrobenzisothiazole and the product yield is 86%.

[0213] 1 H NMR (400MHz, CDCl3) δ7.96–7.92(m,1H),7.77–7.73(m,1H),7.50–7.44(m,1H),7.42–7.36(m,1H).

[0214] 13 C NMR (100MHz, CDCl3) δ153.34,151.08,136.17,126.77,125.84,122.97,121.18.

[0215] Example 28: Preparation of 2-chloro-1-methylbenzimidazole

[0216]

[0217] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 2-amino-1-methylbenzimidazole and the product yield is 50%.

[0218] 1 H NMR (400MHz, CDCl3) δ7.73–7.63(m,1H),7.32–7.21(m,3H),3.74(s,3H).

[0219] 13 C NMR (100MHz, CDCl3) δ141.68,140.98,135.67,123.17,122.72,119.40,109.32,30.55.

[0220] Example 29: Preparation of 2-chloronaphthalene

[0221]

[0222] The specific preparation steps are basically the same as those in Examples 1-1, except that the aromatic amine substrate is 2-aminonaphthalene and the product yield is 45%.

[0223] 1H NMR (400MHz, CDCl3) δ7.87–7.81(m,2H),7.80–7.73(m,2H),7.55–7.45(m,2H),7.43(dd,J=8.7,2.0Hz,1H).

[0224] 13 C NMR (100MHz, CDCl3) δ134.14,131.77,131.69,129.63,127.93,127.20,127.04,126.91,126.72,126.25.

[0225] Example 30: Preparation of 5-chlorobenzisothiazole

[0226]

[0227] The specific preparation steps are basically the same as in Examples 1-1, except that the aromatic amine substrate is 5-aminobenzisothiazole and the product yield is 36%.

[0228] 1 H NMR (400MHz, CDCl3) δ8.85 (s, 1H), 8.04 (s, 1H), 7.89 (d, J = 8.6Hz, 1H), 7.53–7.45 (m, 1H).

[0229] 13 C NMR (100MHz, CDCl3) δ154.11,150.18,137.28,131.41,128.62,123.56,120.73.

[0230] HRMS(ESI)m / z:[M+H] + Calcd for C7H5ClNS169.9826; Found:169.9825.

[0231] Example 31: Preparation of 5-chlorobenzothiazole

[0232]

[0233] The specific preparation steps are basically the same as those in Examples 1-1, except that the aromatic amine substrate is 5-aminobenzisothiazole and the product yield is 33%.

[0234] 1 H NMR (400MHz, CDCl3) δ9.03 (s, 1H), 8.13 (d, J = 1.8Hz, 1H), 7.87 (d, J = 8.6Hz, 1H), 7.43 (dd, J = 8.6, 1.7Hz, 1H).

[0235] 13 C NMR (100MHz, CDCl3) δ155.83,154.27,132.49,132.16,126.31,123.61,122.72.

[0236] Example 32: Preparation of 2,3,5-tribromo-6-methylpyridine

[0237]

[0238] The specific steps include: dissolving 2-amino-3,5-dibromo-6-methylpyridine (26.6 mg, 0.1 mmol, 1.0 eq) and DMAP (30.5 mg, 0.25 mmol, 2.5 eq) in 1 mL of acetonitrile, then adding concentrated nitric acid solution (65%–68% mass concentration, 14.0 μL, 0.2 mmol, 2.0 eq) dropwise, controlling the temperature at 10–20 °C during the dropwise addition process, stirring for 10 min at room temperature after the dropwise addition is complete, then adding SOBr2 to the system, heating to 70 °C and reacting for 1 h, and monitoring the reaction until complete by HPLC.

[0239] The reaction solution was cooled to room temperature, and then saturated sodium bicarbonate solution was added to quench the reaction. Dichloromethane was added for extraction (3 × 5 mL). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, and the concentrate was separated by column chromatography (PE:EtOAc = 5:1 (volume ratio)) to obtain 2,3,5-tribromo-6-methylpyridine (19.6 mg), with a product yield of 60%.

[0240] The product characterization data are as follows:

[0241] 1 H NMR (400MHz, CDCl3) δ7.99 (s, 1H), 2.60 (s, 3H).

[0242] 13 C NMR (100MHz, CDCl3) δ157.12,144.21,141.00,120.83,120.30,24.25.

[0243] HRMS(ESI-TOF)m / z calcd.for C6H5Br3N([M+H] + )327.7967found327.7965.

[0244] Example 33: Preparation of 2-bromo-5-phenylpyrazine

[0245]

[0246] The specific preparation steps are basically the same as in Example 32, except that the aromatic amine substrate is 2-amino-5-phenylpyrazine, the reaction solvent is dichloroethane, and the product yield is 40%.

[0247] The product characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ8.78(d,J=1.1Hz,1H),8.73(d,J=1.1Hz,1H),8.01–7.95(m,2H),7.55–7.46(m,4H).

[0248] 13 C NMR (100MHz, CDCl3) δ151.41,146.93,141.88,139.14,135.26,130.42,129.33,126.97.

[0249] Example 34: Preparation of 5-bromo-1-phenylpyrazole-4-onitrile

[0250]

[0251] The specific preparation steps are basically the same as in Example 33, except that the aromatic amine substrate is 5-amino-1-phenylpyrazole-4-nitrile, and the product yield is 71%.

[0252] The product characterization data are as follows:

[0253] 1 H NMR (400MHz, CDCl3) δ7.98 (s, 1H), 7.57–7.47 (m, 5H).

[0254] 13 C NMR (100MHz, CDCl3) δ143.51,137.84,129.89,129.45,125.61,120.05,112.20,98.01.

[0255] HRMS(ESI-TOF)m / z calcd.for C 10 H7BrN3([M+H) + )247.9818found247.9816.

[0256] Example 35: Preparation of methyl 3-bromobenzoate

[0257]

[0258] The specific preparation steps are basically the same as in Example 33, except that the aromatic amine substrate is methyl 3-aminobenzoate and the product yield is 50%.

[0259] The product characterization data are as follows:

[0260] 1 H NMR (400MHz, CDCl3) δ8.16(t,J=1.6Hz,1H),7.95(d,J=7.8Hz,1H),7.69–7.64(m,1H),7.30(t,J=7.9Hz,1H),3.91(s,3H).

[0261] 13 C NMR (100MHz, CDCl3) δ165.83,135.96,132.70,132.15,130.04,128.25,122.55,52.52.

[0262] Example 36: Preparation of 4-bromobiphenyl

[0263]

[0264] The specific preparation steps are basically the same as in Example 33, except that the aromatic amine substrate is 4-aminobiphenyl and the product yield is 65%.

[0265] The product characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ7.54–7.44(m,4H),7.43–7.36(m,4H),7.36–7.28(m,1H).

[0266] 13 C NMR (100MHz, CDCl3) δ140.20,140.06,131.95,128.99,128.82,127.74,127.02,121.65.

[0267] Example 37: Preparation of 3,6-dichloro-4-bromopyridazine

[0268]

[0269] The specific preparation steps are basically the same as in Example 33, except that the aromatic amine substrate is 3,6-dichloro-4-aminopyridazine, and the product yield is 54%.

[0270] The product characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ7.84 (s, 1H).

[0271] 13 C NMR (100MHz, CDCl3) δ156.53,154.91,133.15,129.62.

[0272] Example 38: Preparation of 2-bromo-6-trifluoromethoxybenzothiazole

[0273]

[0274] The specific preparation steps are basically the same as in Example 33, except that the aromatic amine substrate is 2-amino-6-trifluoromethoxybenzothiazole, and the product yield is 83%.

[0275] The product characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ7.95 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.32 (dd, J = 8.9, 1.5 Hz, 1H).

[0276] 13 C NMR (100MHz, CDCl3) δ150.90, 146.94, 139.83, 138.18, 123.78, 120.61, 120.52 (q, J = 258.0Hz), 113.57.

[0277] Example 39: Preparation of 4-bromo-3,5-dichloro-6-fluoro-2-pyridineoxyacetic acid-methylheptyl ester

[0278]

[0279] The specific preparation steps are basically the same as in Example 32, except that the aromatic amine substrate is 1-methylheptyl fluoride, and the product yield is 87%.

[0280] The product characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ5.05–4.94(m,1H),4.88(s,2H),1.65–1.41(m,2H),1.35–1.15(m,11H),0.93–0.81(m,3H).

[0281] 13 C NMR (100MHz, CDCl3) δ167.26, 155.27 (d, J = 13.9Hz), 154.95 (d, J = 243.1Hz), 138.29, 116.74 (d, J =7.1Hz), 111.19 (d, J = 35.3Hz), 73.03, 64.40, 35.93, 31.82, 29.17, 25.31, 22.69, 19.98, 14.17.

[0282] 19 F NMR (376MHz, CDCl3) δ -70.24.

[0283] HRMS(ESI-TOF)m / z calcd.for C 15 H 20 Br2Cl2FNO3([M+H] + )429.9982found429.9980.

[0284] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing aromatic halides from aromatic amines, characterized in that, Includes the following steps: Concentrated nitric acid solution is added dropwise to a mixed system comprising an organic base and an aromatic amine compound. After the addition is complete, a halogenating agent is added to the reaction system to carry out a halogenation reaction, thereby obtaining the aromatic halide. The aromatic amine compound has the general formula shown in Formula 1: Ar-NH2 Formula 1 In Formula 1, Ar represents an aromatic group or a substituted aromatic group, wherein the aromatic group is selected from 6-10 aryl or 5-10 heteroaryl; The halogenated reagent is selected from chlorinated reagents or brominated reagents; Wherein, the substituents in the substituted aromatic group are selected from one or more of C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, ester, trialkylsilyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, phenyl, phenoxy, benzyloxy, nitro, thiocyanate, and Bpin. The organic base is selected from one or more of N,N-dimethylaminopyridine, triethylamine, pyridine, and diisopropylethylamine; The chlorination reagent is selected from one of thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, sulfonyl chloride, N-chlorosuccinimide, and dichlorohydantoin; The brominating reagent is selected from one of dibromo sulfoxide, bromine, phosphorus tribromide, phosphorus tribromooxy, dibromohydantoin, and N-bromosuccinimide; The aromatic halides refer to compounds in which the amino group of an aromatic amine compound is replaced by a halogen.

2. The method according to claim 1, characterized in that, The aromatic group is selected from one of the following groups: 。 3. The method according to claim 1 or 2, characterized in that, The aromatic amine compound is selected from one of the following compounds:

4. The method according to claim 1 or 2, characterized in that, The molar ratio of the aromatic amine compound, the nitric acid in the concentrated nitric acid solution, the organic base, and the halogenated reagent is 1:(1.0~3.0):(0.1~3.0):(1.0~3.0).

5. The method according to claim 4, characterized in that, The halogenation reaction is carried out at a temperature of 40~90℃.

6. The method according to claim 1, characterized in that, The mixed system also includes an organic solvent selected from one or more of dichloroethane, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, ethylbenzene, xylene, and chlorobenzene.

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