Method for efficiently synthesizing aryl halide through biomimetic catalysis aerobic oxidation halogenation

Abstract

The invention discloses a method for efficiently synthesizing aryl halide through biomimetic catalysis aerobic oxidation halogenation, and belongs to the technical field of organic synthesis. The method is characterized in that under the condition of oxygen or air in the presence of a simple catalyst (alurea) and a cheap reducing agent (ascorbic acid), (hetero) aromatic hydrocarbon (I) and halide salt (II) react to efficiently and specifically obtain halogenated aromatic hydrocarbon (III). Aromatic halide is an important organic synthesis element and a drug molecule building block, but according to the biomimetic catalysis oxidation halogenation method, various brominated, iodinated and chlorinated products can be generated with high yield and high selectivity by utilizing cheap and green halide salt under mild conditions; and the reaction has the advantages of green and cheap reagents, mild conditions, simple operation, easy amplification, wide substrate range, good functional group tolerance, compatibility with unpurified primary raw materials and suitability for precise later modification of complex active molecules, and shows good economic practicability and industrial application prospects.

Description

Technical Field

[0001] The present invention belongs to, but is not limited to, the technical field of organic synthesis, and particularly relates to a method for efficiently synthesizing haloarenes by biomimetic catalytic aerobic oxidation of halides. Background Art

[0002] In the field of organic synthesis, haloarenes (especially bromides and iodides) play an irreplaceable and important role in cross-coupling reactions and are key substrates or synthetic intermediates for constructing various C-C, C-O, and C-N bonds (Chem. Rev. 2016, 116, 6837-7042). In addition, haloarenes are widely present in nature, and more than 5,000 cases of haloarene active natural products have been discovered so far (J. Nat. Prod. 2024, 87, 1285-1305). As important pharmacophoric groups, haloarenes are also present in a variety of pesticide molecules (Pest Manage. Sci. 2017, 73, 1053-1066) and therapeutic drugs (J. Med. Chem. 2014, 57, 9764-9773). And studies have shown that precise halogenation modification of low-activity non-drug molecules can significantly improve the drug-forming ability of compounds. Therefore, it is of great significance to develop a convenient, efficient, and specific halogenation method. The following are some active molecules of haloarene drugs (pesticides):

[0003]

[0004] Traditional chemical halogenation strategies rely on oxidative cationic halogen sources, which require the use of toxic and highly corrosive molecular halogens (such as Cl2, Br2, I2) (Chem. Rev. 2016, 116, 6837 - 7042.), expensive organic halogenating reagents with low atom utilization (such as N - halosuccinimide NXS) (Angew. Chem. Int. Ed. 2018, 57, 12869 - 12873) or stoichiometric strong oxidants (such as oxone) to oxidize inorganic halide salts (Green Chem. 2012, 14, 1125 - 1131), which is an environmentally harmful process. The above - mentioned halogenation methods inevitably lead to production problems such as equipment corrosion, harsh conditions, dangerous operations, low atom utilization, and environmental pollution, and are often accompanied by reaction problems such as poor functional group compatibility, poor reaction selectivity, and over - halogenation. There is a flavin - dependent halogenase in nature that can utilize oxygen in the air to oxidize common inorganic halide salts and efficiently and specifically prepare various halogenated substrates under mild environmental conditions, avoiding the oxidation side reactions caused by harsh oxidative halogen sources in the chemical halogenation process (Science 2005, 309, 2216 - 2219). However, the high production cost, harsh storage and operation conditions, and limited substrate scope of flavin - dependent halogenases greatly limit their use in actual production (Chem. Rev. 2018, 118, 232 - 269). In short, there is an urgent need to develop a new class of atom - economic, green, and highly efficient selective halogenation methods with mild conditions, safe reagents, simple operations, compatibility with various substrates and multiple halogens to provide an efficient and convenient new strategy for the preparation of important halogenated aromatic hydrocarbons. Summary of the Invention

[0005] The object of the present invention is to address the deficiencies in existing chemical halogenation technologies. By simulating the oxidative halogenation process catalyzed by flavin halogenase in vivo, a new method for biomimetic catalytic aerobic oxidation halogenation is developed, which can directly utilize green and inexpensive air (or oxygen) and halide salts, and is mild, convenient, highly efficient, and highly selective for the preparation of various halogenated aromatic hydrocarbon compounds.

[0006] The method of the present invention can achieve the oxidation of halide salts by oxygen and the occurrence of halogenation reactions without the need for special conditions such as photocatalysis, truly simulating the flavin - dependent halogenase in vivo.

[0007] Specifically, the present invention provides a method for the highly efficient synthesis of halogenated aromatic hydrocarbons by biomimetic catalytic aerobic oxidation halogenation, which is characterized in that: under the conditions of oxygen or air in the presence of a catalyst, halide salt MX, a reducing agent, and a solvent, a halogenation reaction is carried out on an aromatic ring compound to obtain a halogenated aromatic hydrocarbon;

[0008] Here, the catalyst is a substituted alloxan or a mono - or poly - hydrate of a substituted alloxan;

[0009] The halogen salt is MX, where M is selected from hydrogen, lithium, sodium, potassium, cesium, beryllium, magnesium, calcium, strontium, barium, iron, cobalt, nickel, copper, zinc, ammonium group or tetraalkylammonium group, and M is preferably lithium; X is selected from bromine, iodine or chlorine;

[0010] The reducing agent is a Hans ester, benzothiazoline derivative, benzimidazoline derivative, LiI, thiol derivative, cysteine, glutathione, ascorbic acid derivative or crude extract containing ascorbic acid with a symmetric or asymmetric structure; optionally, the structure of the reducing agent is:

[0011]

[0012] The solvent is one or a mixture of acetonitrile, chloroacetonitrile, propionitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, cyclopentanol, cyclohexanol, trifluoroethanol, hexafluoroisopropanol, water, nitromethane, nitroethane, benzene, toluene, xylene, mesitylene, fluorobenzene, chlorobenzene, bromobenzene, trifluorotoluene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, tetrachloroethane, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, petroleum ether, diethyl ether, methyl tert-butyl ether, and is preferably acetonitrile.

[0013] In the biomimetic catalytic aerobic oxidation halogenation method of the present invention, the aromatic ring compound has the structure shown in formula (I) to obtain the halogenated aromatic hydrocarbon shown in formula (III):

[0014]

[0015] The molecular structure of the alloxan catalyst is:

[0016]

[0017] Wherein: X in formula (III) is selected from bromine, iodine or chlorine; in formula (I) and formula (III) represents an aryl group or a substituted aryl group, and the aryl group is a phenyl group, a polycyclic aryl group or a heterocyclic aryl group; R 1 , R 2 , R 3 , R 4 , R 5 represents a substituent connected to the aryl group;

[0018] In formula (I), formula (III) and the alloxan catalyst, R 1 , R 2 , R 3 , R4 , R 5 , R 6 , R 7 are each independently selected from the following groups: hydrogen, C1-C10 alkyl, benzyl, substituted or unsubstituted aryl, amino, C1-C10 alkyl-substituted monoalkylamino, C1-C10 alkyl-substituted dialkylamino, benzylamino, C1-C10 alkoxy, C1-C10 alkyl-substituted sulfanyl, halogen, C1-C5 ester group, carbonyl, acylamino, hydroxyl, nitro, carboxyl; wherein, R1, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 may be the same or different; or R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , R 6 and R 7 may combine with each other to jointly form cycloalkyl, heterocycloalkyl, benzocycloalkyl, benzheterocycloalkyl, aromatic ring, heteroaromatic ring, or derivatives of the above cyclic structures.

[0019] In the biomimetic catalytic aerobic oxidation halogenation method described in the present invention, the reaction temperature is 0-70 °C, preferably 25-30 °C (room temperature).

[0020] In the biomimetic catalytic aerobic oxidation halogenation method described in the present invention, the molar ratio of the aryl compound to the halogen salt is 1:1-50, preferably 1:5-10.

[0021] In the biomimetic catalytic aerobic oxidation halogenation method described in the present invention, the molar ratio of the aryl compound to the alloxan catalyst is 1:0.01-1, preferably 1:0.1.

[0022] In the biomimetic catalytic aerobic oxidation halogenation method described in the present invention, the molar ratio of the aryl compound to the reducing agent is 1:0.5-50, preferably 1:1.2-2.

[0023] In the biomimetic catalytic aerobic oxidation halogenation method described in the present invention, the concentration of the aryl compound is 0.01-1.0 M, preferably 0.025 M.

[0024] In the biomimetic catalytic aerobic oxidation halogenation method described in the present invention, the reaction time is 0.1-72 hours, preferably 2 h.

[0025] Under mild room temperature conditions and in the presence of simple and readily available catalysts and reducing agents, the present invention realizes the highly efficient and highly selective halogenation reaction of (hetero)arenes with green inorganic halide salts in an air (or oxygen) system, prepares a variety of important (hetero)aryl halide products with high activity and high selectivity, and has good functional group compatibility. The method of the present invention uses cheap and green inorganic halides to replace toxic volatile halogen elements or uneconomical organic halonium reagents, and the reagents are green and cheap; moreover, the reaction has the advantages of mild conditions, simple operation, and easy scale-up, can be compatible with unpurified primary raw materials, and is suitable for the precise late modification of complex active molecules; therefore, it has the prospect of practical application.

[0026] The inventors compared the halogenation method of the present invention with several other common aromatic ring halogenation strategies in the literature, and the results are as follows:

[0027]

[0028] When N-benzylaniline is used as the substrate and bromination reaction is carried out at room temperature (28 °C), the urea bionic catalytic aerobic oxidation bromination method adopted by the present invention can specifically generate a single target product of p-brominated with a yield of 98%, showing excellent chemoselectivity and stereoselectivity. In contrast, the aryl halogenation methods reported in other literatures can only obtain p-brominated products in medium yields, accompanied by uncontrollable o-brominated, dibrominated and oxidation side reactions, increasing the difficulty of separation and purification.

[0029] The objectives and other advantages of the present invention will be achieved by the structural features clearly pointed out in the claims and the specification. Other features and advantages will be elaborated in detail in the subsequent part of the specification, especially in the description of the embodiments. Detailed Description of the Invention

[0030] To further clarify the objectives, technical solutions and advantages of this patent, the embodiments of the present invention will be introduced in detail below. Unless otherwise specified, all raw materials and reagents required for the reaction are commercially available. And without conflict, the embodiments and the features in the embodiments can be arbitrarily combined with each other. It should be noted that the protection scope of the present invention is not limited to the following embodiments, and any technical solution implemented based on the description of the present invention belongs to the protection scope of the present invention.

[0031] Example 1: Preparation of N-benzyl-4-bromoaniline (Compound 1)

[0032]

[0033] a) Add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (also known as vitamin C) (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) into a 40 mL test tube; stir briefly to dissolve the substrates. Under room temperature conditions, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) into the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0257 g of N-benzyl-4-bromoaniline with a yield of 98%.

[0034] b) Add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) into a 40 mL test tube; stir briefly to dissolve the substrates. Under room temperature conditions, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) into the stirred reaction solution, and stir vigorously for 4 hours in open air. After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0254 g of N-benzyl-4-bromoaniline with a yield of 97%.

[0035] c) Add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), D-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) into a 40 mL test tube; stir briefly to dissolve the substrates. Under room temperature conditions, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) into the stirred reaction solution, and stir vigorously for 4 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0249 g of N-benzyl-4-bromoaniline with a yield of 95%.

[0036] d) In a 40 mL test tube, add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), calcium ascorbate (0.0853 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 4 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0217 g of N-benzyl-4-bromoaniline, with a yield of 83%.

[0037] e) In a 40 mL test tube, add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0252 g of N-benzyl-4-bromoaniline, with a yield of 92%.

[0038] f) In a 40 mL test tube, add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (0.0506 g, 0.2 mmol, 2.0 eq), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0047 g of N-benzyl-4-bromoaniline, with a yield of 18%.

[0039] g) In a 40 mL test tube, add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), N3,N5,2,6-tetramethyl-1,4-dihydropyridine-3,5-dicarboxamide (0.0446 g, 0.2 mmol, 2.0 eq), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0068 g of N-benzyl-4-bromoaniline, with a yield of 26%.

[0040] h) In a 40 mL test tube, add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), 1,1'-(2,6-dimethyl-1,4-dihydropyridine-3,5-diyl)bis(ethan-1-one) (0.0386 g, 0.2 mmol, 2.0 eq), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0063 g of N-benzyl-4-bromoaniline, with a yield of 24%.

[0041] i) In a 40 mL test tube, add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), 2-phenyl-2,3-dihydrobenzo[d]thiazole (0.0416 g, 0.2 mmol, 2.0 eq), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0029 g of N-benzyl-4-bromoaniline, with a yield of 11%.

[0042] j) In a 40 mL test tube, add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), 1,2-diphenyl-2,3-dihydro-1H-benzo[d]imidazole (0.0544 g, 0.2 mmol, 2.0 eq), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0058 g of N-benzyl-4-bromoaniline, with a yield of 22%.

[0043] k) In a 40 mL test tube, add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq), and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1-methylalloxan (0.0016 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0241 g of N-benzyl-4-bromoaniline, with a yield of 92%.

[0044] l) In a 40 mL test tube, add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq), and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-diethylalloxan (0.0020 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0252 g of N-benzyl-4-bromoaniline, with a yield of 96%.

[0045] m) In a 40 mL test tube, add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dibenzylalloxan (0.0032 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0228 g of N-benzyl-4-bromoaniline with a yield of 87%.

[0046] n) In a 40 mL test tube, add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent N,N-dimethylformamide (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0215 g of N-benzyl-4-bromoaniline with a yield of 82%.

[0047] o) In a 40 mL test tube, add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetone (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0199 g of N-benzyl-4-bromoaniline with a yield of 76%.

[0048] p) In a 40 mL test tube, add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), NaBr (0.0515 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0134 g of N-benzyl-4-bromoaniline, with a yield of 51%.

[0049] q) In a 40 mL test tube, add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), NBu4Br (0.1612 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0199 g of N-benzyl-4-bromoaniline, with a yield of 76%.

[0050] r) In a 40 mL test tube, add N-benzylaniline (0.0183 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), 55% aqueous LiBr solution (air conditioner condensate, 0.08 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0230 g of N-benzyl-4-bromoaniline, with a yield of 88%.

[0051] Product characterization: 1 H NMR (400 MHz, Chloroform-d) δ 7.42 - 7.35 (m, 4H), 7.35 - 7.30 (m, 1H), 7.27 (d, J = 8.7 Hz, 2H), 6.54 (d, J = 8.8 Hz, 2H), 4.33 (s, 2H), 4.12 (brs, 1H); 13¹³C NMR (101 MHz, Chloroform-d) δ 147.2, 139.0, 132.1, 128.8, 127.5, 127.5, 114.5, 109.2, 48.4; HRMS (ESI) m / z calculated for C 13 H 13 BrN + ([M+H]) + : 262.0226, found: 262.0238.

[0052] Example 2: Preparation of 4-Bromo-N-ethylaniline (Compound 2)

[0053]

[0054] a) In a 40 mL test tube, add N-ethylaniline (0.0183 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0198 g of 4-bromo-N-ethylaniline, with a yield of 99%.

[0055] b) In a 40 mL test tube, add N-ethylaniline (0.0183 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously for 4 hours in open air. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0194 g of 4-bromo-N-ethylaniline, with a yield of 97%.

[0056] c) In a 40 mL test tube, add N-ethylaniline (0.0183 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. Under room temperature conditions, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0192 g of 4-bromo-N-ethylaniline, with a yield of 96%.

[0057] d) In a 40 mL test tube, add N-ethylaniline (0.0183 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. Under room temperature conditions, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours in open air. After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0184 g of 4-bromo-N-ethylaniline, with a yield of 92%.

[0058] Product characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.8 Hz, 2H), 6.48 (d, J = 8.8 Hz, 2H), 3.12 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 147.5, 132.0, 114.4, 108.8, 38.6, 14.8; HRMS (ESI) m / z calculated for C8H 11 BrN + ([M + H]) + : 200.0069, found: 200.0077.

[0059] Example 3: Preparation of 6-bromo-1,2,3,4-tetrahydroquinoline (Compound 3)

[0060]

[0061] a) In a 40 mL test tube, add 1,2,3,4-tetrahydroquinoline (0.0133 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0198 g of 6-bromo-1,2,3,4-tetrahydroquinoline with a yield of 97%.

[0062] b) In a 40 mL test tube, add 1,2,3,4-tetrahydroquinoline (0.0133 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously for 4 hours in open air. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0194 g of 6-bromo-1,2,3,4-tetrahydroquinoline with a yield of 95%.

[0063] c) In a 40 mL test tube, add 1,2,3,4-tetrahydroquinoline (0.0133 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0195 g of 6-bromo-1,2,3,4-tetrahydroquinoline with a yield of 92%.

[0064] d) In a 40 mL test tube, add 1,2,3,4-tetrahydroquinoline (0.0133 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously in open air for 2 hours. After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 6-bromo-1,2,3,4-tetrahydroquinoline 0.0191 g, with a yield of 90%.

[0065] Product characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.15 - 6.90 (m, 2H), 6.34 (d, J = 8.3 Hz, 1H), 3.83 (brs, 1H), 3.42 - 3.17 (m, 2H), 2.72 (t, J = 6.4 Hz, 2H), 1.91 (dt, J = 11.9, 6.3 Hz, 2H); 13 13C NMR (101 MHz, CDCl3) δ 143.9, 132.0, 129.5, 123.5, 115.6, 108.3, 41.9, 26.9, 21.8; HRMS (ESI) m / z calculated for C9H 11 BrN + ([M + H]) + : 212.0069, found: 212.0076.

[0066] Example 4: Preparation of 4-bromo-N,N-dimethylaniline (Compound 4)

[0067]

[0068] a) In a 40 mL test tube, add N,N-dimethylaniline (0.0121 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq), and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously under an oxygen atmosphere (balloon, 1 atm) for 2 hours. After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 4-bromo-N,N-dimethylaniline 0.0198 g, with a yield of 99%.

[0069] b) In a 40 mL test tube, add N,N-dimethylaniline (0.0121 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 4 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0198 g of 4-bromo-N,N-dimethylaniline, with a yield of 99%.

[0070] c) In a 40 mL test tube, add N,N-dimethylaniline (0.0121 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in an oxygen atmosphere (balloon, 1 atm) for 2 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0194 g of 4-bromo-N,N-dimethylaniline, with a yield of 97%.

[0071] d) In a 40 mL test tube, add N,N-dimethylaniline (0.0121 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 2 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0186 g of 4-bromo-N,N-dimethylaniline, with a yield of 93%.

[0072] Product characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 9.1 Hz, 2H), 6.59 (d, J = 9.0 Hz, 2H), 2.92 (s, 6H); 13 13C NMR (101 MHz, CDCl3) δ 149.6, 131.8, 114.2, 108.6, 40.7; HRMS (ESI) m / z calculated for C8H 11 BrN +([M+H]) + : 200.0069, found: 200.0074.

[0073] Example 5: Preparation of 4-Bromo-N-ethyl-N-hydroxyethylaniline (Compound 5)

[0074]

[0075] a) In a 40 mL test tube, add N-ethyl-N-hydroxyethylaniline (0.0165 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0165 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0242 g of 4-bromo-N-ethyl-N-hydroxyethylaniline, with a yield of 99%.

[0076] b) In a 40 mL test tube, add N-ethyl-N-hydroxyethylaniline (0.0165 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 4 hours in open air. After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0237 g of 4-bromo-N-ethyl-N-hydroxyethylaniline, with a yield of 97%.

[0077] Product Characterization: 1 H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.7 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 3.94 - 3.64 (m, 2H), 3.44 (t, J = 5.7 Hz, 2H), 2.94 (s, 3H), 1.77 (brs, 1H); 13 C NMR (101 MHz, CDCl3) δ 149.1, 132.0, 114.6, 109.1, 60.2, 55.5, 39.0; HRMS (ESI) m / z calculated for C 10 H 15 BrNO + ([M+H])+ : 244.0332, found: 244.0336.

[0078] Example 6: Preparation of 4-Bromo-N-phenylpiperidine (Compound 6)

[0079]

[0080] a) In a 40 mL test tube, add N-phenylpiperidine (0.0161 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. Under room temperature conditions, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0238 g of 4-bromo-N-phenylpiperidine, with a yield of 99%.

[0081] b) In a 40 mL test tube, add N-phenylpiperidine (0.0161 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. Under room temperature conditions, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 4 hours in open air. After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0235 g of 4-bromo-N-phenylpiperidine, with a yield of 98%.

[0082] c) In a 40 mL test tube, add N-phenylpiperidine (0.0161 g, 0.1 mmol, 1.0 eq), Acerola cherry extract (containing 17% vitamin C, 0.1 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. Under room temperature conditions, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0226 g of 4-bromo-N-phenylpiperidine, with a yield of 94%.

[0083] d) In a 40 mL test tube, add N-phenylpiperidine (0.0161 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 2 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0206 g of 4-bromo-N-phenylpiperidine with a yield of 86%.

[0084] Product characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.37 - 7.27 (m, 2H), 6.84 - 6.75 (m, 2H), 3.16 - 3.09 (m, 4H), 1.73 - 1.66 (m, 4H), 1.61 - 1.54 (m, 2H); 13 13C NMR (101 MHz, CDCl3) δ 151.3, 131.9, 118.1, 111.2, 50.6, 25.8, 24.3; HRMS (ESI) m / z calculated for C 11 H 15 BrN + ([M + H]) + : 240.0382, found: 240.0388.

[0085] Example 7: Preparation of 4-bromo-2-methylaniline (Compound 7)

[0086]

[0087] a) In a 40 mL test tube, add 2-methylaniline (0.0107 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq), and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously under an oxygen atmosphere (balloon, 1 atm) for 2 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0182 g of 4-bromo-2-methylaniline with a yield of 98%.

[0088] b) In a 40 mL test tube, add 2-methylaniline (0.0107 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 4 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0180 g of 4-bromo-2-methylaniline with a yield of 97%.

[0089] Product characterization: 1 H NMR (400 MHz, CDCl3) δ 7.16 (s, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 3.59 (brs, 2H), 2.13 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 143.7, 132.9, 129.6, 124.5, 116.4, 110.1, 17.3; HRMS (ESI) m / z calculated for C7H9BrN + ([M + H]) + : 185.9913, found: 185.9915.

[0090] Example 8: Preparation of 4-bromo-2-benzyloxyaniline (Compound 8)

[0091]

[0092] a) In a 40 mL test tube, add 2-benzyloxyaniline (0.0199 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously under an oxygen atmosphere (balloon, 1 atm) for 2 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0272 g of 4-bromo-2-benzyloxyaniline with a yield of 98%.

[0093] b) In a 40 mL test tube, add 2-benzyloxyaniline (0.0199 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 4 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0264 g of 4-bromo-2-benzyloxyaniline with a yield of 95%.

[0094] Product characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.56 - 7.32 (m, 5H), 7.01 (d, J = 2.1 Hz, 1H), 6.95 (dd, J = 8.3, 2.1 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 5.04 (s, 2H), 3.84 (brs, 2H); 13 13C NMR (101 MHz, CDCl3) δ 147.0, 136.5, 135.7, 128.7, 128.3, 127.8, 124.1, 115.9, 115.2, 109.4, 70.7; HRMS (ESI) m / z calculated for C 13 H 13 BrNO + ([M + H]) + : 278.0175, found: 278.0178.

[0095] Example 9: Preparation of 4-bromo-2-methylthioaniline (Compound 9)

[0096]

[0097] In a 40 mL test tube, add 2-aminophenyl methyl sulfide (0.0139 g, 0.1 mmol, 1.0 eq), calcium ascorbate (0.0853 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0038 g, 0.02 mmol, 0.2 eq) to the stirred reaction solution and stir vigorously under an oxygen atmosphere (balloon, 1 atm) for 12 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0201 g of 4-bromo-2-methylthioaniline with a yield of 92%.

[0098] Product Characterization: 1 H NMR(400MHz,CDCl3)δ7.42(d,J=2.3Hz,1H),7.16(dd,J=8.5,2.3Hz,1H),6.59(dd,J=8.4,1.0Hz,1H),4.23(brs,2H),2.36(s,3H); 13 C NMR(101MHz,CDCl3)δ145.9,134.8,131.4,122.5,116.3,109.8,17.6;HRMS(ESI)m / z calculated forC7H9BrNS + ([M+H]) + :217.9634,found:217.9637.

[0099] Example 10: Preparation of 4-Bromo-2-fluoroaniline (Compound 10)

[0100]

[0101] Add 2-fluoroaniline (0.0111 g, 0.1 mmol, 1.0 eq), calcium ascorbate (0.0853 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) into a 40 mL test tube; stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0038 g, 0.02 mmol, 0.2 eq) into the stirred reaction solution, and stir vigorously for 12 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0148 g of 4-bromo-2-fluoroaniline with a yield of 78%.

[0102] Product Characterization: 1 H NMR(400MHz,CDCl3)δ7.14(d,J=10.5Hz,1H),7.05(d,J=8.4Hz,1H),6.71-6.57(m,1H),3.73(brs,2H); 13 C NMR(101MHz,CDCl3)δ151.5(d,J=243.3Hz),133.9(d,J=12.5Hz),127.5(d,J=3.5Hz),118.8(d,J=22.2Hz),117.9(d,J=4.7Hz),109.0(d,J=9.3Hz); 19 F NMR(376MHz,CDCl3)δ-132.3;HRMS(ESI)m / z calculated forC6H6BrFN+ ([M+H]) + : 189.9662, found: 189.9669.

[0103] Example 11: Preparation of 4-bromo-3-iodoaniline (Compound 11)

[0104]

[0105] Add 3-iodoaniline (0.0219 g, 0.1 mmol, 1.0 eq), calcium ascorbate (0.0853 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and solvent acetonitrile (4 mL) into a 40 mL test tube; stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0038 g, 0.02 mmol, 0.2 eq) into the stirred reaction solution, and stir vigorously for 12 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0274 g of 4-bromo-3-iodoaniline with a yield of 92%.

[0106] Product characterization: 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 2.7 Hz, 1H), 6.52 (dd, J = 8.6, 2.7 Hz, 1H), 3.67 (brs, 2H); 13 C NMR (101 MHz, CDCl3) δ 146.4, 132.7, 126.2, 117.2, 116.6, 101.5; HRMS (ESI) m / z calculated for C6H6BrIN + ([M+H]) + : 297.8723, found: 297.8730.

[0107] Example 12: Preparation of 2-bromo-4-methylaniline (Compound 12)

[0108]

[0109] a) 4-Methylaniline (0.0107 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) were added to a 40 mL test tube; briefly stirred to dissolve the substrates. At room temperature, 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) was added to the stirred reaction solution, and the mixture was vigorously stirred for 2 h under an oxygen atmosphere (balloon, 1 atm). After the reaction was completed, it was concentrated under reduced pressure, and purified by flash column chromatography to obtain 4-bromo-2-methylaniline 0.0153 g, with a yield of 82%.

[0110] b) 4-Methylaniline (0.0107 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) were added to a 40 mL test tube; briefly stirred to dissolve the substrates. At room temperature, 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) was added to the stirred reaction solution, and the mixture was vigorously stirred for 4 h in open air. After the reaction was completed, it was concentrated under reduced pressure, and purified by flash column chromatography to obtain 2-bromo-4-methylaniline 0.0147 g, with a yield of 79%.

[0111] Product characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 3.93 (s, 2H), 2.23 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 141.7, 132.8, 129.2, 129.1, 115.9, 109.4, 20.2; HRMS (ESI) m / z calculated for C7H9BrN + ([M + H]) + : 185.9913, found: 285.9910.

[0112] Example 13: Preparation of 2-bromo-3-methoxy-4-methylaniline (Compound 13)

[0113]

[0114] a) In a 40 mL test tube, add 3-methoxy-4-methylaniline (0.0137 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0214 g of 2-bromo-3-methoxy-4-methylaniline with a yield of 99%.

[0115] b) In a 40 mL test tube, add 3-methoxy-4-methylaniline (0.0137 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously for 4 hours in open air. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0212 g of 2-bromo-3-methoxy-4-methylaniline with a yield of 98%.

[0116] Product characterization: 1 H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 6.27 (s, 1H), 3.95 (brs, 2H), 3.75 (s, 3H), 2.09 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 157.9, 142.7, 133.4, 118.3, 99.3, 98.8, 55.5, 15.2; HRMS (ESI) m / z calculated for C8H 11 BrNO + ([M + H]) + : 216.0019, found: 216.0022.

[0117] Example 14: N-(2-amino-5-bromophenyl)acetamide (Compound 14)

[0118]

[0119] Add 2'-aminoacetanilide (0.0150 g, 0.1 mmol, 1.0 eq), calcium ascorbate (0.0853 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) into a 40 mL test tube; stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0038 g, 0.02 mmol, 0.2 eq) into the stirred reaction solution, and stir vigorously for 12 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0220 g of N-(2-amino-5-bromophenyl)acetamide with a yield of 96%.

[0120] Product characterization: 1 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.45 (s, 1H), 7.01 (dd, J = 8.5, 2.4 Hz, 1H), 6.66 (d, J = 8.5 Hz, 1H), 5.12 (s, 2H), 2.04 (s, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ 168.5, 140.9, 127.9, 126.9, 124.9, 117.1, 105.9, 23.4; HRMS (ESI) m / z calculated for C8H 10 BrN2O + ([M + H]) + : 228.9971, found: 228.9965.

[0121] Example 15: Preparation of 4-bromo-2,6-diisopropylaniline (Compound 15)

[0122]

[0123] a) Add 2,6-diisopropylaniline (0.0177 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) into a 40 mL test tube; stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) into the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0253 g of 4-bromo-2,6-diisopropylaniline with a yield of 99%.

[0124] b) 2,6 - Diisopropylaniline (0.0177 g, 0.1 mmol, 1.0 eq), L - ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) were added to a 40 mL test tube; stirred briefly to dissolve the substrates. At room temperature, 1,3 - dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) was added to the stirred reaction solution, and the mixture was vigorously stirred in open air for 4 h. After the reaction was completed, it was concentrated under reduced pressure, and purified by flash column chromatography to obtain 0.0251 g of 4 - bromo - 2,6 - diisopropylaniline, with a yield of 98%.

[0125] c) 2,6 - Diisopropylaniline (0.0177 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.) and the solvent acetonitrile (4 mL) were added to a 40 mL test tube; stirred briefly to dissolve the substrates. At room temperature, 1,3 - dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) was added to the stirred reaction solution, and the mixture was vigorously stirred under an oxygen atmosphere (balloon, 1 atm) for 2 h. After the reaction was completed, it was concentrated under reduced pressure, and purified by flash column chromatography to obtain 0.0246 g of 4 - bromo - 2,6 - diisopropylaniline, with a yield of 96%.

[0126] d) 2,6 - Diisopropylaniline (0.0177 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.) and the solvent acetonitrile (4 mL) were added to a 40 mL test tube; stirred briefly to dissolve the substrates. At room temperature, 1,3 - dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) was added to the stirred reaction solution, and the mixture was vigorously stirred in open air for 2 h. After the reaction was completed, it was concentrated under reduced pressure, and purified by flash column chromatography to obtain 0.0233 g of 4 - bromo - 2,6 - diisopropylaniline, with a yield of 91%.

[0127] Product characterization: 1 H NMR (400 MHz, CDCl3) δ 7.12 (s, 2H), 3.71 (brs, 2H), 2.88 (hept, J = 6.8 Hz, 2H), 1.26 (d, J = 6.8 Hz, 12H); 13 C NMR (101 MHz, CDCl3) δ 139.4, 134.7, 125.9, 111.3, 28.2, 22.4; HRMS (ESI) m / z calculated for C12 H 19 BrN + ([M+H]) + :256.0695, found:256.0699.

[0128] Example 16: Preparation of Methyl 4-Bromo-2-amino-6-methylbenzoate (Compound 16)

[0129]

[0130] In a 40 mL test tube, add methyl 2-amino-6-methylbenzoate (0.0165 g, 0.1 mmol, 1.0 eq), calcium ascorbate (0.0853 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0038 g, 0.02 mmol, 0.2 eq) to the stirred reaction solution, and stir vigorously for 12 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0220 g of methyl 4-bromo-2-amino-6-methylbenzoate, with a yield of 90%.

[0131] Product Characterization: 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.6 Hz, 1H), 6.42 (d, J = 8.7 Hz, 1H), 4.70 (brs, 2H), 3.90 (s, 3H), 2.42 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 169.2, 146.7, 137.8, 135.5, 117.6, 115.8, 113.6, 52.0, 22.1; HRMS (ESI) m / z calculated for C9H 11 BrNO2 + ([M+H]) + :243.9968, found:243.9972.

[0132] Example 17: Preparation of 1-Bromo-2-naphthylamine (Compound 17)

[0133]

[0134] a) In a 40 mL test tube, add 2-naphthylamine (0.0143 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0218 g of 1-bromo-2-naphthylamine, with a yield of 98%.

[0135] b) In a 40 mL test tube, add 2-naphthylamine (0.0143 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 4 hours in open air. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0215 g of 1-bromo-2-naphthylamine, with a yield of 97%.

[0136] c) In a 1000 mL beaker, add 2-naphthylamine (1.43 g, 10.0 mmol, 1.0 eq), L-ascorbic acid (3.52 g, 20.0 mmol, 2.0 eq), 55% aqueous LiBr solution (air conditioner condensate, 8.0 g, 5.0 eq. LiBr) and the solvent acetonitrile (400 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.188 g, 1.0 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 4 hours in open air. After the reaction is completed, concentrate under reduced pressure to remove the excess solvent, add 500 mL and stir for 30 min to precipitate a brown solid. Filter out the solid and wash the filter cake with water, then dry to obtain 2.15 g of 1-bromo-2-naphthylamine, with a yield of 97%.

[0137] d) In a 1000 mL beaker, add 2-naphthylamine (2.86 g, 20.0 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 20 g), LiBr (17.37 g, 200 mmol, 10.0 eq.), and the solvent acetonitrile (400 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.376 g, 2 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 4 hours. After the reaction is completed, concentrate under reduced pressure to remove the excess solvent, add 1000 mL and stir for 30 min to precipitate a brown solid. Filter out the solid and wash the filter cake with water, then dry to obtain 4.17 g of 1-bromo-2-naphthylamine with a yield of 94%.

[0138] Product characterization: 1 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.56 - 7.47 (m, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 4.35 (brs, 2H); 13 13C NMR (101 MHz, CDCl3) δ 142.2, 133.2, 128.7, 128.2, 127.8, 125.0, 123.0, 117.8, 104.1; HRMS (ESI) m / z calculated for C 10 H9BrN + ([M + H]) + : 221.9913, found: 221.9921.

[0139] Example 18: Preparation of 5-bromo-6-aminoquinoxaline (Compound 18)

[0140]

[0141] a) In a 40 mL test tube, add 6-aminoquinoxaline (0.0145 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq), and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously under an oxygen atmosphere (balloon, 1 atm) for 4 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0220 g of 1-bromo-6-aminoquinoxaline with a yield of 98%.

[0142] b) In a 40 mL test tube, add 6 - aminoquinoxaline (0.0145 g, 0.1 mmol, 1.0 eq), L - ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3 - dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 4 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0193 g of 5 - bromo - 6 - aminoquinoxaline with a yield of 86%.

[0143] Product characterization: 1 H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 1.9 Hz, 1H), 8.59 (d, J = 1.9 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 4.81 (brs, 2H); 13 C NMR (101 MHz, CDCl3) δ 146.1, 145.4, 142.3, 141.3, 138.8, 129.6, 121.5, 102.9; HRMS (ESI) m / z calculated for C8H7BrN3 + ([M + H]) + : 223.9818, found: 223.9824.

[0144] Example 19: Preparation of 4 - bromo - 2,3,6 - trimethylphenol (Compound 19)

[0145]

[0146] In a 40 mL test tube, add 2,3,6 - trimethylphenol (0.0136 g, 0.1 mmol, 1.0 eq), calcium ascorbate (0.0853 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3 - dimethylalloxan (0.0038 g, 0.02 mmol, 0.2 eq) to the stirred reaction solution and stir vigorously under an oxygen atmosphere (balloon, 1 atm) for 12 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0198 g of 4 - bromo - 2,3,6 - trimethylphenol with a yield of 92%.

[0147] Product characterization: 11H NMR (400 MHz, CDCl3) δ 6.57 (s, 1H), 4.69 (s, 1H), 2.40 (s, 3H), 2.34 (s, 3H), 2.21 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 152.2, 137.8, 136.1, 121.6, 119.2, 115.0, 24.1, 20.6, 12.9; HRMS (ESI) m / z calculated for C9H 12 BrO + ([M + H]) + : 215.0066, found: 215.0061.

[0148] Example 20: Preparation of 1 - bromo - 2,7 - dihydroxynaphthalene (Compound 20)

[0149]

[0150] Add 2,7 - dihydroxynaphthalene (0.0160 g, 0.1 mmol, 1.0 eq), calcium ascorbate (0.0853 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and solvent acetonitrile (4 mL) into a 40 mL test tube; stir briefly to dissolve the substrate. At room temperature, add 1,3 - dimethylalloxan (0.0038 g, 0.02 mmol, 0.2 eq) into the stirred reaction solution, and stir vigorously for 12 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0239 g of 1 - bromo - 2,7 - dihydroxynaphthalene, with a yield of 87%.

[0151] Product characterization: 1 1H NMR (400 MHz, DMSO - d6) δ 10.33 (s, 1H), 9.92 (s, 1H), 7.66 (dd, J = 13.7, 8.8 Hz, 2H), 7.29 (d, J = 2.3 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 6.89 (dd, J = 8.7, 2.3 Hz, 1H); 13 13C NMR (101 MHz, DMSO - d6) δ 157.1, 152.6, 134.6, 130.1, 128.6, 123.2, 115.8, 114.7, 106.8, 102.6; HRMS (ESI) m / z calculated for C 10 H8BrO2 + ([M + H]) +: 238.9702, found: 238.9705.

[0152] Example 21: Preparation of 2-bromo-1,3,5-trimethoxybenzene (Compound 21)

[0153]

[0154] Add 1,3,5-trimethoxybenzene (0.0168 g, 0.1 mmol, 1.0 eq), calcium ascorbate (0.0853 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) into a 40 mL test tube; stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0038 g, 0.02 mmol, 0.2 eq) into the stirred reaction solution, and stir vigorously for 12 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0242 g of 2-bromo-1,3,5-trimethoxybenzene with a yield of 98%.

[0155] Product characterization: 1 H NMR (400 MHz, CDCl3) δ 6.16 (s, 2H), 3.86 (s, 6H), 3.81 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 160.6, 157.6, 92.1, 91.7, 56.5, 55.6; HRMS (ESI) m / z calculated for C9H 12 BrO3 + ([M + H]) + : 246.9964, found: 246.9969.

[0156] Example 22: Preparation of 3-bromo-1-methylindole (Compound 22)

[0157]

[0158] a) In a 40 mL test tube, add 1-methylindole (0.0131 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. Under room temperature conditions, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0206 g of 3-bromo-1-methylindole, with a yield of 98%.

[0159] b) In a 40 mL test tube, add 1-methylindole (0.0131 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. Under room temperature conditions, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 4 hours in open air. After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0200 g of 3-bromo-1-methylindole, with a yield of 95%.

[0160] Product characterization: 1 H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.8 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.27 - 7.22 (m, 1H), 7.07 (s, 1H), 3.76 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 136.3, 127.8, 127.3, 122.7, 120.2, 119.3, 109.6, 89.4, 33.1; HRMS (ESI) m / z calculated for C9H9BrN + ([M + H]) + : 209.9913, found: 209.9920.

[0161] Example 23: Preparation of 3-bromo-indole (Compound 23)

[0162]

[0163] a) In a 40 mL test tube, add indole (0.0117 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously for 4 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0192 g of 3-bromo-indole with a yield of 98%.

[0164] b) In a 40 mL test tube, add indole (0.0117 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously for 4 hours in open air. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0192 g of 3-bromo-indole with a yield of 98%.

[0165] Product characterization: 1 H NMR (400 MHz, CDCl3) δ 8.15 (brs, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.31 - 7.19 (m, 3H); 13 C NMR (101 MHz, CDCl3) δ 135.4, 127.0, 123.4, 123.3, 120.8, 119.3, 111.5, 91.8; HRMS (ESI) m / z calculated for C8H7BrN + ([M + H]) + : 195.9756, found: 195.9762.

[0166] Example 24: Preparation of 3-bromo-2-phenylindole (Compound 24)

[0167]

[0168] Add 2-phenylindole (0.0193 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) into a 40 mL test tube; stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) into the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0269 g of 3-bromo-2-phenylindole with a yield of 99%.

[0169] Product characterization: 1 H NMR (400 MHz, CDCl3) δ 8.28 (brs, 1H), 7.87 - 7.79 (m, 2H), 7.64 (dd, J = 7.3, 1.7 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.46 - 7.37 (m, 2H), 7.30 - 7.21 (m, 2H); 13 C NMR (101 MHz, CDCl3) δ 135.4, 134.4, 131.5, 129.0, 128.9, 128.5, 127.9, 123.6, 121.0, 119.6, 111.2, 90.2; HRMS (ESI) m / z calculated for C 14 H 11 BrN + ([M + H]) + : 272.0069, found: 272.0075.

[0170] Example 25: Preparation of 3-bromo-5-benzyloxyindole (Compound 25)

[0171]

[0172] a) Add 5-benzyloxyindole (0.0223 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) into a 40 mL test tube; stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) into the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0299 g of 3-bromo-5-benzyloxyindole with a yield of 99%.

[0173] b) In a 40 mL test tube, add 5-benzyloxyindole (0.0223 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 4 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0299 g of 3-bromo-5-benzyloxyindole, with a yield of 99%.

[0174] c) In a 40 mL test tube, add 5-benzyloxyindole (0.0223 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously under an oxygen atmosphere (balloon, 1 atm) for 2 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0296 g of 3-bromo-5-benzyloxyindole, with a yield of 98%.

[0175] d) In a 40 mL test tube, add 5-benzyloxyindole (0.0223 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 2 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0263 g of 3-bromo-5-benzyloxyindole, with a yield of 87%.

[0176] Product characterization: 1 H NMR (400 MHz, CDCl3) δ 8.09 (brs, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.50 - 7.34 (m, 3H), 7.29 - 7.07 (m, 3H), 7.02 (dd, J = 8.9, 2.5 Hz, 1H), 5.16 (s, 2H); 1313C NMR (101 MHz, CDCl3) δ 154.1, 137.3, 130.5, 128.7, 128.1, 127.9, 127.3, 124.2, 114.5, 112.5, 101.9, 91.1, 70.9; HRMS (ESI) m / z calculated for C 15 H 13 BrN + ([M + H]) + : 302.0175, found: 302.0191.

[0177] Example 26: Preparation of 3-Bromo-5-nitroindole (Compound 26)

[0178]

[0179] 5-Nitroindole (0.0162 g, 0.1 mmol, 1.0 eq), calcium ascorbate (0.0853 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) were added to a 40 mL test tube; briefly stirred to dissolve the substrate. At room temperature, 1,3-dimethylalloxan (0.0038 g, 0.02 mmol, 0.2 eq) was added to the stirred reaction solution, and the mixture was vigorously stirred for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction was completed, it was concentrated under reduced pressure, and 3-bromo-5-nitroindole 0.0224 g was obtained by rapid column chromatography purification with a yield of 93%.

[0180] Product characterization: 1 1H NMR (400 MHz, DMSO-d6) δ 12.19 (brs, 1H), 8.27 (d, J = 2.3 Hz, 1H), 8.04 (dd, J = 8.9, 2.2 Hz, 1H), 7.84 (s, 1H), 7.60 (d, J = 9.0 Hz, 1H); 13 13C NMR (101 MHz, DMSO-d6) δ 141.3, 138.5, 129.0, 125.6, 117.4, 114.9, 112.9, 91.0; HRMS (ESI) m / z calculated for C8H6BrN2O2 + ([M + H]) + : 240.9607, found: 240.9608.

[0181] Example 27: Preparation of Methyl 3-Bromoindole-5-carboxylate (Compound 27)

[0182]

[0183] a) In a 40 mL test tube, add methyl indole-5-carboxylate (0.0175 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. Under room temperature conditions, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0251 g of methyl 3-bromoindole-5-carboxylate, with a yield of 99%.

[0184] b) In a 40 mL test tube, add methyl indole-5-carboxylate (0.0175 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. Under room temperature conditions, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 4 hours in open air. After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0231 g of methyl 3-bromoindole-5-carboxylate, with a yield of 91%.

[0185] Product characterization: 1 H NMR (400 MHz, DMSO-d6) δ 11.88 (brs, 1H), 8.10 (s, 1H), 7.80 (dd, J = 8.6, 1.6 Hz, 1H), 7.76 - 7.64 (m, 1H), 7.53 (d, J = 8.6 Hz, 1H), 3.86 (s, 3H); 13 C NMR (101 MHz, DMSO-d6) δ 166.8, 138.0, 126.9, 125.9, 123.0, 121.5, 120.5, 112.3, 90.1, 51.9; HRMS (ESI) m / z calculated for C 10 H9BrNO2 + ([M + H]) + : 253.9811, found: 253.9822.

[0186] Example 28: Preparation of 3-bromo-7-indolecarboxylic acid (Compound 28)

[0187]

[0188] In a 40 mL test tube, add 7-indolecarboxylic acid (0.0161 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0238 g of 3-bromo-7-indolecarboxylic acid with a yield of 99%.

[0189] Product characterization: 1 1H NMR (400 MHz, DMSO-d6) δ 13.24 (brs, 1H), 11.39 (brs, 1H), 7.85 (t, J = 6.7 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.62 - 7.45 (m, 1H), 7.23 (t, J = 7.7 Hz, 1H); 13 13C NMR (101 MHz, DMSO-d6) δ 167.5, 134.1, 127.7, 126.4, 125.2, 123.6, 119.5, 114.4, 89.5; HRMS (ESI) m / z calculated for C9H7BrNO2 + ([M + H]) + : 239.9655, found: 239.9658.

[0190] Example 29: Preparation of 3-bromo-7-azaindole (Compound 29)

[0191]

[0192] In a 40 mL test tube, add 7-azaindole (0.0118 g, 0.1 mmol, 1.0 eq), calcium ascorbate (0.0853 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0038 g, 0.02 mmol, 0.2 eq) to the stirred reaction solution, and stir vigorously for 12 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0189 g of 3-bromo-7-azaindole with a yield of 96%.

[0193] Product characterization: 11H NMR (400 MHz, DMSO-d6) δ 12.09 (brs, 1H), 8.29 (dd, J = 4.7, 1.6 Hz, 1H), 7.83 (dd, J = 7.9, 1.6 Hz, 1H), 7.71 (s, 1H), 7.16 (dd, J = 7.9, 4.7 Hz, 1H); 13 13C NMR (101 MHz, DMSO-d6) δ 147.2, 143.9, 126.4, 125.6, 118.7, 116.3, 87.2; HRMS (ESI) m / z calculated for C7H6BrN2 + ([M + H]) + : 196.9709, found: 196.9713.

[0194] Example 30: Preparation of 4-bromo-1-methyl-1H-benzo[d]imidazol-5-amine (Compound 30)

[0195]

[0196] a) In a 40 mL test tube, add 1-methyl-1H-benzo[d]imidazol-5-amine (0.0147 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0217 g of 4-bromo-1-methyl-1H-benzo[d]imidazol-5-amine, with a yield of 96%.

[0197] b) In a 40 mL test tube, add 1-methyl-1H-benzo[d]imidazol-5-amine (0.0147 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 4 hours in open air. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0197 g of 4-bromo-1-methyl-1H-benzo[d]imidazol-5-amine, with a yield of 87%.

[0198] Product characterization: 11H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 3.95 (brs, 2H), 3.70 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 143.5, 143.2, 139.9, 128.3, 113.1, 109.0, 98.7, 31.3; HRMS (ESI) m / z calculated for C8H9BrN3 + ([M + H]) + : 225.9974, found: 225.9979.

[0199] Example 31: Preparation of 4 - bromo - julolidine (Compound 31)

[0200]

[0201] a) Add julolidine (0.0173 g, 0.1 mmol, 1.0 eq), L - ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and solvent acetonitrile (4 mL) to a 40 mL test tube; stir briefly to dissolve the substrate. At room temperature, add 1,3 - dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0249 g of 4 - bromo - julolidine, with a yield of 99%.

[0202] b) Add julolidine (0.0173 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.) and solvent acetonitrile (4 mL) to a 40 mL test tube; stir briefly to dissolve the substrate. At room temperature, add 1,3 - dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0245 g of 4 - bromo - julolidine, with a yield of 97%.

[0203] c) In a 40 mL test tube, add julolidine (0.0173 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 2 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 4-bromo-julolidine 0.0240 g, with a yield of 95%.

[0204] Product characterization: 1 H NMR (400 MHz, CDCl3) δ 6.88 (s, 2H), 3.17 - 3.06 (m, 4H), 2.71 (t, J = 6.5 Hz, 4H), 1.94 (dt, J = 12.8, 6.3 Hz, 4H); 13 C NMR (101 MHz, CDCl3) δ 142.0, 129.3, 123.7, 107.3, 50.0, 27.6, 21.9; HRMS (ESI) m / z calculated for C 12 H 15 BrN + ([M + H]) + : 252.0382, found: 252.0391.

[0205] Example 32: Preparation of 9-bromovindoline (Compound 32)

[0206]

[0207] a) In a 40 mL test tube, add vindoline (0.0456 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq), and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously under an oxygen atmosphere (balloon, 1 atm) for 2 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 9-bromovindoline 0.0524 g, with a yield of 98%.

[0208] b) Add vindoline (1.00 g, 2.2 mmol, 1.0 eq), L-ascorbic acid (1.55 g, 8.8 mmol, 4.0 eq), LiBr (1.91 g, 22 mmol, 10.0 eq) and the solvent acetonitrile (40 mL) into a 1000 mL round-bottom flask; stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.042 g, 0.22 mmol, 0.1 eq) into the stirred reaction solution and stir vigorously in the open air for 1 hour. After the reaction is completed, add 500 mL of water, continue to stir for 30 min to precipitate a white solid. Filter out the solid and wash the filter cake with water, then dry to obtain 1.15 g of 9-bromo-vindoline with high purity, and the yield is 98%.

[0209] c) Add vindoline (0.0456 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.2 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.) and the solvent acetonitrile (4 mL) into a 40 mL test tube; stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) into the stirred reaction solution and stir vigorously under an oxygen atmosphere (balloon, 1 atm) for 2 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0525 g of 9-bromo-vindoline, and the yield is 98%.

[0210] d) Add vindoline (0.0456 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.2 g), LiBr (0.0870 g, 1.0 mmol, 10.0 eq.) and the solvent acetonitrile (4 mL) into a 40 mL test tube; stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) into the stirred reaction solution and stir vigorously in the open air for 2 hours. After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0519 g of 9-bromo-vindoline, and the yield is 97%.

[0211] Product characterization: 11H NMR (400 MHz, CDCl3) δ 9.51 (brs, 1H), 7.09 (s, 1H), 6.08 (s, 1H), 5.85 (dd, J = 10.6, 4.6 Hz, 1H), 5.42 (s, 1H), 5.22 (d, J = 10.2 Hz, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 3.74 (s, 1H), 3.54 - 3.31 (m, 2H), 2.81 (d, J = 16.1 Hz, 1H), 2.67 (s, 3H), 2.62 (s, 1H), 2.51 (q, J = 9.5 Hz, 1H), 2.37 - 2.21 (m, 2H), 2.06 (s, 3H), 1.68 - 1.61 (m, 1H), 1.14 - 0.99 (m, 1H), 0.51 (t, J = 7.3 Hz, 3H); 3 13C NMR (101 MHz, CDCl3) δ 171.9, 170.9, 156.9, 153.1, 130.4, 126.5, 126.1, 124.3, 100.0, 94.5, 83.5, 79.6, 76.3, 67.2, 56.4, 52.9, 52.4, 52.0, 51.2, 44.1, 43.0, 38.5, 31.1, 21.2, 7.7; HRMS (ESI) m / z calculated for C 25 H 32 BrN2O6 + ([M + H]) + : 535.1438, found: 535.1439.

[0212] Example 33: Preparation of 4 - Bromo - N - ethyl - N - (2 - hydroxy - 3 - sulfopropyl) - 3 - methylaniline (Compound 33)

[0213]

[0214] In a 40 mL test tube, add sodium N-ethyl-N-(2-hydroxy-3-sulfopropyl)-3-methylaniline (TOOS) (0.0295 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0342 g of 4-bromo-N-ethyl-N-(2-hydroxy-3-sulfopropyl)-3-methylaniline, with a yield of 97%.

[0215] Product characterization: 1 1H NMR (400 MHz, DMSO-d6) δ 7.21 (d, J = 8.9 Hz, 1H), 6.71 (d, J = 3.1 Hz, 1H), 6.48 (dd, J = 9.0, 3.2 Hz, 1H), 5.04 (d, J = 2.8 Hz, 1H), 4.14 - 3.94 (m, 1H), 3.52 - 3.35 (m, 3H), 3.13 (dd, J = 14.9, 7.3 Hz, 1H), 2.70 - 2.50 (m, 5H), 2.24 (s, 3H), 1.03 (t, J = 6.9 Hz, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ 147.4, 137.0, 132.0, 114.2, 111.4, 108.5, 66.0, 55.6, 55.2, 45.0, 22.9, 11.3; HRMS (ESI) m / z calculated for C 12 H 18 BrNNaO4S + ([M+Na]) + : 374.0032, found: 374.0041.

[0216] Example 34: Preparation of 5-bromo-N-hydroxyethyl-3,3-dimethyl-6-nitroindolinospiropyran (Compound 34)

[0217]

[0218] Add N-hydroxyethyl-3,3-dimethyl-6-nitroindolinospiropyran (0.0352 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) into a 40 mL test tube; stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) into the stirred reaction solution, and stir vigorously for 2 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0392 g of 5-bromo-N-hydroxyethyl-3,3-dimethyl-6-nitroindolinospiropyran, with a yield of 91%.

[0219] Product characterization: 1 H NMR (400 MHz, CDCl3) δ 8.07 - 7.94 (m, 2H), 7.29 - 7.26 (m, 1H), 7.16 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 10.4 Hz, 1H), 6.76 (d, J = 8.9 Hz, 1H), 6.55 (d, J = 8.3 Hz, 1H), 5.86 (d, J = 10.3 Hz, 1H), 3.81 - 3.67 (m, 2H), 3.48 - 3.38 (m, 1H), 3.34 - 3.23 (m, 1H), 1.61 (brs, 1H), 1.26 (s, 3H), 1.19 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 159.1, 146.3, 141.4, 138.3, 130.6, 128.7, 126.2, 125.3, 123.0, 121.5, 118.5, 115.6, 111.8, 108.6, 106.7, 61.0, 53.0, 46.2, 25.9, 20.0; HRMS (ESI) m / z calculated for C 20 H 20 BrN2O4 + ([M + H]) + : 431.0601, found: 431.0612.

[0220] Example 35: Preparation of 4-bromo-benzoaza-15-crown-5 (Compound 35)

[0221]

[0222] Add benzoaza-15-crown-5 (0.0295 g, 0.1 mmol, 1.0 eq), calcium ascorbate (0.0853 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) into a 40 mL test tube; stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0038 g, 0.02 mmol, 0.2 eq) into the stirred reaction solution, and stir vigorously for 12 h under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0370 g of 4-bromo-benzoaza-15-crown-5 with a yield of 99%.

[0223] Product characterization: 1 H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.8 Hz, 2H), 6.52 (d, J = 9.1 Hz, 2H), 3.72 (t, J = 6.2 Hz, 4H), 3.70 - 3.59 (m, 12H), 3.55 (t, J = 6.2 Hz, 4H); 13 C NMR (101 MHz, CDCl3) δ 146.7, 132.0, 113.2, 107.7, 71.5, 70.3, 70.2, 68.5, 52.7; HRMS (ESI) m / z calculated for C 16 H 25 BrNO4 + ([M + H]) + : 374.0961, found: 374.0962.

[0224] Example 36: Preparation of 4-bromo-3,8-diamino-6-phenylphenanthridine (Compound 36)

[0225]

[0226] Add 3,8-diamino-6-phenylphenanthridine (0.0285 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0352 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) into a 40 mL test tube; stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) into the stirred reaction solution, and stir vigorously for 4 h under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure and purify by flash column chromatography to obtain 0.0328 g of 4-bromo-N-ethylaniline with a yield of 90%.

[0227] Product Characterization: 1 H NMR(400MHz,DMSO-d6)δ8.41(dd,J=9.0,2.3Hz,1H),8.33(dd,J=9.0,2.6Hz,1H),7.76-7.64(m,2H),7.64-7.47(m,3H),7.31-7.13(m,2H),7.13-6.92(m,1H),5.67-5.51(m,2H),3.38-3.35(m,2H); 13 C NMR(101MHz,DMSO-d6)δ159.5,147.1,145.2,140.3,139.7,129.6,128.3,128.2,124.6,124.6,122.8,121.4,121.1,117.2,116.4,107.4,106.0;HRMS(ESI)m / z calculated for C 19 H 15 BrN3 + ([M+H]) + :364.0444,found:364.0453.

[0228] Example 37: Preparation of 4-Bromo-xanthotoxin (Compound 37)

[0229]

[0230] Add xanthotoxin(0.0202g,0.1mmol,1.0eq),calcium ascorbate(0.0853g,0.2mmol,2.0eq),LiBr(0.0435g,0.5mmol,5.0eq) and solvent acetonitrile(4mL) into a 40mL test tube; Stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan(0.0038g,0.02mmol,0.2eq) into the stirred reaction solution, and stir vigorously for 12 hours under an oxygen atmosphere(balloon,1atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0267g of 4-bromo-xanthotoxin, with a yield of 95%.

[0231] Product Characterization: 1 H NMR(400MHz,DMSO-d6)δ10.98(brs,1H),8.19(d,J=2.2Hz,1H),8.14(d,J=9.9Hz,1H),6.98(d,J=2.2Hz,1H),6.53(d,J=9.8Hz,1H); 1313C NMR(101MHz,DMSO-d6)δ159.4,148.4,144.5,142.8,140.6,130.2,126.8,115.8,115.1,107.1,100.7;HRMS(ESI)m / z calculated for C 11 H6BrO4 + ([M+H]) + :280.9444,found:280.9456.

[0232] Example 38: Preparation of 3-Bromo-7-diethylamino-4-methylcoumarin (Compound 38)

[0233]

[0234] In a 40 mL test tube, 7-diethylamino-4-methylcoumarin (0.0231 g, 0.1 mmol, 1.0 eq), calcium ascorbate (0.0853 g, 0.2 mmol, 2.0 eq), LiBr (0.0435 g, 0.5 mmol, 5.0 eq) and the solvent acetonitrile (4 mL) were added; the substrate was dissolved by brief stirring. At room temperature, 1,3-dimethylalloxan (0.0038 g, 0.02 mmol, 0.2 eq) was added to the stirred reaction solution, and the mixture was vigorously stirred for 12 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction was completed, it was concentrated under reduced pressure, and purified by flash column chromatography to obtain 0.0285 g of 3-bromo-7-diethylamino-4-methylcoumarin, with a yield of 92%.

[0235] Product characterization: 1 1H NMR(400MHz,CDCl3)δ7.40(d,J=9.0Hz,1H),6.59(dd,J=9.1,2.6Hz,1H),6.46(d,J=2.6Hz,1H),3.40(q,J=7.1Hz,4H),2.51(s,3H),1.20(t,J=7.1Hz,6H); 13 13C NMR(101MHz,CDCl3)δ158.3,154.6,151.6,150.7,126.2,109.1,109.0,105.7,97.4,44.9,19.2,12.5;HRMS(ESI)m / z calculated for C 14 H 17 BrNO2 + ([M+H]) + :310.0437,found:310.0446.

[0236] Example 39: Preparation of 4-Iodo-N,N-Dimethylaniline (Compound 39)

[0237]

[0238] a) In a 10 mL test tube, add N,N-dimethylaniline (0.0121 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0211 g, 0.12 mmol, 1.2 eq), LiI (0.134 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (1 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 2 hours. After the reaction is completed, add 10 mL of water and stir for 30 min to quench the reaction, extract with ethyl acetate (5 mL × 3), wash the organic phase successively with saturated Na2SO3 and brine solutions, dry over Na2SO4, concentrate under reduced pressure to remove the solvent, and purify by flash column chromatography to obtain 0.0242 g of 4-iodo-N,N-dimethylaniline with a yield of 98%.

[0239] b) In a 10 mL test tube, add N,N-dimethylaniline (0.0121 g, 0.1 mmol, 1.0 eq), LiI (0.134 g, 1.0 mmol, 10.0 eq.), acetic acid (20 μL), and the solvent acetonitrile (2 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0038 g, 0.02 mmol, 0.2 eq) to the stirred reaction solution and stir vigorously in open air for 2 hours. After the reaction is completed, add 10 mL of water and stir for 30 min to quench the reaction, extract with ethyl acetate (5 mL × 3), wash the organic phase successively with saturated Na2SO3 and brine solutions, dry over Na2SO4, concentrate under reduced pressure to remove the solvent, and purify by flash column chromatography to obtain 0.0227 g of 4-iodo-N,N-dimethylaniline with a yield of 92%.

[0240] c) In a 10 mL test tube, add N,N-dimethylaniline (0.0121 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiI (0.134 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (1 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously in open air for 2 hours. After the reaction is completed, add 10 mL of water and stir for 30 min to quench the reaction. Extract with ethyl acetate (5 mL × 3). Wash the organic phase successively with saturated Na2SO3 and brine solutions, dry over Na2SO4, concentrate under reduced pressure to remove the solvent, and purify by flash column chromatography to obtain 0.0240 g of 4-iodo-N,N-dimethylaniline with a yield of 91%.

[0241] d) In a 1000 mL beaker, add N,N-dimethylaniline (6.10 g, 50 mmol, 1 eq), L-ascorbic acid (10.57 g, 60 mmol, 1.2 eq), LiI (66.93 g, 500 mmol, 10 eq), and the solvent acetonitrile (500 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.94 g, 5.0 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously in open air for 2 hours. After the reaction is completed, pour it into 5000 mL of water and continue to stir for 30 min to precipitate a white solid. Filter out the precipitate, wash the filter cake with water, and dry to obtain 11.31 g of 4-iodo-N,N-dimethylaniline with a yield of 92%.

[0242] Product characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 9.0 Hz, 2H), 6.50 (d, J = 9.0 Hz, 2H), 2.93 (s, 6H); 13 13C NMR (101 MHz, CDCl3) δ 150.1, 137.7, 114.9, 77.6, 40.5; HRMS (ESI) m / z calculated for C8H 11 IN + ([M + H]) + : 247.9931, found: 247.9936.

[0243] Example 40: Preparation of 4-iodo-N-phenylpiperidine (Compound 40)

[0244]

[0245] Add N-phenylpiperidine (0.0161 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0211 g, 0.12 mmol, 1.2 eq), LiI (0.134 g, 1.0 mmol, 10.0 eq.) and the solvent acetonitrile (1 mL) into a 10 mL test tube; stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) into the stirred reaction solution, and stir vigorously in the open air for 2 hours. After the reaction is completed, add 10 mL of water and stir for 30 min to quench the reaction, extract with ethyl acetate (5 mL×3), wash the organic phase successively with saturated Na2SO3 and brine solutions, dry over Na2SO4, concentrate under reduced pressure to remove the solvent, and purify by flash column chromatography to obtain 0.0276 g of 4-bromoiodo-N-phenylpiperidine with a yield of 96%.

[0246] Product characterization: 1 H NMR (400 MHz, CDCl3) δ 7.54 - 7.43 (m, 2H), 6.72 - 6.66 (m, 2H), 3.16 - 3.10 (m, 4H), 1.73 - 1.65 (m, 4H), 1.60 - 1.55 (m, 2H); 13 C NMR (101 MHz, CDCl3) δ 151.8, 137.8, 118.6, 80.6, 50.3, 25.7, 24.3; HRMS (ESI) m / z calculated for C 11 H 15 IN + ([M + H]) + : 288.0244, found: 288.0249.

[0247] Example 41: Preparation of 4-iodo-N-ethylaniline (Compound 41)

[0248]

[0249] a) In a 10 mL test tube, add N-ethylaniline (0.0121 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0211 g, 0.12 mmol, 1.2 eq), LiI (0.134 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (1 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 2 hours. After the reaction is completed, add 10 mL of water and stir for 30 min to quench the reaction, extract with ethyl acetate (5 mL × 3), wash the organic phase successively with saturated Na2SO3 and brine solutions, dry over Na2SO4, concentrate under reduced pressure to remove the solvent, and purify by flash column chromatography to obtain 0.0230 g of 4-iodo-N-ethylaniline, with a yield of 93%.

[0250] b) In a 10 mL test tube, add N-ethylaniline (0.0121 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiI (0.134 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (1 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 2 hours. After the reaction is completed, add 10 mL of water and stir for 30 min to quench the reaction, extract with ethyl acetate (5 mL × 3), wash the organic phase successively with saturated Na2SO3 and brine solutions, dry over Na2SO4, concentrate under reduced pressure to remove the solvent, and purify by flash column chromatography to obtain 0.0240 g of 4-iodo-N-ethylaniline, with a yield of 91%.

[0251] Product characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.7 Hz, 2H), 6.38 (d, J = 8.8 Hz, 2H), 3.59 (brs, 1H), 3.12 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.2 Hz, 4H); 13 13C NMR (101 MHz, CDCl3) δ 148.1, 137.9, 115.0, 77.7, 38.4, 14.8; HRMS (ESI) m / z calculated for C8H 11 IN + ([M + H]) + : 247.9931, found: 247.9935.

[0252] Example 42: Preparation of 4-Iodo-1,2,3,4-tetrahydroquinoline (Compound 42)

[0253]

[0254] Add 1,2,3,4-tetrahydroquinoline (0.0133 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0211 g, 0.12 mmol, 1.2 eq), LiI (0.134 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (1 mL) to a 10 mL test tube; stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 2 hours. After the reaction is completed, add 10 mL of water and stir for 30 min to quench the reaction. Extract with ethyl acetate (5 mL × 3). Wash the organic phase successively with saturated Na2SO3 and brine solutions, dry over Na2SO4, concentrate under reduced pressure to remove the solvent, and purify by flash column chromatography to obtain 0.0228 g of 4-iodo-1,2,3,4-tetrahydroquinoline with a yield of 88%.

[0255] Product characterization: 1 H NMR (400 MHz, CDCl3) δ 7.26 - 7.09 (m, 2H), 6.24 (d, J = 8.3 Hz, 1H), 3.85 (brs, 1H), 3.34 - 3.24 (m, 2H), 2.71 (t, J = 6.4 Hz, 2H), 1.90 (p, J = 6.1 Hz, 2H); 13 C NMR (101 MHz, CDCl3) δ 144.5, 137.8, 135.3, 124.1, 116.2, 77.3, 41.8, 26.8, 21.7; HRMS (ESI) m / z calculated for C9H 11 IN + ([M + H]) + : 259.9931, found: 259.9935.

[0256] Example 43: Preparation of 4-Iodo-2,6-diisopropylaniline (Compound 43)

[0257]

[0258] a) In a 10 mL test tube, add 2,6 - diisopropyl aniline (0.0177 g, 0.1 mmol, 1.0 eq), L - ascorbic acid (0.0211 g, 0.12 mmol, 1.2 eq), LiI (0.134 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (1 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3 - dimethyl alloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 2 hours. After the reaction is completed, add 10 mL of water and stir for 30 min to quench the reaction, extract with ethyl acetate (5 mL × 3), wash the organic phase successively with saturated Na2SO3 and brine solutions, dry over Na2SO4, concentrate under reduced pressure to remove the solvent, and purify by flash column chromatography to obtain 0.0291 g of 4 - iodo - 2,6 - diisopropyl aniline, with a yield of 96%.

[0259] b) In a 10 mL test tube, add 2,6 - diisopropyl aniline (0.0177 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiI (0.134 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (1 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3 - dimethyl alloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 2 hours. After the reaction is completed, add 10 mL of water and stir for 30 min to quench the reaction, extract with ethyl acetate (5 mL × 3), wash the organic phase successively with saturated Na2SO3 and brine solutions, dry over Na2SO4, concentrate under reduced pressure to remove the solvent, and purify by flash column chromatography to obtain 0.0279 g of 4 - iodo - 2,6 - diisopropyl aniline, with a yield of 92%.

[0260] Product characterization: 1 1H NMR (600 MHz, CDCl3) δ 7.28 (s, 2H), 3.74 (brs, 2H), 2.85 (hept, J = 6.8 Hz, 2H), 1.25 (d, J = 6.8 Hz, 12H); 13 13C NMR (151 MHz, CDCl3) δ 140.2, 135.1, 131.8, 81.2, 28.0, 22.4; HRMS (ESI) m / z calculated for C 12 H 19 IN + ([M + H]) + : 304.0557, found: 304.0553.

[0261] Example 44: Preparation of 1-Iodo-2-naphthylamine (Compound 44)

[0262]

[0263] a) In a 10 mL test tube, add 2-naphthylamine (0.0143 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0211 g, 0.12 mmol, 1.2 eq), LiI (0.134 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (1 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously in open air for 2 hours. After the reaction is completed, add 10 mL of water and stir for 30 min to quench the reaction. Extract with ethyl acetate (5 mL × 3). Wash the organic phase successively with saturated Na2SO3 and brine solutions, dry over Na2SO4, concentrate under reduced pressure to remove the solvent, and purify by flash column chromatography to obtain 0.0245 g of 1-iodo-2-naphthylamine, with a yield of 91%.

[0264] b) In a 10 mL test tube, add 2-naphthylamine (0.0143 g, 0.1 mmol, 1.0 eq), acerola cherry extract (containing 17% vitamin C, 0.1 g), LiI (0.134 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (1 mL); stir briefly to dissolve the substrates. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution, and stir vigorously in open air for 2 hours. After the reaction is completed, add 10 mL of water and stir for 30 min to quench the reaction. Extract with ethyl acetate (5 mL × 3). Wash the organic phase successively with saturated Na2SO3 and brine solutions, dry over Na2SO4, concentrate under reduced pressure to remove the solvent, and purify by flash column chromatography to obtain 0.0229 g of 1-iodo-2-naphthylamine, with a yield of 85%.

[0265] Product Characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.58 - 7.49 (m, 1H), 7.37 - 7.27 (m, 1H), 6.96 (dd, J = 8.8, 1.8 Hz, 1H), 4.45 (brs, 2H); 1313C NMR (101 MHz, CDCl3) δ 145.6, 135.5, 129.9, 129.8, 128.4, 128.2, 128.1, 123.0, 117.0, 83.2; HRMS (ESI) m / z calculated for C 10 H9IN + ([M + H]) + : 269.9774, found: 269.9782.

[0266] Example 45: Preparation of 1-Iodo-2,7-dihydroxynaphthalene (Compound 45)

[0267]

[0268] a) In a 10 mL test tube, add 2,7-dihydroxynaphthalene (0.0160 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0211 g, 0.12 mmol, 1.2 eq), LiI (0.134 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (1 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 2 hours. After the reaction is completed, add 10 mL of water and stir for 30 min to quench the reaction. Extract with ethyl acetate (5 mL × 3). Wash the organic phase successively with saturated Na2SO3 and brine solutions, dry over Na2SO4, concentrate under reduced pressure to remove the solvent, and purify by flash column chromatography to obtain 0.0269 g of 1-iodo-2,7-dihydroxynaphthalene with a yield of 94%.

[0269] b) In a 40 mL test tube, add 2,7-dihydroxynaphthalene (0.0160 g, 0.1 mmol, 1.0 eq), Acerola cherry extract (containing 17% vitamin C, 0.1 g), LiI (0.134 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (1 mL); stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 2 hours. After the reaction is completed, add 10 mL of water and stir for 30 min to quench the reaction. Extract with ethyl acetate (5 mL × 3). Wash the organic phase successively with saturated Na2SO3 and brine solutions, dry over Na2SO4, concentrate under reduced pressure to remove the solvent, and purify by flash column chromatography to obtain 0.0266 g of 1-iodo-2,7-dihydroxynaphthalene with a yield of 93%.

[0270] Product Characterization: 11H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 9.89 (s, 1H), 7.63 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 2.2 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 6.86 (dd, J = 8.7, 2.2 Hz, 1H); 13 13C NMR (101 MHz, DMSO-d6) δ 157.4, 155.7, 137.3, 130.2, 129.7, 123.0, 115.7, 113.8, 111.9, 81.9; HRMS (ESI) m / z calculated for C 10 9H8IO2 + ([M + H]) + : 286.9563, found: 286.9569.

[0271] Example 46: Preparation of 2-Iodo-1,3,5-trimethoxybenzene (Compound 46)

[0272]

[0273] Add 1,3,5-trimethoxybenzene (0.0168 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0211 g, 0.12 mmol, 1.2 eq), LiI (0.134 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (1 mL) to a 10 mL test tube; stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 2 hours. After the reaction is completed, add 10 mL of water and stir for 30 min to quench the reaction, extract with ethyl acetate (5 mL × 3), wash the organic phase successively with saturated Na2SO3 and brine solutions, dry over Na2SO4, concentrate under reduced pressure to remove the solvent, and purify by flash column chromatography to obtain 0.0288 g of 2-iodo-1,3,5-trimethoxybenzene with a yield of 98%.

[0274] Product Characterization: 1 1H NMR (400 MHz, CDCl3) δ 6.14 (s, 2H), 3.86 (s, 6H), 3.82 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 162.3, 160.0, 91.4, 66.9, 56.6, 55.7; HRMS (ESI) m / z calculated for C9H 12 9IO3 + ([M + H]) +: 294.9826, found: 294.9835.

[0275] Example 47: Preparation of 2-Iodo-3-methoxy-4-methylaniline (Compound 47)

[0276]

[0277] Add 3-methoxy-4-methylaniline (0.0137 g, 0.1 mmol, 1.0 eq), L-ascorbic acid (0.0211 g, 0.12 mmol, 1.2 eq), LiI (0.134 g, 1.0 mmol, 10.0 eq.), and the solvent acetonitrile (1 mL) to a 10 mL test tube; stir briefly to dissolve the substrate. At room temperature, add 1,3-dimethylalloxan (0.0019 g, 0.01 mmol, 0.1 eq) to the stirred reaction solution and stir vigorously in open air for 2 hours. After the reaction is completed, add 10 mL of water and stir for 30 min to quench the reaction. Extract with ethyl acetate (5 mL × 3). Wash the organic phase successively with saturated Na2SO3 and brine solutions, dry over Na2SO4, concentrate under reduced pressure to remove the solvent, and purify by flash column chromatography to obtain 0.0242 g of 2-iodo-3-methoxy-4-methylaniline with a yield of 92%.

[0278] Product Characterization: 1 1H NMR (400 MHz, CDCl3) δ 7.33 (s, 1H), 6.28 (s, 1H), 3.95 (brs, 2H), 3.76 (s, 3H), 2.07 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 159.1, 145.7, 139.5, 119.2, 98.0, 72.4, 55.4, 15.1; HRMS (ESI) m / z calculated for C8H 11 INO + ([M + H]) + : 263.9880, found: 263.9883.

[0279] Example 48: Preparation of p-Chloroacetanilide (Compound 48)

[0280]

[0281] Add N-acetylaniline (0.0135 g, 0.1 mmol, 1.0 eq), D-ascorbic acid (0.0712 g, 0.4 mmol, 4.0 eq), LiCl (0.0420 g, 1.0 mmol, 10.0 eq), fuming nitric acid (16 μL) and the solvent acetonitrile (8 mL) into a 40 mL test tube; stir briefly to dissolve the substrates. At 40 °C, add 1,3-dimethylalloxan (0.0038 g, 0.02 mmol, 0.2 eq) into the stirred reaction solution, and stir vigorously for 4 hours under an oxygen atmosphere (balloon, 1 atm). After the reaction is completed, concentrate under reduced pressure, and purify by flash column chromatography to obtain 0.0075 g of p-chloroacetanilide with a yield of 45%.

[0282] Product characterization: 1 1H NMR (400 MHz, DMSO) δ 10.07 (s, 1H), 7.60 (d, J = 8.9 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H), 2.04 (s, 3H); 13 13C NMR (101 MHz, DMSO) δ 168.5, 138.3, 128.6, 126.5, 120.5, 24.0; HRMS (ESI) m / z calculated for C8H9ClNO + ([M + H]) + : 170.0367, found: 170.0366.

Claims

1. A method for efficiently synthesizing halogenated aromatic hydrocarbons by bionic catalytic aerobic oxidation of halogens, characterized in that: Under the conditions of oxygen or air in the presence of a catalyst, a halogen salt MX, a reducing agent, and a solvent, an aromatic ring compound is subjected to a halogenation reaction to obtain a halogenated aromatic hydrocarbon; Here, the catalyst is a substituted alloxan or a mono- or poly-hydrate of a substituted alloxan; The halogen salt is MX, where M is selected from hydrogen, lithium, sodium, potassium, cesium, beryllium, magnesium, calcium, strontium, barium, iron, cobalt, nickel, copper, zinc, ammonium group or tetraalkylammonium group, and M is preferably lithium; X is selected from bromine, iodine or chlorine; The reducing agent is a Hantzsch ester with a symmetric or asymmetric structure, a benzothiazoline derivative, a benzimidazoline derivative, LiI, a thiol derivative, cysteine, glutathione, an ascorbic acid derivative or a crude extract containing ascorbic acid; Optionally, the structure of the reducing agent is: The solvent is acetonitrile, chloroacetonitrile, propionitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, cyclopentanol, cyclohexanol, trifluoroethanol, hexafluoroisopropanol, water, nitromethane, nitroethane, benzene, toluene, xylene, mesitylene, fluorobenzene, chlorobenzene, bromobenzene, trifluorotoluene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, tetrachloroethane, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, petroleum ether, diethyl ether, methyl tert-butyl ether, or a mixture of one or more of them, and preferably acetonitrile.

2. The method for highly efficiently synthesizing halogenated aromatic hydrocarbons by biomimetic catalytic aerobic oxidation of halogen as described in claim 1, wherein, The aromatic ring compound has the structure shown in formula (I) to obtain the halogenated aromatic hydrocarbon shown in formula (III): The molecular structure of the alloxan catalyst is: Wherein: X in formula (III) is selected from bromine, iodine or chlorine; in formula (I) and formula (III), represents an aryl or substituted aryl, and the aryl is phenyl, polycyclic aryl or heterocyclic aryl; R 1 , R 2 , R 3 , R 4 , R 5 represent substituents connected to the aryl; In formula (I), formula (III), and the alloxan catalyst, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 are each independently selected from the following groups: hydrogen, C1-C10 alkyl, benzyl, substituted or unsubstituted aryl, amino, C1-C10 alkyl-substituted monoalkylamino, C1-C10 alkyl-substituted dialkylamino, benzylamino, C1-C10 alkoxy, C1-C10 alkyl-substituted sulfanyl, halogen, C1-C5 ester group, acylamino, hydroxy, nitro, carboxyl; wherein, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 may be the same or different; or R 1 and R 2 、R 2 and R 3 、R 3 and R 4 、R 4 and R 5 、R 6 and R 7 may combine with each other to jointly form cycloalkyl, heterocycloalkyl, benzocycloalkyl, benzheterocycloalkyl, aromatic ring, heteroaromatic ring, or derivatives of the above cyclic structures.

3. The method for highly efficiently synthesizing halogenated aromatic hydrocarbons by biomimetic catalytic aerobic oxidation of halogen as claimed in claim 1 or 2, wherein: The reaction temperature of the halogenation reaction is 0 to 70 °C, preferably 25 to 30 °C (room temperature).

4. The method for highly efficiently synthesizing halogenated aromatic hydrocarbons by bionic catalytic aerobic oxidation of halogen as claimed in claim 1 or 2, characterized in that: The molar ratio of the aryl compound to the halogen salt is 1:1 to 50, preferably 1:5 to 10.

5. The method for highly efficiently synthesizing halogenated aromatic hydrocarbons by biomimetic catalytic aerobic oxidation of halogen as claimed in claim 1 or 2, wherein: The molar ratio of the aryl compound to the alloxan catalyst is 1:0.01 to 1, preferably 1:0.

1.

6. The method for highly efficiently synthesizing halogenated aromatic hydrocarbons by bionic catalytic aerobic oxidation of halogen as claimed in claim 1 or 2, characterized in that: The molar ratio of the aryl compound to the reducing agent is 1:0.5 to 50, preferably 1:1.2 to 2.

7. The method for efficiently synthesizing halogenated aromatic hydrocarbons by bionic catalytic aerobic oxidation of halogen as claimed in claim 1 or 2, characterized in that: The concentration of the aryl compound is 0.01 to 1.0 M, preferably 0.025 M.

8. The method for highly efficiently synthesizing halogenated aromatic hydrocarbons by bionic catalytic aerobic oxidation of halogen as claimed in claim 1 or 2, wherein: The reaction time is 0.1 to 72 hours, preferably 2 h.

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