Method for iron-catalyzed carbon-hydrogen bond hydroxyl nitration of aromatic compound

Abstract

The invention discloses a method for catalyzing carbon-hydrogen bond hydroxyl nitration of an aromatic compound by iron, which comprises the following steps: in a solvent, by taking nitrite as a nitro source, hydrogen peroxide as an oxidizing agent, iron as a catalyst and amino acid and derivatives thereof as ligands, catalyzing the aromatic ring of the aromatic compound to carry out carbon-hydrogen bond hydroxyl nitration reaction; the hydroxyl and nitro disubstituted aromatic compound is generated. According to the method, the hydroxyl and nitro disubstituted aromatic compound can be synthesized in one step, and the steps are simple and convenient; the used catalyst and oxidant are wide in source and low in cost; reaction conditions are mild, and selectivity is high; the nitro source is low in toxicity and high in safety; the functional group compatibility of the substrate is good, and the application range of the substrate is wide; the drug molecules and the drug molecule derivatives can be compatible, so that the hydroxyl nitration reaction of the aromatic compound is realized. According to the method disclosed by the invention, under optimized reaction conditions, the yield of the separated target product can reach 84%.

Description

Technical Field

[0001] The invention belongs to the field of catalytic synthesis technology and fine chemical synthesis, and in particular relates to a method for iron-catalyzed carbon-hydrogen bond hydroxynitration of aromatic compounds. Background Art

[0002] Nitrophenols are a class of organic compounds with a specific chemical structure, containing one or more nitro groups (-NO 2 ) group and phenolic hydroxyl (-OH) group. Nitrophenol compounds have a wide range of applications in many fields and are important raw materials for explosives, dyes, pesticides, medicines, preservatives, adhesives, etc. For example: sodium nitrophenolate is a broad-spectrum plant growth regulator; entacapone and opicapone can treat Parkinson's disease and schizophrenia; chloronitrophenol is used as a contact herbicide, etc. At the same time, hydroxyl and nitro groups are both key intermediates in organic synthesis and are used for later functionalization, which can provide a large number of other functional groups. Therefore, finding an efficient method for the hydroxynitration of aromatic compounds is one of the important topics in current organic chemistry research.

[0003] There are two ways to industrially synthesize nitrophenol compounds. One is that aromatic compounds are prepared into phenol compounds by methods such as cumene oxidation or sulfonation alkaline dissolution, and then directly react with nitric acid to generate nitrophenol compounds under the action of high temperature, high pressure and catalyst. This method has complicated steps and high energy consumption. The second is that chlorobenzene is nitrated under the action of a mixed acid of concentrated nitric acid and concentrated sulfuric acid to obtain p-nitrochlorobenzene, and then hydrolyzed in the presence of sodium hydroxide to generate p-nitrophenol. The substrate of this method needs to be pre-functionalized, and dangerous strong acids are used as nitro sources. The conditions are harsh and the safety is low. The above methods all require two or more steps to react to obtain nitrophenol compounds, and there are problems such as complicated steps, poor tolerance of functional groups, high energy consumption, multiple purifications, and low yields. At present, most studies use phenol as a substrate for nitration. The formation of such compounds is generally carried out by nitration of phenol. The difficulty lies in the need to first synthesize phenol, separate and purify the phenolic product, and then carry out a secondary reaction nitration. It has not yet been achieved that the aromatic ring of the aromatic compound undergoes a carbon-hydrogen bond hydroxynitration reaction in a one-step reaction to generate a hydroxyl and nitro disubstituted aromatic compound. Summary of the invention

[0004] Purpose of the invention: In view of the problems existing in the prior art, the present invention provides a method for iron-catalyzed carbon-hydrogen bond hydroxynitration of aromatic compounds. The method of the present invention not only provides an economical and applicable new method for the synthesis of nitrophenol compounds, but also realizes the one-step synthesis of hydroxyl and nitro disubstituted aromatic compounds, and solves the problems of cumbersome reaction steps, harsh conditions, pre-functionalization of reaction substrates, and use of complex nitro source reagents, resulting in low overall reaction yield, poor functional group compatibility, narrow scope of application, high waste discharge, and environmental protection, unsafety, and uneconomical.

[0005] The method of the present invention only requires one step of reaction, and has the characteristics of wide source of catalyst, low cost and environmental protection; low cost and low toxicity of oxidant; low cost and mildness of nitro source reagent, stability and low toxicity; wide source and stable substrate; mild reaction conditions, good selectivity and high yield; good compatibility of substrate functional groups and wide application range of substrate; drug molecules and drug molecule derivatives are compatible, and can well realize the carbon-hydrogen bond hydroxynitration reaction of aromatic ring.

[0006] Technical solution: In order to achieve the above-mentioned purpose, the present invention provides a method for iron-catalyzed carbon-hydrogen bond hydroxylation and nitration of aromatic compounds, comprising the following steps: in a solvent, using nitrite as a nitration reagent, hydrogen peroxide as an oxidant, iron as a catalyst, and amino acids or their derivatives as ligands, to catalyze the carbon-hydrogen bond hydroxylation and nitration of the aromatic ring of the aromatic compound to generate a hydroxyl-nitro disubstituted aromatic compound;

[0007] The general reaction formula is as follows:

[0008]

[0009] In the formula: Ar represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, and M represents a metal ion or a non-metal ion.

[0010] Wherein, the aryl or heteroaryl contains 1-4 aromatic rings, and the heteroaryl contains 1-3 N, S or O atoms as heteroatoms.

[0011] The aryl group is phenyl, biphenyl or naphthyl; the heteroaryl group is carbazolyl, 2-benzoxazolinone, 2,3-dihydrobenzofuranyl or 3,4-dihydro-2(1H)quinolinone.

[0012] Wherein, the substituted aryl group mono- or poly-substituted hydrogen on the aromatic ring, the substituent is selected from hydrogen, methyl, methoxy, halogen, 1,2-methylenedioxy, amide, carbonyl, ester, cyano, nitro, pyrrolidone, morpholino, phenyl, phenoxy or benzyloxy.

[0013] Wherein, the nitrite is selected from any one of sodium nitrite, potassium nitrite, calcium nitrite, silver nitrite, iron nitrite, copper nitrite, cobalt nitrite, tert-butyl nitrite or ammonium nitrite.

[0014] Wherein, the iron is selected from any one of ferrous trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, ferrous chloride, ferrous acetylacetonate, ferrous acetylacetonate, ferrous 2,2,6,6-tetramethyl-3,5-heptanedione, ferrous 2,2,6,6-tetramethyl-3,5-heptanedione, ferrous 1,3-diphenylpropanedione, ferrous 1,3-diphenylpropanedione, ferrous benzoylacetonate, ferrous benzoylacetonate, ferrous ferrocyanide, ferrous ferrocyanide, ferrous acetate, ferrous sulfate, ammonium ferrous sulfate, ferrous sulfate, ferrous oxalate, ferrous oxalate, ferrous fluoride, ferrous fluoride, ferrous bromide, ferrous bromide, ferrous iodide, ferric iodide, ferric chloride, iron (III) perchlorate hydrate, 1,1'-bis(diphenylphosphino)ferrocene, ferrous phthalocyanine, ferric nitrate, ferric oxide or ferric oxide.

[0015] Wherein, the ligand is selected from any one of S-acetamidomethyl-N-tert-butyloxycarbonyl-L-cysteine, N-acetyl-L-cysteine, N,N'-bis(tert-butyloxycarbonyl)-L-cystine, L-serine, D-cystine, aspartic acid, D-arginine, isoserine, L-threonine, L-tyrosine, BOC-L-proline, BOC-glycine-glycine-glycine, 2-allyl-N-FMOC-L-glycine, BOC-D-phenylalanine, L-cysteine, D-serine, β-thiovaline, D-proline, D-valine, L-proline, L-phenylalanine, N-BOC-N'-trityl-L-histidine, L-tryptophan, N-BOC-L-leucine, L-histidine, BOC-L-glutamate, L-cystine or L-homocysteine.

[0016] Wherein, the solvent is an organic solvent, water or an aqueous solution of an organic solvent, and the organic solvent is selected from methanol, ethanol, ethylene glycol, n-propanol, isopropanol, 1,3-propylene glycol, glycerol, n-butanol, isobutanol, tert-butanol, trifluoroethanol, 2-methyl-2-butanol, 3-methoxybutanol, sec-butanol, tert-amyl alcohol, 4-methyl-2-pentanol, isopentanol, 2-pentanol, 3-pentanol, cyclopentanol, n-pentanol, polyethylene glycol 200-10000, acetonitrile, benzonitrile, toluene, acetone, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-diformamide, N,N-diacetamide, ethyl acetate, 1,4-dioxane or tetrahydrofuran; when the solvent is an aqueous solution of an organic solvent, the volume ratio of the organic solvent to water is 1:(0.1-5).

[0017] Wherein, the molar ratio of the aromatic compound, nitrite, hydrogen peroxide, amino acid or its derivative, and iron catalyst is 1:(2-50):(2-50):(0.002-20):(0.001-10).

[0018] Wherein, the reaction temperature is 25-100° C. and the reaction time is 1-24 hours.

[0019] The iron catalyst in the method of the present invention has the characteristics of high natural abundance, low price and low toxicity. A specific amino acid ligand is used to coordinate with the iron catalyst to form a highly active catalytic species to realize the aromatic ring hydroxynitration reaction, which has high activity and selectivity. In addition, the method of the present invention uses mild reagents and a mild environment to solve the problem of harsh reaction conditions; a hydroxyl and nitro disubstituted aromatic compound is synthesized in one step; the reaction directly attacks the aromatic ring without pre-functionalization, iron is used as a catalyst, and no precious metals and complex nitro sources are used. The method of the present invention has the advantages of a wide range of catalyst sources, low cost and environmental protection; a wide range of oxidant sources and low cost; mild reaction conditions and high selectivity; good compatibility of substrate functional groups and a wide range of substrate applications. Under optimized reaction conditions, the yield of the target product after separation can reach 84%.

[0020] The present invention can obtain a hydroxyl-nitro disubstituted compound through a one-step reaction, thereby simplifying the reaction steps. The present invention can realize hydroxylation and nitration in the reaction process through a one-pot method, without the need to separate the intermediate product.

[0021] In the specific method of the present invention, iron catalyzes hydrogen peroxide as an oxidant to realize the hydroxylation reaction of aromatic compounds. After adding a nitro source on this basis, the original substrate will not be directly nitrated, but the aromatic ring is activated due to the electron-donating property of the hydroxyl group, and it is easier to nitrate phenolic compounds to obtain hydroxyl and nitro disubstituted compounds. In the prior art, phenolic compounds are generally separated by hydroxylation first, and then the phenolic compounds are nitrated. The present invention synthesizes hydroxyl and nitro disubstituted aromatic compounds in one step, avoids the separation process of intermediate phenolic products, and has simple steps. The present invention avoids the existing synthesis of nitrophenolic compounds by phenol as a substrate, and adopts an aromatic ring without a hydroxyl group to directly synthesize nitrophenolic compounds, which is more practical.

[0022] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0023] (1) The present invention provides a method for iron-catalyzed carbon-hydrogen bond hydroxynitration of aromatic compounds promoted by amino acid and derivative ligands. The method only requires one step of reaction and has the unique advantages of cheap catalysts, ligands and oxidants, wide sources and environmental protection; the nitro source is relatively cheap and low in toxicity; the reaction conditions are mild and highly selective; the substrate source is wide, stable and easy to handle; the substrate functional group compatibility is good and the substrate has a wide range of application; experimental results prove that the reaction is suitable for the hydroxynitration reaction of drug molecules and their derivatives;

[0024] (2) The method for hydroxynitration of aromatic carbon-hydrogen bonds provided by the present invention is simple, easy and safe, and can directly obtain the hydroxyl and nitro disubstituted products of aromatic compounds in one step. Under optimized reaction conditions, the yield of the target product after separation can reach 84%, which is a universal, efficient, economical and environmentally friendly method for hydroxynitration of aromatic CH bonds;

[0025] (3) The reason why the method of the present invention can use ideal iron as a catalyst for the reaction is that the key is the use of amino acid ligands, which are coordinated with the iron catalyst to form a highly active catalytic species, so that the reaction can be carried out under very mild conditions to carry out the hydroxynitration reaction of the carbon-hydrogen bond of aromatic compounds, especially for drug molecules and their derivatives. An ideal catalytic effect can also be achieved.

[0026] (4) The nitrophenol compounds synthesized by the method of the present invention can be used as drugs or bioactive molecules, and are also important organic intermediates, and are widely used in the synthesis of pharmaceutical intermediates and high value-added fine chemicals (for example, the product compound 29 is an intermediate for platelet aggregation inhibitor drugs (A. Iyobe, M. Uchida, K. Kamata, Y. Hotei, H. Kusama, H. Harada, Chem. Pharm. Bull., 2001, 49, 822-829.). DETAILED DESCRIPTION

[0027] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0028] The experimental methods described in the examples are conventional methods unless otherwise specified; the reagents and materials described can be obtained from commercial sources or simply prepared by existing technologies unless otherwise specified.

[0029] The specific structures of the substrates and products in the examples are shown in Table 1.

[0030] The reaction substrates 1a-1ai in the present invention are all reported compounds, and the product compounds 1-8, 10, 11, 13, 14, 16, 17, 18, 19, 19', 20, 20', 21, 21', 29, 30, 33, 35 are all known compounds.

[0031] Example 1

[0032] Synthesis of compound 1

[0033] In air, ferric nitrate (0.05 mmol), N-acetyl-L-cysteine ​​(0.1 mmol), substrate 1a (0.5 mmol), sodium nitrite (2.5 mmol), dichloromethane (2.0 mL) and hydrogen peroxide (2.5 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 40°C for 1 h. After the reaction was completed, the product 1 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.05) with a yield of 37%.

[0034] Example 2

[0035] Synthesis of compound 2

[0036] In air, ferrous chloride (0.5 mmol), D-proline (1.0 mmol), substrate 1b (0.5 mmol), silver nitrite (2.0 mmol), isopropanol (2.0 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 60°C for 1 h. After the reaction was completed, the product 2 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.05) with a yield of 59%.

[0037] Example 3

[0038] Synthesis of compound 3

[0039] In air, ferric sulfate (0.05 mmol), BOC-L-glutamic acid (0.1 mmol), substrate 1c (0.5 mmol), potassium nitrite (2.0 mmol), methanol (2.0 mL) and hydrogen peroxide (3.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 80°C for 1 h. After the reaction was completed, the product 3 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.1) with a yield of 67%.

[0040] Example 4

[0041] Synthesis of compound 4

[0042] In air, ferrous trifluoromethanesulfonate (0.05 mmol), L-serine (0.1 mmol), substrate 1d (0.5 mmol), calcium nitrite (3.0 mmol), ethanol (2.0 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 80°C for 1 h. After the reaction was completed, the product 4 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.2) with a yield of 64%.

[0043] Example 5

[0044] Synthesis of compound 5

[0045] In air, ferrous trifluoromethanesulfonate (0.05 mmol), D-cystine (0.1 mmol), substrate 1e (0.5 mmol), ferrous nitrite (3.5 mmol), ethylene glycol (2.0 mL) and hydrogen peroxide (2.5 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 80°C for 1 h. After the reaction was completed, the product 5 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.2) with a yield of 44%.

[0046] Example 6

[0047] Synthesis of compound 6

[0048] In air, ferrous sulfate (0.05 mmol), L-threonine (0.2 mmol), substrate 1f (0.5 mmol), ferrous nitrite (1.0 mmol), ethylene glycol (2.0 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and the reaction mixture was stirred at 80°C for 1 h. After the reaction was completed, the product 6 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.2) with a yield of 49%.

[0049] Example 7

[0050] Synthesis of compound 7

[0051] In air, ferrous oxalate (0.05 mmol), L-tyrosine (0.02 mmol), substrate 1 g (0.5 mmol), ammonium nitrite (4.0 mmol), n-butanol (2.0 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 25°C for 1 h. After the reaction was completed, the product 7 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.05) with a yield of 69%.

[0052] Example 8

[0053] Synthesis of compound 8

[0054] In air, ferric oxalate (0.05 mmol), BOC-L-proline (0.1 mmol), substrate 1h (0.5 mmol), copper nitrite (2.0 mmol), isobutanol (2.0 mL) and hydrogen peroxide (3.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 50°C for 3 h. After the reaction was completed, the product 8 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.1) with a yield of 67%.

[0055] 1 H NMR (400 MHz, CDCl 3 ): δ11.04(s,1H),7.46(s,1H),6.55(s,1H),3.96(s,3H),3.89ppm(s,3H); 13 C NMR (100 MHz, CDCl 3 ): δ158.0,153.3,143.3,125.7,105.0,100.6,56.7,56.4ppm.

[0056] Example 9

[0057] Synthesis of compound 9

[0058] In air, ferrous fluoride (0.1 mmol), BOC-glycine-glycine-glycine (0.3 mmol), substrate 1i (0.5 mmol), cobalt nitrite (3.0 mmol), toluene (2.0 mL) and hydrogen peroxide (3.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 60°C for 3 h. After the reaction was completed, the product 9 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.1) with a yield of 77%.

[0059] 1 H NMR (400 MHz, CDCl 3 ): δ10.78(s,1H),7.32(s,1H),4.07(s,3H),3.94(s,3H),3.86ppm(s,3H); 13 C NMR (100 MHz, CDCl 3 ): δ151.2,147.1,145.8,141.8,128.2,100.9,61.5,61.4,56.3ppm.

[0060] Example 10

[0061] Synthesis of compound 10

[0062] In air, ferric fluoride (0.1 mmol), D-valine (0.2 mmol), substrate 1j (0.5 mmol), tert-butyl nitrite (2.0 mmol), dimethyl sulfoxide (4.0 mL) and hydrogen peroxide (3.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 25°C for 3 h. After the reaction was completed, the product 10 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.1) with a yield of 80%.

[0063] 1 H NMR (400 MHz, CDCl 3 ): δ11.39(s,1H),7.46(s,1H),6.56(s,1H),6.07ppm(s,2H); 13 C NMR (100 MHz, CDCl 3 ): δ156.0,155.6,141.8,127.2,103.0,102.4,98.7ppm.

[0064] Embodiment 11

[0065] Synthesis of compound 11

[0066] In air, ferric chloride (0.1 mmol), L-proline (0.04 mmol), substrate 1k (0.5 mmol), tert-butyl nitrite (2.0 mmol), dimethyl sulfoxide (1.5 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 25°C for 3 h. After the reaction was completed, the product 11 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:5) with a yield of 57%.

[0067] Example 12

[0068] Synthesis of compound 12

[0069] In air, ferrous iodide (0.15 mmol), L-histidine (0.3 mmol), substrate 1l (0.5 mmol), calcium nitrite (3.0 mmol), acetonitrile (2.0 mL) and hydrogen peroxide (3.0 mmol) were added to a 25 mL reaction bottle in sequence, mixed evenly at room temperature, and the reaction mixture was stirred at 40°C for 3 h. After the reaction was completed, the product 12 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:5) with a yield of 50%.

[0070] 1 H NMR (400MHz, CD 3 SOCD 3 ): δ10.29(s,1H),10.06(s,1H),8.24(s,1H),7.58(s,1H),2.22(s,3H),2.03ppm(s,3H); 13 C NMR (100MHz, CD 3 SOCD 3 ): δ168.9,147.8,134.7,131.4,129.8,129.1,112.1,24.3,16.7ppm.

[0071] Embodiment 13

[0072] Synthesis of compound 13

[0073] In air, ferric iodide (0.2 mmol), N-BOC-L-leucine (0.5 mmol), substrate 1m (0.5 mmol), potassium nitrite (2.0 mmol), N,N-diformamide (2.0 mL) and hydrogen peroxide (1.5 mmol) were added to a 25 mL reaction bottle in sequence, mixed evenly at room temperature, and the reaction mixture was stirred at 80°C for 3 h. After the reaction was completed, the product 13 was directly separated by chromatography (dichloromethane: methanol V / V = 10:1) with a yield of 55%.

[0074] Embodiment 14

[0075] Synthesis of compound 14

[0076] In air, ferrous trifluoromethanesulfonate (0.1 mmol), L-tryptophan (0.4 mmol), substrate 1n (0.5 mmol), potassium nitrite (4.0 mmol), 1,2-dichloroethane (2.0 mL) and hydrogen peroxide (4.0 mmol) were added to a 25 mL reaction bottle in sequence, mixed evenly at room temperature, and the reaction mixture was stirred at 90°C for 3 h. After the reaction was completed, the product 14 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:5) with a yield of 66%.

[0077] Embodiment 15

[0078] Synthesis of compound 15

[0079] In air, ferrous acetylacetonate (0.05 mmol), L-phenylalanine (0.1 mmol), substrate 1o (0.5 mmol), silver nitrite (2.0 mmol), dichloromethane (1.0 mL), water (1.0 mL) and hydrogen peroxide (4.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 60 ° C for 3 h. After the reaction was completed, the product 15 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 1:1) with a yield of 49%.

[0080] 1 H NMR (400MHz, CD 3 COCD 3 ): δ10.05(s,1H),7.58(d,J=8.5Hz,1H),7.51(d,J=8.5Hz,1H),2.54(s,3H),2.29ppm(s,3H); 13 C NMR (100MHz, CD 3 COCD 3): δ194.6,172.3,142.0,140.3,132.8,127.1,122.3,121.0,27.0,22.6ppm.

[0081] Example 16

[0082] Synthesis of compound 16

[0083] In air, ferrous bromide (0.1 mmol), aspartic acid (0.2 mmol), substrate 1p (0.5 mmol), sodium nitrite (2.0 mmol), ethyl acetate (2.0 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 40°C for 3 h. After the reaction was completed, the product 16 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.3) with a yield of 53%.

[0084] Embodiment 17

[0085] Synthesis of compound 17

[0086] In air, ferric bromide (0.05 mmol), S-acetylaminomethyl-N-tert-butyloxycarbonyl-L-cysteine ​​(0.15 mmol), substrate 1q (0.5 mmol), calcium nitrite (2.0 mmol), sec-butyl alcohol (2.0 mL) and hydrogen peroxide (3.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 30° C. for 6 h. After the reaction was completed, the product 17 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.1) with a yield of 43%.

[0087] Embodiment 18

[0088] Synthesis of compound 18

[0089] In air, ferric iodide (0.2 mmol), N-acetyl-L-cysteine ​​(0.4 mmol), substrate 1r (0.5 mmol), sodium nitrite (3.0 mmol), tetrahydrofuran (2.0 mL) and hydrogen peroxide (3.5 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 80°C for 6 h. After the reaction was completed, the product 18 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.2) with a yield of 45%.

[0090] Embodiment 19

[0091] Synthesis of compound 19

[0092] In air, ferrous acetylacetonate (0.05 mmol), N,N'-bis(tert-butyloxycarbonyl)-L-cystine (0.1 mmol), substrate 1s (0.5 mmol), sodium nitrite (2.5 mmol), 1,4-dioxane (2.0 mL) and hydrogen peroxide (2.5 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 70°C for 3 h. After the reaction was completed, the product 19 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.3) with a yield of 39%.

[0093] 1 H NMR (400MHz, CD 3 COCD 3 ): δ9.27(s,1H),7.62(d,J=8.6Hz,1H),7.20(d,J=8.6Hz,1H),4.01(s,3H),2.53ppm(s,3H); 13 C NMR (100MHz, CD 3 COCD 3 ): δ199.3,157.7,144.7,143.3,127.8,127.6,116.2,61.5,31.7ppm.

[0094] Synthesis of compound 19'

[0095] In air, ferrous acetylacetonate (0.05 mmol), N,N'-bis(tert-butyloxycarbonyl)-L-cystine (0.1 mmol), substrate 1s (0.5 mmol), sodium nitrite (2.5 mmol), 1,4-dioxane (2.0 mL) and hydrogen peroxide (2.5 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 70°C for 3 h. After the reaction was completed, the product 19' was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.3) with a yield of 39%.

[0096] 1 H NMR (400 MHz, CDCl 3 ): δ7.63(s,1H),6.85(s,1H),4.01(s,3H),2.50ppm(s,3H); 13 C NMR (100 MHz, CDCl 3 ): δ199.9,151.2,146.8,138.0,133.7,112.8,106.9,56.7,30.3ppm.

[0097] In this example, the same reaction has two products, and the Rf values ​​are different under the developing solvent of petroleum ether:ethyl acetate V / V=10:0.3. The same is true for the subsequent examples.

[0098] Embodiment 20

[0099] Synthesis of compound 20

[0100] In air, ferric acetylacetonate (0.5 mmol), D-arginine (1.5 mmol), substrate 1t (0.5 mmol), ammonium nitrite (2.0 mmol), acetonitrile (1.5 mL), water (0.5 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 100°C for 3 h. After the reaction was completed, the product 20 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.3) with a yield of 40%.

[0101] 1 H NMR (400 MHz, CDCl 3 ): δ7.53(s,1H),7.14(s,1H),6.36(s,1H),4.02(s,3H),3.92ppm(s,3H); 13 C NMR (100 MHz, CDCl 3 ): δ166.3,149.9,147.4,140.3,123.0,114.7,106.9,56.7,53.3ppm.

[0102] Synthesis of Compound 20'

[0103] In air, ferric acetylacetonate (0.5 mmol), D-arginine (1.5 mmol), substrate 1t (0.5 mmol), ammonium nitrite (2.0 mmol), acetonitrile (1.5 mL), water (0.5 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 100° C. for 3 h. After the reaction was completed, the product 20′ was directly separated by chromatography (petroleum ether: ethyl acetate V / V=10:0.3) with a yield of 40%.

[0104] 1 H NMR (400 MHz, CDCl 3 ): δ7.49(s,1H),7.43(d,J=8.5Hz,1H),6.99(d,J=8.5Hz,1H),3.99(s,3H),3.86ppm(s,3H); 13 C NMR (100 MHz, CDCl 3): δ164.5,151.3,140.6,136.7,122.3,117.6,116.2,56.8,52.9ppm.

[0105] Embodiment 21

[0106] Synthesis of compound 21

[0107] In air, ferrous ferrocyanide (0.05 mmol), isoserine (0.1 mmol), substrate 1u (0.5 mmol), copper nitrite (3.0 mmol), cyclopentanol (2.0 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 90°C for 3 h. After the reaction was completed, the product 21 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.3) with a yield of 32%.

[0108] 1 H NMR (400MHz, CD 3 SOCD 3 ): δ12.20(s,1H),7.79(d,J=1.9Hz,1H),7.74(s,1H),3.84(s,3H),2.70ppm(s,3H); 13 C NMR (100MHz, CD 3 SOCD 3 ): δ104.0,150.5,147.9,138.3,124.1,122.5,115.8,56.6,28.5ppm.

[0109] Synthesis of Compound 21'

[0110] In air, ferrous ferrocyanide (0.05 mmol), isoserine (0.1 mmol), substrate 1u (0.5 mmol), copper nitrite (3.0 mmol), cyclopentanol (2.0 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 90° C. for 3 h. After the reaction was completed, the product 21′ was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.3) with a yield of 32%.

[0111] 1 H NMR (400 MHz, CDCl 3 ): δ12.28(s,1H),7.75(d,J=3.2Hz,1H),7.63(d,J=3.2Hz,1H),3.86(s,3H),2.70ppm(s,3H); 13 C NMR (100 MHz, CDCl3 ): δ201.3,150.8,150.2,136.8,125.0,123.8,115.1,56.3,29.0ppm.

[0112] Embodiment 22

[0113] Synthesis of compound 22

[0114] In air, ferric ferrocyanide (0.1 mmol), 2-allyl-N-FMOC-L-glycine (0.2 mmol), substrate 1v (0.5 mmol), cobalt nitrite (3.0 mmol), 4-methyl-2-pentanol (2.0 mL) and hydrogen peroxide (2.5 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 60°C for 6 h. After the reaction was completed, the product 22 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:5) with a yield of 43%.

[0115] Embodiment 23

[0116] Synthesis of compound 23

[0117] In air, ammonium ferrous sulfate (0.05 mmol), BOC-D-phenylalanine (0.1 mmol), substrate 1w (0.5 mmol), tert-butyl nitrite (2.0 mmol), polyethylene glycol-2000 (1.0 g), water (1.0 mL) and hydrogen peroxide (3.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 80°C for 6 h. After the reaction was completed, the product 23 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:3) with a yield of 75%.

[0118] 1 H NMR (400 MHz, CDCl 3 ): δ10.43(s,1H),8.16(dd,J=9.1,2.8Hz,1H),8.12(d,J=2.8Hz,1H),7.17(d,J=9.1 Hz,1H),3.87(t,J=7.0Hz,2H),2.63(t,J=8.1Hz,2H),2.21ppm(p,J=7.9,7.5Hz,2H); 13 C NMR (100 MHz, CDCl 3 ): δ174.4,151.8,132.5,130.2,120.2,114.5,48.6,32.4,17.8ppm.

[0119] Embodiment 24

[0120] Synthesis of compound 24

[0121] In air, iron (III) perchlorate hydrate (0.001 mmol), D-serine (0.002 mmol), substrate 1x (0.5 mmol), sodium nitrite (2.0 mmol), dimethyl sulfoxide (1.5 mL), water (0.5 mL) and hydrogen peroxide (3.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 80°C for 1 h. After the reaction was completed, the product 24 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:3) with a yield of 61%.

[0122] 1 H NMR (400 MHz, CDCl 3 ): δ8.09(d,J=2.7Hz,1H),8.06(dd,J=8.9,2.7Hz,1H),7.04(d,J=8.9Hz,1H),3.90(t,J=4.6Hz,4H),2.92ppm(t,J=4.6Hz,4H); 13 C NMR (100 MHz, CDCl 3 ): δ157.4,141.2,138.8,123.4,118.1,114.5,67.3,52.7ppm.

[0123] Embodiment 25

[0124] Synthesis of compound 25

[0125] In air, ferrous phthalocyanine (0.02 mmol), β-thiovaline (0.04 mmol), substrate 1y (0.5 mmol), potassium nitrite (2.0 mmol), acetone (2.0 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 70 ° C for 3 h. After the reaction was completed, the product 25 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:1) with a yield of 54%.

[0126] Embodiment 26

[0127] Synthesis of compound 26

[0128] In air, ferric nitrate (0.02 mmol), N-BOC-N'-trityl-L-histidine (0.04 mmol), substrate 1z (0.5 mmol), potassium nitrite (3.0 mmol), N,N-diethylamide (1.5 mL), water (0.5 mL) and hydrogen peroxide (3.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 50°C for 3 h. After the reaction was completed, the product 26 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:1) with a yield of 59%.

[0129] Embodiment 27

[0130] Synthesis of compound 27

[0131] In air, 2,2,6,6-tetramethyl-3,5-heptanedione ferrous acid (0.05 mmol), L-cystine (0.1 mmol), substrate 1aa (0.5 mmol), sodium nitrite (4.0 mmol), methanol (1.5 mL), water (0.5 mL) and hydrogen peroxide (4.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 80°C for 6 h. After the reaction was completed, the product 27 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:2) with a yield of 21%.

[0132] Synthesis of compound 27'

[0133] In air, 2,2,6,6-tetramethyl-3,5-heptanedione ferrous acid (0.05 mmol), L-cystine (0.1 mmol), substrate 1aa (0.5 mmol), sodium nitrite (4.0 mmol), methanol (1.5 mL), water (0.5 mL) and hydrogen peroxide (4.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 80°C for 6 h. After the reaction was completed, the product 27' was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:2) with a yield of 21%.

[0134] Embodiment 28

[0135] Synthesis of compound 28

[0136] In air, 2,2,6,6-tetramethyl-3,5-heptanedione iron (0.08 mmol), L-homocystine (0.32 mmol), substrate 1ab (0.5 mmol), sodium nitrite (2.0 mmol), dimethyl sulfoxide (1.5 mL), water (0.5 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 90°C for 3 h. After the reaction was completed, the product 28 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:3) with a yield of 39%.

[0137] Embodiment 29

[0138] Synthesis of compound 29

[0139] In air, 1,3-diphenylpropanedione ferrous acid (0.1 mmol), BOC-L-glutamic acid (0.4 mmol), substrate 1ac (0.5 mmol), calcium nitrite (2.0 mmol), dimethyl sulfoxide (4.0 mL) and hydrogen peroxide (2.5 mmol) were added to a 25 mL reaction bottle in sequence, mixed evenly at room temperature, and the reaction mixture was stirred at 90 ° C for 3 h. After the reaction was completed, the product 29 was directly separated by chromatography (dichloromethane: methanol V / V = 10:1) with a yield of 54%.

[0140] 1 H NMR (400MHz, CD 3 SOCD 3 ): δ10.15(s,1H),7.41(s,1H),6.98(s,1H),2.91(t,J=7.7Hz,2H),2.44ppm(t,J=7.7Hz,2H); 13 C NMR (100MHz, CD 3 SOCD 3 ): δ170.1,148.6,134.5,134.4,131.3,118.9,110.3,30.0,25.5ppm.

[0141] Embodiment 30

[0142] Synthesis of compound 30

[0143] In air, 1,3-diphenylpropanedione iron (0.05 mmol), L-serine (0.1 mmol), substrate 1ad (0.5 mmol), silver nitrite (2.5 mmol), acetonitrile (1.0 mL), water (1.0 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 40 ° C for 12 h. After the reaction was completed, the product 30 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:1) with a yield of 39%.

[0144] Embodiment 31

[0145] Synthesis of compound 31

[0146] In air, ferrous benzoylacetonate (0.08 mmol), L-proline (0.16 mmol), substrate 1ae (drug molecule, nicotinamide) (0.5 mmol), silver nitrite (3.0 mmol), ethanol (1.5 mL), water (0.5 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 100 ° C for 3 h. After the reaction was completed, the product 31 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:5) with a yield of 63%.

[0147] 1 H NMR (400MHz, CD 3 SOCD 3 ): δ10.84(s,1H),10.58(s,1H),9.11(d,J=2.3Hz,1H),8.77(d,J=4.8Hz,1H),8.45(d,J=2.6Hz,1H),8.29( dd,J=8.1,2.1Hz,1H),7.88(dd,J=9.0,2.6Hz,1H),7.58(dd,J=8.0,4.8Hz,1H),7.16ppm(d,J=9.0Hz,1H); 13 C NMR (100MHz, CD 3 SOCD 3 ): δ164.5,152.7,149.3,149.1,136.1,135.9,131.1,130.6,128.6,124.0,119.9,116.8ppm.

[0148] Embodiment 32

[0149] Synthesis of compound 32

[0150] In air, iron benzoyl acetonate (0.02 mmol), BOC-glycine-glycine-glycine (0.04 mmol), substrate 1af (drug molecule, chlorzoxazone) (0.5 mmol), calcium nitrite (3.0 mmol), n-propanol (2.0 mL) and hydrogen peroxide (3.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 70 ° C for 12 h. After the reaction was completed, the product 32 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 1:1) with a yield of 56%.

[0151] 1 H NMR (400MHz, CD 3 COCD 3 ): δ8.01(s,1H),7.93ppm(s,1H); 13 C NMR (100MHz, CD 3 SOCD 3 ): δ154.1,138.3,122.8,122.0,119.2,118.9,117.0ppm.

[0152] Embodiment 33

[0153] Synthesis of compound 33

[0154] In air, 1,1'-bis(diphenylphosphino)ferrocene (0.5mmol), L-cysteine ​​(1.0mmol), substrate 1ag (drug molecule, phenoxyacetic acid) (0.5mmol), calcium nitrite (3.0mmol), isopentanol (2.0mL) and hydrogen peroxide (2.0mmol) were added to a 25mL reaction bottle in sequence, mixed evenly at room temperature, and the reaction mixture was stirred at 90°C for 3h. After the reaction was completed, the product 33 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:3) with a yield of 84%.

[0155] Embodiment 34

[0156] Synthesis of compound 34

[0157] In air, iron oxide (0.04 mmol), L-histidine (0.08 mmol), substrate 1ah (drug molecule, pyriproxyfen) (0.5 mmol), ammonium nitrite (3.0 mmol), N,N-diformamide (1.5 mL) and water (0.5 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 90 ° C for 24 h. After the reaction was completed, the product 34 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:2) with a yield of 41%.

[0158] 1 H NMR (400 MHz, CDCl 3 ): δ10.35(s,1H),8.15(dd,J=5.2,2.0Hz,1H),7.62–7.53(m,1H),7.29(d d,J=9.2,3.0Hz,1H),7.12(d,J=9.1Hz,1H),6.94(m,4H),6.87(dd,J=6.4, 4.8Hz,1H),6.75(d,J=8.3Hz,1H),5.59(td,J=6.2,4.8Hz,1H),4.20(dd,J=9.9,5.3Hz,1H),4.09(dd,J=9.9,4.8Hz,1H),1.49ppm(d,J=6.4Hz,3H); 13 C NMR (100 MHz, CDCl 3 ): δ163.1,155.8,151.3,150.8,149.6,146.7,138.8,133.2,128.6,121.0,120.5,116.8,116.1,111.8,111.7,71.0,69.3,17.0ppm.

[0159] Embodiment 35

[0160] Synthesis of compound 35

[0161] In air, ferroferric oxide (0.1 mmol), BOC-L-glutamic acid (0.5 mmol), substrate 1ai (drug molecule, phenylalanine) (0.5 mmol), ammonium nitrite (3.0 mmol), acetonitrile (2 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 90 ° C for 6 h. After the reaction was completed, the product 34 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:5) with a yield of 35%.

[0162] 1 H NMR (400 MHz, CDCl 3 ): δ10.43(s,1H),7.83(d,J=2.2Hz,1H),7.34(dd,J=8.6,2.2Hz,1H),7.07(d,J=8.6Hz,1H),6.29(s,1H),4 .86(dd,J=13.1,5.8Hz,1H),3.74(s,3H),3.26(dd,J=13.8,6.0Hz,1H),3.20–3.16(m,1H),1.98ppm(s,3H); 13C NMR (100 MHz, CDCl 3 ): δ71.5,169.9,154.4,138.4,133.1,128.5,125.0,120.0,52.9,52.4,36.5,22.8ppm.

[0163] Synthesis of compound 35'

[0164] In air, ferroferric oxide (0.1 mmol), BOC-L-glutamic acid (0.5 mmol), substrate 1ai (0.5 mmol), ammonium nitrite (3.0 mmol), acetonitrile (2 mL) and hydrogen peroxide (2.0 mmol) were added to a 25 mL reaction bottle in sequence, and mixed evenly at room temperature. The reaction mixture was stirred at 90°C for 6 h. After the reaction was completed, the product 34 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:5) with a yield of 34%.

[0165] 1 H NMR (400 MHz, CDCl 3 ): δ11.00(s,1H),8.01(d,J=6.9Hz,1H),7.44(dd,J=17.4,5.3Hz,1H),6.95–6.89(t,1H),6.24(s,1 H),4.88(t,1H),3.71(s,3H),3.14(d,J=5.6Hz,1H),3.02(dd,J=14.1,6.0Hz,1H),1.94ppm(s,3H); 13 C NMR (100 MHz, CDCl 3 ): δ171.9,169.9,153.9,138.7,133.5,127.6,124.1,119.5,52.4,52.0,32.0,22.8ppm.

[0166] The raw materials and product structural formulas of Examples 1 to 35 and the corresponding experimental results are shown in Table 1 below:

[0167] Table 1

[0168]

[0169]

[0170]

[0171]

[0172]

[0173] Embodiment 36

[0174] The method of Example 36 is the same as that of Example 33, except that the molar ratio of the aromatic compound, nitrite, hydrogen peroxide, amino acid derivative, and iron catalyst is 1:2:2:0.002:0.001.

[0175] Embodiment 37

[0176] The method of Example 37 is the same as that of Example 33, except that the molar ratio of the aromatic compound, nitrite, hydrogen peroxide, amino acid derivative, and iron catalyst is 1:50:50:20:10.

[0177] Embodiment 38

[0178] The method of Example 38 is the same as that of Example 33, except that the molar ratio of the aromatic compound, nitrite, hydrogen peroxide, amino acid derivative, and iron catalyst is 1:30:30:20:10.

[0179] Embodiment 39

[0180] The method of Example 39 is the same as that of Example 33, except that the solvent is all water and the total volume remains unchanged.

[0181] Comparative Example 1

[0182] The method of Comparative Example 1 is the same as that of Example 33, except that no iron catalyst is added and the yield of the target product is 0.

[0183] Comparative Example 2

[0184] The method of Comparative Example 2 is the same as that of Example 33, except that: without adding amino acid ligands, the reaction yield is greatly reduced, and the yield is less than 40%.

[0185] Comparative Example 3

[0186] The method of Comparative Example 3 is the same as that of Example 33, except that no oxidant is added and the yield of the target product is 0.

[0187] Comparative Example 4

[0188] Comparative Example 4 is the same as Example 33, except that: the non-amino acid ligand 1,10-phenanthroline is used, and the yield is only 8%. In addition, the use of other phosphorus-containing ligands, such as ethyldiphenylphosphine, diethylphenylphosphine; or nitrogen-containing ligands, such as neocuproine, is not effective and the yield is very low.

[0189] The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment, it is not used to limit the present invention. The various iron catalysts in the present invention can theoretically coordinate with amino acid ligands to form highly active iron catalyst species, which is conducive to the smooth progress of the reaction; amino acid ligands are promoters for the hydroxynitration reaction, and their coordination effect with iron is utilized. The various amino acids and their derivatives given in theory have coordination functions and should be able to achieve similar effects; various substituents on the aromatic ring affect the electron cloud density in the ring and the steric hindrance during the reaction, that is, the modification of the substituent only affects the reaction to a certain extent, and does not play a decisive role in the occurrence of the reaction. It is not difficult for any technician familiar with this profession to understand that without departing from the scope of the technical solution of the present invention, when changes or modifications can be made to obtain corresponding embodiments, for example, the substituents can be replaced, changed or modified within the scope of the present invention, and the method of the present invention can be realized. However, any modification, modification or equivalent and equivalent changes made to the above embodiments according to the present invention without departing from the purpose of the technical solution of the present invention still belong to the scope of the technical solution of the present invention.

Claims

1. A method for iron-catalyzed carbon-hydrogen bond hydroxylation and nitration of aromatic compounds, characterized in that: The method comprises the following steps: in a solvent, using nitrite as a nitrating agent, hydrogen peroxide as an oxidant, iron as a catalyst, and amino acids or their derivatives as ligands, catalyzing a carbon-hydrogen bond hydroxynitration reaction of the aromatic ring of an aromatic compound to generate a hydroxyl-nitro disubstituted aromatic compound; The general reaction formula is as follows: In the formula: Ar represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, and M represents a metal ion or a non-metal ion.

2. The method for iron-catalyzed aromatic compound carbon-hydrogen bond hydroxynitration according to claim 1, characterized in that: The aryl or heteroaryl group contains 1 to 4 aromatic rings, and the heteroaryl group contains 1 to 3 N, S or O atoms as heteroatoms.

3. The method for iron-catalyzed aromatic compound carbon-hydrogen bond hydroxynitration according to claim 1, characterized in that: The aryl group is phenyl, biphenyl or naphthyl; the heteroaryl group is carbazolyl, 2-benzoxazolinone, 2,3-dihydrobenzofuranyl or 3,4-dihydro-2(1H)quinolinone.

4. The method for iron-catalyzed aromatic compound carbon-hydrogen bond hydroxynitration according to claim 1, characterized in that: The substituted aryl or heteroaryl group may be a mono- or poly-substituted hydrogen atom on an aromatic or heteroaromatic ring, wherein the substituent is selected from hydrogen, methyl, methoxy, halogen, 1,2-methylenedioxy, amide, carbonyl, ester, cyano, nitro, pyrrolidone, morpholino, phenyl, phenoxy or benzyloxy.

5. The method for iron-catalyzed carbon-hydrogen bond hydroxynitration of aromatic compounds according to claim 1, characterized in that: The nitrite is preferably selected from any one of sodium nitrite, potassium nitrite, calcium nitrite, silver nitrite, iron nitrite, copper nitrite, cobalt nitrite, tert-butyl nitrite or ammonium nitrite.

6. The method for iron-catalyzed carbon-hydrogen bond hydroxylation and nitration of aromatic compounds according to claim 1, characterized in that: The iron is selected from any one of ferrous trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, ferrous chloride, ferrous acetylacetonate, ferrous acetylacetonate, ferrous 2,2,6,6-tetramethyl-3,5-heptanedione ferrous, ferrous 2,2,6,6-tetramethyl-3,5-heptanedione, ferrous 1,3-diphenylpropanedione, ferrous 1,3-diphenylpropanedione, ferrous benzoylacetonate, ferrous benzoylacetonate, ferrous ferrocyanide, ferrous ferrocyanide, ferrous acetate, ferrous sulfate, ammonium ferrous sulfate, ferrous sulfate, ferrous oxalate, ferrous oxalate, ferrous fluoride, ferrous fluoride, ferrous bromide, ferrous bromide, ferrous iodide, ferric chloride, iron (III) perchlorate hydrate, 1,1'-bis(diphenylphosphino)ferrocene, ferrous phthalocyanine, ferric nitrate, ferric oxide or ferric oxide.

7. The method for iron-catalyzed carbon-hydrogen bond hydroxynitration of aromatic compounds according to claim 1, characterized in that: The ligand is selected from any one of S-acetamidomethyl-N-tert-butyloxycarbonyl-L-cysteine, N-acetyl-L-cysteine, N,N'-bis(tert-butyloxycarbonyl)-L-cystine, L-serine, D-cystine, aspartic acid, D-arginine, isoserine, L-threonine, L-tyrosine, BOC-L-proline, BOC-glycine-glycine-glycine, 2-allyl-N-FMOC-L-glycine, BOC-D-phenylalanine, L-cysteine, D-serine, β-thiovaline, D-proline, D-valine, L-proline, L-phenylalanine, N-BOC-N'-trityl-L-histidine, L-tryptophan, N-BOC-L-leucine, L-histidine, BOC-L-glutamate, L-cystine or L-homocysteine.

8. The method for iron-catalyzed aromatic compound carbon-hydrogen bond hydroxynitration according to claim 1, characterized in that: The solvent is an organic solvent, water or an aqueous solution of an organic solvent, and the organic solvent is selected from methanol, ethanol, ethylene glycol, n-propanol, isopropanol, 1,3-propylene glycol, glycerol, n-butanol, isobutanol, tert-butanol, trifluoroethanol, 2-methyl-2-butanol, 3-methoxybutanol, sec-butanol, tert-amyl alcohol, 4-methyl-2-pentanol, isopentanol, 2-pentanol, 3-pentanol, cyclopentanol, n-pentanol, polyethylene glycol 200-10000, acetonitrile, benzonitrile, toluene, acetone, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-diformamide, N,N-diacetamide, ethyl acetate, 1,4-dioxane or tetrahydrofuran; when the solvent is an aqueous solution of an organic solvent, the volume ratio of the organic solvent to water is 1:(0.1-5).

9. The method for iron-catalyzed aromatic compound carbon-hydrogen bond hydroxynitration according to claim 1, characterized in that: The molar ratio of the aromatic compound, nitrite, hydrogen peroxide, amino acid or its derivative, and iron catalyst is 1:(2-50):(2-50):(0.002-20):(0.001-10).

10. The method for iron-catalyzed aromatic compound carbon-hydrogen bond hydroxynitration according to claim 1, characterized in that: The reaction temperature is 25 to 100° C. and the reaction time is 1 to 24 hours.

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