Method for synthesizing phenolic compound through hydroxylation reaction of aromatic compound under catalysis of iron

Abstract

The invention discloses a method for synthesizing phenolic compounds by catalyzing hydroxylation reaction of aromatic compounds by iron, which comprises the following step: in a solvent, catalyzing and oxidizing aromatic compounds to synthesize phenolic compounds by taking iron as a catalyst and amino acid or derivatives thereof as ligands under the action of an oxidizing agent and a reducing agent. According to the method, the phenolic compound is synthesized by carrying out hydroxylation on the C-H bond of the catalytic oxidation aromatic compound. The method has the advantages that the catalyst is wide in source and low in cost; the oxidant is wide in source, safe and environment-friendly; the compatibility of substrate functional groups is good, and the reaction selectivity is good; complex small molecules can be well converted into hydroxylated products, and the like. According to the method disclosed by the invention, under optimized reaction conditions, the yield of the separated target product can reach 95%.

Description

Technical Field

[0001] The invention belongs to the field of catalytic synthesis technology and fine chemical synthesis, and particularly relates to a method for synthesizing phenolic compounds through an iron-catalyzed hydroxylation reaction of aromatic compounds. Background Art

[0002] Phenolic compounds are not only widely present in drug molecules and natural products, but also very important intermediates in organic synthesis. For example, paracetamol, which belongs to the acetanilide antipyretic analgesic, can also be used in the synthesis of the drug paracetamol, as well as an organic synthesis intermediate, a photographic chemical and a stabilizer for hydrogen peroxide. Salicylic acid is a phenol derivative, which is clinically applicable to cholecystitis, choledochitis, cholelithiasis and post-cholecystectomy syndrome. Eugenol is naturally present in essential oils such as clove oil, clove basil oil and cinnamon oil. In addition, phenol itself is one of the most important bulk chemicals, and millions of tons are produced from benzene through a three-step isopropylbenzene process every year, but the process has disadvantages such as low yield, the generation of acetone as a by-product, and high energy consumption. Therefore, the synthesis method based on the direct hydroxylation of the CH bond of aromatic compounds is of great significance.

[0003] There are still some challenges in the current CH bond hydroxylation of aromatic compounds. For example, although transition metal catalysts have been developed for direct hydrocarbon hydroxylation of aromatics, this method usually requires the pre-installation of directing groups and is limited to ortho-hydroxylation (Z. Iqbal, A. Joshi, S. Ranjan De, Adv. Synth. Catal. 2020, 362, 5301-5351.). Non-directed methods have also been reported, such as the use of iron catalysis with amino acid ligands (L. Cheng, H. Wang, H. Cai, J. Zhang, X. Gong, W. Han, Science, 2021, 374, 77-81.) or the use of stoichiometric dangerous peroxides under metal-free conditions (L. Tanwar, J. T. Ritter, J. Am. Chem. Soc. 2019, 141, 17983-17988.), and the use of solvent-based benzene as a reaction substrate (K. Hirose, K. Ohkubo, S. Fukuzumi, Chem. AEur. J. 2016, 22, 12904.). These severely limit the large-scale application of this method. 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 synthesizing phenolic compounds by iron-catalyzed hydroxylation of aromatic compounds. The present invention is a method for hydroxylating the CH bonds of aromatic compounds by iron-catalyzed oxygen oxidation. The method of the present invention not only provides an economical and applicable new method for the synthesis of phenolic compounds, but also solves a series of problems existing in the existing CH bond hydroxylation reaction of aromatic compounds, such as harsh reaction conditions, the need to pre-install directing groups, the need to use hazardous peroxides, the need to use solvent amounts of benzene as a substrate with a limited substrate range, and the presence of over-oxidized products.

[0005] The method of the invention only needs one step of reaction, and has the characteristics of wide source of catalyst, low cost and environmental protection; uses cheap, environmentally friendly and safer oxygen as an oxidant; has wide source of substrate and only needs 1 equivalent of benzene as substrate to obtain hydroxylated product; has mild reaction conditions, avoids the problem of excessive oxidation of products, has good selectivity and high yield; has good compatibility of substrate functional groups and wide application range of substrate; drug molecules and drug molecule derivatives are compatible, and can well realize CH bond hydroxylation of aromatic ring.

[0006] Technical solution: In order to achieve the above-mentioned purpose, the method for synthesizing phenolic compounds by iron-catalyzed hydroxylation of aromatic compounds of the present invention comprises the following steps: in a solvent, oxygen is used as an oxidant, iron is used as a catalyst, and amino acids or their derivatives are used as ligands, and aromatic compounds are catalytically oxidized to synthesize phenolic compounds under the action of a reducing agent;

[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; the aryl group or heteroaryl group contains 1 to 4 aromatic rings, and the heteroaryl group contains a N atom as a heteroatom.

[0010] Wherein, the aryl group is phenyl, pyrenyl or biphenyl; and the heteroaryl group is a nitrogen-containing heteroaryl group.

[0011] Wherein, the heteroaryl group is benzothienyl, pyridyl or indolyl.

[0012] Wherein, the substituent in the substituted aryl or substituted heteroaryl is selected from methyl, isopropyl, methoxy, aryl, ester, fluorine, chlorine, bromine, iodine, carbonyl, carboxyl, ester, cyano, nitro, trifluoromethyl, aldehyde, boric acid, hydroxyl or acetyl protected amino or N-tert-butyloxycarbonyl protected amino.

[0013] Wherein, the heteroaryl group is benzothienyl, pyridyl or indolyl.

[0014] Wherein, the iron is selected from any one or more of 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, ferric tetroxide, ferrous trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, ferrous chloride, ferrous acetylacetonate, ferrous acetylacetonate, 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, ferrous benzoyl acetonate, ferrous benzoyl acetonate, ferrous ferrocyanide, and ferric ferrocyanide.

[0015] Wherein, the ligand is selected from any one or more of L-serine, L-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, L-homocystine, S-acetamidomethyl-N-tert-butyloxycarbonyl-L-cysteine, N-acetyl-L-cysteine, and N,N'-bis(tert-butyloxycarbonyl)-L-cystine.

[0016] Wherein, the reducing agent is selected from any one or more of sodium ascorbate, ascorbic acid, formic acid, sodium formate, benzaldehyde, glutathione, uracil, glucose, lithium formate, D-glucuronic acid, sodium 2-thioglycolate, and calcium ascorbate.

[0017] 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, glycerol, n-butanol, isobutanol, tert-butanol, trifluoroethanol, 2-methyl-2-butanol, 3-methoxybutanol, tert-amyl alcohol, 4-methyl-2-pentanol, isopentanol, 2-pentanol, cyclopentanol, n-pentanol, 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).

[0018] The molar ratio of the aromatic compound, the reducing agent, the amino acid or its derivative, and the iron catalyst is 1:(1-10):(0.002-20):(0.001-10).

[0019] Wherein, the reaction temperature is 25-100° C. and the reaction time is 1-24 hours.

[0020] The iron catalyst in the method of the present invention has the characteristics of large 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. This catalytic species works together with a reducing agent, oxygen, a solvent, etc., and has high activity and selectivity. In addition, the method of the present invention uses oxygen at normal pressure, which is an environmentally friendly and safer oxidant, to avoid the use of dangerous peroxides; the reaction directly attacks the aromatic ring without pre-functionalization, and only requires 1 equivalent of benzene as a reaction substrate, avoiding the use of benzene in the amount of solvent, and has high atomic economy; iron is a catalyst, no precious metals are used, and the effect is significant; the reaction conditions are mild, avoiding the problem of over-oxidation. The method of the present invention has the advantages of a wide source of catalysts, low cost and environmental protection; the oxidant is environmentally friendly and pollution-free; the reaction conditions are mild and the selectivity is good; the substrate functional group compatibility is good and the substrate has a wide range of applications. Under optimized reaction conditions, the yield of the target product after separation can reach 95%.

[0021] The present invention first oxidizes low-valent iron to high-valent iron under acidic conditions with oxygen, and generates hydroxyl radicals at the same time. Hydroxyl radicals undergo electrophilic addition with aromatic rings, and aromatic rings are oxidized and dehydrogenated to obtain phenolic compounds. High-valent iron is reduced by a reducing agent and converted into low-valent iron, thereby completing the catalytic cycle. The existing effective method for obtaining aromatic ring carbon-hydrogen bond oxidation usually uses hydrogen peroxide, metal catalyst palladium and titanium dioxide, but the number of direct hydroxylations and their selectivity are still limited. The present invention uses oxygen as an oxidant and an oxygen source, and directly adds oxygen in oxygen molecules to aromatic molecules. The oxidant is environmentally friendly and pollution-free and safer. The present invention adopts a reducing agent activation strategy, and by introducing amino acids or their derivatives, coordinates with iron catalysts to form highly active catalytic species, and atmospheric pressure oxygen is used as an oxidant. The reaction conditions are mild and safer, thereby solving the problems of poor tolerance of functional groups, the presence of over-oxidized products, and the use of dangerous peroxides as oxidants in the existing aromatic compound CH bond hydroxylation methods. As shown in the embodiments of the present invention, electron-withdrawing, electron-donating groups and easily oxidizable groups can be tolerated. The present invention adopts a reducing agent activation strategy, so that the method can efficiently utilize oxygen as an oxidant, and achieves high-yield and high-selectivity conversion from benzene compounds to phenolic compounds, which is difficult to achieve with current catalytic methods.

[0022] The synthesis method of the present invention does not require a directing group, adopts a reducing agent activation strategy, uses oxygen as an oxidant, and iron as a catalyst, has high activity, good selectivity, and mild and safe reaction conditions. The method of the present invention uses equivalent benzene as a substrate to achieve efficient hydroxylation without using a solvent amount of benzene as a reaction substrate, thereby reflecting the high activity of the method of the present invention and more practical value.

[0023] The method of the present invention does not require pre-functionalization, adopts a reducing agent activation strategy, uses an iron catalyst, and oxygen is used as an oxidant, and the reaction conditions are milder and safer. The raw material, such as benzene, only needs to use 1 equivalent as a reaction substrate, avoiding the use of benzene in the amount of solvent, and the atom economy is high. Electron-withdrawing groups such as carbonyl, carboxyl cyano, etc., electron-donating groups such as methyl, methoxy, etc., and easily oxidizable groups such as aldehyde groups can all be tolerated. The present invention uses oxygen as an oxidant to achieve direct hydroxylation of aromatic CH, avoiding the existing use of unstable hydrogen peroxide as an oxidant, while avoiding over-oxidized products.

[0024] In the embodiment of the present invention, hydroxylation can be achieved by using an equivalent amount of benzene as a substrate, without using a solvent amount of benzene as a reaction substrate, thereby reflecting that the method of the present invention has high activity and greater practical value.

[0025] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0026] (1) The present invention provides a method for the iron-catalyzed CH bond hydroxylation of aromatic compounds promoted by amino acid and derivative ligands. The method requires only one step of reaction and has the unique advantages of safe, environmentally friendly, wide-source and environmentally friendly catalysts, ligands and oxidants; mild reaction conditions and high selectivity; wide, stable and easy-to-handle substrate sources; good compatibility of substrate functional groups and a wide range of substrate applications; experimental results prove that the reaction is suitable for the hydroxylation of drug molecules and their derivatives;

[0027] (2) The iron-catalyzed CH bond hydroxylation method provided by the present invention is simple, easy and safe, and the hydroxylation product of the aromatic compound can be directly obtained in one step. Under the optimized reaction conditions, the yield of the target product after separation can reach 95%. It is a universal, efficient, economical and environmentally friendly method for the CH bond hydroxylation of aromatic compounds;

[0028] (3) The reason why the method of the present invention can use ideal iron as a catalyst for the reaction is that the key lies in adopting a reducing agent activation strategy and using amino acid ligands to coordinate with the iron catalyst. Under the action of oxygen, highly active catalytic species are formed, thereby enabling the reaction to be carried out under very mild conditions for the hydroxylation of the CH bonds of aromatic compounds, especially for drug molecules and their derivatives. An ideal catalytic effect can also be achieved.

[0029] (4) The phenolic 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, acetanilide in Example 18 of the present invention can be directly synthesized into para-hydroxyacetanilide (acetaminophen) by the method of the present invention, which can be used as an antipyretic and analgesic. DETAILED DESCRIPTION

[0030] 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.

[0031] 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.

[0032] The specific structures of the substrates and products in the examples are shown in Table 1.

[0033] The reaction substrates 1a-1ai and product compounds in the present invention are all reported compounds.

[0034] The oxygen in the embodiments is under normal pressure oxygen conditions, that is, the content of normal pressure oxygen refers to the concentration of oxygen under 1 atmosphere or refers to the oxygen inhaled under standard atmospheric pressure (101.325 kPa). Under normal pressure, the density of oxygen is 1.429 kg / m 3 , its concentration is generally around 21%.

[0035] Example 1

[0036] Synthesis of compound 1

[0037] In oxygen, ferrous oxalate (0.05 mmol), L-cystine (0.1 mmol), substrate 1a (0.5 mmol), ethanol (2.0 mL) and ascorbic acid (3 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 80 ° C for 9 h. After the reaction was completed, the product 1 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:0.5) with a yield of 79%.

[0038] 1H NMR (400MHz, CDCl3): δ7.71(d,J=8.0Hz,1H),7.31(d,J=2.0Hz,1H),7.11(dd,J=8.0,2.0Hz, 1H),3.65(t,J=7.4Hz,2H),1.84(s,1H),1.64(m,2H),1.35(m,2H),0.94(t,J=7.4Hz,3H)ppm. 13 C NMR (100MHz, CDCl3): δ168.5,168.5,161.5,134.8,125.3,123.8,120.3,110.5,37.9,30.7,20.1,13.6ppm.

[0039] Example 2

[0040] Synthesis of compound 2

[0041] In oxygen, ferric chloride (0.1 mmol), L-homocystine (0.2 mmol), substrate 2a (1 mmol), methanol (2.0 mL) and formic acid (3 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 80°C for 10 h. After the reaction was completed, the product 2 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:3) with a yield of 78%.

[0042] 1 H NMR (400MHz, CDCl3): δ7.91 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.93 (brs, 1H), 2.57 (s, 3H) ppm. 13 C NMR (100MHz, CDCl3): δ197.2,160.1,131.0,130.3,115.3,26.4ppm.

[0043] Example 3

[0044] Synthesis of compound 3

[0045] In oxygen, ferrous trifluoromethanesulfonate (0.1 mmol), aspartic acid (0.3 mmol), substrate 3a (1 mmol), tert-butyl alcohol (2.0 mL) and sodium formate (3 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 25 °C for 14 h. After the reaction was completed, the product 3 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:3) with a yield of 76%.

[0046] 1H NMR (400MHz, CDCl3): δ7.96 (d, J = 8.8Hz, 2H), 6.87 (d, J = 8.7Hz, 2H), 5.82 (brs, 1H), 3.89 (s, 3H) ppm. 13 C NMR (100MHz, CDCl3): δ167.0,159.9,131.9,122.6,115.2,52.0ppm.

[0047] Example 4

[0048] Synthesis of compound 4

[0049] In oxygen, ferrous chloride (0.1mmol), S-acetylaminomethyl-N-tert-butyloxycarbonyl-L-cysteine ​​(1.0mmol), substrate 4a (1mmol), isopropanol (1.5mL), water (2.5mL) and benzaldehyde (3mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 80℃ for 12h. The reaction was completed, and the product 4 was directly separated by chromatography (petroleum ether: dichloromethane V / V=10:5) with a yield of 70%.

[0050] 1 H NMR (400MHz, CDCl3): δ7.56 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H) ppm. 13 CNMR (100MHz, CDCl3): δ159.4,134.3,119.1,116.3,104.1ppm.

[0051] Example 5

[0052] Synthesis of compound 5

[0053] In oxygen, ferrous acetylacetonate (0.02 mmol), BOC-L-glutamic acid (0.04 mmol), substrate 5a (1 mmol), glycerol (1.5 mL) and water (0.5 mL), and uracil (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 60 ° C for 8 h. After the reaction was completed, 5 mL of water was added, and ether was extracted (5 mL × 3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was separated (petroleum ether: ethyl acetate V / V = 10:1) to obtain product 5 with a yield of 53%.

[0054] Example 6

[0055] Synthesis of compound 6

[0056] In oxygen, ferric acetylacetonate (0.08 mmol), L-tyrosine (0.16 mmol), substrate 6a (1 mmol), n-butanol (2.0 mL) and glucose (5 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 85 °C for 8 h. After the reaction was completed, the product 6 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 1:1) with a yield of 73%.

[0057] 1 H NMR (400MHz, CD3COCD3): δ9.26 (brs, 1H), 7.91 (d, J = 8.8Hz, 2H), 6.91 (d, J = 8.8Hz, 2H) ppm. 13 C NMR (100MHz, CD3COCD3): δ167.5,162.6,132.7,122.6,115.9ppm.

[0058] Example 7

[0059] Synthesis of compound 7

[0060] Iron trifluoromethanesulfonate (0.05 mmol), L-cystine (0.1 mmol), substrate 7a (1 mmol), acetonitrile (2.0 mL), and glutathione (1.5 mmol) were added to a 25 mL reaction bottle in oxygen. After mixing well at room temperature, the reaction mixture was reacted at 60°C for 24 h. After the reaction was completed, the product 7 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:1) with a yield of 65%.

[0061] 1 H NMR (400MHz, CDCl3): δ7.19 (dt, J=8.8, 2.6Hz, 2H), 6.77 (dt, J=8.8, 2.6Hz, 2H), 4.86 (brs, 1H)ppm. 13 C NMR (100MHz, CDCl3): δ154.1, 129.5, 125.7, 116.6ppm.

[0062] Example 8

[0063] Synthesis of compound 8

[0064] In oxygen, ferrous fluoride (0.1mmol), N,N'-bis(tert-butyloxycarbonyl)-L-cystine (0.4mmol), substrate 8a (1mmol), acetonitrile (1.5mL), water (1.5mL) and formic acid (1mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 80℃ for 7h. After the reaction was completed, 5mL of water was added, and extracted with ethyl acetate (5mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed (petroleum ether: ethyl acetate V / V=10:1) to obtain product 8 with a yield of 59%.

[0065] Example 9

[0066] Synthesis of compound 9

[0067] In oxygen, ferrous iodide (0.08 mmol), N-acetyl-L-cysteine ​​(0.32 mmol), substrate 9a (1 mmol), trifluoroethanol (2.0 mL) and sodium formate (2 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 60°C for 12 h. After the reaction was completed, the product 9 was directly separated by chromatography (petroleum ether: dichloromethane V / V = 10:5) with a yield of 60%.

[0068] Example 10

[0069] Synthesis of compound 10

[0070] In oxygen, ferrous sulfate (0.05 mmol), L-cysteine ​​(0.1 mmol), substrate 10a (0.5 mmol), dimethyl sulfoxide (1.5 mL), water (0.5 mL) and sodium formate (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 80 ° C for 8 h. After the reaction was completed, 5 mL of water was added, and ethyl acetate was extracted (5 mL × 3), the organic phases were combined, washed with water (5 mL × 3), and the organic phases were collected. The solvent was evaporated under reduced pressure and separated by column chromatography (petroleum ether: dichloromethane V / V = 10:5) to obtain product 10 with a yield of 58%.

[0071] Embodiment 11

[0072] Synthesis of compound 11

[0073] In oxygen, ferric iodide (0.05 mmol), aspartic acid (0.1 mmol), substrate 11a (0.5 mmol), 1,3-propylene glycol (4.0 mL) and sodium formate (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 25 ° C for 24 h. After the reaction was completed, 5 mL of water was added, and ethyl acetate was extracted (5 mL × 3), the organic phases were combined, washed with water (5 mL × 3), and the organic phases were collected. The solvent was evaporated under reduced pressure and separated by column chromatography (petroleum ether: dichloromethane V / V = 10:5) to obtain product 11 with a yield of 45%.

[0074] Example 12

[0075] Synthesis of compound 12

[0076] In oxygen, ferrous fluoride (0.02 mmol), BOC-glycine-glycine-glycine (0.2 mmol), substrate 12a (0.5 mmol), dichloromethane (2.0 mL) and uracil (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing well at room temperature, the reaction mixture was reacted at 60 ° C for 12 h. After the reaction was completed, the product 12 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:7) with a yield of 62%.

[0077] 1 H NMR (400MHz, CDCl3): δ10.60(brs,1H),9.82(brs,1H),7.08(dd,J=8.8,3.0Hz,1H),7.01(d,J=3.0Hz,1H),6.90(d,J=8.8Hz,1H)ppm. 13 C NMR (100MHz, CDCl3): δ196.0,155.9,148.3,125.4,120.2,118.7,118.0ppm.

[0078] Embodiment 13

[0079] Synthesis of compound 13

[0080] In oxygen, ferrocyanide (0.005 mmol), L-serine (0.1 mmol), substrate 13a (0.5 mmol), dimethyl sulfoxide (2.0 mL) and uracil (1 mmol) were added to a 25 mL reaction bottle in sequence. After being mixed evenly at room temperature, the reaction mixture was reacted at 70 ° C for 7 h. After the reaction was completed, the product 13 was directly separated by chromatography (petroleum ether: ether V / V = 10:4) with a yield of 53%.

[0081] 1H NMR (400MHz, CDCl3): δ8.66 (dd, J=6.8, 1.8Hz, 1H), 7.84 (dd, J=6.8, 1.8Hz, 1H), 7 .49–7.43(m,3H),7.29(t,J=7.8Hz,1H),6.78(d,J=7.8Hz,1H),5.60(brs,1H)ppm. 13 C NMR (100MHz, CDCl3): δ153.0,141.4,138.5,135.0,127.0,125.9,125.8,124.4,123.7,122.1,115.2,110.4ppm.

[0082] Embodiment 14

[0083] Synthesis of compound 14

[0084] In oxygen, ferric ferrocyanide (0.05 mmol), BOC-L-proline (0.002 mmol), substrate 14a (0.5 mmol), acetonitrile (1.0 mL), water (1.0 mL) and uracil (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 60 ° C for 10 h. After the reaction was completed, 5 mL of water was added, and ethyl acetate (5 mL × 3) was used for extraction. The organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed (petroleum ether: ethyl acetate V / V = 10:1) to obtain product 14 with a yield of 62%.

[0085] 1 H NMR (400MHz, CDCl3): δ7.53(t,J=6.8Hz,2H),7.47(d,J=8.8Hz,2H),7.41(t,J=7.2Hz,2H),7.30(t,J=7.2Hz,1H),6.90(t,J=8.8Hz,2H),4.82(brs,1H). 13 C NMR (100MHz, CDCl3): δ154.9,140.7,134.0,128.7,128.3,126.7,115.6ppm.

[0086] Embodiment 15

[0087] Synthesis of compound 15

[0088] In oxygen, ferrous phthalocyanine (0.02 mmol), L-histidine (0.15 mmol), substrate 15a (0.5 mmol), 1,2-dichloroethane (2.0 mL) and uracil (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 70 ° C for 8 h. After the reaction was completed, 5 mL of water was added, and ethyl acetate (5 mL × 3) was used for extraction. The organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed (petroleum ether: ethyl acetate V / V = 15:1) to obtain product 15 with a yield of 45%.

[0089] Example 16

[0090] Synthesis of compound 16

[0091] In oxygen, ferrous trifluoromethanesulfonate (0.05 mmol), BOC-D-phenylalanine (0.1 mmol), substrate 16a (0.5 mmol), ethyl acetate (2.0 mL) and formic acid (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 90°C for 3 h. After the reaction was completed, the product 16 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:3) with a yield of 63%.

[0092] 1 H NMR (400MHz, CDCl3): δ6.81-6.78(m,2H),6.78-6.74(m,2H),4.46(brs,1H),3.76(s,3H)ppm. 13 C NMR (100MHz, CDCl3): δ153.8, 149.4, 116.0, 114.8, 55.8ppm.

[0093] Embodiment 17

[0094] Synthesis of compound 17

[0095] In oxygen, 1,3-diphenylpropanedione iron (0.04 mmol), L-cysteine ​​(0.04 mmol), substrate 17a (0.5 mmol), N,N-diethylamide (2.0 mL) and formic acid (1 mmol) were added to a 25 mL reaction bottle in sequence, mixed evenly at room temperature, and the reaction mixture was reacted at 90°C for 6 h. After the reaction was completed, the product 17 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:3) with a yield of 75%.

[0096] 1H NMR (400MHz, CDCl3): δ7.17 (d, J = 8.8 Hz, 2H), 6.74 (dt, J = 8.8, 2.8 Hz, 2H), 6.33 (brs, 1H), 5.14 (brs, 1H), 1.51 (s, 9H) ppm. 13 C NMR (100MHz, CDCl3): δ153.5,151.9,131.1,121.3,115.7,80.4,28.4ppm.

[0097] Embodiment 18

[0098] Synthesis of compound 18

[0099] In oxygen, ferrous oxalate (0.1 mmol), BOC-L-proline (0.1 mmol), substrate 18a (0.5 mmol), 1,4-dioxane (2.0 mL) and formic acid (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 60 ° C for 8 h. After the reaction was completed, the product 18 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 1:1) with a yield of 67%.

[0100] 1 H NMR (400MHz, CD3COCD3): δ8.94(brs,1H),8.17(brs,1H),7.46–7.42(m,2H),6.76–6.72(m,2H),2.02(s,3H)ppm. 13 C NMR (100MHz, CD3COCD3): δ168.2, 154.2, 132.7, 121.6, 115.8, 24.0ppm.

[0101] Embodiment 19

[0102] Synthesis of compound 19

[0103] In oxygen, ferrous sulfate (0.05 mmol), D-valine (0.15 mmol), substrate 19a (0.5 mmol), toluene (2.0 mL) and formic acid (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 60°C for 12 h. After the reaction was completed, the product 19 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 1:1) with a yield of 68%.

[0104] 1H NMR (400MHz, CD3COCD3): δ9.81(brs,1H),9.23(brs,1H),7.46(d,J=8.6Hz,1H),7.06(d,J=2.2Hz,1H),6.97(dd,J=8.6,2.2Hz,1H),2.20(s,3H)ppm. 13 C NMR (100MHz, CD3COCD3): δ171.2,150.1,127.3,123.9,123.3,121.1,117.9,23.6ppm.

[0105] Embodiment 20

[0106] Synthesis of compound 20

[0107] In oxygen, 1,3-diphenylpropanedione ferrous acid (0.08 mmol), BOC-L-glutamic acid (0.4 mmol), substrate 20a (0.5 mmol), tetrahydrofuran (1.0 mL), water (1.0 mL) and lithium formate (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 90 ° C for 4 h. After the reaction was completed, 5 mL of water was added, and ether was extracted (5 mL × 3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was separated (petroleum ether: ethyl acetate V / V = 20:3) to obtain product 20 with a yield of 80%.

[0108] 1 H NMR (400MHz, CDCl3): δ6.18(s,2H),5.10(brs,1H),3.86(s,6H),3.76(s,3H)ppm. 13 C NMR (100MHz, CDCl3): δ153.0,147.3,129.0,91.7,56.2,55.7ppm.

[0109] Embodiment 21

[0110] Synthesis of compound 21

[0111] In oxygen, ferrous chloride (0.05 mmol), BOC-D-phenylalanine (0.03 mmol), substrate 21a (0.5 mmol), sec-butyl alcohol (2.0 mL) and lithium formate (2 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 50 °C for 24 h. After the reaction was completed, the product 21 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:1) with a yield of 85%.

[0112] 1H NMR (400MHz, CDCl3): δ10.64(brs,1H),6.82(d,J=2.8Hz,1H),6.67(d,J=2.8Hz,1H),3.94(s,3H),3.86(s,3H),3.77(s,3H)ppm. 13 C NMR (100MHz, CDCl3): δ170.6,151.7,149.2,147.0,111.3,106.7,101.0,56.1,55.7,52.4ppm.

[0113] Embodiment 22

[0114] Synthesis of compound 22

[0115] In oxygen, ammonium ferrous sulfate (0.1 mmol), N,N'-bis(tert-butyloxycarbonyl)-L-cystine (0.4 mmol), substrate 22a (0.5 mmol), ethylene glycol (2.0 mL) and lithium formate (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 70°C for 9 h. After the reaction was completed, the product 22 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:1) with a yield of 83%.

[0116] 1 H NMR (400MHz, CDCl3): δ12.22(brs,1H),6.72–6.69(m,2H),3.88(s,3H),3.80(s,3H),2.62(s,3H)ppm. 13 C NMR (100MHz, CDCl3): δ204.4,151.4,149.7,147.8,118.5,107.0,102.4,56.2,55.8,27.1ppm.

[0117] Embodiment 23

[0118] Synthesis of compound 23

[0119] Iron (III) perchlorate hydrate (0.05 mmol), L-tryptophan (0.5 mmol), substrate 23a (0.5 mmol), glycerol (2.0 mL), and lithium formate (1.5 mmol) were added to a 25 mL reaction bottle in oxygen. After mixing well at room temperature, the reaction mixture was reacted at 100 ° C for 2 h. After the reaction was completed, the product 23 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:1) with a yield of 80%.

[0120] 1H NMR (400MHz, CDCl3): δ10.69(s,1H),9.89(s,1H),6.75(d,J=2.8Hz,1H),6.59(d,J=2.8Hz,1H),3.90(s,3H),3.82(s,3H)ppm. 13 C NMR (100MHz, CDCl3): δ196.1,152.8,149.1,146.6,119.5,107.9,103.9,56.3,55.8ppm.

[0121] Embodiment 24

[0122] Synthesis of compound 24

[0123] In oxygen, iron oxide (0.2 mmol), L-homocystine (0.1 mmol), substrate 24a (0.5 mmol), cyclopentanol (2.0 mL) and ascorbic acid (2 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 60 ° C for 9 h. After the reaction was completed, 5 mL of water was added, and ethyl acetate was extracted (5 mL × 3), the organic phases were combined, washed with water (5 mL × 3), and the organic phases were collected. The solvent was evaporated under reduced pressure and separated by column chromatography (petroleum ether: dichloromethane V / V = 10:7) to obtain product 24 with a yield of 54%.

[0124] Embodiment 25

[0125] Synthesis of compound 25

[0126] In oxygen, iron benzoyl acetonate (0.05 mmol), N-BOC-L-leucine (0.1 mmol), substrate 25a (0.5 mmol), tert-amyl alcohol (1.5 mL) and water (0.5 mL), and ascorbic acid (2 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 80 ° C for 3 h. After the reaction was completed, 5 mL of water was added, and extracted with ethyl acetate (5 mL × 3), the organic phases were combined, washed with water (5 mL × 3), and the organic phases were collected. The solvent was evaporated under reduced pressure and separated by column chromatography (petroleum ether: dichloromethane V / V = 10:7) to obtain product 25 with a yield of 87%.

[0127] 1 H NMR (400MHz, DMSO-d6): δ10.65(brs,1H),8.34(d,J=9.0Hz,1H),8.12(dd,J=8.0 ,5.2Hz,3H),8.06–7.94(m,3H),7.89(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H)ppm. 13CNMR (100MHz, DMSO-d6): δ152.2,131.4,131.3,127.4,126.2,126.1,125.5,125.4,124.5,123.9,123.8,123.6,121.4,118.1,113.2ppm.

[0128] Embodiment 26

[0129] Synthesis of compound 26

[0130] In oxygen, ferric oxalate (0.05 mmol), 2-allyl-N-FMOC-L-glycine (0.08 mmol), substrate 26a (0.5 mmol), methyl p-toluate (1 mmol), tert-amyl alcohol (2.0 mL) and ascorbic acid (1 mmol) were added to a 25 mL reaction bottle in sequence. After mixing well at room temperature, the reaction mixture was reacted at 40 ° C for 12 h. After the reaction was completed, the product 26 was directly separated by chromatography (petroleum ether: ether V / V = 10:3) with a yield of 55%.

[0131] 1 H NMR (400MHz, CDCl3): δ7.25 (t, J = 7.4Hz, 2H), 6.94 (t, J = 7.4Hz, 1H), 6.84 (d, J = 8.4Hz, 2H), 4.80 (brs, 1H) ppm. 13 C NMR (100MHz, CDCl3): δ155.4, 129.7, 120.8, 115.2ppm.

[0132] Embodiment 27

[0133] Synthesis of compound 27

[0134] In oxygen, 2,2,6,6-tetramethyl-3,5-heptanedione ferrous acid (0.05mmol), D-serine (0.1mmol), substrate 27a (0.5mmol), isobutyl alcohol (1.5mL), water (0.5mL) and sodium 2-thioglycolate (2mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 70°C for 6h. After the reaction was completed, the product 27 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:5) with a yield of 68%.

[0135] 1 H NMR (400MHz, CDCl3): δ6.89-6.86(m,2H),6.84-6.80(m,2H),5.20(brs,2H)ppm. 13C NMR (100MHz, CDCl3): δ143.4, 121.3, 115.5ppm.

[0136] Embodiment 28

[0137] Synthesis of compound 28

[0138] In oxygen, ferrous iodide (0.05 mmol), D-arginine (0.1 mmol), substrate 28a (0.5 mmol), benzonitrile (2 mL) and sodium 2-thioglycolate (2 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 80 ° C for 14 h. After the reaction was completed, the product 28 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 1:1) with a yield of 57%.

[0139] 1 H NMR (400MHz, CD3COCD3): δ7.68 (brs, 3H), 6.51 (t, J = 8.0Hz, 1H), 6.36 (d, J = 8.0Hz, 2H) ppm. 13 C NMR (100MHz, CD3COCD3): δ146.7,133.7,119.9,108.0ppm.

[0140] Embodiment 29

[0141] Synthesis of compound 29

[0142] In oxygen, 1,1'-bis(diphenylphosphino)ferrocene (0.02mmol), L-cystine (0.1mmol), substrate 29a (0.5mmol), N,N-diformamide (1.5mL), water (0.5mL) and sodium 2-thioglycolate (2mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 25℃ for 15h. After the reaction was completed, the product 29 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 1:1) with a yield of 90%.

[0143] 1 H NMR (400MHz, CD3COCD3): δ8.54(brs,2H),7.47(d,J=2.0Hz,1H),7.44(dd,J=8.2,2.0Hz,1H),6.89(d,J=8.2Hz,1H),2.46(s,3H)ppm. 13 C NMR (100MHz, CD3COCD3): δ196.2,150.8,145.7,131.0,122.8,115.6,115.1,26.2ppm.

[0144] Embodiment 30

[0145] Synthesis of compound 30

[0146] In oxygen, 2,2,6,6-tetramethyl-3,5-heptanedione iron (0.1mmol), N-BOC-N'-trityl-L-histidine (0.2mmol), substrate 30a (0.5mmol), ethanol (2.0mL) and sodium 2-thioglycolate (2mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 60°C for 12h. After the reaction was completed, the product 30 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 40:3) with a yield of 61%.

[0147] 1 H NMR (400MHz, CDCl3): δ6.78(d,J=8.0Hz,1H),6.76(d,J=2.0Hz,1H),6.66(dd,J=8.0,2 .0Hz,1H),5.20(brs,1H)5.07(brs,1H),2.85-2.75(m,1H),1.20(d,J=6.9Hz,6H)ppm. 13 C NMR (100MHz, CDCl3): δ143.3,142.4,141.2,118.7,115.2,113.5,33.4,24.2ppm.

[0148] Embodiment 31

[0149] Synthesis of compound 31

[0150] In oxygen, 2,2,6,6-tetramethyl-3,5-heptanedione iron (0.1 mmol), N-BOC-N'-trityl-L-histidine (0.2 mmol), substrate 31a (0.5 mmol), ethanol (2.0 mL) and sodium 2-thioglycolate (2 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 60°C for 12 h. After the reaction was completed, the product 31 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 40:3) with a yield of 65%.

[0151] 1 H NMR (400MHz, CDCl3): δ12.51(brs,1H),7.66(dd,J=5.2,3.2Hz,2H),7.60–7.55(m ,1H),7.53–7.48(m,2H),7.13(s,1H),6.57(s,1H),5.23(s,1H),3.99(s,3H)ppm. 13C NMR (100MHz, CDCl3): δ200.0,160.1,153.8,138.2,137.7,131.4,128.7,128.3,116.7,111.7,99.9,56.3ppm.

[0152] Embodiment 32

[0153] Synthesis of compound 32

[0154] In oxygen, 2,2,6,6-tetramethyl-3,5-heptanedione iron (0.1 mmol), N-BOC-N'-trityl-L-histidine (0.2 mmol), substrate 32a (0.5 mmol), ethanol (2.0 mL) and lithium formate (1.5 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 80°C for 9 h. After the reaction was completed, the product 32 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:3) with a yield of 70%.

[0155] 1 H NMR (400MHz, CD3COCD3): δ8.94(brs,1H),8.10(brs,1H),7.32(d,J=2.4Hz,1H), 7.27(dd,J=8.4,2.4Hz,1H),6.72(d,J=8.4Hz,1H),2.15(s,3H),2.03(s,3H)ppm. 13 CNMR (100MHz, CD3COCD3): δ168.5,152.3,132.3,124.9,123.1,119.0,115.2,24.0,16.3ppm.

[0156] Embodiment 33

[0157] Synthesis of compound 33

[0158] In oxygen, 1,3-diphenylpropanedione iron (0.04mmol), N-BOC-N'-trityl-L-histidine (0.2mmol), substrate 33a (0.5mmol), ethanol (2.0mL) and sodium 2-thioglycolate (2mmol) were added to a 25mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 60℃ for 12h. After the reaction was completed, the product 33 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 1:1) with a yield of 95%.

[0159] 1H NMR (400MHz, DMSO-d6): δ9.55(brs,1H),8.92(brs,1H),8.54(brs,1H),7.13(d,J =2.4Hz,1H),6.74(dd,J=8.4,2.4Hz,1H),6.60(d,J=8.4Hz,1H),1.96(s,3H)ppm. 13 CNMR (100MHz, DMSO-d6): δ167.4,144.8,141.0,131.5,115.2,110.1,107.7,23.9ppm.

[0160] Embodiment 34

[0161] Synthesis of compound 34

[0162] In oxygen, 2,2,6,6-tetramethyl-3,5-heptanedione iron (0.1 mmol), N-BOC-N'-trityl-L-histidine (0.2 mmol), substrate 34a (0.5 mmol), ethanol (2.0 mL) and sodium 2-thioglycolate (2 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 70°C for 12 h. After the reaction was completed, the product 34 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 2:1) with a yield of 80%.

[0163] 1 H NMR (400MHz, CD3COCD3): δ10.20(brs,1H),8.78(brs,1H),7.11(s,1H),6.93(s,1H)ppm. 13 C NMR (100MHz, CD3COCD3): δ155.1,149.3,144.2,124.5,115.8,115.2,100.1ppm.

[0164] Embodiment 35

[0165] Synthesis of compound 35

[0166] In oxygen, 1,3-diphenylpropanedione iron (0.04 mmol), N-BOC-N'-trityl-L-histidine (0.2 mmol), substrate 35a (0.5 mmol), ethanol (2.0 mL) and lithium formate (1.5 mmol) were added to a 25 mL reaction bottle in sequence. After mixing evenly at room temperature, the reaction mixture was reacted at 60°C for 12 h. After the reaction was completed, the product 35 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 40:3) with a yield of 70%.

[0167] 1H NMR (400MHz, CDCl3): δ7.76(d,J=8.4Hz,1H),7.01(d,J=2.4Hz,1H),6.93(dd,J=8.4,2.4Hz,1H),6.53(brs,1H),3.91(s,3H),3.87(s,3H)ppm. 13 C NMR (100MHz, CDCl3): δ169.2,166.9,159.0,135.7,131.9,121.9,117.2,115.3,52.9,52.5ppm.

[0168] The raw materials and product structural formulas of Examples 1 to 35 and the corresponding experimental results are shown in Table 1 below:

[0169] Table 1

[0170]

[0171]

[0172]

[0173]

[0174] Embodiment 36

[0175] The method of Example 36 is the same as that of Example 33, except that the molar ratio of the aromatic compound, the reducing agent, the amino acid or its derivative, and the iron catalyst is 1:1:0.8:0.4.

[0176] Embodiment 37

[0177] The method of Example 37 is the same as that of Example 33, except that the molar ratio of the aromatic compound, the reducing agent, the amino acid or its derivative, and the iron catalyst is 1:10:20:10.

[0178] Embodiment 38

[0179] The method of Example 38 is the same as that of Example 33, except that the solvent is all water and the total volume remains unchanged.

[0180] Comparative Example 1

[0181] 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.

[0182] Comparative Example 2

[0183] 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 20%.

[0184] Comparative Example 3

[0185] The method of Comparative Example 3 is the same as that of Example 33, except that: under nitrogen conditions, the yield of the target product is 0.

[0186] Comparative Example 4

[0187] Comparative Example 4 is the same as the method of Example 33, except that: using non-amino acid ligand 1,10-phenanthroline, the productive rate is only 10%. In addition, using other phosphorus-containing ligands, such as ethyl diphenyl phosphine, triphenyl phosphine, bis (triphenylphosphine) ammonium chloride, the effect is not good, and the productive rate is very low.

[0188] 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 hydroxylation reaction of aromatic compounds, and the effect of their coordination 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; hydroxylation occurs by breaking the carbon-hydrogen bond, and the various substituents on the aromatic ring affect the size of the electron cloud density in the ring and the size of 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. Any technician familiar with this profession will not be difficult 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. Any modification, alteration or 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 shall still fall within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing phenolic compounds by hydroxylation of aromatic compounds catalyzed by iron, characterized in that: The method comprises the following steps: in a solvent, oxygen is used as an oxidant, iron is used as a catalyst, amino acids or their derivatives are used as ligands, and under the action of a reducing agent, aromatic compounds are catalytically oxidized to synthesize phenolic compounds; 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; the aryl group or heteroaryl group contains 1 to 4 aromatic rings, and the heteroaryl group contains a N atom as a heteroatom.

2. The method for synthesizing phenolic compounds by hydroxylation of aromatic compounds catalyzed by iron according to claim 1, characterized in that: The aryl group is phenyl, pyrenyl or biphenyl; the heteroaryl group is a nitrogen-containing heteroaryl group.

3. The method for synthesizing phenolic compounds by hydroxylation of aromatic compounds catalyzed by iron according to claim 1, characterized in that: The heteroaryl group is preferably benzothienyl, pyridyl or indolyl.

4. The method for synthesizing phenolic compounds by hydroxylation of aromatic compounds catalyzed by iron according to claim 1, characterized in that: The substituents in the substituted aryl or substituted heteroaryl are selected from methyl, isopropyl, methoxy, aryl, ester, fluorine, chlorine, bromine, iodine, carbonyl, carboxyl, ester, cyano, nitro, trifluoromethyl, aldehyde, boric acid, hydroxyl or acetyl protected amino or N-tert-butyloxycarbonyl protected amino.

5. The method for synthesizing phenolic compounds by hydroxylation of aromatic compounds catalyzed by iron according to claim 1, characterized in that: The iron is selected from any one or more of 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, ferric tetroxide, ferrous trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, ferrous chloride, ferrous acetylacetonate, ferrous acetylacetonate, 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, ferrous benzoylacetonate, ferrous benzoylacetonate, ferrous ferrocyanide, and ferric ferrocyanide.

6. The method for synthesizing phenolic compounds by hydroxylation of aromatic compounds catalyzed by iron according to claim 1, characterized in that: The ligand is selected from any one or more of L-serine, L-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, L-homocysteine, S-acetamidomethyl-N-tert-butyloxycarbonyl-L-cysteine, N-acetyl-L-cysteine, and N,N'-bis(tert-butyloxycarbonyl)-L-cystine.

7. The method for synthesizing phenolic compounds by hydroxylation of aromatic compounds catalyzed by iron according to claim 1, characterized in that: The reducing agent is selected from any one or more of sodium ascorbate, ascorbic acid, formic acid, sodium formate, benzaldehyde, glutathione, uracil, glucose, lithium formate, D-glucuronic acid, sodium 2-thioglycolate, and calcium ascorbate.

8. The method for synthesizing phenolic compounds by hydroxylation of aromatic compounds catalyzed by iron 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, glycerol, n-butanol, isobutanol, tert-butanol, trifluoroethanol, 2-methyl-2-butanol, 3-methoxybutanol, tert-amyl alcohol, 4-methyl-2-pentanol, isopentanol, 2-pentanol, cyclopentanol, n-pentanol, 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 synthesizing phenolic compounds by hydroxylation of aromatic compounds catalyzed by iron according to claim 1, characterized in that: The molar ratio of the aromatic compound, the reducing agent, the amino acid or its derivative, and the iron catalyst is 1:(1-10):(0.002-20):(0.001-10).

10. The method for synthesizing phenolic compounds by hydroxylation of aromatic compounds catalyzed by iron according to claim 1, characterized in that: The reaction temperature is 25-100° C. and the reaction time is 1-24 hours.

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