A method for synthesizing phenolic compounds by iron-catalyzed hydroxylation of aromatic compounds.

Abstract

This invention discloses a method for synthesizing phenolic compounds by iron-catalyzed hydroxylation of aromatic compounds. The method includes the following steps: in a solvent, iron acts as a catalyst, amino acids or their derivatives as ligands, and phenolic compounds are synthesized by catalytic oxidation of aromatic compounds under the action of an oxidizing agent and a reducing agent. This invention synthesizes phenolic compounds by catalytic oxidation of the C-H bonds of aromatic compounds. The method of this invention has advantages such as widely available and inexpensive catalysts; widely available, safe, and environmentally friendly oxidants; good compatibility of substrate functional groups and good reaction selectivity; and the ability to effectively convert complex small molecules into hydroxylated products. Under optimized reaction conditions, the yield of the target product after separation can reach 95%.

Description

Technical Field

[0001] This invention belongs to the fields of catalytic synthesis technology and fine chemical synthesis, specifically relating to a method for synthesizing phenolic compounds by iron-catalyzed hydroxylation of aromatic compounds. Background Technology

[0002] Phenolic compounds are not only widely found in drug molecules and natural products, but also serve as crucial intermediates in organic synthesis. For example, acetaminophen, belonging to the acetanilide class of antipyretic analgesics, is also used in the synthesis of the drug paracetamol, as an intermediate in organic synthesis, a photographic chemical, and a stabilizer for hydrogen peroxide. Salicylenol, a phenolic derivative, is clinically used for cholecystitis, cholangitis, cholelithiasis, and post-cholecystectomy syndrome. Eugenol is naturally found in essential oils such as clove oil, clove basil oil, and cinnamon oil. Furthermore, phenol itself is one of the most important bulk chemicals, with millions of tons produced annually from benzene via a three-step cumene process. However, this process has drawbacks, such as low yield, the formation of acetone as a byproduct, and high energy consumption. Therefore, synthetic methods based on the direct hydroxylation of aromatic compounds via the CH bond are of significant importance.

[0003] Several challenges remain in the current research on the CH-hydroxylation of aromatic compounds. For example, while transition metal catalysts have been developed for the direct hydrocarbon hydroxylation of aromatics, these methods typically require pre-installed directing groups and are 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 those using iron catalysis with amino acid ligands (L. Cheng, H. Wang, H. Cai, J. Zhang, X. Gong, W. Han, Science, 2021, 374, 77-81.) or methods using stoichiometric hazardous peroxides under metal-free conditions (L. Tanwar, J.). T. Ritter, J. Am. Chem. Soc. 2019, 141, 17983-17988., and the use of a solvent amount of benzene as the reaction substrate (K. Hirose, K. Ohkubo, S. Fukuzumi, Chem. AEur. J. 2016, 22, 12904.). These limitations severely restrict the large-scale application of this method. Summary of the Invention

[0004] Objective of the Invention: To address the problems existing in the prior art, this invention provides a method for synthesizing phenolic compounds through iron-catalyzed hydroxylation of aromatic compounds. This invention is a method for hydroxylating aromatic compounds by oxygen oxidation with iron. This method 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 hydroxylation of aromatic compounds with CH bonds, such as harsh reaction conditions, the need for pre-installation of directing groups, the need for the use of hazardous peroxides, the need for a limited amount of benzene as a substrate and the existence of over-oxidized products.

[0005] The method of this invention requires only one reaction step and features a wide range of readily available, inexpensive, and environmentally friendly catalysts; it uses inexpensive, environmentally friendly, and safer oxygen as an oxidant; the substrate is widely available and only one equivalent of benzene is needed to obtain the hydroxylated product; the reaction conditions are mild, avoiding the problem of excessive oxidation of the product, and it has good selectivity and high yield; the substrate has good functional group compatibility and a wide range of applicability; it is compatible with drug molecules and drug molecule derivatives, and can effectively achieve the CH bond hydroxylation of aromatic rings.

[0006] Technical solution: In order to achieve the above objectives, the present invention provides a method for synthesizing phenolic compounds by iron-catalyzed hydroxylation of aromatic compounds, comprising 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 under the action of a reducing agent, aromatic compounds are catalytically oxidized to synthesize phenolic compounds;

[0007] The general formula for the reaction 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 1-4 aromatic rings, and the heteroaryl group contains N atoms as heteroatoms.

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

[0011] The heteroaryl group is benzothiophene, pyridinyl, or indolyl.

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

[0013] The heteroaryl group is benzothiophene, pyridinyl, or indolyl.

[0014] The iron is selected from any one or more of the following: ferrous acetate, ferrous sulfate, ferrous ammonium sulfate, ferric sulfate, ferrous oxalate, ferric oxalate, ferrous fluoride, ferric fluoride, ferrous bromide, ferric bromide, ferrous iodide, ferric iodide, ferric chloride, ferric perchlorate (III) hydrate, 1,1'-bis(diphenylphosphine)ferrocene, ferrous phthalocyanine, ferric nitrate, iron oxide, iron tetroxide, ferrous trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, ferrous chloride, ferrous acetylacetone, ferric acetylacetone, ferrous 2,2,6,6-tetramethyl-3,5-heptadecyl iron, ferric 2,2,6,6-tetramethyl-3,5-heptadecyl iron, ferrous 1,3-diphenylpropanedione, ferric 1,3-diphenylpropanedione, ferric benzoylacetone, ferric benzoylacetone, ferrous ferric ferricyanide, and ferric ferricyanide.

[0015] The ligand is selected from any one or more of the following: L-serine, L-cysteine, 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'-triphenylmethyl-L-histidine, L-tryptophan, N-BOC-L-leucine, L-histidine, BOC-L-glutamic acid, L-cysteine, L-homocysteine, S-acetamidomethyl-N-tert-butoxycarbonyl-L-cysteine, N-acetyl-L-cysteine, and N,N'-bis(tert-butoxycarbonyl)-L-cysteine.

[0016] 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-mercaptoacetate, and calcium ascorbate.

[0017] Wherein, the solvent is an organic solvent, water, or an aqueous solution of an organic solvent, wherein 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-amyl alcohol, isoamyl alcohol, 2-amyl alcohol, cycloamyl alcohol, n-amyl alcohol, acetonitrile, benzonitrile, toluene, acetone, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dicarboxamide, 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, reducing agent, amino acid or its derivative, and iron catalyst is 1:(1-10):(0.002-20):(0.001-10).

[0019] The reaction is carried out at a temperature of 25–100°C for 1–24 hours.

[0020] The iron catalyst in the method of this invention is characterized by its high natural abundance, low cost, and low toxicity. Specific amino acid ligands are used to coordinate with the iron catalyst, forming a highly active catalytic species. This catalytic species, in conjunction with the reducing agent, oxygen, and solvent, exhibits high activity and selectivity. Furthermore, the method of this invention uses atmospheric oxygen, an environmentally friendly and safer oxidant, avoiding the use of hazardous peroxides; the reaction directly attacks the aromatic ring without pre-functionalization, and requires only one equivalent of benzene as the substrate, avoiding the use of solvent-level benzene, resulting in high atom economy; iron is used as the catalyst, eliminating the use of precious metals and demonstrating significant effectiveness; the reaction conditions are mild, avoiding the problem of over-oxidation. The method of this invention has the advantages of a widely available, inexpensive, and environmentally friendly catalyst; an environmentally friendly and pollution-free oxidant; mild reaction conditions and good selectivity; good compatibility of substrate functional groups; and a wide range of substrate applicability. Under optimized reaction conditions, the yield of the target product after separation can reach 95%.

[0021] This invention first oxidizes low-valent iron to high-valent iron under acidic conditions with oxygen, simultaneously generating hydroxyl radicals. These hydroxyl radicals undergo electrophilic addition with aromatic rings, leading to the oxidative dehydrogenation of the aromatic rings to yield phenolic compounds. The high-valent iron is then reduced back to low-valent iron by a reducing agent, thus completing the catalytic cycle. Existing effective methods for obtaining aromatic ring C-H bond oxidation typically use hydrogen peroxide, palladium metal catalysts, and titanium dioxide, but the quantity and selectivity of direct hydroxylation remain limited. This invention uses oxygen as both the oxidant and oxygen source, directly adding oxygen from the oxygen molecule into the aromatic molecule. This oxidant is environmentally friendly, pollution-free, and safer. This invention employs a reducing agent activation strategy, introducing amino acids or their derivatives to coordinate with the iron catalyst, forming a highly active catalytic species. Using oxygen at ambient pressure as the oxidant provides milder and safer reaction conditions, thus solving problems such as poor functional group tolerance, the presence of over-oxidized products, and the use of hazardous peroxides as oxidants in existing aromatic compound C-H bond hydroxylation methods. As demonstrated in the embodiments of this invention, electron-withdrawing, electron-donating, and easily oxidized groups are all tolerated. This invention employs a reducing agent activation strategy, enabling the method to efficiently utilize oxygen as an oxidant and achieve high-yield and highly selective conversion of benzene compounds into phenolic compounds, which is difficult to achieve with current catalytic methods.

[0022] The synthesis method of this invention does not require a directing group, employs a reducing agent activation strategy, uses oxygen as an oxidant and iron as a catalyst, exhibiting high activity and good selectivity, and operates under mild and safe reaction conditions. Furthermore, the method of this invention achieves efficient hydroxylation using only equivalent amounts of benzene as substrates, without requiring solvent amounts of benzene as a reaction substrate, thus demonstrating the high activity and practical value of this method.

[0023] The method of this invention does not require prefunctionalization, employs a reducing agent activation strategy, uses an iron catalyst, and uses oxygen as the oxidant, resulting in milder and safer reaction conditions. Only one equivalent of benzene is needed as the reaction substrate, avoiding the use of a solvent amount of benzene, thus achieving high atom economy. Electron-withdrawing groups such as carbonyl, carboxyl, and cyano groups, electron-donating groups such as methyl and methoxy groups, and easily oxidized groups such as aldehyde groups are all tolerated. This invention uses oxygen as the oxidant to achieve direct hydroxylation of aromatic CH groups, avoiding the use of unstable hydrogen peroxide as the oxidant in existing methods, and also avoiding products of over-oxidation.

[0024] In this embodiment of the invention, hydroxylation can be achieved using an equivalent amount of benzene as a substrate, without the need for a solvent amount of benzene as a reaction substrate. This demonstrates 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) This invention provides a method for iron-catalyzed CH bond hydroxylation of aromatic compounds promoted by amino acids and their derivatives. This method requires only one step and has the unique advantages of safe, environmentally friendly, and widely available catalysts, ligands, and oxidants; mild reaction conditions and high selectivity; widely available, stable, and easy-to-process substrates; good compatibility of substrate functional groups and a wide range of substrate applicability; experimental results demonstrate that the reaction is suitable for the hydroxylation of drug molecules and their derivatives.

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

[0028] (3) The reason why the method of the present invention can use ideal iron as a catalyst is that it adopts a reducing agent activation strategy and uses amino acid ligands to coordinate with the iron catalyst. Under the action of oxygen, a highly active catalytic species is formed, which enables the reaction to carry out the CH bond hydroxylation reaction of aromatic compounds under very mild conditions. In particular, it can also achieve ideal catalytic effects on drug molecules and their derivatives.

[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. They are widely used in the synthesis of pharmaceutical intermediates and high-value-added fine chemicals. For example, in Example 18 of the present invention, acetanilide can be directly synthesized into p-hydroxyacetanilide (p-acetaminophen) by the method of the present invention, which can be used as an antipyretic analgesic. Detailed Implementation

[0030] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0031] Unless otherwise specified, the experimental methods described in the embodiments are conventional methods; unless otherwise specified, the reagents and materials can be obtained commercially or through simple preparation using existing technologies.

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

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

[0034] The oxygen used in the examples is all under normal pressure conditions. That is, the oxygen content at normal pressure refers to the concentration of oxygen at 1 atmosphere or the oxygen inhaled at standard atmospheric pressure (101.325 kPa). At normal pressure, the density of oxygen is 1.429 kg / m³. 3 Its concentration is generally around 21%.

[0035] Example 1

[0036] Synthesis of Compound 1

[0037] In a 25 mL reaction flask, ferrous oxalate (0.05 mmol), L-cysteine ​​(0.1 mmol), substrate 1a (0.5 mmol), ethanol (2.0 mL), and ascorbic acid (3 mmol) were added sequentially in oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 80 °C for 9 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 10:0.5) yielded product 1 in 79% yield.

[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 a 25 mL reaction flask, ferric chloride (0.1 mmol), L-homocysteine ​​(0.2 mmol), substrate 2a (1 mmol), methanol (2.0 mL), and formic acid (3 mmol) were added sequentially in oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 80 °C for 10 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 10:3) yielded product 2 in 78% yield.

[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 a 25 mL reaction flask, ferrous trifluoromethanesulfonate (0.1 mmol), aspartic acid (0.3 mmol), substrate 3a (1 mmol), tert-butanol (2.0 mL), and sodium formate (3 mmol) were added sequentially in oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 25 °C for 14 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 10:3) yielded product 3 in 76% yield.

[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 a 25 mL reaction flask, ferrous chloride (0.1 mmol), S-acetaminomethyl-N-tert-butoxycarbonyl-L-cysteine ​​(1.0 mmol), substrate 4a (1 mmol), isopropanol (1.5 mL), water (2.5 mL), and benzaldehyde (3 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 80 °C for 12 h. Upon completion of the reaction, direct chromatography (petroleum ether:dichloromethane V / V = 10:5) yielded product 4 in 70% yield.

[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 a 25 mL reaction flask, ferrous acetylacetone (0.02 mmol), BOC-L-glutamic acid (0.04 mmol), substrate 5a (1 mmol), glycerol (1.5 mL), water (0.5 mL), and uracil (1 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 60 °C for 8 h. Upon completion of the reaction, 5 mL of water was added, and the mixture was extracted with diethyl ether (5 mL × 3). The organic phases were combined, and after solvent removal under reduced pressure, column chromatography (petroleum ether: ethyl acetate V / V = 10:1) was performed to give product 5 in 53% yield.

[0054] Example 6

[0055] Synthesis of Compound 6

[0056] In a 25 mL reaction flask, 0.08 mmol of acetylacetone iron, 0.16 mmol of L-tyrosine, 1 mmol of substrate 6a, 2.0 mL of n-butanol, and 5 mmol of glucose were added sequentially in oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 85 °C for 8 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 1:1) yielded product 6 in 73% yield.

[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] In a 25 mL reaction flask, ferric trifluoromethanesulfonate (0.05 mmol), L-cysteine ​​(0.1 mmol), substrate 7a (1 mmol), acetonitrile (2.0 mL), and glutathione (1.5 mmol) were added sequentially to oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 60 °C for 24 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 10:1) yielded product 7 in 65% yield.

[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 a 25 mL reaction flask, ferrous fluoride (0.1 mmol), N,N'-bis(tert-butyloxycarbonyl)-L-cysteine ​​(0.4 mmol), substrate 8a (1 mmol), acetonitrile (1.5 mL), water (1.5 mL), and formic acid (1 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 80 °C for 7 h. Upon completion of the reaction, 5 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, and after solvent removal under reduced pressure, the mixture was separated by column chromatography (petroleum ether:ethyl acetate V / V = 10:1) to give product 8 in 59% yield.

[0065] Example 9

[0066] Synthesis of Compound 9

[0067] In a 25 mL reaction flask, 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 sequentially in oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 60 °C for 12 h. Upon completion of the reaction, direct chromatography (petroleum ether:dichloromethane V / V = 10:5) yielded product 9 in 60% yield.

[0068] Example 10

[0069] Synthesis of Compound 10

[0070] In a 25 mL reaction flask, 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 sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 80 °C for 8 h. At the end of the reaction, 5 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with water (5 mL × 3), and the organic phase was collected. After removing the solvent under reduced pressure, the mixture was separated by column chromatography (petroleum ether: dichloromethane V / V = 10:5) to give product 10 in 58% yield.

[0071] Example 11

[0072] Synthesis of Compound 11

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

[0074] Example 12

[0075] Synthesis of Compound 12

[0076] In a 25 mL reaction flask, 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 sequentially to oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 60 °C for 12 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 10:7) yielded product 12 in 62% yield.

[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] Example 13

[0079] Synthesis of Compound 13

[0080] In a 25 mL reaction flask, ferrous ferricyanide (0.005 mmol), L-serine (0.1 mmol), substrate 13a (0.5 mmol), dimethyl sulfoxide (2.0 mL), and uracil (1 mmol) were added sequentially in oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 70 °C for 7 h. Upon completion of the reaction, direct chromatography (petroleum ether: diethyl ether V / V = 10:4) yielded product 13 in 53% yield.

[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] Example 14

[0083] Synthesis of Compound 14

[0084] In a 25 mL reaction flask, ferric ferricyanide (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 sequentially in oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 60 °C for 10 h. Upon completion of the reaction, 5 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, and after solvent removal under reduced pressure, column chromatography (petroleum ether:ethyl acetate V / V = 10:1) was performed to obtain product 14 in 62% yield.

[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] Example 15

[0087] Synthesis of Compound 15

[0088] In an oxygen-rich environment, 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 sequentially to a 25 mL reaction flask. After thorough mixing at room temperature, the reaction mixture was reacted at 70 °C for 8 h. Upon completion of the reaction, 5 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, and after solvent removal under reduced pressure, the mixture was separated by column chromatography (petroleum ether:ethyl acetate V / V = 15:1) to give product 15 in 45% yield.

[0089] Example 16

[0090] Synthesis of Compound 16

[0091] In a 25 mL reaction flask, 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 sequentially to oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 90 °C for 3 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 20:3) yielded product 16 in 63% yield.

[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] Example 17

[0094] Synthesis of Compound 17

[0095] In a 25 mL reaction flask, 0.04 mmol of 1,3-diphenylpropanedione iron, 0.04 mmol of L-cysteine, 0.5 mmol of substrate 17a, 2.0 mL of N,N-diacetamide, and 1 mmol of formic acid were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 90 °C for 6 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 20:3) yielded product 17 in 75% yield.

[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] Example 18

[0098] Synthesis of Compound 18

[0099] In a 25 mL reaction flask, 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 sequentially in oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 60 °C for 8 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 1:1) yielded product 18 in 67% yield.

[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] Example 19

[0102] Synthesis of Compound 19

[0103] In a 25 mL reaction flask, 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 sequentially in oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 60 °C for 12 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 1:1) yielded product 19 in 68% yield.

[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] Example 20

[0106] Synthesis of Compound 20

[0107] In a 25 mL reaction flask, ferrous 1,3-diphenylpropanedione (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 sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 90 °C for 4 h. Upon completion of the reaction, 5 mL of water was added, and the mixture was extracted with diethyl ether (5 mL × 3). The organic phases were combined, and after solvent removal under reduced pressure, the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 20:3) to give product 20 in 80% yield.

[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] Example 21

[0110] Synthesis of Compound 21

[0111] In a 25 mL reaction flask, ferrous chloride (0.05 mmol), BOC-D-phenylalanine (0.03 mmol), substrate 21a (0.5 mmol), sec-butanol (2.0 mL), and lithium formate (2 mmol) were added sequentially in oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 50 °C for 24 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 10:1) yielded product 21 in 85% yield.

[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] Example 22

[0114] Synthesis of Compound 22

[0115] In a 25 mL reaction flask, ferrous ammonium sulfate (0.1 mmol), N,N'-bis(tert-butyloxycarbonyl)-L-cysteine ​​(0.4 mmol), substrate 22a (0.5 mmol), ethylene glycol (2.0 mL), and lithium formate (1 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 70 °C for 9 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 10:1) yielded product 22 in 83% yield.

[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] Example 23

[0118] Synthesis of Compound 23

[0119] In a 25 mL reaction flask, ferric perchlorate (III) 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 sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 100 °C for 2 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 10:1) yielded product 23 in 80% yield.

[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] Example 24

[0122] Synthesis of Compound 24

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

[0124] Example 25

[0125] Synthesis of Compound 25

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

[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] Example 26

[0129] Synthesis of Compound 26

[0130] In a 25 mL reaction flask, ferric oxalate (0.05 mmol), 2-allyl-N-FMOC-L-glycine (0.08 mmol), substrate 26a (0.5 mmol), methyl p-toluene (1 mmol), tert-amyl alcohol (2.0 mL), and ascorbic acid (1 mmol) were added sequentially in oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 40 °C for 12 h. Upon completion of the reaction, direct chromatography (petroleum ether:diethyl ether V / V = 10:3) yielded product 26 in 55% yield.

[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] Example 27

[0133] Synthesis of Compound 27

[0134] In a 25 mL reaction flask, ferrous 2,2,6,6-tetramethyl-3,5-heptadecane (0.05 mmol), D-serine (0.1 mmol), substrate 27a (0.5 mmol), isobutanol (1.5 mL), water (0.5 mL), and sodium 2-mercaptoacetate (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 70 °C for 6 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 10:5) yielded product 27 in 68% yield.

[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] Example 28

[0137] Synthesis of Compound 28

[0138] In a 25 mL reaction flask, ferrous iodide (0.05 mmol), D-arginine (0.1 mmol), substrate 28a (0.5 mmol), benzonitrile (2 mL), and sodium 2-mercaptoacetate (2 mmol) were added sequentially in oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 80 °C for 14 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 1:1) yielded product 28 in 57% yield.

[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] Example 29

[0141] Synthesis of Compound 29

[0142] In a 25 mL reaction flask, 1,1'-bis(diphenylphosphine)ferrocene (0.02 mmol), L-cysteine ​​(0.1 mmol), substrate 29a (0.5 mmol), N,N-dicarboxamide (1.5 mL), water (0.5 mL), and sodium 2-mercaptoacetate (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 25 °C for 15 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 1:1) yielded product 29 in 90% yield.

[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] Example 30

[0145] Synthesis of Compound 30

[0146] In a 25 mL reaction flask, 0.1 mmol of 2,2,6,6-tetramethyl-3,5-heptadecyl iron, 0.2 mmol of N-BOC-N'-triphenylmethyl-L-histidine, 0.5 mmol of substrate 30a, 2.0 mL of ethanol, and 2 mmol of sodium 2-mercaptoacetate were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 60 °C for 12 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 40:3) yielded product 30 in 61% yield.

[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] Example 31

[0149] Synthesis of Compound 31

[0150] In a 25 mL reaction flask, 0.1 mmol of 2,2,6,6-tetramethyl-3,5-heptadecyl iron, 0.2 mmol of N-BOC-N'-triphenylmethyl-L-histidine, 0.5 mmol of substrate 31a, 2.0 mL of ethanol, and 2 mmol of sodium 2-mercaptoacetate were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 60 °C for 12 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 40:3) yielded product 31 in 65% of the product.

[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] Example 32

[0153] Synthesis of Compound 32

[0154] In a 25 mL reaction flask, 0.1 mmol of 2,2,6,6-tetramethyl-3,5-heptadecyl iron, 0.2 mmol of N-BOC-N'-triphenylmethyl-L-histidine, 0.5 mmol of substrate 32a, 2.0 mL of ethanol, and 1.5 mmol of lithium formate were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 80 °C for 9 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 10:3) yielded product 32 in 70% yield.

[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] Example 33

[0157] Synthesis of Compound 33

[0158] In a 25 mL reaction flask, 0.04 mmol of 1,3-diphenylpropanedione, 0.2 mmol of N-BOC-N'-triphenylmethyl-L-histidine, 0.5 mmol of substrate 33a, 2.0 mL of ethanol, and 2 mmol of sodium 2-mercaptoacetate were added sequentially to oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 60 °C for 12 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 1:1) yielded product 33 in 95% yield.

[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] Example 34

[0161] Synthesis of Compound 34

[0162] In a 25 mL reaction flask, 0.1 mmol of 2,2,6,6-tetramethyl-3,5-heptadecyl iron, 0.2 mmol of N-BOC-N'-triphenylmethyl-L-histidine, 0.5 mmol of substrate 34a, 2.0 mL of ethanol, and 2 mmol of sodium 2-mercaptoacetate were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 70 °C for 12 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 2:1) yielded product 34 in 80% yield.

[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] Example 35

[0165] Synthesis of Compound 35

[0166] In a 25 mL reaction flask, 0.04 mmol of 1,3-diphenylpropanedione, 0.2 mmol of N-BOC-N'-triphenylmethyl-L-histidine, 0.5 mmol of substrate 35a, 2.0 mL of ethanol, and 1.5 mmol of lithium formate were added sequentially in oxygen. After thorough mixing at room temperature, the reaction mixture was reacted at 60 °C for 12 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 40:3) yielded product 35 in 70% yield.

[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 structural formulas of the raw materials and products in Examples 1-35 and the corresponding experimental results are shown in Table 1 below:

[0169] Table 1

[0170]

[0171]

[0172]

[0173]

[0174] Example 36

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

[0176] Example 37

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

[0178] Example 38

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

[0180] Comparative Example 1

[0181] Comparative Example 1 uses the same method as Example 33, except that no iron catalyst is added and the yield of the target product is 0.

[0182] Comparative Example 2

[0183] Comparative Example 2 uses the same method as Example 33, except that no amino acid ligands are added, which greatly reduces the reaction yield to less than 20%.

[0184] Comparative Example 3

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

[0186] Comparative Example 4

[0187] Comparative Example 4 follows the same method as Example 33, except that it uses a non-amino acid ligand, 1,10-phenanthroline, with a yield of only 10%. Furthermore, other phosphorus-containing ligands, such as ethyldiphenylphosphine, triphenylphosphine, and bis(triphenylphosphine)ammonium chloride, also showed poor results and very low yields.

[0188] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the invention. Theoretically, various iron catalysts in this invention can coordinate with amino acid ligands to form highly active iron catalyst species, thereby facilitating the smooth progress of the reaction. Amino acid ligands are promoters for the hydroxylation reaction of aromatic compounds, utilizing their ability to coordinate with iron. Theoretically, various amino acids and their derivatives all possess coordination functions and should achieve similar effects. Hydroxylation involves the breaking of carbon-hydrogen bonds, while various substituents on the aromatic ring affect the electron cloud density within the ring and the steric hindrance during the reaction. That is, the modification of substituents only affects the reaction to a certain extent and does not play a decisive role in the occurrence of the reaction. Anyone skilled in the art will readily understand that, without departing from the scope of the technical solution of this invention, variations or modifications can be made to obtain corresponding embodiments. For example, the substituents can be replaced, changed, or modified within the scope of this invention to achieve the method of this invention. Any modifications, alterations, or equivalent changes made to the above embodiments based on the present invention without departing from the spirit of the present invention shall still fall within the scope of the present invention.

Claims

1. A method for synthesizing phenolic compounds by iron-catalyzed hydroxylation of aromatic compounds, characterized in that, The process includes the following steps: In a solvent, oxygen acts as an oxidant, iron as a catalyst, and amino acids or their derivatives as ligands. 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 is phenyl, pyrene, or biphenyl; the heteroaryl group is benzothiophene, pyridinyl, or indolyl; the substituent in the substituted aryl group or the substituted heteroaryl group is selected from methyl, isopropyl, methoxy, fluorine, chlorine, bromine, iodine, carboxyl, cyano, nitro, trifluoromethyl, aldehyde, borate, hydroxyl or acetyl-protected amino group or N-tert-butoxycarbonyl-protected amino group; 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-mercaptoacetate, and calcium ascorbate. The ligand is selected from any one or more of the following: L-serine, L-cysteine, 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'-triphenylmethyl-L-histidine, L-tryptophan, N-BOC-L-leucine, L-histidine, BOC-L-glutamic acid, L-cysteine, L-homocysteine, S-acetamidomethyl-N-tert-butoxycarbonyl-L-cysteine, N-acetyl-L-cysteine, and N,N'-bis(tert-butoxycarbonyl)-L-cysteine. The iron is selected from any one or more of the following: ferrous acetate, ferrous sulfate, ferrous ammonium sulfate, ferric sulfate, ferrous oxalate, ferric oxalate, ferrous fluoride, ferric fluoride, ferrous bromide, ferric bromide, ferrous iodide, ferric iodide, ferric chloride, ferric perchlorate (III) hydrate, 1,1'-bis(diphenylphosphine)ferrocene, ferrous phthalocyanine, ferric nitrate, ferric oxide, ferrous trifluoromethanesulfonate, ferric trifluoromethanesulfonate, ferrous chloride, ferrous acetylacetone, ferric acetylacetone, ferrous 2,2,6,6-tetramethyl-3,5-heptadecyl iron, ferric 2,2,6,6-tetramethyl-3,5-heptadecyl iron, ferrous 1,3-diphenylpropanedione, ferric 1,3-diphenylpropanedione, ferric benzoylacetone, ferric benzoylacetone, ferrous ferric ferricyanide, and ferric ferricyanide.

2. The method for synthesizing phenolic compounds by iron-catalyzed hydroxylation of aromatic compounds according to claim 1, characterized in that, The solvent is an organic solvent, water, or an aqueous solution of an organic solvent. 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-amyl alcohol, isoamyl alcohol, 2-amyl alcohol, cycloamyl alcohol, n-amyl alcohol, acetonitrile, benzonitrile, toluene, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dicarboxamide, 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).

3. The method for synthesizing phenolic compounds by iron-catalyzed hydroxylation of aromatic compounds according to claim 1, characterized in that, The molar ratio of the aromatic compound, reducing agent, ligand, and iron catalyst is 1:(1-10):(0.002-20):(0.001-10).

4. The method for synthesizing phenolic compounds by iron-catalyzed hydroxylation of aromatic compounds according to claim 1, characterized in that, The reaction is carried out at a temperature of 25–100°C for 1–24 hours.

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