A method for hydroxylating of alkenes by iron catalysis

Abstract

This invention discloses an iron-catalyzed method for the hydroxylation of alkenes. The method includes the following steps: in a solvent, using nitrostyrene compounds and alkenes as substrates, peroxides as oxidants, iron as catalysts, and amino acids and their derivatives as ligands, the hydroxylation of alkenes is catalyzed to generate alkenylated alcohols. This method can synthesize alkenylated alcohols in one step, is simple, and utilizes widely available and inexpensive catalysts and oxidants. The reaction conditions are mild and highly selective. It uses 1-2 equivalents of olefin substrates, exhibiting good functional group compatibility and a wide range of substrate applicability. Drug molecules and their derivatives are compatible, achieving the hydroxylation of alkenes. Under optimized reaction conditions, the yield of the target product after separation can reach 86%.

Description

Technical Field

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

[0002] Alcohols are an important class of organic compounds with wide applications in chemistry, materials science, medicine, and biology. For example, tanshinone has antibacterial, anti-inflammatory, blood-activating, and wound-healing effects; ergosterol is also a pharmaceutical intermediate and an important chemical raw material; lignans are natural plant extracts; and warfarin is an anticoagulant commonly used in clinical medicine. Bifunctionalization of alkenes is a powerful method for constructing multifunctional compounds, rapidly increasing molecular complexity and playing a significant role in the synthesis of target molecules. Furthermore, hydroxyl and alkenyl groups serve as key intermediates in organic synthesis, used for later functionalization, and can provide a large number of other functional groups. Therefore, simultaneously introducing aryl alkenes and hydroxyl groups through alkenes holds great potential for biological and pharmaceutical applications.

[0003] Several challenges remain in current olefin bifunctionalization reactions, such as limited substrates, numerous reaction steps (Y.-J. Jang et al. / Tetrahedron. 2004, 60, 6565–6574), the fact that most methods utilize ring-opening of epoxides, resulting in high reaction temperatures and uneconomical results (L. Jin-Song, Z. Hai-Pin, Chem. Commun. 2019, 55, 11123–11126), the use of noble metal catalysis, and the predominance of cyclic compounds as substrates (T. Shenghan, Malcolm E. Tessensohn, Richard D. Webster, and Z. Jianrong Steve, ACS Catal. 2018, 8, 7439−7444). Furthermore, the limited expansion to complex molecules severely restricts 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 the hydroxylation of alkenes by iron-catalyzed oxidation. This invention is a method for the hydroxylation of alkenes by iron-catalyzed oxidation with a suitable oxidant. This method not only provides an economical and applicable new method for the synthesis of alcohols, but also introduces olefin functional groups, which is beneficial for the further transformation of subsequent compounds. This method solves a series of problems existing in the hydroxylation reaction, such as multiple reaction steps, low reaction yield, and the need to use noble metal catalysts.

[0005] The method of this invention requires only one reaction step, uses a small amount of olefin substrate, and features a wide range of catalyst sources that are inexpensive and environmentally friendly; the oxidant is inexpensive and has low toxicity; the substrate is widely available and stable; the reaction conditions are mild and the selectivity is good; the substrate functional groups are compatible and the substrate has a wide range of applicability; the reaction conditions are mild, the selectivity is good and the yield is high; it is compatible with drug molecules and drug molecule derivatives, and can effectively achieve the hydroxylation reaction of alkenes.

[0006] Technical solution: In order to achieve the above objectives, the present invention provides a method for iron-catalyzed hydroxylization of alkenes, comprising the following steps: in a solvent, using nitrostyrene compounds and alkenes as substrates, peroxides as oxidants, iron as catalysts, and amino acids or their derivatives as ligands, catalyzing the hydroxylization of alkenes to generate alkenyl alcohol compounds.

[0007] The general formula for the reaction is as follows:

[0008] ;

[0009] In the formula: R1 represents hydrogen, C1-C4 alkyl, methoxy, tert-butyl, cyano, trifluoromethyl, trifluoromethoxy, or halogen; R2 represents hydrogen or alkyl; R3 represents alkyl; or R2 and R3 form a cycloalkene compound.

[0010] In this context, R1 represents the substituent on the aryl group in nitrostyrene-type aromatic hydrocarbons, where R1 is an electron-donating or electron-withdrawing group; R2 and R3 are the substituents at both ends of the olefin, where R2 and R3 are electron-donating or electron-withdrawing groups.

[0011] Preferably, R1 represents a substituent in the aromatic ring, where R1 monosubstituted a hydrogen atom on the aromatic ring, and R1 can be hydrogen, methyl, methoxy, tert-butyl, cyano, trifluoromethyl, trifluoromethoxy, or a halogen.

[0012] Preferably, the alkyl group is generally methyl.

[0013] Wherein, R1 is a C1-C4 alkyl, methoxy, cyano, trifluoromethyl, trifluoromethoxy, or halogen; R2 is hydrogen or alkyl; and R3 is an alkyl chain linked to halogen, oxygen, sulfur, or nitrogen.

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

[0015] The ligands are selected from glycine-glycine-glycine, BOC-glycine-glycine-glycine, L-serine, D-cysteine, D-arginine, isoserine, L-threonine, D-serine, L-tyrosine, D-proline, D-valine, BOC-L-proline, L-histidine, BOC-D-phenylalanine, L-cysteine, β-thiovaline, L-proline, L-phenylalanine, and N-BOC-N'-yl-Hydrogenase. - Triphenylmethyl-L-histidine, L-tryptophan, N-BOC-L-leucine, BOC-L-glutamic acid, L-cysteine, L-homocysteine, S-acetamidomethyl-N-tert-butoxycarbonyl-L-cysteine, N-acetyl-L-cysteine, N,N'-bis(tert-butoxycarbonyl)-L-cysteine, Boc-L-cysteine, aspartic acid, 2-allyl-N-FMOC-L-glycine, or any one or more of these.

[0016] The oxidant is selected from any one or more of the following: per-tert-butyl hydroperoxide, hydrogen peroxide, peracetic acid, m-chloroperoxybenzoic acid, benzoyl peroxide, benzoyl peroxide-tert-butyl ester, di-tert-butyl peroxide, dicumyl peroxide, 2-butanone peroxide, or bis(trimethylsilyl) peroxide.

[0017] Wherein, the solvent is an organic solvent, water, or an aqueous solution of an organic solvent, wherein the organic solvent is selected from acetonitrile, toluene, acetone, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-diacetamide, N,N-dicarboxamide, ethyl acetate, 1,4-dioxane or tetrahydrofuran, methanol, ethanol, ethylene glycol, n-propanol, isopropanol, 1,3-propanediol, n-butanol, isoamyl alcohol, 2-pentanol, 3-pentanol, cyclopentanol, trifluoroethanol, isobutanol, tert-butanol, sec-butanol, tert-pentanol, 3-methoxybutanol, 4-methyl-2-pentanol, n-pentanol; 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 nitrostyrene compound, alkene compound, hydrogen peroxide, amino acid or its derivative, and iron catalyst is 1:(0.5-2):(2-60):(0.001-20):(0.002-10).

[0019] The reaction is carried out at a temperature of 25–120°C for 1–48 hours.

[0020] The method of this invention utilizes iron as a catalyst, which 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 oxidant and solvent, enables the alkylating agent to form alkyl radicals that attack nitrostyrene-based reagents, exhibiting high activity and selectivity. Furthermore, the method of this invention uses mild reagents and a mild environment, overcoming the problem of harsh reaction conditions. The reaction directly attacks nitrostyrene-based reagents without pre-functionalization. Iron is used as the catalyst, eliminating the need for precious metals, and the effect is significant. The method of this invention offers advantages such as a widely available, inexpensive, and environmentally friendly catalyst; a widely available and inexpensive oxidant; mild reaction conditions and high selectivity; good compatibility with substrate functional groups and a wide range of substrate applications; compatibility with drug molecules and drug derivatives, and excellent ability to achieve olefin hydroxylation reactions. Under optimized reaction conditions, the yield of the target product after separation can reach 86%.

[0021] This invention first forms a complex between low-valent iron and an amino acid, then a high-valent iron-oxygen intermediate is formed under the action of an oxidant. This intermediate then undergoes a radical addition reaction with an alkene, followed by a radical addition-elimination reaction between the alkyl radical and a nitrostyrene compound, ultimately forming the target compound. Practical application has demonstrated excellent results. This is the first time that an amino acid-ligand-promoted iron-catalyzed method has been applied to the hydroxylation of olefins. Unlike existing synthetic routes for hydroxyl compounds, which typically involve the reduction ring-opening / coupling reaction of epoxides, this method involves a single-electron transfer between the olefin and the iron catalyst to form a radical cation intermediate. Further deprotonation yields an alkyl radical, which then couples with a nitrostyrene compound, exhibiting excellent selectivity and activity for this type of synthesis. This provides a new method and mechanism for the synthesis of nitrostyrene compounds. By introducing amino acids or their derivatives to coordinate with the iron catalyst, the activity and selectivity of the iron catalysis are improved, thus solving a series of problems existing in current olefin bifunctionalization reactions, such as demanding reaction conditions, low reaction efficiency, the need for a large excess of alkene substrate, and the requirement for noble metal catalysts.

[0022] In this invention, the ligand first forms a complex with iron, then the oxidant oxidizes the low-valent iron to a high-valent ferrite intermediate, generating a corresponding high-valent ferrite radical cationic intermediate. This intermediate then reacts with olefins; due to its electrophilic nature, it interacts with positions in the olefin molecule with higher electron density to form corresponding alkyl radicals. Under the action of H₂O, a β-hydroxy radical is generated, which then reacts with nitrostyrene to generate the target product. The key design concept is to use amino acid ligands to form a high-valent ferrite intermediate with iron, which then interacts with positions in the olefin molecule with higher electron density to form a corresponding alkyl radical, subsequently reacting with nitrostyrene to generate the target product. Advantages: By coordinating amino acids or their derivatives with the iron catalyst, the catalytic activity and selectivity of the iron catalyst can be enhanced. For example, this method has good compatibility with olefins, especially with electron-deficient olefins, and also shows good results in the expansion of complex molecules.

[0023] This invention is based on the formation of a high-valent ferrite intermediate from an amino acid ligand and iron, generating a corresponding radical cationic intermediate. This intermediate can interact with positions in olefin molecules with high electron cloud density to form corresponding alkyl radicals. Therefore, this system can selectively add to olefins to produce the target product. This invention has good compatibility with alkenes, especially with electron-deficient alkenes and inner alkenes. Furthermore, this invention has high reactivity and good compatibility with complex molecules and various modified drug molecules.

[0024] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0025] (1) This invention provides a method for iron-catalyzed hydroxylylation of alkenes promoted by amino acids and their derivative ligands. This method requires only one reaction step and does not require complicated steps. It has the unique advantages of inexpensive, widely available and environmentally friendly catalysts, ligands and oxidants. The reaction conditions are mild and highly selective. The substrates are widely available, stable and easy to handle. The substrate functional groups are compatible and the substrates have a wide range of applications. Experimental results show that the reaction has the advantage of generating hydroxylylated products. However, there is no good method in the prior art to form highly active catalyst species.

[0026] (2) The hydroxylating method of olefins provided by the present invention is simple, easy and safe. The hydroxylated compounds can be obtained directly in one step. Under optimized reaction conditions, the yield of the target product after separation can reach 86%. Moreover, the amount of olefin used can be controlled at 1-2 equivalents, which can better reduce the reaction cost. It is a general, efficient, economical and environmentally friendly method for generating hydroxylated compounds.

[0027] (3) The present invention uses iron as the catalytic core to realize the hydroxylation reaction of olefins. The key is to introduce amino acid ligands, which can coordinate with iron catalysts to form highly active catalytic species. This not only allows the reaction to proceed efficiently under extremely mild conditions, but also shows excellent catalytic effects on drug molecules and their derivatives. It has excellent adaptability and practicality.

[0028] (4) The hydroxyl groups synthesized by the method of the present invention can be used as drugs or bioactive molecules, and are also important organic intermediates, which are widely used in the synthesis of pharmaceutical intermediates and high value-added fine chemicals. Detailed Implementation

[0029] 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.

[0030] 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.

[0031] The specific structures of the substrates and products in the embodiments are shown in Table 1.

[0032] The reaction substrates 1a-1m and 2a-2k used in this invention are all previously reported compounds.

[0033] In this invention, compounds 1, 3, 5, 14, 23, and 24 are all known compounds.

[0034] The CAS numbers for the compounds are as follows: Compound 1 CAS: 1675229-26-1; Compound 3 CAS: 2235411-58-0; Compound 5 CAS: 2235411-54-6; Compound 14 CAS: 732285-54-0; Compound 23 CAS: 99464-29-6; Compound 24 CAS: 2235411-79-5.

[0035] Example 1

[0036] Synthesis of Compound 1

[0037] In an air-filled reaction flask, ferric perchlorate (III) hydrate (0.05 mmol), Boc-L-cysteine ​​(0.1 mmol), substrate 1a (0.5 mmol), cyclohexene (1 mmol), dichloromethane (2.0 mL), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 60 °C. oThe reaction was carried out at C for 1 h. After the reaction was completed, the product was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:1) to give product 1 in 74% yield.

[0038] 1 H NMR (400 MHz, CDCl3): δ 7.38 (d, J = 7.0 Hz, 2H), 7.34–7.29 (m,2H), 7.22 (t, J = 7.2 Hz, 1H), 6.53 (d, J = 15.9 Hz, 1H), 6.07 (dd, J = 15.9,8.9 Hz, 1H), 3.38–3.33 (m, 1H), 2.08–2.06 (m, 2H), 1.83–1.70 (m, 5H), 1.33–1.25 (m, 3H) ppm. 13 C NMR (100 MHz, CDCl3): δ 137.0, 132.1, 132.1, 128.6,127.4, 126.2, 73.2, 50.7, 33.8, 31.4, 25.2, 24.8 ppm.

[0039] Example 2

[0040] Synthesis of Compound 2

[0041] In an air-filled reaction flask, ferric chloride (0.05 mmol), S-acetaminomethyl-N-tert-butoxycarbonyl-L-cysteine ​​(0.1 mmol), substrate 1b (0.5 mmol), cyclohexene (1 mmol), isopropanol (2.0 mL), and hydrogen peroxide (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 40 °C. o The reaction was refluxed at C for 1 h. After the reaction was completed, the product was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 10:1) to give product 2 in 78% yield.

[0042] 1 H NMR (400 MHz, CDCl3): δ 7.16 (s, 1H), 7.13–7.04 (m, 2H), 6.48 (d, J = 15.9 Hz, 1H), 6.00 (dd, J = 15.9, 8.9 Hz, 1H), 3.33 (td, J = 10.0, 4.4 Hz, 1H), 2.25 (d,J = 4.2 Hz, 6H), 2.08–2.00 (m, 2H), 1.82–1.79 (m, 2H), 1.71–1.69 (m, 1H), 1.34–1.26 (m, 4H) ppm. 13 C NMR (100 MHz, CDCl3): δ 136.6, 135.9,134.7, 132.0, 130.8, 129.8, 127.4, 123.7, 73.2, 50.6, 33.7, 31.5, 25.2, 24.8,19.7, 19.5ppm.

[0043] Example 3

[0044] Synthesis of Compound 3

[0045] In an air-filled reaction flask, ferric chloride (0.05 mmol), aspartic acid (0.1 mmol), substrate 1c (0.5 mmol), cyclohexene (1 mmol), glycerol (2.0 mL), and hydrogen peroxide (3 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 25°C. o The reaction was carried out at C for 3 h. After the reaction was completed, the product was directly separated by chromatography (petroleum ether: dichloromethane V / V = 10:2) to give product 3 in 63% yield.

[0046] 1 H NMR (400 MHz, CDCl3): δ 7.22–7.16 (m, 3H), 7.05 (d, J = 7.3 Hz, 1H), 6.50 (d, J = 15.9 Hz, 1H), 6.06 (dd, J = 15.9, 8.9 Hz, 1H), 3.34 (td, J = 10.0, 4.5 Hz, 1H), 2.34 (s, 3H), 2.09–2.04 (m, 2H), 1.83–1.79 (m, 3H), 1.71(d, J = 8.9 Hz, 1H), 1.36–1.23 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ 138.1,136.9, 132.1, 131.8, 128.4, 128.2, 126.8, 123.3, 73.2, 50.6, 33.7, 31.4,25.2, 24.8, 21.4 ppm.

[0047] Example 4

[0048] Synthesis of Compound 4

[0049] In an air-filled reaction flask, ferrous chloride (0.05 mmol), L-homocysteine ​​(0.1 mmol), substrate 1d (0.5 mmol), cyclohexene (1 mmol), n-butanol (1.5 mL), water (2.5 mL), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 80 °C. o The reaction was carried out at C for 1 h. After the reaction was completed, 5 mL of water was added and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: dichloromethane V / V = 10:4) to give product 4, with a yield of 62%.

[0050] 1 H NMR (400 MHz, CDCl3): δ 7.27 (d, J = 8.9 Hz, 2H), 7.12 (d, J = 7.9Hz, 2H), 6.50 (d, J = 15.9 Hz, 1H), 6.01 (dd, J = 15.8, 8.9 Hz, 1H), 3.33 (d, J = 4.2 Hz, 1H), 2.33 (s, 3H), 2.09–1.99 (m, 2H), 1.83–1.79 (m, 3H), 1.71–1.70 (m, 1H), 1.33–1.26 (m, 1H) ppm. 13 C NMR (100 MHz, CDCl3): δ 137.2, 134.2,131.9, 131.0, 129.2, 126.0, 73.2, 50.6, 33.7, 31.4, 25.2, 24.8, 21.2 ppm.

[0051] Example 5

[0052] Synthesis of Compound 5

[0053] In an air-filled reaction flask, ferrous fluoride (0.02 mmol), BOC-L-glutamic acid (0.04 mmol), substrate 1e (0.5 mmol), cyclohexene (1 mmol), tert-butanol (1.5 mL), water (0.5 mL), and hydrogen peroxide (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 60 °C. o The reaction was carried out at C for 48 h. After the reaction was completed, 5 mL of water was added and the mixture was extracted with diethyl ether (5 mL × 3). The organic phases were combined, the solvent was removed under reduced pressure, and the product was separated by column chromatography (petroleum ether: ethyl acetate V / V = 10:2) to give product 5, with a yield of 58%.

[0054] 1 H NMR (400 MHz, CDCl3): δ 7.31 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8Hz, 2H), 6.47 (d, J = 15.9 Hz, 1H), 5.91 (dd, J = 15.8, 8.9 Hz, 1H), 3.80 (s,3H), 3.32 (td, J = 10.0, 4.3 Hz, 1H), 2.08–2.00 (m, 2H), 1.82–1.71 (m, 3H), 1.35–1.24 (m, 5H) ppm. 13 C NMR (100 MHz, CDCl3): δ 159.0, 131.4, 129.8, 127.3,113.9, 73.2, 55.3, 50.6, 33.7, 31.5, 25.2, 24.8 ppm.

[0055] Example 6

[0056] Synthesis of Compound 6

[0057] In an air-filled reaction flask, ferrous chloride (0.08 mmol), L-cysteine ​​(0.16 mmol), substrate 1f (0.5 mmol), cyclohexene (1 mmol), methanol (2.0 mL), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 85°C. o The reaction was carried out at C for 3 h. After the reaction was completed, the product 6 was obtained by direct chromatography (petroleum ether: ethyl acetate V / V = 10:3) with a yield of 71%.

[0058] 1H NMR (400 MHz, CDCl3): δ 7.36–7.31 (m, 4H), 6.52 (d, J = 15.8 Hz, 1H), 6.03 (dd, J = 15.8, 8.9 Hz, 1H), 3.33 (td, J = 10.0, 4.4 Hz, 1H), 2.08–2.03 (m, 2H), 1.82–1.79 (m, 3H), 1.72–1.69 (m, 1H), 1.32 (s, 12H) ppm. 13 C NMR (100 MHz, CDCl3): δ 150.5, 134.2, 131.8, 131.2, 125.9, 125.5, 73.2, 50.7,34.5, 33.7, 31.4, 31.3, 25.2, 24.8 ppm.

[0059] Example 7

[0060] Synthesis of Compound 7

[0061] In a 25 mL reaction flask under normal nitrogen pressure, ferrous fluoride (0.05 mmol), L-tyrosine (0.1 mmol), 1 g of substrate (0.5 mmol), cyclohexene (1 mmol), dimethyl sulfoxide (2.0 mL), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was heated to 90 °C. o The reaction was carried out at C for 1 h. After the reaction was completed, the product was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:3) to give product 7 in 82% yield.

[0062] 1 H NMR (400 MHz, CDCl3): δ 7.32 (t, J = 7.9 Hz, 1H), 6.86 (dd, J =18.0, 9.7 Hz, 2H), 6.63 (d, J = 16.0 Hz, 1H), 6.11 (dd, J = 16.0, 8.8 Hz, 1H), 3.35 (td, J= 10.0, 4.3 Hz, 1H), 2.32 (s, 3H), 2.10–2.03 (m, 2H), 1.83–1.79 (m, 2H), 1.72–1.69 (m, 1H), 1.35–1.24 (m, 4H) ppm. 13 C NMR (100 MHz, CDCl3): δ 159.9 (d, J = 248.7 Hz), 139.1 (d, J = 8.1 Hz), 133.8 (d, J = 4.8Hz), 126.9 (d, J = 4.8 Hz), 124.8 (d, J = 2.9 Hz), 124.3 (d, J = 3.3 Hz), 121.8 (d, J = 12.1 Hz), 116.2 (d, J = 22.0 Hz), 73.2, 50.9, 33.9, 31.4, 25.1,24.8, 21.0 ppm. 19 F NMR (376 MHz, CDCl3): δ -119.2 ppm.

[0063] Example 8

[0064] Synthesis of Compound 8

[0065] In an air-filled reaction flask, ferrous fluoride (0.1 mmol), N-acetyl-L-cysteine ​​(0.2 mmol), substrate 1h (0.5 mmol), cyclohexene (1 mmol), 1,3-propanediol (1.5 mL), water (1.5 mL), and hydrogen peroxide (1 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 80 °C. o The reaction was carried out at C for 5 h. After the reaction was completed, 5 mL of water was added and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 10:3) to give product 8, with a yield of 72%.

[0066] 1 H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4Hz, 2H), 6.51 (d, J= 15.9 Hz, 1H), 6.28 (dd, J = 15.9, 8.6 Hz, 1H), 3.38 (h, J = 4.5 Hz, 1H), 2.14–2.04 (m, 2H), 1.82–1.71 (m, 4H), 1.36–1.25 (m, 3H) ppm. 13 C NMR (100 MHz, CDCl3): δ 141.6, 136.7, 132.3, 130.0, 126.6, 119.0, 110.3,73.3, 50.3, 34.3, 31.2, 25.0, 24.7 ppm.

[0067] Example 9

[0068] Synthesis of Compound 9

[0069] In an air-filled reaction flask, ferric iodide (0.08 mmol), N,N'-bis(tert-butyloxycarbonyl)-L-cysteine ​​(0.32 mmol), substrate 1i (0.5 mmol), cyclohexene (1 mmol), trifluoroethanol (2.0 mL), and hydrogen peroxide (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 60 °C. o The reaction was carried out at C for 2 h. After the reaction was completed, the product was directly separated by chromatography (petroleum ether: dichloromethane V / V = 10:5) to give product 9, with a yield of 69%.

[0070] 1 H NMR (400 MHz, CDCl3): δ 7.35–7.31 (m, 2H), 6.99 (t, J = 8.7 Hz, 2H), 6.48 (d, J = 15.9 Hz, 1H), 5.99 (dd, J = 15.9, 8.8 Hz, 1H), 3.34 (td, J= 10.0, 4.4 Hz, 1H), 2.07–2.02 (m, 2H), 1.82–1.79 (m, 3H), 1.72–1.68 (m, 1H), 1.38–1.26 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ 162.1 (d, J = 246.5 Hz), 133.2 (d, J = 3.3 Hz), 131.9 (d, J = 2.2 Hz), 130.6, 127.6 (d, J = 8.1 Hz), 115.4 (d, J = 21.6 Hz), 73.3, 50.4, 34.0, 31.4, 25.2, 24.8 ppm. 19 F NMR (376MHz, CDCl3): δ -114.8 ppm.

[0071] Example 10

[0072] Synthesis of Compound 10

[0073] In a nitrogen atmosphere at atmospheric pressure, ferrous fluoride (0.05 mmol), L-cysteine ​​(0.1 mmol), substrate 1j (0.5 mmol), cyclohexene (0.5 mmol), acetonitrile (1.5 mL), water (0.5 mL), and hydrogen peroxide (1 mmol) were added sequentially to a reaction flask. After thorough mixing at room temperature, the reaction mixture was heated to 80 °C. o The reaction was carried out at C for 8 h. After the reaction was completed, 5 mL of water was added and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with water (5 mL × 3), collected, and separated by column chromatography (petroleum ether: diethyl ether V / V = 10:2) after removing the solvent under reduced pressure to obtain product 10 with a yield of 78%.

[0074] 1 H NMR (400 MHz, CDCl3): δ 7.30–7.26 (m, 3H), 7.26–7.25 (m, 1H), 6.46(d, J = 15.9 Hz, 1H), 6.07 (dd, J = 15.9, 8.7 Hz, 1H), 3.34 (td, J = 10.0,4.5 Hz, 1H), 2.10–2.02 (m, 2H), 1.87–1.76 (m, 3H), 1.71–1.69 (m, 1H), 1.32–1.26 (m, 3H) ppm. 13 C NMR (100 MHz, CDCl3): δ 135.6, 133.0, 132.9, 130.5,128.6, 127.3, 73.3, 50.4, 34.0, 31.4, 25.1, 24.8 ppm.

[0075] Example 11

[0076] Synthesis of Compound 11

[0077] In a nitrogen atmosphere at atmospheric pressure, ferric iodide (0.05 mmol), L-serine (0.1 mmol), substrate 1k (0.5 mmol), cyclohexene (1 mmol), acetonitrile (4.0 mL), and hydrogen peroxide (1 mmol) were added sequentially to a reaction flask. After thorough mixing at room temperature, the reaction mixture was incubated at 25°C. o The reaction was carried out at C for 24 h. After the reaction was completed, 5 mL of water was added and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with water (5 mL × 3), collected, and separated by column chromatography (petroleum ether: diethyl ether V / V = 10:1) after removing the solvent under reduced pressure to obtain product 11 with a yield of 80%.

[0078] 1 H NMR (400 MHz, CDCl3): δ 7.42 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.6Hz, 2H), 6.45 (d, J = 15.9 Hz, 1H), 6.08 (dd, J = 15.9, 8.7 Hz, 1H), 3.34(td, J = 10.0, 4.5 Hz, 1H), 2.07–2.02 (m, 2H), 1.82–1.69 (m, 5H), 1.35–1.27(m, 3H) ppm. 13 C NMR (100 MHz, CDCl3): δ 136.0, 133.1, 131.6, 130.6, 127.7,121.0, 73.2, 50.5, 34.0, 31.3, 25.1, 24.7 ppm.

[0079] Example 12

[0080] Synthesis of Compound 12

[0081] In an air-filled reaction flask, ferrous chloride (0.02 mmol), BOC-glycine-glycine-glycine (0.2 mmol), substrate 1 L (0.5 mmol), cyclohexene (1 mmol), dimethyl sulfoxide (2.0 mL), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was heated to 95 °C. oThe reaction was carried out at C for 12 h. After the reaction was completed, the product 12 was obtained by direct chromatography (petroleum ether: ethyl acetate V / V = 10:3) with a yield of 86%.

[0082] 1 H NMR (400 MHz, CDCl3): δ 7.55 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.3Hz, 2H), 6.54 (d, J = 15.9 Hz, 1H), 6.22 (dd, J = 15.9, 8.6 Hz, 1H), 3.38(td, J = 9.9, 4.4 Hz, 1H), 2.11–2.06 (m, 2H), 1.84–1.78 (m, 3H), 1.73–1.70 (m, 1H), 1.36–1.27 (m, 4H) ppm. 13 C NMR (100 MHz, CDCl3): δ 140.6, 135.2,130.4, 129.6, 129.1 (d, J = 32.3 Hz), 126.3, 125.5 (q, J = 3.7 Hz), 122.9,73.3, 50.4, 34.2, 31.3, 25.1, 24.7 ppm. 19 F NMR (376 MHz, CDCl3): δ -62.43ppm.

[0083] Example 13

[0084] Synthesis of Compound 13

[0085] In an air-filled reaction flask, ferrous phthalocyanine (0.001 mmol), L-histidine (0.1 mmol), substrate 1m (0.5 mmol), cyclohexene (1 mmol), dichloromethane (2.0 mL), and hydrogen peroxide (3 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 50 °C. o The reaction was carried out at C for 3 h. After the reaction was completed, the product 13 was obtained by direct chromatography (petroleum ether: diethyl ether V / V = 10:7) with a yield of 76%.

[0086] 1 H NMR (400 MHz, CDCl3): δ 7.38 (d, J= 8.7 Hz, 2H), 7.15 (d, J = 8.6Hz, 2H), 6.50 (d, J = 15.9 Hz, 1H), 6.08 (dd, J = 15.9, 8.8 Hz, 1H), 3.35 (h, J = 4.5 Hz, 1H), 2.08–2.04 (m, 2H), 1.84–1.80 (m, 2H), 1.72–1.70 (m, 1H), 1.35–1.21 (m, 5H) ppm. 13 C NMR (100 MHz, CDCl3): δ 148.3, 135.9, 133.4, 130.3,127.3, 121.1, 120.5 (d, J = 257.1 Hz), 73.3, 50.4, 34.1, 31.4, 25.1, 24.8ppm. 19 F NMR (376 MHz, CDCl3): δ -57.90 ppm.

[0087] Example 14

[0088] Synthesis of Compound 14

[0089] In an air-filled reaction flask, ferric ferricyanide (0.05 mmol), BOC-L-proline (0.002 mmol), trans-β-nitrostyrene (0.5 mmol), substrate 2a (1 mmol), ethyl acetate (1.0 mL), water (1.0 mL), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 60 °C. o The reaction was carried out at C for 2 h. After the reaction was completed, 5 mL of water was added and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 20:1) to give product 14, with a yield of 72%.

[0090] 1 H NMR (400 MHz, CDCl3): δ 7.39–7.37 (m, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.3 Hz, 1H), 6.49 (d, J = 15.9 Hz, 1H), 5.99 (dd, J= 15.8, 9.0 Hz, 1H), 3.65 (dd, J = 10.6, 5.1 Hz, 1H), 3.50 (dd, J = 10.6, 8.2 Hz,1H), 2.42–2.36 (m, 1H), 1.37–1.28 (m, 6H), 0.89 (t, J = 6.5 Hz, 3H) ppm. 13 CNMR (100 MHz, CDCl3): δ 137.0, 132.5, 131.6, 128.5, 127.3, 126.1, 66.1, 46.5,30.9, 29.4, 22.8, 14.0 ppm.

[0091] Example 15

[0092] Synthesis of Compound 15

[0093] In a nitrogen atmosphere at atmospheric pressure, ferrous fluoride (0.02 mmol), aspartic acid (0.15 mmol), trans-β-nitrostyrene (0.5 mmol), substrate 2b (1 mmol), toluene (2.0 mL), and hydrogen peroxide (1.5 mmol) were added sequentially to a reaction flask. After thorough mixing at room temperature, the reaction mixture was incubated at 70 °C. o The reaction was carried out at C for 6 h. After the reaction was completed, 5 mL of water was added and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, the solvent was removed under reduced pressure, and the product was separated by column chromatography (petroleum ether: ethyl acetate V / V = 40:1) to give product 15, with a yield of 64%.

[0094] 1 H NMR (400 MHz, CDCl3): δ 7.38–7.35 (m, 2H), 7.33–7.28 (m, 2H), 7.26–7.21 (m, 1H), 6.55 (d, J = 16.0 Hz, 1H), 6.10 (dd, J = 16.0, 8.4 Hz, 1H), 4.30 (dd, J = 11.1, 5.6 Hz, 1H), 4.21 (dd, J = 11.1, 6.6 Hz, 1H), 3.69 (dd, J = 5.9, 1.8 Hz, 2H), 2.78–2.73 (m, 1H), 2.11–2.03 (m, 4H) ppm.13 C NMR (100MHz, CDCl3): δ 171.5, 136.7, 133.3, 128.6, 127.6, 126.5, 126.2, 64.2, 62.7,44.9, 20.9 ppm.

[0095] Example 16

[0096] Synthesis of Compound 16

[0097] In an air-filled reaction flask, ferrous trifluoromethanesulfonate (0.05 mmol), BOC-D-phenylalanine (0.1 mmol), trans-β-nitrostyrene (0.5 mmol), substrate 2c (1 mmol), acetonitrile (2.0 mL), and potassium persulfate (1 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 90°C. o The reaction was carried out at C for 3 h. After the reaction was completed, the product 16 was obtained by direct chromatography (petroleum ether: ethyl acetate V / V = 40:7) with a yield of 73%.

[0098] 1 H NMR (400 MHz, CDCl3): δ 7.38 (d, J = 7.0 Hz, 2H), 7.31 (t, J = 7.6Hz, 2H), 7.23 (t, J = 7.2 Hz, 1H), 6.50 (d, J = 15.9 Hz, 1H), 5.98 (dd, J =15.9, 9.0 Hz, 1H), 3.65 (dd, J = 10.6, 5.3 Hz, 1H), 3.56–3.51 (m, 3H), 2.43–2.36 (m, 1H), 1.84–1.75 (m, 2H), 1.59–1.50 (m, 2H), 1.47–1.34 (m, 2H) ppm. 13 CNMR (100 MHz, CD3Cl3): δ 137.0, 132.7, 131.0, 128.6, 127.4, 126.2, 66.0, 46.2,44.8, 32.6, 30.4, 24.5 ppm.

[0099] Example 17

[0100] Synthesis of Compound 17

[0101] In air, ferrous oxalate (0.04 mmol), BOC-L-glutamic acid (0.04 mmol), trans-β-nitrostyrene (0.5 mmol), substrate 2d (1 mmol), 1,4-dioxane (2.0 mL), and hydrogen peroxide (1.5 mmol) were added sequentially to the reaction flask. After thorough mixing at room temperature, the reaction mixture was incubated at 90°C. o The reaction was carried out at C for 6 h. After the reaction was completed, the product 17 was obtained by direct chromatography (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 63%.

[0102] 1 H NMR (400 MHz, CDCl3): δ 7.39–7.37 (m, 2H), 7.33–7.29 (m, 2H), 7.24(tt, J = 7.2, 1.4 Hz, 1H), 6.50 (d, J = 15.9 Hz, 1H), 5.98 (dd, J = 15.9, 9.0Hz, 1H), 3.64 (dd, J = 10.6, 5.3 Hz, 1H), 3.53 (dd, J = 10.6, 7.9 Hz, 1H), 3.40 (td, J = 6.8, 1.3 Hz, 3H), 2.42–2.37 (m, 1H), 1.94–1.84 (m, 3H), 1.57–1.48 (m, 3H) ppm. 13 C NMR (100 MHz, CDCl3): δ 136.9, 132.7, 130.9, 128.6,127.4, 126.1, 66.0, 46.2, 33.6, 32.7, 30.2, 25.8 ppm.

[0103] Example 18

[0104] Synthesis of Compound 18

[0105] In an air-filled reaction flask, 1,3-diphenylpropanedione iron (0.1 mmol), BOC-L-proline (0.1 mmol), trans-β-nitrostyrene (0.5 mmol), substrate 2e (0.5 mmol), N,N-diacetamide (2.0 mL), and hydrogen peroxide (1 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 50 °C. oThe reaction was carried out at C for 10 h. After the reaction was completed, the product 18 was obtained by direct chromatography (petroleum ether: dichloromethane V / V = 10:3) with a yield of 75%.

[0106] 1 H NMR (400 MHz, CDCl3): δ 7.38 (d, J = 7.0 Hz, 2H), 7.30 (t, J = 7.5Hz, 2H), 7.24–7.20 (m, 1H), 6.49 (d, J = 15.9 Hz, 1H), 6.33 (dd, J = 15.9, 7.8 Hz, 1H), 4.27 (d, J = 3.2 Hz, 1H), 2.82 (dq, J = 6.8, 3.7 Hz, 1H), 2.63–2.45 (m, 2H), 1.14 (t, J = 7.3 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl3): δ 212.1, 137.1, 131.9, 130.2, 128.5, 127.3, 126.2, 79.7, 40.7, 31.9, 13.6, 7.5 ppm.

[0107] Example 19

[0108] Synthesis of Compound 19

[0109] In an air-filled reaction flask, ferrous 1,3-diphenylpropanedione (0.05 mmol), BOC-D-phenylalanine (0.15 mmol), trans-β-nitrostyrene (0.5 mmol), substrate 2f (1 mmol), 1,2-dichloroethane (2.0 mL), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 60 °C. o The reaction was carried out at C for 12 h. After the reaction was completed, the product 19 was obtained by direct chromatography (petroleum ether: dichloromethane V / V = 10:5) with a yield of 80%.

[0110] 1 H NMR (400 MHz, CDCl3): δ 7.40–7.26 (m, 5H), 6.63 (d, J= 15.8 Hz, 1H), 6.09 (dd, J = 15.9, 8.1 Hz, 1H), 4.40 (q, J = 7.3 Hz, 1H), 3.57–3.50 (m,2H), 3.27–3.09 (m, 3H), 2.77 (s, 1H) ppm. 13 C NMR (100 MHz, CDCl3): δ 135.7,134.7, 128.7, 128.3, 126.4, 124.7, 72.1, 57.9, 56.2, 48.3 ppm.

[0111] Example 20

[0112] Synthesis of Compound 20

[0113] In an air-filled, modified reaction flask, ferric perchlorate (III) hydrate (0.08 mmol), D-valine (0.4 mmol), trans-β-nitrostyrene (0.5 mmol), 2 g of substrate (1 mmol), ethylene glycol (1.0 mL), water (1.0 mL), and hydrogen peroxide (1 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was heated to 100 °C. o The reaction was carried out at C for 2 h. After the reaction was completed, 5 mL of water was added and the mixture was extracted with diethyl ether (5 mL × 3). The organic phases were combined, the solvent was removed under reduced pressure, and the product was separated by column chromatography (petroleum ether: ethyl acetate V / V = 20:3) to give product 20, with a yield of 79%.

[0114] 1 H NMR (400 MHz, CDCl3): δ 7.38 (d, J = 7.9 Hz, 2H), 7.30 (t, J = 7.6Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 6.52 (d, J = 16.0 Hz, 1H), 6.30 (dd, J =15.9, 7.2 Hz, 1H), 4.01 (d, J = 10.9 Hz, 1H), 3.75 (s, 1H), 2.62 (ddt, J=13.7, 4.3, 2.2 Hz, 1H), 2.48–2.38 (m, 2H), 2.17–2.12 (m, 1H), 2.02–1.98 (m,1H), 1.79–1.68 (m, 2H) ppm. 13 C NMR (100 MHz, CDCl3): δ 210.2, 137.0, 130.8,130.4, 128.4, 127.3, 126.3, 78.5, 51.3, 39.1, 30.0, 25.7 ppm.

[0115] Example 21

[0116] Synthesis of Compound 21

[0117] In an air-filled reaction flask, ferrous chloride (0.05 mmol), L-cysteine ​​(0.03 mmol), trans-β-nitrostyrene (0.5 mmol), substrate 2h (1 mmol), cyclopentanol (2.0 mL), and hydrogen peroxide (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 50 °C. o The reaction was carried out at C for 24 h. After the reaction was completed, the product 21 was obtained by direct chromatography (petroleum ether: ethyl acetate V / V = 20:1), with a yield of 61%.

[0118] 1 H NMR (400 MHz, CDCl3): δ 7.36 (d, J = 7.1 Hz, 2H), 7.30 (t, J = 7.4Hz, 2H), 7.24–7.20 (m, 1H), 6.49 (d, J = 16.0 Hz, 1H), 6.11 (dd, J = 16.0,8.4 Hz, 1H), 4.87–4.86 (m, J = 7.0 Hz, 1H), 3.68 (dd, J = 11.5, 5.1 Hz, 1H),3.62–3.57 (m, J = 6.7 Hz, 1H), 3.43–3.35 (m, 1H), 3.34–3.26 (m, 1H), 2.57–2.48 (m, 1H), 1.44 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ 157.3, 136.9,132.4, 128.5, 128.1, 127.5, 126.1, 79.9, 62.6, 46.0, 41.1, 28.3 ppm.

[0119] Example 22

[0120] Synthesis of Compound 22

[0121] In an air-filled reaction flask, ferric oxide (0.1 mmol), L-homocysteine ​​(0.4 mmol), trans-β-nitrostyrene (0.5 mmol), substrate 2i (1 mmol), tetrahydrofuran (2.0 mL), and hydrogen peroxide (1 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 70 °C. o The reaction was carried out at C for 3 h. After the reaction was completed, the product 22 was obtained by direct chromatography (petroleum ether: ethyl acetate V / V = 10:1), with a yield of 51%.

[0122] 1 H NMR (400 MHz, CDCl3): δ 7.39–7.33 (m, 2H), 7.31 (td, J = 7.5, 2.0Hz, 2H), 7.23 (td, J = 7.1, 1.8 Hz, 1H), 6.48 (d, J = 15.8 Hz, 1H), 5.93(ddd, J = 15.9, 9.2, 2.2 Hz, 1H), 3.57 (ddd, J = 10.6, 5.1, 2.2 Hz, 1H), 3.44–3.39 (m, 1H), 2.53–2.51 (m, 1H), 0.74–0.59 (m, 2H), 0.08–0.02 (m, 9H)ppm. 13 C NMR (100 MHz, CDCl3): δ 137.0, 133.2, 131.7, 128.6, 127.3, 126.1,68.4, 42.7, 18.8, -0.8 ppm.

[0123] Example 23

[0124] Synthesis of Compound 23

[0125] In an air-filled reaction flask, ferrous ammonium sulfate (0.05 mmol), L-tryptophan (0.5 mmol), trans-β-nitrostyrene (0.5 mmol), substrate 2j (2 mmol), sec-butanol (2.0 mL), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was heated to 100 mL. o The reaction was carried out at C for 2 h. After the reaction was completed, the product 23 was obtained by direct chromatography (petroleum ether: ethyl acetate V / V = 20:1), with a yield of 49%.

[0126] 1 H NMR (400 MHz, CDCl3): δ 7.35–7.26 (m, 6H), 7.24–7.19 (m, 4H), 6.44(d, J = 16.0 Hz, 1H), 6.10 (dd, J = 15.9, 8.2 Hz, 1H), 3.69 (dd, J = 10.6, 4.9 Hz, 1H), 3.58 (dd, J = 10.6, 7.1 Hz, 1H), 2.86–2.77 (m, 2H), 2.76–2.67(m, 2H) ppm. 13 C NMR (100 MHz, CDCl3): δ 139.5, 137.0, 132.4, 130.6, 129.2, 128.5, 128.3, 127.4, 126.2, 126.1, 65.2, 47.5, 37.8 ppm.

[0127] Example 24

[0128] Synthesis of Compound 24

[0129] In an air-filled reaction flask, benzoyl acetone iron (0.2 mmol), N,N'-bis(tert-butoxycarbonyl)-L-cysteine ​​(0.1 mmol), trans-β-nitrostyrene (0.5 mmol), substrate 2k (2 mmol), tert-amyl alcohol (2.0 mL), and hydrogen peroxide (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 60 °C. o The reaction was carried out at C for 9 h. After the reaction was completed, 5 mL of water was added and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with water (5 mL × 3), collected, and separated by column chromatography (petroleum ether: dichloromethane V / V = 10:4) after removing the solvent under reduced pressure to obtain product 24 with a yield of 57%.

[0130] 1 H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 7.3 Hz, 2H), 7.34–7.22(m, 5H),7.01–6.93 (m, 3H), 6.61 (d, J = 16.1 Hz, 1H), 6.23 (dd, J = 16.0, 8.3 Hz,1H), 4.18–4.08 (m, 2H), 3.95–3.84 (m, 2H), 3.00–2.93 (m, 1H) ppm. 13 C NMR (100MHz, CDCl3): δ 158.6, 136.8, 133.2, 129.5, 128.6, 127.6, 126.8, 126.2, 121.0,114.6, 68.9, 64.0, 45.2 ppm.

[0131] Example 25

[0132] Synthesis of Compound 25

[0133] In an air-filled reaction flask, benzoyl acetone iron (0.05 mmol), D-serine (0.1 mmol), trans-β-nitrostyrene (0.5 mmol), substrate 2L (1 mmol), glycerol (1.5 mL), water (0.5 mL), and hydrogen peroxide (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 80 °C. o The reaction was carried out at C for 3 h. After the reaction was completed, ammonia (0.5 mL, 25%) was added and stirred for 1 h. Immediately afterwards, 5 mL of water was added and the mixture was extracted with diethyl ether (5 mL × 3). The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: dichloromethane V / V = 10:3) to give product 25, with a yield of 54%.

[0134] 1 H NMR (400 MHz, CDCl3): δ 7.37 (d, J = 7.1 Hz, 2H), 7.30 (t, J = 7.6Hz, 2H), 7.26–7.17 (m, 2H), 7.17 (t, J = 8.1 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.62 (d, J= 8.4 Hz, 1H), 6.49 (d, J = 15.9 Hz, 1H), 5.99 (dd, J = 15.9, 9.0 Hz, 1H), 3.94 (t, J = 6.5 Hz, 2H), 3.65 (dd, J = 10.6, 5.4 Hz, 1H), 3.53(dd, J = 10.6, 7.8 Hz, 1H), 2.41 (tq, J = 8.9, 4.2 Hz, 1H), 2.14 (s, 3H), 1.84–1.73 (m, 2H), 1.60–1.51 (m, 2H), 1.48–1.38 (m, 2H) ppm. 13 C NMR (100 MHz, CDCl3): δ 168.4, 159.5, 139.0, 137.0, 132.5, 131.2, 129.6, 128.5, 127.3, 126.2, 111.8, 110.6, 106.2, 67.7, 66.0, 46.3, 30.8, 29.1, 24.6, 23.7 ppm.

[0135] Example 26

[0136] Synthesis of Compound 26

[0137] In an air-filled reaction flask, ferric oxide (0.05 mmol), N-BOC-L-leucine (0.08 mmol), trans-β-nitrostyrene (0.5 mmol), substrate 2 mL (1 mmol), isobutanol (2.0 mL), and hydrogen peroxide (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 40 °C. o The reaction was carried out at C for 2 h. After the reaction was completed, the product 26 was obtained by direct chromatography (petroleum ether: diethyl ether V / V = 10:3), with a yield of 58%.

[0138] 1 H NMR (400 MHz, CDCl3): δ 8.33 (dd, J = 8.1, 1.7 Hz, 1H), 8.06 (s,1H), 7.78 (td, J = 7.6, 1.5 Hz, 1H), 7.72 (d, J= 6.7 Hz, 1H), 7.55–7.50 (m,1H), 7.35–7.26 (m, 4H), 7.25–7.20 (m, 1H), 6.53 (d, J = 16.0 Hz, 1H), 6.17(dd, J = 16.0, 8.7 Hz, 1H), 4.30–4.15 (m, 2H), 3.66 (qd, J = 11.6, 5.2 Hz,2H), 2.99–2.84 (m, 1H) ppm. 13 C NMR (100 MHz, CDCl3): δ 162.1, 148.0, 146.8,136.5, 134.6, 133.8, 128.6, 127.8, 127.5, 127.5, 126.8, 126.3, 126.2, 121.6,62.1, 47.6, 45.4 ppm.

[0139] Example 27

[0140] Synthesis of Compound 27

[0141] In an air-filled reaction flask, Fe(TMHD)3 (CAS:14876-47-2) (0.05 mmol), 2-allyl-N-FMOC-L-glycine (0.1 mmol), trans-β-nitrostyrene (0.5 mmol), substrate 2n (1 mmol), N,N-dicarboxamide (1.5 mL), water (0.5 mL), and hydrogen peroxide (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 70 °C. o The reaction was carried out at C for 6 h. After the reaction was completed, ammonia (0.5 mL, 25%) was added and the mixture was stirred for 1 h. Immediately afterwards, 5 mL of water was added and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: dichloromethane V / V = 10:5) to give product 27, with a yield of 48%.

[0142] 1 H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.4Hz, 2H), 7.36 (d, J = 7.1 Hz, 2H), 7.31 (t, J= 7.5 Hz, 2H), 7.24 (t, J = 7.0Hz, 1H), 6.51 (d, J = 15.9 Hz, 1H), 5.99 (dd, J = 15.8, 9.0 Hz, 1H), 4.40–4.30 (m, 2H), 3.65 (dd, J = 10.6, 5.4 Hz, 1H), 3.54 (dd, J = 10.6, 7.8 Hz,1H), 3.10–3.05 (m, 4H), 2.47–2.38 (m, 1H), 1.86–1.73 (m, 4H), 1.57–1.51 (m,4H), 1.48–1.38 (m, 2H), 0.86 (t, J = 7.4 Hz, 6H) ppm. 13 C NMR (100 MHz, CDCl3): δ 165.3, 144.1, 136.9, 133.6, 132.8, 131.0, 130.1, 128.6, 127.5, 126.9, 126.1, 66.0, 65.4, 49.9, 46.2, 30.6, 28.6, 23.6, 21.9, 11.1 ppm.

[0143] Example 28

[0144] Synthesis of Compound 28

[0145] In a 25 mL reaction flask, ferric iodide (0.05 mmol), N-BOC-N'-triphenylmethyl-L-histidine (0.1 mmol), trans-β-nitrostyrene (0.5 mmol), substrate 2O (1 mmol), ethanol (2 mL), and hydrogen peroxide (3 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 80 °C. o The reaction was carried out at C for 24 h. After the reaction was completed, the product 28 was obtained by direct chromatography (petroleum ether: ethyl acetate V / V = 20:1), with a yield of 53%.

[0146] 1 H NMR (400 MHz, CDCl3): δ 9.82 (s, 1H), 7.44–7.36 (m, 4H), 7.30 (td, J= 6.7, 1.8 Hz, 2H), 7.25–7.20 (m, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.49 (d, J = 15.9 Hz, 1H), 5.99 (dd, J = 15.9, 9.0 Hz, 1H), 4.09 (t, J = 6.7 Hz, 2H), 3.87 (s, 3H), 3.65 (dd, J = 10.6, 5.3 Hz, 1H), 3.54 (dd, J = 10.7, 7.7 Hz, 1H), 2.42 (tq, J = 8.9, 4.7 Hz, 1H), 1.93–1.86 (m, 2H), 1.74–1.67 (m, 2H), 1.64–1.60 (m, 1H) ppm. 13 C NMR (100 MHz, CDCl3): δ 190.9, 154.0, 149.8, 132.6,131.0, 129.8, 128.5, 127.4, 126.8, 126.1, 111.3, 109.2, 68.9, 66.0, 55.9,46.3, 30.8, 28.8, 23.6 ppm.

[0147] Example 29

[0148] Synthesis of Compound 29

[0149] In a 25 mL reaction flask, Fe(TMHD)3 (CAS:14876-47-2) (0.02 mmol), L-cysteine ​​(0.1 mmol), trans-β-nitrostyrene (0.5 mmol), substrate 2p (1 mmol), tert-amyl alcohol (1.5 mL), water (0.5 mL), and hydrogen peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 25 °C. o The reaction was carried out at C for 6 h. After the reaction was completed, ammonia (0.5 mL, 25%) was added and the mixture was stirred for 1 h. Immediately afterwards, 5 mL of water was added and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was separated by column chromatography (petroleum ether: ethyl acetate V / V = 20:3) to give product 29, with a yield of 44%.

[0150] 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.8 Hz, 2H), 7.74 (s, 1H), 7.64 (d, J = 6.0 Hz, 1H), 7.62–7.57 (m, 1H), 7.52–7.46 (m, 3H), 7.41 (d, J =6.0 Hz, 1H), 7.35 (d, J = 7.8 Hz, 2H), 7.29 (t, J = 7.6 Hz, 2H), 7.21 (t, J =7.2 Hz, 1H), 6.45 (d, J = 15.9 Hz, 1H), 5.94 (dd, J = 16.8, 9.8 Hz, 1H), 4.06(t, J = 6.5 Hz, 2H), 3.81–3.74 (m, 1H), 3.62–3.56 (m, 1H), 3.48 (t, J = 8.3Hz, 1H), 2.36–2.28 (m, 1H), 1.79 (s, 3H), 1.62–1.57 (m, 2H), 1.55–1.50 (m,4H) ppm. 13 C NMR (100 MHz, CDCl3): δ 196.6, 178.2, 174.1, 140.9, 137.8, 137.4,137.0, 132.5, 131.5, 131.1, 130.1, 129.2, 129.0, 128.5, 128.5, 128.3, 127.4,126.1, 65.9, 64.8, 46.2, 45.4, 30.6, 28.5, 23.5, 18.4 ppm.

[0151] Example 30

[0152] Synthesis of Compound 30

[0153] In an air-filled reaction flask, 1,1'-bis(diphenylphosphine)ferrocene (0.1 mmol), D-arginine (0.2 mmol), trans-β-nitrostyrene (0.5 mmol), substrate 2q (1 mmol), acetonitrile (2.0 mL), and hydrogen peroxide (1 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was incubated at 60 °C.o The reaction was carried out at C for 12 h. After the reaction was completed, the product 30 was obtained by direct chromatography (petroleum ether: ethyl acetate V / V = 40:7), with a yield of 39%.

[0154] 1 H NMR (400 MHz, CDCl3): δ 7.68–7.63 (m, 2H), 7.49–7.44 (m, 2H), 7.37–7.34 (m, 2H), 7.32–7.27 (m, 2H), 7.24–7.19 (m, 1H), 6.96 (d, J = 2.6 Hz, 1H), 6.88 (d, J = 9.0 Hz, 1H), 6.67 (dd, J = 8.9, 2.6 Hz, 1H), 6.45 (d, J = 15.9Hz, 1H), 5.95 (dd, J = 15.8, 9.0 Hz, 1H), 4.09 (td, J = 6.6, 1.6 Hz, 2H),3.83 (s, 3H), 3.66 (d, J = 5.5 Hz, 1H), 3.63 (s, 2H), 3.58 (dd, J = 10.6, 5.3Hz, 1H), 3.48 (dd, J = 10.6, 7.7 Hz, 1H), 2.36 (s, 3H), 1.71–1.57 (m, 4H), 1.37–1.32 (m, 2H) ppm. 13 C NMR (100 MHz, CDCl3): δ 170.9, 168.3, 156.0, 139.2,136.9, 135.9, 133.9, 132.5, 131.2, 131.0, 130.8, 130.6, 129.1, 128.5, 127.4,126.1, 114.9, 112.7, 111.5, 101.4, 65.9, 64.8, 55.7, 46.2, 30.6, 30.4, 28.6,23.5, 13.3 ppm.

[0155] The structural formulas of the raw materials and products of Examples 1-30 and the corresponding experimental results are shown in Table 1 below:

[0156] Table 1 .

[0157] Example 31

[0158] Example 31 uses the same method as Example 12, except that the molar ratio of nitrostyrene reagent, alkene substrate, hydrogen peroxide, amino acid derivative, and iron catalyst is 1:2:3:0.005:0.003.

[0159] Example 32

[0160] Example 32 uses the same method as Example 12, except that the molar ratio of nitrostyrene reagent, alkene substrate, hydrogen peroxide, amino acid derivative, and iron catalyst is 1:1:50:20:10.

[0161] Example 33

[0162] Example 33 uses the same method as Example 12, except that the molar ratio of nitrostyrene reagent, alkene substrate, hydrogen peroxide, amino acid derivative, and iron catalyst is 1:1.5:50:20:10.

[0163] Example 34

[0164] Example 34 uses the same method as Example 12, except that the solvent is entirely water and the total volume remains unchanged.

[0165] Comparative Example 1

[0166] The method of Comparative Example 1 is the same as that of Example 12, except that no iron catalyst is added and the yield of the target product is 0.

[0167] Comparative Example 2

[0168] Comparative Example 2 uses the same method as Example 12, except that no amino acid ligands are added, which greatly reduces the reaction yield to less than 20%.

[0169] Comparative Example 3

[0170] Comparative Example 3 uses the same method as Example 12, except that no oxidant is added and the yield of the target product is 0.

[0171] Comparative Example 4

[0172] Comparative Example 4 followed the same method as Example 12, except that it used a non-amino acid ligand, 1,10-phenanthroline, with a yield of only 6%. Furthermore, other phosphorus-containing ligands, such as triphenylphosphine, tris(pentafluorophenyl)phosphine, and bis(triphenylphosphine)ammonium chloride, were also ineffective, resulting in very low yields.

[0173] 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 of olefin hydroxylation reactions, utilizing their ability to coordinate with iron. Theoretically, various amino acids and their derivatives all possess coordination functions and should achieve similar effects. 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 present 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 the present invention to achieve the method of the present 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 are still within the scope of the present invention.

Claims

1. A method for hydroxylating of alkenes by iron-catalyzed oxidation, characterized in that, The steps include: in a solvent, using nitrostyrene compounds and alkenes as substrates, peroxides as oxidants, iron as catalysts, and amino acids or their derivatives as ligands, catalyzing the hydroxylation of alkenes to generate alkenylated alcohols; The general formula for the reaction is as follows: ； In the formula: R1 is a C1-C4 alkyl, methoxy, tert-butyl, cyano, trifluoromethyl, trifluoromethoxy, or halogen; R2 represents hydrogen or alkyl; R3 represents alkyl, or R2 and R3 form a cycloalkene compound.

2. The method for hydroxylating of olefins by iron-catalyzed oxidation according to claim 1, characterized in that, R1 represents the substituent on the aryl group in nitrostyrene, where R1 is an electron-donating or electron-withdrawing group; R2 and R3 are the substituents at both ends of the olefin, where R2 and R3 are electron-donating or electron-withdrawing groups.

3. The method for hydroxylating of olefins by iron-catalyzed oxidation according to claim 1, characterized in that, R1 is methyl, methoxy, cyano, trifluoromethyl, trifluoromethoxy, or halogen; R2 represents hydrogen or alkyl.

4. The method for iron-catalyzed hydroxylation of alkenes according to claim 1, characterized in that, R3 is preferably an alkyl chain linked to halogen, oxygen, sulfur, or nitrogen.

5. The method for hydroxylating of olefins by iron-catalyzed oxidation according to claim 1, characterized in that, The iron is selected from any one or more of the following: ferrous perchlorate (III) hydrate, ferrous acetate, ferrous sulfate, ferric oxalate, ferrous fluoride, ferric fluoride, ferrous bromide, ferric bromide, ferrous iodide, ferric iodide, ferric chloride, 1,1'-bis(diphenylphosphine)ferrocene, ferrous phthalocyanine, ferric nitrate, ferrous 2,2,6,6-tetramethyl-3,5-heptadecyl iron, ferric 2,2,6,6-tetramethyl-3,5-heptadecyl iron, ferrous 1,3-diphenylpropanedione, ferrous ammonium sulfate, ferric sulfate, ferrous oxalate, ferric oxide, iron tetroxide, ferrous trifluoromethanesulfonate, ferric trifluoromethanesulfonate, ferrous chloride, ferrous acetylacetone, ferric acetylacetone, ferric 1,3-diphenylpropanedione, ferrous benzoylacetone, ferric benzoylacetone, ferrous ferric ferric cyanide, and ferric ferric cyanide.

6. The method for iron-catalyzed hydroxylation of alkenes according to claim 1, characterized in that, The ligands are selected from glycine-glycine-glycine, BOC-glycine-glycine-glycine, L-serine, D-cysteine, D-arginine, isoserine, L-threonine, D-serine, L-tyrosine, D-proline, D-valine, BOC-L-proline, L-histidine, BOC-D-phenylalanine, L-cysteine, β-thiovaline, L-proline, L-phenylalanine, N-BOC-N'-trimethylammonium chloride, L-thiovaline, L-proline, L-phenylalanine, and N-BOC-N'-trimethylammonium chloride. The following are one or more of the following: benzyl-L-histidine, L-tryptophan, N-BOC-L-leucine, BOC-L-glutamic acid, L-cysteine, L-homocysteine, S-acetamidomethyl-N-tert-butoxycarbonyl-L-cysteine, N-acetyl-L-cysteine, N,N'-bis(tert-butoxycarbonyl)-L-cysteine, Boc-L-cysteine, aspartic acid, and 2-allyl-N-FMOC-L-glycine.

7. The method for iron-catalyzed hydroxylation of alkenes according to claim 1, characterized in that, The oxidant is selected from any one or more of the following: per-tert-butyl hydroperoxide, hydrogen peroxide, peracetic acid, m-chloroperoxybenzoic acid, benzoyl peroxide, benzoyl peroxide-tert-butyl ester, di-tert-butyl peroxide, dicumyl peroxide, 2-butanone peroxide, or bis(trimethylsilyl)peroxide.

8. The method for iron-catalyzed hydroxylation of alkenes 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 one or more of the following: acetonitrile, toluene, acetone, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-diacetamide, N,N-dicarboxamide, ethyl acetate, 1,4-dioxane or tetrahydrofuran, methanol, ethanol, ethylene glycol, n-propanol, isopropanol, 1,3-propanediol, n-butanol, isoamyl alcohol, 2-pentanol, 3-pentanol, cyclopentanol, trifluoroethanol, isobutanol, tert-butanol, sec-butanol, tert-pentanol, 3-methoxybutanol, 4-methyl-2-pentanol, n-pentanol, and glycerol. When the solvent is an aqueous solution of an organic solvent, the volume ratio of the organic solvent to water is 1:(0.1-5).

9. The method for iron-catalyzed hydroxylation of alkenes according to claim 1, characterized in that, The molar ratio of the nitrostyrene compound, alkene compound, peroxide, amino acid or its derivative, and iron catalyst is 1:(0.5-2):(2-60):(0.001-20):(0.002-10).

10. The method for iron-catalyzed hydroxylation of alkenes according to claim 1, characterized in that, The reaction is carried out at a temperature of 25–120°C for 1–48 hours.

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