A method for iron-catalyzed methylation of quinone compounds

Abstract

This invention discloses a method for iron-catalyzed methylation of quinone compounds, comprising the following steps: in a solvent, using 2-aryl-2-propanols as methylating agents, peroxides as oxidants, iron as catalysts, and amino acids or their derivatives as ligands, oxidizing the C(sp) group of aromatic compounds. 2 The H-bond undergoes methylation to generate methyl-substituted quinone compounds. This invention offers advantages such as readily available, inexpensive, and environmentally friendly catalysts; readily available, inexpensive oxidants that do not generate hazardous waste; mild, stable, and inexpensive methylating agents; mild reaction conditions with high selectivity and high yield; widely available and stable substrates; good compatibility of substrate functional groups and a wide range of substrate applications; compatibility with complex molecules and natural products, enabling effective methylation of quinone compounds. Under optimized reaction conditions, the yield of the target product after separation can reach 80%.

Description

Technical Field

[0001] This invention belongs to the fields of catalytic synthesis technology and fine chemical synthesis, specifically relating to an iron-catalyzed method for the methylation of quinone compounds, and more particularly, the iron-catalyzed oxidation of quinone compounds with a suitable oxidant to achieve the C(sp) methylation of quinones. 2 A method for direct methylation of the -H bond. Background Technology

[0002] The methyl group is the smallest organic group found in nature and is widely present in drug molecules and natural products. Methylation is a fundamental reaction in medicinal chemistry; introducing a methyl group into a drug molecule can significantly alter its biological activity. For example, introducing a methyl group into the drug molecule PLD2IC... 50 In this process, its efficacy can be increased by 590 times; researchers call this phenomenon the "magical methyl effect" (Heike). Tim Cernak* Angew. Chem. Int. Ed., 2013, 52(47): 12256-12267.). Therefore, methylation has always been a hot topic in the field of chemistry, and efficient methylation methods have been continuously explored by researchers. To date, methylation has made great progress.

[0003] Since the early work of Minisci (Minisci F., Bernardi R. Tetrahedron, 1971, 27(15): 3575-3579.) and others, radical methylation reactions have made successful progress; meanwhile, transition metal-catalyzed CH bond-activated methylation reactions have also developed rapidly in the past few decades. Methods for obtaining methylated products through cross-coupling have good chemoselectivity, but require pre-functionalization of the substrate, increasing the number of reaction steps and cost. In contrast, CH bond-activated methylation methods are more popular, and researchers have made great progress in this area in recent decades, but there are still some areas that need further improvement. For example, Tremont's group (Samuel J. Tremont, Hayat Ur Rahman J. Am. Chem. Soc. 1984, 106, 19, 5759–5760) reported a reaction for the methylation of the ortho-CH bond of acetanilide compounds in 1984. This reaction used a stoichiometric amount of palladium as a catalyst and a high stoichiometric amount of iodomethane as a methylating agent. Although the methylation of the CH bond was achieved, it was not economical or environmentally friendly. In 2019, Shen Liang's group (Zhengbao Xu*, Liang Shen*, Synlett 2019;30(16):1909-1913) used tert-butanol as a methylating agent and achieved the methylation of quinone compounds under iron catalysis. However, it used expensive high-iodine reagents, and the reaction process was not easy to control, easily forming polymethylated products. In the same year, Wang Jiyu's team (Jian Yang, Ji-YuWang*, Tetrahedron, 2019, 75(50): 130729.), used TBPB as the oxidant and methyl source, but the use of the noble metal bismuth catalysis is not economical. The above methods have made phased progress in the synthesis of methylated quinone compounds, but they still have the shortcomings of requiring noble metal catalysis, the selectivity problem of polymethylation, and the difficulty in using them for the later modification of complex molecules, which limits their large-scale application; therefore, it is particularly important to develop a method for the methylation of complex quinone molecules by a low-cost metal catalysis with high activity and good selectivity. Summary of the Invention

[0004] Objective of the Invention: To address the problems existing in the prior art, this invention provides a method for iron-catalyzed methylation of quinone compounds, comprising the following steps: using mono- or di-substituted 2-aryl-2-propanol as a methylating agent, peroxide as an oxidant, iron as a catalyst, and amino acids or their derivatives as ligands, oxidizing the C(sp) group of quinone compounds in a solvent. 2 The -H bond undergoes methylation to form methyl-substituted quinone compounds;

[0005] The general formula for the reaction is as follows:

[0006]

[0007] Where: R 1 R represents a substituent on the aromatic ring in quinone compounds. 1 Hydrogen atoms on mono- or di-substituted benzene rings; R 2 R represents a substituent on the double bond of a quinone compound. 2 Monosubstituted hydrogen on a double bond; R 3 R represents the substituent on the aryl group in 2-aryl-2-propanol. 3 Hydrogen on a monosubstituted or polysubstituted aromatic ring.

[0008] Wherein, the R 1 R represents a substituent on the aromatic ring in quinone compounds. 1 The hydrogen atom on a mono- or di-substituted benzene ring, R 1 It can be nitro, methoxy, or methyl, etc.

[0009] Wherein, the R 2 It can be hydrogen, methyl, methoxy, ethoxy, isopropoxyphenoxy, halogen, acetoxy, or methylthio, etc.

[0010] Among them, R 3 R represents the substituent on the aryl group in 2-aryl-2-propanol. 3 The hydrogen atom on the mono- or poly-substituted aromatic ring, R 3 It can be hydrogen, 3-methoxy, 2-chloro, 4-bromine, 3,5-dimethyl or 4-carboxyl, etc.

[0011] The mono- or di-substituted 2-aryl-2-propanol is selected from 2-phenyl-2-propanol (CAS: 617-94-7), 2-(3-methoxyphenyl)prop-2-ol (CAS: 55311-42-7), 2-(2-chlorophenyl)prop-2-ol (CAS: 3670-15-3), 2-(4-bromophenyl)prop-2-ol (CAS: 2077-19-2), 2-(3,5-dimethylphenyl)prop-2-ol (CAS: 34696-74-7), or 4-(2-hydroxy-2-propyl)benzoic acid (CAS: 3609-50-5), etc.

[0012] The iron is selected from any one or more of the following: ferrous trifluoromethanesulfonate, ferric trifluoromethanesulfonate, ferrous chloride, ferrous acetylacetone, ferric acetylacetone, ferric ferric ferric cyanide, ferrous acetate, ferric benzoylacetone, ferrous sulfate, ferrous ammonium sulfate, ferric sulfate, ferrous oxalate, ferric oxalate, ferrous fluoride, ferric fluoride, ferrous bromide, ferric bromide, ferrous iodide, ferrous chloride, ferric chloride, ferric perchlorate hydrate, 1,1'-bis(diphenylphosphine)ferrocene, ferrous phthalocyanine, ferric nitrate, iron oxide, or iron(II,III) oxide.

[0013] The ligand is selected from any one or more of the following: S-acetaminomethyl-N-tert-butoxycarbonyl-L-cysteine, N-acetyl-L-cysteine, N,N'-bis(tert-butoxycarbonyl)-L-cysteine, L-serine, D-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, or L-homocysteine.

[0014] The oxidant is selected from any one or more of potassium persulfate, ammonium persulfate, sodium persulfate, tert-butyl hydroperoxide, hydrogen peroxide, peracetic acid, m-chloroperoxybenzoic acid, benzoyl peroxide, di-tert-butyl peroxide, potassium monopersulfate, dicumyl peroxide, 2-butanone peroxide, or bis(trimethylsilyl) peroxide.

[0015] Wherein, the solvent is an organic solvent, water, or an aqueous solution of an organic solvent. The organic solvent is selected from methanol, ethanol, ethylene glycol, n-propanol, isopropanol, 1,3-propanediol, glycerol, n-butanol, isobutanol, tert-butanol, trifluoroethanol, 2-methyl-2-butanol, 3-methoxybutanol, sec-butanol, tert-amyl alcohol, 4-methyl-2-amyl alcohol, isoamyl alcohol, 2-amyl alcohol, 3-amyl alcohol, cycloamyl alcohol, n-amyl alcohol, polyethylene glycol 200-10000, 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:(0.1-10).

[0016] The molar ratio of the quinone compound, mono- or di-substituted 2-aryl-2-propanol, peroxide, amino acid or its derivative, and iron catalyst is 1:(1.2–50):(2–50):(0.002–20):(0.001–10); the reaction temperature is 40–120 °C, and the reaction time is 0.5–48 hours.

[0017] The iron catalyst in 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 oxidants and solvents, exhibits high activity and selectivity. Furthermore, the method uses mild reagents and a mild environment, overcoming the problem of harsh reaction conditions. Mono- or di-substituted 2-phenyl-2-propanol is low-cost, readily available, non-toxic, and non-explosive. No pre-functionalization is required; iron is used as the catalyst, eliminating the need for precious metals, and the effect is significant. This invention is the first to use specific mono- or di-substituted 2-phenyl-2-propanol as the methyl source for methylation reactions. Compared to existing reported methods that do not use such methyl sources, this method offers high conversion rates, economic efficiency, and environmental friendliness.

[0018] This invention is the first to apply iron-amino acid coordination species to quinone methylation reactions, exhibiting higher catalytic activity and stability compared to previous noble metal catalysis. Regarding the starting materials, it offers broader compatibility with functional groups in the substrates and, for the first time, uses 2-phenyl-2-propanol, which boasts high conversion rates and is economical and environmentally friendly, as the methyl source. This invention cleverly utilizes amino acid compounds as ligands to regulate the high activity and ideal selectivity of inexpensive and readily available iron-catalyzed quinone methylation, enabling its application in the later stages of complex molecule modification. It solves a series of challenging problems in this type of reaction, broadening its applications, particularly in the synthesis of active pharmaceutical molecules.

[0019] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0020] (1) This invention provides a method for iron-catalyzed methylation of quinone compounds promoted by amino acids or their derivatives. This method requires only one step, does not require the participation of acids or bases, and has the unique advantages of inexpensive, widely available, and environmentally friendly catalysts, ligands, and oxidants. The reaction conditions are mild, and the selectivity and yield are high. The substrates are widely available, stable, and easy to process. The substrates have good functional group compatibility and a wide range of applicability. The reaction has the advantage of being suitable for the methylation of complex small molecules.

[0021] (2) The methylation method provided by the present invention is simple, easy to implement and safe. It can directly obtain the methylated product of quinone compounds in one step. Under optimized reaction conditions, the yield of the target product after separation can be as high as 80%. It is a universal, efficient, economical and environmentally friendly methylation method.

[0022] (3) The key to the success of the method in this invention in using ideal iron as a catalyst lies in the use of amino acid ligands to coordinate with the iron catalyst, forming a highly active catalytic species. This allows the reaction to proceed under very mild conditions for the methylation of aromatic compounds, achieving ideal catalytic effects, especially for complex substrates. This invention cleverly utilizes amino acid compounds as ligands to regulate the high activity and ideal selectivity of inexpensive and readily available iron-catalyzed methylation of quinones, enabling its application in the later stages of complex molecule modification. This solves a series of challenging problems associated with this type of reaction, broadening its applications, particularly in the synthesis of active pharmaceutical molecules.

[0023] (4) The methylated quinone compounds 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, heterocycles and high value-added fine chemicals. Detailed Implementation

[0024] 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.

[0025] 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.

[0026] The specific structures of the substrates and products in the embodiments are shown in Table 1.

[0027] In the embodiments of this invention, all substrates are known compounds. Among the products of this invention, compounds 8, 9, 24, and 25 are compounds synthesized for the first time, and NMR mass spectrometry data have been provided; the rest are known compounds.

[0028] Among them are 2-phenyl-2-propanol (CAS: 617-94-7), 2-(3-methoxyphenyl)prop-2-ol (CAS: 55311-42-7), 2-(2-chlorophenyl)prop-2-ol (CAS: 3670-15-3), 2-(4-bromophenyl)prop-2-ol (CAS: 2077-19-2), 2-(3,5-dimethylphenyl)prop-2-ol (CAS: 34696-74-7), and 4-(2-hydroxy-2-propyl)benzoic acid (CAS: 3609-50-5).

[0029] Example 1

[0030] Synthesis of Compound 1

[0031] In a 25 mL reaction flask, ferric sulfate (0.06 mmol), BOC-L-proline (0.09 mmol), substrate 1a (0.5 mmol), ethanol (1.5 mL), water (0.5 mL), 2-phenyl-2-propanol (1 mmol), and potassium persulfate (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 80 °C for 5 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 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 = 40:1) to give product 1 in 75% yield.

[0032] Example 2

[0033] Synthesis of Compound 2

[0034] In a 25 mL reaction flask, ferrous phthalocyanine (0.01 mmol), L-tryptophan (0.2 mmol), substrate 2a (0.5 mmol), dimethyl sulfoxide (1.5 mL), water (0.5 mL), 2-(3-methoxyphenyl)prop-2-ol (1.5 mmol), and dicumyl peroxide (1 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 65 °C for 4 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 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 = 30:1) to give product 2 in 68% yield.

[0035] Example 3

[0036] Synthesis of Compound 3

[0037] In a 25 mL reaction flask, ferric fluoride (0.035 mmol), BOC-L-glutamic acid (0.04 mmol), substrate 3a (0.5 mmol), dichloromethane (2.0 mL), 2-(2-chlorophenyl)prop-2-ol (1.5 mmol), and potassium persulfate (1.2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was refluxed at 55 °C for 6 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 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 = 30:1) to give product 3 in 69% yield.

[0038] Example 4

[0039] Synthesis of Compound 4

[0040] In a 25 mL reaction flask, ferric ferricyanide (0.02 mmol), S-acetaminomethyl-N-tert-butoxycarbonyl-L-cysteine ​​(0.08 mmol), substrate 4a (0.5 mmol), ethanol (2.0 mL), water (0.5 mL), 2-(4-bromophenyl)prop-2-ol (2 mmol), and m-chloroperoxybenzoic acid (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 90 °C for 3 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: dichloromethane V / V = 20:1) to give product 4 in 71% yield.

[0041] 1 H NMR (400MHz, CDCl3): δ8.06-8.01(m,2H),7.70-7.64(m,2H),5.02-4.93(m,1H),2.09(s,3H),1.35ppm(d,J=6.2Hz,6H); 1 3C NMR (100MHz, CDCl3): δ185.8,181.4,156.8,133.6,133.5,133.1,132.1,131.5,126.13,126.1,76.2,23.0,9.7ppm; Mp:116.3–117.9℃.

[0042] Example 5

[0043] Synthesis of Compound 5

[0044] In a 25 mL reaction flask, ferrous oxalate (0.07 mmol), BOC-glycine-glycine-glycine (0.1 mmol), substrate 5a (0.5 mmol), acetone (2.0 mL), water (1.0 mL), 2-(3,5-dimethylphenyl)prop-2-ol (2.5 mmol), and benzoyl peroxide (1.2 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, 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 = 40:1) to give product 5 in 73% yield.

[0045] Example 6

[0046] Synthesis of Compound 6

[0047] In a 25 mL reaction flask, ferric oxalate (0.08 mmol), L-histidine (0.7 mmol), substrate 6a (0.5 mmol), N,N-diacetamide (1.5 mL), water (0.5 mL), 4-(2-hydroxy-2-propyl)benzoic acid (3 mmol), and tert-butyl hydroperoxide (3 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 75 °C for 4 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 = 40:1) to give product 6 in 62% yield.

[0048] Example 7

[0049] Synthesis of Compound 7

[0050] In a 25 mL reaction flask, ferric nitrate (0.03 mmol), BOC-L-glutamic acid (0.1 mmol), substrate 7a (0.5 mmol), isoamyl alcohol (2.0 mL), water (1.5 mL), 2-phenyl-2-propanol (2.5 mmol), and peracetic acid (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 95 °C for 1 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 = 20:1) was performed to obtain product 7 in 77% yield.

[0051] 1 H NMR (400MHz, CDCl3): δ8.06-8.01(m,2H),7.70-7.64(m,2H),5.02-4.93(m,1H),2.09(s,3H),1.35ppm(d,J=6.2Hz,6H); 13 C NMR (100MHz, CDCl3): δ185.8,181.4,156.8,133.6,133.5,133.1,132.1,131.5,126.13,126.1,76.2,23.0,9.7ppm; Mp:116.3–117.9℃.

[0052] Example 8

[0053] Synthesis of Compound 8

[0054] In a 25 mL reaction flask, 1,1'-bis(diphenylphosphine)ferrocene (0.11 mmol), N,N'-bis(tert-butoxycarbonyl)-L-cysteine ​​(0.4 mmol), substrate 8a (0.5 mmol), 4-methyl-2-pentanol (2.0 mL), water (1.5 mL), 2-(3-methoxyphenyl)prop-2-ol (2 mmol), and sodium persulfate (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 100 °C for 6 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 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 = 15:1) to give product 8, with a yield of 80%.

[0055] 1 H NMR (400MHz, CDCl3): δ8.09-8.05(m,2H),7.71-7.68(m,2H),2.89(t,J=7.8Hz,2H), 2.63(t,J=7.8Hz,2H),2.45(q,J=7.3Hz,2H),2.21(s,3H),1.07ppm(t,J=7.3Hz,3H); 13 C NMR (100MHz, CDCl3): δ209.8,185.0,184.7,145.9,144.0,133.5,133.4,132.1,132.07,126.3,126.2,40.5,35.8,21.7,12.7,7.8ppm; HRMS(ESI)calcd.for C 16 H 16 O3Na + [M+Na + ]m / z 279.0992,found 279.0992.

[0056] Example 9

[0057] Synthesis of Compound 9

[0058] In a 25 mL reaction flask, 0.08 mmol of acetylacetone iron, 0.1 mmol of L-serine, 0.5 mmol of substrate 9a, 1.0 mL of 1,3-propanediol, 1.0 mL of water, 1.5 mmol of 2-(2-chlorophenyl)prop-2-ol, and 2 mmol of peracetic acid were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 80 °C for 12 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 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 = 15:1) to give product 9 in 74% yield.

[0059] 1 H NMR (400MHz, CDCl3): δ8.06-8.01(m,2H),7.70-7.64(m,2H),5.02-4.93(m,1H),2.09(s,3H),1.35ppm(d,J=6.2Hz,6H); 13 C NMR (100MHz, CDCl3): δ185.8,181.4,156.8,133.6,133.5,133.1,132.1,131.5,126.13,126.1,76.2,23.0,9.7ppm; Mp:116.3–117.9℃; HRMS(ESI)calcd.for C 23 H 22 O3H + [M+H + ]m / z347.16417,found 347.1644.

[0060] Example 10

[0061] Synthesis of Compound 10

[0062] In a 25 mL reaction flask, ferrous sulfate (0.06 mmol), L-phenylalanine (0.1 mmol), substrate 10a (0.5 mmol), tetrahydrofuran (2.0 mL), water (1.0 mL), 2-(4-bromophenyl)prop-2-ol (1.5 mmol), and hydrogen peroxide (1.3 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 70 °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: diethyl ether V / V = 40:1) to give product 10 in 62% yield.

[0063] 1 H NMR (400MHz, CDCl3): δ8.06-8.01(m,2H),7.70-7.64(m,2H),5.02-4.93(m,1H),2.09(s,3H),1.35ppm(d,J=6.2Hz,6H); 13 C NMR (100MHz, CDCl3): δ185.8,181.4,156.8,133.6,133.5,133.1,132.1,131.5,126.13,126.1,76.2,23.0,9.7ppm; Mp:116.3–117.9℃.

[0064] Example 11

[0065] Synthesis of Compound 11

[0066] In a 25 mL reaction flask, ferric fluoride (0.03 mmol), L-serine (0.04 mmol), substrate 11a (0.5 mmol), 1,4-dioxane (2.0 mL), and water (0.2 mL), 2-(3,5-dimethylphenyl)prop-2-ol (1 mmol), and dicumyl peroxide (1 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 50 °C for 18 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: diethyl ether V / V = 10:3) to give product 11 in 68% yield.

[0067] Example 12

[0068] Synthesis of Compound 12

[0069] In a 25 mL reaction flask, ferric trifluoromethanesulfonate (0.02 mmol), β-thiovaline (0.3 mmol), cysteine ​​(0.04 mmol), substrate 12a (0.5 mmol), acetonitrile (1.0 mL), and water (1.0 mL) were added sequentially, along with 4-(2-hydroxy-2-propyl)benzoic acid (2 mmol) and potassium persulfate (2 mmol). After thorough mixing at room temperature, the reaction mixture was reacted at 100 °C for 2 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 = 20:1) was performed to obtain product 12 in 62% yield.

[0070] Example 13

[0071] Synthesis of Compound 13

[0072] In a 25 mL reaction flask, ferric perchlorate (III) hydrate (0.01 mmol), BOC-glycine-glycine-glycine (0.02 mmol), substrate 13a (0.5 mmol), 1,2-dichloroethane (2.0 mL), water (0.4 mL), 2-(4-bromophenyl)prop-2-ol (2.5 mmol), and bis(trimethylsilyl)peroxide (1 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 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 = 15:1) to give product 13 in 64% yield.

[0073] Example 14

[0074] Synthesis of Compound 14

[0075] In a 25 mL reaction flask, 0.16 mmol of iron oxide, 0.3 mmol of β-thiovaline, 0.5 mmol of substrate 14a, 2.0 mL of dimethyl sulfoxide, 0.5 mL of water, 2 mmol of 2-(3,5-dimethylphenyl)prop-2-ol, and 1.5 mmol of ammonium persulfate were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 60 °C for 2 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 = 20:1) to give product 14 in 60% yield.

[0076] Example 15

[0077] Synthesis of Compound 15

[0078] In a 25 mL reaction flask under normal nitrogen pressure, ferrous acetylacetone (0.09 mmol), 2-allyl-N-FMOC-L-glycine (0.03 mmol), substrate 15a (0.5 mmol), dimethyl sulfoxide (1.5 mL), water (0.5 mL), 2-phenyl-2-propanol (2 mmol), and ammonium persulfate (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 90 °C for 6 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 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 = 10:1) to give product 15 in 61% yield.

[0079] 1 H NMR (400MHz, CDCl3): δ8.08-8.06(m,2H),7.70-7.68(m,2H),7.10(d,J=8.4Hz,2H),6.73(d,J=8.5Hz,2H),3.95(s,2H),2.25ppm(s,3H); 13 C NMR (100MHz, CDCl3): δ185.5,184.8,154.1,145.6,144.1,133.5,133.49,132.0 ,131.97,130.0,129.8,126.4,126.3,115.5,31.5,13.2ppm; Mp:170.3-170.6℃.

[0080] Example 16

[0081] Synthesis of Compound 16

[0082] In a 25 mL reaction flask, ferrous acetate (0.04 mmol), isoserine (0.35 mmol), substrate 16a (0.5 mmol), trifluoroethanol (2.0 mL), water (1.0 mL), 2-(3,5-dimethylphenyl)prop-2-ol (3 mmol), and tert-butyl hydroperoxide (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 100 °C for 18 h. 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 = 5:1) to give product 16 in 78% yield.

[0083] Example 17

[0084] Synthesis of Compound 17

[0085] In a 25 mL reaction flask, ferric bromide (0.15 mmol), L-threonine (0.06 mmol), substrate 17a (0.5 mmol), acetonitrile (2.0 mL), water (1.5 mL), 2-(3-methoxyphenyl)prop-2-ol (2.5 mmol), and di-tert-butyl peroxide (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 120 °C for 15 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 10:3) yielded product 17 in 72% yield.

[0086] Example 18

[0087] Synthesis of Compound 18

[0088] In a 25 mL reaction flask, ferrous oxalate (0.1 mmol), N-BOC-N'-triphenylmethyl-L-histidine (0.1 mmol), substrate 18a (0.5 mmol), glycerol (1.5 mL), water (0.5 mL), 2-phenyl-2-propanol (1 mmol), and benzoyl peroxide (1 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 80 °C for 6 h. Upon completion of the reaction, direct chromatography (petroleum ether:dichloromethane V / V = 20:1) yielded product 18 in 59% yield.

[0089] 1 H NMR (400MHz, CDCl3): δ7.83(s,1H),7.79(s,1H),6.76(s,1H),2.38(s,6H),2.16ppm(s,3H); 13C NMR (100MHz, CDCl3): δ185.8,185.4,147.9,143.4,143.3,135.5,130.2,130.1,127.5,127.1,20.2,16.4ppm; Mp:71.5-72.6℃.

[0090] Example 19

[0091] Synthesis of Compound 19

[0092] In a 25 mL reaction flask, ferrous ammonium sulfate (0.06 mmol), BOC-D-phenylalanine (0.1 mmol), substrate 19a (0.5 mmol), isopropanol (1.5 mL), water (2.5 mL), 2-(3-methoxyphenyl)prop-2-ol (1.5 mmol), and m-chloroperoxybenzoic acid (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 75 °C for 12 h. Upon completion of the reaction, direct chromatography (petroleum ether:dichloromethane V / V = 10:1) yielded product 19 in 48% yield.

[0093] 1 H NMR (400MHz, CDCl3): δ8.63(s,1H),8.59(s,1H),8.07-8.03(m,2H),7.70-7.67(m,2H),6.95(s,1H),2.25ppm(s,3H); 13 C NMR (100MHz, CDCl3): δ185.2,184.6,149.7,137.2,134.8,134.76,130.2,130 .1,129.4,129.36,128.9,128.86,128.61,128.4,16.8ppm; Mp:183.1-184.5℃.

[0094] Example 20

[0095] Synthesis of Compound 20

[0096] In a 25 mL reaction flask, ferrous phthalocyanine (0.08 mmol), L-tyrosine (0.16 mmol), substrate 20a (0.5 mmol), methanol (0.5 mL), water (1.5 mL), 2-(3,5-dimethylphenyl)prop-2-ol (1.25 mmol), and peracetic acid (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 120 °C for 2 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 = 10:1) to give product 20 in 77% yield.

[0097] Example 21

[0098] Synthesis of Compound 21

[0099] In a 25 mL reaction flask, ferric chloride (0.05 mmol), L-tryptophan (0.25 mmol), substrate 21a (0.5 mmol), ethanol (1.0 mL), water (2.0 mL), 2-phenyl-2-propanol (0.75 mmol), and hydrogen peroxide (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 80 °C for 18 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 10:1) yielded product 21 in 73% yield.

[0100] Example 22

[0101] Synthesis of Compound 22

[0102] In a 25 mL reaction flask, ferric perchlorate (III) hydrate (0.04 mmol), BOC-glycine-glycine-glycine (0.15 mmol), substrate 22a (0.5 mmol), cyclopentanol (2.0 mL), water (2.0 mL), 2-(2-chlorophenyl)prop-2-ol (1.1 mmol), and potassium persulfate (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 110 °C for 1.5 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 10:1) yielded product 22 in 75% yield.

[0103] 1 H NMR (400MHz, CDCl3): δ5.81(s,1H),3.77(s,3H),2.18(s,3H),1.38ppm(s,9H); 13 C NMR (100MHz, CDCl3): δ187.5,184.3,159.5,151.7,141.1,105.5,56.2,37.0,31.0,14.6ppm.

[0104] Example 23

[0105] Synthesis of Compound 23

[0106] Benzoyl acetone iron (0.1 mmol), L-homocysteine ​​(0.25 mmol), substrate 23a (0.5 mmol), isoamyl alcohol (2.0 mL), water (2.0 mL), 2-(4-bromophenyl)prop-2-ol (0.8 mmol), and sodium persulfate (2.5 mmol) were added sequentially to a 25 mL reaction flask in air. After thorough mixing at room temperature, the reaction mixture was reacted at 85 °C for 4 h. Upon completion of the reaction, direct chromatography (petroleum ether:ethyl acetate V / V = 20:1) yielded product 23 in 80% yield.

[0107] 1 H NMR (400MHz, CDCl3): δ7.23(d,J=8.0Hz,2H),7.03(d,J=8.0Hz,2H),2.39(s,3H),2.08(s,3H),2.05(s,3H),1.95ppm(s,3H); 13 C NMR (100MHz, CDCl3): δ188.1,186.7,143.4,140.8,140.6,140.5,138.2,130.4,129.3,128.7,21.3,14.0,12.5,12.45ppm; Mp:62.0-62.5℃.

[0108] Example 24

[0109] Synthesis of Compound 24

[0110] In a 25 mL reaction flask, ferrous acetate (0.12 mmol), D-valine (0.12 mmol), substrate 24a (0.5 mmol), dimethyl sulfoxide (1.0 mL), water (3.0 mL), 2-phenyl-2-propanol (1 mmol), and potassium persulfate (2 mmol) were added sequentially. 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 = 10:1) to give product 24a in 61% yield.

[0111] 1 H NMR (400MHz, CDCl3): δ6.54(s,1H),2.52(s,3H),2.14(s,3H),1.27ppm(s,9H); 13C NMR (100MHz, CDCl3): δ185.2,183.3,157.1,147.2,141.9,131.4,35.7,29.2,17.5,13.8ppm; HRMS(ESI)calcd.for C 12 H 17 O2S + [M+H + ]m / z225.09438,found 225.0947.

[0112] Example 25

[0113] Synthesis of Compound 25

[0114] In a 25 mL reaction flask, ferric trifluoromethanesulfonate (0.08 mmol), BOC-L-glutamic acid (0.1 mmol), substrate 25a (0.5 mmol), toluene (1.0 mL), water (3.0 mL), 2-(3-methoxyphenyl)prop-2-ol (1 mmol), and dicumyl peroxide (2 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 100 °C for 18 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 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 = 4:1) to give product 25 in 80% yield.

[0115] 1 H NMR (400MHz, CDCl3): δ9.53 (s, 1H), 7.31-7.28 (m, 4H), 7.22-7.18 (m, 1H), 4.35 (t, J = 7.7Hz, 1H), 2 .66-2.59(m,1H),2.49-2.44(m,1H),2.43-2.37(m,2H),2.10(s,3H),2,00(s,3H),1.98ppm(s,3H); 13 C NMR (100MHz, CDCl3): δ187.6,186.9,179.3,144.6,142.1,141.1,140.9,140.3,128.4,127.8,126.4,42.7,32.4,26.5,12.5,12.4ppm.

[0116] Example 26

[0117] Synthesis of Compound 26

[0118] In a 25 mL reaction flask, ferric trifluoromethanesulfonate (0.08 mmol), BOC-L-proline (0.1 mmol), substrate 26a (0.5 mmol), acetonitrile (2.0 mL), water (2.0 mL), 2-phenyl-2-propanol (1.5 mmol), and potassium persulfate (1.5 mmol) were added sequentially. After thorough mixing at room temperature, the reaction mixture was reacted at 100 °C for 12 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 = 4:1) to give product 26a in 60% yield.

[0119] 1 H NMR (400MHz, CDCl3): δ2.76-2.72(m,2H),2.08(s,3H),2.06(s,3H),1.59-1.55(m,3H),1.52- 1.47(m,3H),1.41-1.24(m,9H),1.16-1.11(m,4H),1.09-1.03(m,4H),0.86-0.82ppm(m,15H); 13 C NMR (100MHz, CDCl3): δ184.1,179.6,149.3,141.0,140.7,135.1,72.6,42.1,39.3,37.5,37.4,37.4,37.2, 32.8,32.7,27.9,26.5,26.0,24.8,24.5,22.7,22.6,21.3,19.7,19.7,13.2,12.6ppm; HRMS(ESI)calcd.for C 28 H 47 BrO3Na + [M+Na + ]m / z533.2601,found 533.2606.

[0120] The structural formulas of the raw materials and products in Examples 1-26 and the corresponding experimental results are shown in Table 1 below:

[0121] Table 1

[0122]

[0123]

[0124]

[0125] Example 27

[0126] Example 27 uses the same method as Example 23, except that the solvent is N,N-diacetamide and water, and the volume ratio of the organic solvent to water is 2:1.

[0127] Example 28

[0128] Example 28 uses the same method as Example 23, except that the reaction temperature is 65°C and the reaction time is 15 hours.

[0129] Example 29

[0130] Example 29 uses the same method as Example 23, except that the solvent is entirely water and the total volume remains unchanged.

[0131] Comparative Example 1

[0132] The method of Comparative Example 1 is the same as that of Example 23, except that no iron catalyst is added and the yield of the target product is 0.

[0133] Comparative Example 2

[0134] The method of Comparative Example 2 is the same as that of Example 23, except that no amino acid ligands are added, which greatly reduces the reaction yield to less than 20%.

[0135] Comparative Example 3

[0136] Comparative Example 3 uses the same method as Example 23, except that no oxidant is added and the yield of the target product is 0.

[0137] Comparative Example 4

[0138] Comparative Example 4 uses the same method as Example 23, except that it uses a non-amino acid ligand 1,10-phenanthroline, and the yield is only 6%.

[0139] Comparative Example 5

[0140] Comparative Example 5 uses the same method as Example 23, except that porphyrin iron is used as a catalyst and the yield of the target product is 0.

[0141] Comparative Example 6

[0142] Comparative Example 6 uses the same method as Example 23, except that potassium permanganate is used as the oxidant and the yield of the target product is only 16%.

[0143] Comparative Example 7 uses the same method as Example 23, except that the methylating agent used is tert-butanol, and the yield of the target product is only 5%.

[0144] 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 and improving selectivity. Amino acid ligands are promoters of methylation 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 peroxides are oxidants. The reaction on quinone substrates involves the activation of carbon-hydrogen bonds, while the various substituents on the quinone compound structure 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 shall still fall within the scope of the present invention.

Claims

1. A method for iron-catalyzed methylation of quinone compounds, characterized in that, The process includes the following steps: using mono- or di-substituted 2-phenyl-2-propanol as a methylating agent, peroxide as an oxidizing agent, iron as a catalyst, and amino acids or their derivatives as ligands, to oxidize the C(sp) group of quinone compounds in a solvent. 2 The -H bond undergoes methylation to form methyl-substituted quinone compounds; The general formula for the reaction is as follows: ； Where: R 1 R represents a substituent on the benzene ring in quinone compounds. 1 Hydrogen atoms on mono- or di-substituted benzene rings; R 2 R represents a substituent on the double bond of a quinone compound. 2 Monosubstituted hydrogen on a double bond; R 3 R represents the substituent on the phenyl group in 2-phenyl-2-propanol. 3 Hydrogen atoms on mono- or di-substituted benzene rings; The R 1 It is nitro, methoxy, or methyl; R 2 It can be hydrogen, methyl, methoxy, ethoxy, isopropoxyphenoxy, halogen, acetoxy, or methylthio; R 3 It can be hydrogen, 3-methoxy, 2-chloro, 4-bromo, 3,5-dimethyl, or 4-carboxyl; The iron is selected from any one or more of the following: ferrous trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, ferrous chloride, ferrous acetylacetone, ferrous acetylacetone, ferric ferric ferricyanide, ferrous acetate, ferric benzoylacetone, ferrous sulfate, ferrous ammonium sulfate, ferric sulfate, ferrous oxalate, ferric oxalate, ferrous fluoride, ferrous fluoride, ferrous bromide, ferric bromide, ferrous iodide, ferrous chloride, ferric chloride, ferric perchlorate hydrate, 1,1'-bis(diphenylphosphine)ferrocene, ferrous phthalocyanine, or ferric nitrate. The ligand is selected from any one or more of the following: S-acetaminomethyl-N-tert-butoxycarbonyl-L-cysteine, N-acetyl-L-cysteine, N,N'-bis(tert-butoxycarbonyl)-L-cysteine, L-serine, D-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, or L-homocysteine.

2. The method for iron-catalyzed methylation of quinone compounds according to claim 1, characterized in that, The oxidant is selected from any one or more of potassium persulfate, ammonium persulfate, sodium persulfate, tert-butyl hydroperoxide, hydrogen peroxide, peracetic acid, m-chloroperoxybenzoic acid, benzoyl peroxide, di-tert-butyl peroxide, potassium monopersulfate, dicumyl peroxide, 2-butanone peroxide, or bis(trimethylsilyl) peroxide.

3. The method for iron-catalyzed methylation of quinone 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, ethylene glycol, n-propanol, isopropanol, 1,3-propanediol, glycerol, n-butanol, isobutanol, tert-butanol, trifluoroethanol, 2-methyl-2-butanol, 3-methoxybutanol, sec-butanol, tert-amyl alcohol, 4-methyl-2-amyl alcohol, isoamyl alcohol, 2-amyl alcohol, 3-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:(0.1-10).

4. The method for iron-catalyzed methylation of quinone compounds according to claim 1, characterized in that, The molar ratio of the quinone compound, mono- or di-substituted 2-phenyl-2-propanol, peroxide, amino acid or its derivative, and iron catalyst is 1:(1.2–50):(2–50):(0.002–20):(0.001–10); the reaction temperature is 40–120 °C, and the reaction time is 0.5–48 hours.

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