Process for the meta-amination of aryl amines and phenols

Abstract

The application belongs to the technical field of organic synthesis and relates to a method for meta-amination of arylamines and phenols. The method uses quinone (imine) alcohol compounds as substrates, and realizes meta-selective amination by reacting with N -sulfilimines or N -sulfilimines or The application has mild reaction conditions and simple operation, and is suitable for late functionalization of various bioactive natural products and drug molecules.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis, specifically to a method for meta-carbon-hydrogen bond (CH bond) amination of aniline and phenolic compounds, for the efficient construction of aniline and phenolic derivatives containing amino or substituted amino groups at the meta position. Background Technology

[0002] Meta-amined aniline and phenol are not only fundamental skeletons in numerous bioactive compounds, but also play indispensable roles in industrial and scientific research fields such as pharmaceuticals, pesticides, polymers, and dyes. Their importance lies not only in their versatility as synthetic building blocks, but also in their ability to precisely and subtly regulate the electronic distribution, spatial conformation, and physicochemical properties of molecules, directly influencing their biological activity or material function. For example, the leukemia treatment drug imatinib contains a meta-amined aniline structure, which inhibits Bcr-Abl tyrosine kinase; the cystic fibrosis treatment drug ivacathotor contains a meta-amined phenol skeleton. Furthermore, the classic antihypertensive drug phentolamine is also based on a meta-amined phenol skeleton, exerting its antihypertensive effect by blocking α-receptors. Therefore, the development and research of meta-amined aniline and phenol compounds is not only an in-depth exploration of the chemical properties of aromatic compounds, but also provides valuable scientific evidence and material basis for the discovery of molecular entities with higher activity.

[0003] For a long time, the precise structural modification of aniline and phenol derivatives to construct more valuable functional molecules has been one of the core topics in synthetic chemistry and medicinal chemistry research. Developing such modification strategies has provided a rich molecular library and synthetic pathways for new drug development, functional material design, and fine chemical synthesis. However, achieving highly selective amination of the meta-CH bonds in aniline and phenol derivatives remains a persistent challenge in synthetic chemistry, stemming from the inherent electronic properties of aniline and phenol. In electron-rich aromatic compounds like aniline and phenol, the strongly electron-donating amino and hydroxyl groups significantly activate the ortho and para-CH bonds through conjugation, making these sites thermodynamically and kinetically far more reactive than the meta-position. This fundamentally leads to a severe challenge in the synthesis of meta-substituted aniline and phenol derivatives. Therefore, directly achieving meta-functionalization, especially the meta-amination of aniline or phenol, has long been both a pursuit in the field of synthesis and a major scientific challenge.

[0004] In the meta-selective amination of aniline or phenol, traditional synthetic routes rely on multi-step transformations starting from pre-functionalized precursors. For example, a classic approach attempts to synthesize meta-substituted nitrobenzene derivatives, followed by the reduction of the nitro group to the target amino group (see: Inorg. Chem. Front., 2025, 12, 8407-8423). However, the bottleneck of this route lies in the inherent difficulty of constructing the meta-substituted nitrobenzene ring, typically requiring lengthy steps from specific starting materials, leading to poor atom economy and low overall yield.

[0005] To address the challenge of achieving high meta-selectivity, transition metal-catalyzed CH amination strategies assisted by directing groups have become mainstream in this field. For example, CN109311813A discloses a universal ligand for palladium-catalyzed meta-CH functionalization. The core of this approach is to temporarily introduce a strong coordinating group onto the amino or hydroxyl group, thereby guiding the metal catalyst (such as palladium, rhodium, or iridium) to preferentially activate the ortho-CH bond. Subsequently, through ingenious ligand design and reaction condition control, it is attempted to force the metal center to deviate from the conventional ortho mode and instead attack the more spatially unfavorable meta position. While this strategy has made progress in controlling selectivity, its inherent limitations are also significant: First, the installation and final removal of the directing group introduce additional synthetic steps, reducing overall efficiency and atom economy; second, achieving unconventional meta-selectivity often relies on structurally complex and expensive specialized ligands, along with the use of high-cost noble metal catalysts, which greatly increases application costs and may lead to metal residue problems; finally, the highly specific combination of catalysts and directing groups usually means that this method is only effective for a limited range of structurally simple substrates, and its applicability to complex drug molecules or natural product derivatives containing multiple sensitive functional groups is often poor.

[0006] In summary, meta-amination of aniline and phenol compounds has significant application value. Existing synthetic techniques have successfully overcome the selective bottleneck of long-range meta-CH bond activation, but still have obvious limitations, typically relying on pre-modified directing groups, specific substrates, noble metal catalysts, or complex ligands. Therefore, developing a novel, mild, readily available, and universal strategy for the meta-amination of electron-rich aromatics remains of significant research value. Summary of the Invention

[0007] In view of the aforementioned state of the prior art, the present invention aims to provide a method for the meta-CH bond amination of aniline and phenol derivatives under mild conditions without the need for directing groups and noble metal catalysts. The inventors of this invention have discovered that, under transition metal-free catalytic conditions, efficient and highly regioselective synthesis of meta-aminoanilines and phenolic compounds can be achieved through a tandem reaction involving quinone alcohols and iminoquinone alcohols with aryl / alkyl / sulfonyl / acylsulfinimides. This invention is based on the aforementioned findings.

[0008] Therefore, one object of the present invention is to provide a method for the meta-amination of aromatic amines and phenols. Compared with existing preparation strategies that use oxidants and transition metal catalysts, the present invention utilizes inexpensive and readily prepared p-quinols and iminoquinols to react with aryl / alkyl / sulfonyl / acylsulfinimides, achieving meta-amination of aniline and phenol compounds without transition metal catalysis or oxidants, and the reaction is environmentally friendly.

[0009] A second objective of this invention is to provide a method for synthesizing meta-amined aniline compounds using the above-described meta-amined method.

[0010] A third objective of this invention is to provide a method for synthesizing meta-amined phenolic compounds using the above-described meta-amined method.

[0011] The technical solution for achieving the above-mentioned objectives of this invention can be summarized as follows: A method for meta-amination of aromatic amines and phenols, wherein the method uses quinone alcohol compounds or imine quinone alcohol compounds obtained from simple aniline or phenol by oxidation with iodobenzene acetate (PIDA) as substrates, and... N -sulfinylimide or N -The sulfinyl chloride electrophilic reagent reaction achieves the meta-amination of aromatic amines and phenols.

[0012] According to the present invention, preferably, the meta-amination reaction is carried out in an alkaline and solvent environment; more preferably, the alkaline is selected from sodium carbonate, potassium carbonate, potassium bicarbonate, pyridine, DMAP, triethylamine, tetramethylguanidine, DBN, LiHMDS, sodium methoxide or DBU, and the solvent is DMF (N,N-dimethylformamide), MeCN (acetonitrile), 1,4-dioxane, DCM (dichloromethane), CHCl3 (chloroform), toluene, Et2O (diethyl ether) or THF (tetrahydrofuran).

[0013] According to the present invention, preferably, the meta-amine reaction temperature is -78 ℃ to 150 ℃, more preferably 0 ℃ to 25 ℃.

[0014] A method for synthesizing a meta-aminoaniline compound includes the following steps: In an air atmosphere, compound (I) and a base were added to a solvent, followed by the addition of compound (II) to react. After the reaction was completed, the meta-aminoaniline compound (III) was obtained by purification. Wherein, R is one of alkyl, aryl, heteroaryl, halogen, ester, alkoxy, silyl, sulfonyl, sulfinyl, and phosphoryl groups. 1 It is one of methanesulfonyl, p-toluenesulfonyl, and tert-butoxycarbonyl; R 2 It is one of alkyl, alkoxy, aryl, and heteroaryl; R 3 R 4 [N] is one of the following: substituted or unsubstituted aryl, heteroaryl, alkyl, allyl, or hydrogen atom; .

[0015] A method for synthesizing a meta-aminophenol compound, comprising the following steps: In an air atmosphere, compound (IV) and a base were added to a solvent, followed by the addition of compound (II) to react. After the reaction was completed, the mixture was purified to obtain meta-aminophenol compound (V). Wherein, R is one of alkyl, aryl, heteroaryl, halogen, ester, alkoxy, silyl, sulfonyl, sulfinyl, and phosphoryl groups. 2 It is one of alkyl, alkoxy, aryl, and heteroaryl; R 3 R 4 [N] is one of the following: substituted or unsubstituted aryl, heteroaryl, alkyl, allyl, or hydrogen atom; .

[0016] According to the present invention, the reaction process can be tracked by TLC.

[0017] According to the present invention, the preferred purification method is as follows: after the reaction is completed, the reaction mixture is concentrated, and the crude product is purified and separated by column chromatography. The eluent for column chromatography is petroleum ether: ethyl acetate = 10:1 (volume ratio) to obtain the target compound (III) or (V).

[0018] According to the present invention, preferably, the molar ratio of compound (I) to compound (II) is 1:1 to 1:2, more preferably 1:1.2; and the molar ratio of compound (IV) to compound (II) is 1:1 to 1:2, more preferably 1:1.2.

[0019] According to the present invention, preferably, the base is selected from sodium carbonate, potassium carbonate, potassium bicarbonate, pyridine, DMAP, triethylamine, tetramethylguanidine, DBN, LiHMDS, sodium methoxide, or DBU. More preferably, in the synthesis of aniline compound (III), the base is triethylamine; and in the synthesis of phenol compound (V), the base is tetramethylguanidine.

[0020] According to the present invention, preferably, the molar ratio of compound (I) to base is 1:1 to 1:3, more preferably 1:2; the molar ratio of compound (IV) to base is 1:1 to 1:3, more preferably 1:2.

[0021] According to the present invention, preferably, the solvent is DMF (N,N-dimethylformamide), MeCN (acetonitrile), 1,4-dioxane, DCM (dichloromethane), CHCl3 (chloroform), toluene, Et2O (diethyl ether), or THF (tetrahydrofuran); more preferably, it is DMF.

[0022] According to the present invention, preferably, the reaction temperature is -78 ℃ to 150 ℃, more preferably 0 ℃ to 25 ℃.

[0023] According to the present invention, preferably, the meta-aminoaniline compound is at least one of the following compounds having the following structure: .

[0024] According to the present invention, preferably, the meta-aminophenol compound is at least one of the following compounds having the following structure: .

[0025] The beneficial effects of this invention are as follows: 1. This invention provides a novel synthetic strategy with mild conditions and simple steps: For the first time, this invention achieves highly regioselective meta-amination of quinones and iminequinone alcohols under mild conditions without transition metal catalysts or the installation and removal of directing groups. This provides an efficient and practical solution to the long-standing synthetic challenge of meta-functionalization of aromatic amines and phenolic derivatives.

[0026] 2. The reaction is simple to operate and highly selective: the reaction can usually proceed smoothly at around room temperature, without the need for strong acids, strong bases, or noble metal catalysts, making the operation safe and simple. This method exhibits specific meta-selectivity, effectively overcoming the inherent ortho / para substitution tendency of electron-rich aromatic rings.

[0027] 3. Broad substrate applicability and good yield: This method is applicable to a variety of quinone alcohols and iminoquinone alcohols with different substitution modes, and can be combined with various substrates. NThe sulfinyl amination reagent reacted smoothly, and a series of structurally diverse meta-amined aromatic amines and phenol derivatives were synthesized in good to excellent yields.

[0028] 4. Great potential for late-stage modification of complex molecules: This method has good functional group compatibility and has been successfully applied to the late-stage functionalization of several bioactive molecules and drug analogs, allowing the direct introduction of amino functional groups onto their core skeletons. This provides a powerful tool for the structural optimization and diverse derivatization of lead compounds in medicinal chemistry. Attached Figure Description

[0029] Figure 1 The 4-methyl-N-[4-methyl-3-(pyrazine-2-amino)phenyl]benzenesulfonamide prepared in Example 1 1 H-NMR spectrum; Figure 2 The 4-methyl-N-[4-methyl-3-(pyrazine-2-amino)phenyl]benzenesulfonamide prepared in Example 1 13 C-NMR spectrum; Figure 3 The 4-methyl-N-[4-methyl-3-(quinoline-5-amino)phenyl]benzenesulfonamide prepared in Example 2 1 H-NMR spectrum; Figure 4 The 4-methyl-N-[4-methyl-3-(quinoline-5-amino)phenyl]benzenesulfonamide prepared in Example 2 13 C-NMR spectrum; Figure 5 The 4-methyl-N-[4-methyl-3-(morpholin-4-yl)phenyl]benzenesulfonamide prepared in Example 3 1 H-NMR spectrum; Figure 6 The 4-methyl-N-[4-methyl-3-(morpholin-4-yl)phenyl]benzenesulfonamide prepared in Example 3 13 C-NMR spectrum; Figure 7 The 4-methyl-N-[2-(phenylamino)-[1,1'-biphenyl]-4-phenyl]benzenesulfonamide prepared in Example 4 1 H-NMR spectrum; Figure 8 The 4-methyl-N-[2-(phenylamino)-[1,1'-biphenyl]-4-phenyl]benzenesulfonamide prepared in Example 4 13 C-NMR spectrum; Figure 9The N-[3-([2-(2,6-dioxopiperidin-3-phenyl)-1-oxoisoindoline-4-yl]amino)-4-methylphenyl]-4-methylbenzenesulfonamide prepared in Example 5 1 H-NMR spectrum; Figure 10 The N-[3-([2-(2,6-dioxopiperidin-3-phenyl)-1-oxoisoindoline-4-yl]amino)-4-methylphenyl]-4-methylbenzenesulfonamide prepared in Example 5 13 C-NMR spectrum; Figure 11 The 2-(diethylamino)ethyl 4-[(2-methyl-5-((4-methylphenyl)sulfonamido)phenyl)amino]benzoic acid ester prepared in Example 6 1 H-NMR spectrum; Figure 12 The 2-(diethylamino)ethyl 4-[(2-methyl-5-((4-methylphenyl)sulfonamido)phenyl)amino]benzoic acid ester prepared in Example 6 13 C-NMR spectrum; Figure 13 The 5-chloro-N-[2-(diethylamino)ethyl]-2-methoxy-4-[(2-methyl-5-((4-methylphenyl)sulfonamido)phenyl)amino]benzamide prepared in Example 7 1 H-NMR spectrum; Figure 14 The 5-chloro-N-[2-(diethylamino)ethyl]-2-methoxy-4-[(2-methyl-5-((4-methylphenyl)sulfonamido)phenyl)amino]benzamide prepared in Example 7 13 C-NMR spectrum; Figure 15 The 4-methyl-3-(quinoline-5-ylamino)phenol prepared in Example 8 1 H-NMR spectrum; Figure 16 The 4-methyl-3-(quinoline-5-ylamino)phenol prepared in Example 8 13 C-NMR spectrum; Figure 17 The 7-(phenylamino)-2,3-dihydro-1H-inden-5-ol prepared in Example 9 1 H-NMR spectrum; Figure 18 The 7-(phenylamino)-2,3-dihydro-1H-inden-5-ol prepared in Example 9 13 C-NMR spectrum; Figure 19The 4-hydroxy-2-(phenylamino)phenethyl ester of 2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid prepared in Example 10 1 H-NMR spectrum; Figure 20 The 4-hydroxy-2-(phenylamino)phenethyl ester of 2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid prepared in Example 10 13 C-NMR spectrum; Figure 21 The 4-hydroxy-2-(phenylamino)phenethyl ester of 2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid prepared in Example 10 19 F-NMR spectrum. Detailed Implementation

[0030] This invention provides a method for meta-amination of aromatic amines with phenolic derivatives, using quinone (imine) alcohols as substrates, under conditions without metals or directing groups, and with... N -sulfinylimide or N The method utilizes electrophilic reagents such as sulfinyl chlorides to achieve meta-selective amination, yielding a variety of structurally diverse meta-amined aromatic amines and phenolic derivatives in good yields. This method features mild reaction conditions, simple operation, and is suitable for late-stage functionalization of various bioactive natural products and drug molecules.

[0031] In one or more preferred embodiments, the meta-amination reaction is carried out in an alkaline and solvent environment; preferably, the alkaline is selected from sodium carbonate, potassium carbonate, potassium bicarbonate, pyridine, DMAP, triethylamine, tetramethylguanidine, DBN, LiHMDS, sodium methoxide, or DBU, and the solvent is DMF (N,N-dimethylformamide), MeCN (acetonitrile), 1,4-dioxane, DCM (dichloromethane), CHCl3 (chloroform), toluene, Et2O (diethyl ether), or THF (tetrahydrofuran).

[0032] In one or more preferred embodiments, the meta-amine reaction temperature is -78 °C to 150 °C, preferably 0 °C to 25 °C.

[0033] According to the present invention, a meta-amination reaction is carried out using a quinone alcohol compound (I) as a starting material to obtain a meta-aminoaniline compound (III), which has the following structure: .

[0034] According to the present invention, a meta-amination reaction is carried out using an iminoquinone alcohol compound (IV) as a starting material to obtain a meta-aminophenol compound (V), which has the following structure: .

[0035] According to the present invention, the technical route of the meta-amination method of aromatic amines and phenolic derivatives can be summarized as follows: .

[0036] This invention also provides a method for synthesizing meta-aminoaniline compounds, comprising the following steps: In an air atmosphere, compound (I) and a base were added to a solvent, followed by the addition of compound (II) to react. After the reaction was completed, the meta-aminoaniline compound (III) was obtained by purification. Wherein, R is one of alkyl, aryl, heteroaryl, halogen, ester, alkoxy, silyl, sulfonyl, sulfinyl, and phosphoryl groups. 1 It is one of methanesulfonyl, p-toluenesulfonyl, and tert-butoxycarbonyl; R 2 It is one of alkyl, alkoxy, aryl, and heteroaryl; R 3 R 4 [N] is one of the following: substituted or unsubstituted aryl, heteroaryl, alkyl, allyl, or hydrogen atom; .

[0037] This invention also provides a method for synthesizing meta-aminophenol compounds, comprising the following steps: In an air atmosphere, compound (IV) and a base were added to a solvent, followed by the addition of compound (II) to react. After the reaction was completed, the mixture was purified to obtain meta-aminophenol compound (V). Wherein, R is one of alkyl, aryl, heteroaryl, halogen, ester, alkoxy, silyl, sulfonyl, sulfinyl, and phosphoryl groups. 2 It is one of alkyl, alkoxy, aryl, and heteroaryl; R 3 R 4 [N] is one of the following: substituted or unsubstituted aryl, heteroaryl, alkyl, allyl, or hydrogen atom; .

[0038] In one or more preferred embodiments, compound (II) is N - One of sulfinyl imide or aminosulfinyl chloride.

[0039] According to the present invention, the reaction process can be tracked by TLC.

[0040] In one or more preferred embodiments, the purification method is as follows: after the reaction is completed, the reaction mixture is concentrated, and the crude product is purified and separated by column chromatography with petroleum ether: ethyl acetate = 10:1 (volume ratio) as the eluent to obtain the target compound (III) or (V).

[0041] In one or more preferred embodiments, the molar ratio of compound (I) to compound (II) is 1:1 to 1:2, preferably 1:1.2; the molar ratio of compound (IV) to compound (II) is 1:1 to 1:2, preferably 1:1.2.

[0042] In one or more preferred embodiments, the base is selected from sodium carbonate, potassium carbonate, potassium bicarbonate, pyridine, DMAP, triethylamine, tetramethylguanidine, DBN, LiHMDS, sodium methoxide, or DBU. Preferably, in the synthesis of aniline compound (III), the base is triethylamine; in the synthesis of phenol compound (V), the base is tetramethylguanidine.

[0043] In one or more preferred embodiments, the molar ratio of compound (I) to base is 1:1 to 1:3, more preferably 1:2; the molar ratio of compound (IV) to base is 1:1 to 1:3, more preferably 1:2.

[0044] In one or more preferred embodiments, the solvent is DMF (N,N-dimethylformamide), MeCN (acetonitrile), 1,4-dioxane, DCM (dichloromethane), CHCl3 (chloroform), toluene, Et2O (diethyl ether), or THF (tetrahydrofuran); preferably DMF.

[0045] According to the present invention, the reaction temperature is -78 ℃ to 150 ℃, more preferably 0 ℃ to 25 ℃.

[0046] In one or more preferred embodiments, the meta-aminoaniline compound is at least one of compounds having the following structure: .

[0047] In one or more preferred embodiments, the meta-aminophenol compound is at least one of compounds having the following structure: .

[0048] According to the present invention, a preferred embodiment of the method for synthesizing meta-aminoaniline compound (III) includes the following steps: at room temperature, adding the appropriate amount of [missing information] to a stirred mixture of compound (I) (1.0 mmol), triethylamine (2.0 mmol, 2.0 equivalent), and anhydrous DMF (10 mL). N-Sylenylimide or aminosulfinyl chloride (II) (1.2 mmol, 1.2 equivalents). After stirring for 2 hours (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give meta-aminoaniline compound (III).

[0049] According to the present invention, a preferred embodiment of the method for synthesizing meta-aminophenol compound (V) includes the following steps: at room temperature, adding the appropriate amount of [missing information - likely a specific ingredient or component] to a stirred mixture of compound (IV) (1.0 mmol), tetramethylguanidine (2.0 mmol, 2.0 equivalent), and anhydrous DMF (10 mL). N -Sylenylimide or aminosulfinyl chloride (II) (1.2 mmol, 1.2 equivalents). After stirring for 2 hours (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give meta-aminophenol compounds (V).

[0050] This invention provides a novel synthetic strategy that successfully achieves highly selective meta-amination of quinone (imine) alcohols under mild conditions without metal catalysts or additional directing groups.

[0051] To make the technical solution and advantages of the present invention clearer, the meta-amination reaction of aniline and phenol of the present invention will be further described in detail below with reference to specific embodiments. It should be noted that these embodiments are illustrative and not intended to limit the scope of protection of the present invention.

[0052] Example 1: 4-Methyl-N-[4-methyl-3-(pyrazin-2-ylamino)-phenyl]benzenesulfonamide

[0053] At room temperature, sulfinyl-2-pyrazinylimine (1.2 mmol, 1.2 equivalents) was added to a stirred mixture of compound (I) N-(4-hydroxy-4-methylcyclohexyl-2,5-diene-1-yl)-4-methylbenzenesulfonamide (1.0 mmol), triethylamine (2.0 mmol, 2.0 equivalents), and anhydrous DMF (10 mL). After stirring for 2 h (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give meta-aminoaniline compound (III) 4-methyl-N-[4-methyl-3-(pyrazin-2-ylamino)-phenyl]benzenesulfonamide 259 mg, 73% yield (based on 1.0 mmol scale).

[0054] 1 H NMR (500 MHz, DMSO- d 6 ): δ 10.09 (s, 1H), 8.54 (s, 1H), 8.13 (d, J =1.5 Hz, 1H), 8.01 (dd, J = 2.8, 1.5 Hz, 1H), 7.89 (d, J = 2.7 Hz, 1H), 7.67–7.65(m, 2H), 7.43 (d, J = 2.2 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.2 Hz, 1H), 6.75 (dd, J = 8.2, 2.3 Hz, 1H), 2.32 (s, 3H), 2.10 (s, 3H); 13 C NMR (126MHz, DMSO- d 6 ): δ 152.9, 143.1, 141.3, 138.3, 136.8, 135.9, 133.9, 133.6,130.9, 129.6, 126.8, 126.4, 115.7, 114.7, 20.9, 17.5; HRMS (ESI) m / z calcdfor [C 18 H 19 N4O2S] + [M+H] +: 355.1223, found: 355.1233. Example 2: 4-Methyl-N-[4-methyl-3-(quinoline-5-ylamino)phenyl]benzenesulfonamide

[0055] At room temperature, the corresponding sulfinyl 5-quinolinylimine (1.2 mmol, 1.2 equivalent) was added to a stirred mixture of compound (I) N-(4-hydroxy-4-methylcyclohexyl-2,5-diene-1-yl)-4-methylbenzenesulfonamide (1.0 mmol), triethylamine (2.0 mmol, 2.0 equivalent), and anhydrous DMF (10 mL). After stirring for 2 h (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give meta-aminoaniline compound (III) 4-methyl-N-[4-methyl-3-(quinolin-5-ylamino)phenyl]benzenesulfonamide 343 mg, 85% yield (based on 1.0 mmol scale).

[0056] 1 H NMR (500 MHz, DMSO- d 6 ): δ 9.98 (s, 1H), 9.25–9.25 (m, 1H), 8.44 (d, J = 5.9 Hz, 1H), 7.97 (dd, J = 5.9, 1.1 Hz, 1H), 7.74 (s, 1H), 7.60–7.58 (m,1H), 7.54–7.52 (m, 2H), 7.45 (t, J = 7.9 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.09(d, J = 8.2 Hz, 1H), 6.76 (dd, J = 8.2, 2.3 Hz, 1H), 6.71 (d, J = 2.2 Hz, 1H), 6.66(dd, J = 7.6, 1.0 Hz, 1H), 2.34 (s, 3H), 2.08 (s, 3H); 13 C NMR (126 MHz, DMSO- d6 ): δ 152.4, 143.1, 142.1, 141.9, 140.3, 136.6, 136.4, 131.3, 129.6, 129.4,127.9, 127.8, 126.7, 126.3, 119.0, 115.7, 115.1, 114.9, 114.0, 21.0, 17.2;HRMS (ESI) m / z calcd for [C 23 H 22 N3O2S] + [M+H] + : 404.1427, found: 404.1425. Example 3: 4-Methyl-N-[4-methyl-3-(morpholin-4-yl)phenyl]benzenesulfonamide

[0057] At room temperature, morpholinosulfinyl chloride (1.2 mmol, 1.2 equivalents) was added to a stirred mixture of compound (I) N-(4-hydroxy-4-methylcyclohexyl-2,5-diene-1-yl)-4-methylbenzenesulfonamide (1.0 mmol), triethylamine (2.0 mmol, 2.0 equivalents), and anhydrous DMF (10 mL). After stirring for 2 h (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give meta-aminoaniline compound (III) 4-methyl-N-[4-methyl-3-(morpholino-4-yl)phenyl]benzenesulfonamide 274 mg, 79% yield (based on 1.0 mmol scale).

[0058] 1 H NMR (500 MHz, DMSO- d 6 ): δ 10.04 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 2.3 Hz, 1H), 6.69(dd, J = 8.1, 2.2 Hz, 1H), 3.68 (t, J= 4.4 Hz, 4H), 2.68 (t, J = 4.6 Hz, 4H), 2.29(s, 3H), 2.10 (s, 3H); 13 C NMR (126 MHz, DMSO- d 6 ): δ 151.4, 143.1, 136.7,136.3, 131.3, 129.6, 127.3, 126.8, 114.8, 111.0, 66.5, 51.7, 21.0, 17.0; HRMS(ESI) m / z calcd for [C 18 H 23 N2O3S] + [M+H] + : 347.1424, found: 347.1430. Example 4: 4-Methyl-N-[2-(phenylamino)-[1,1'-biphenyl]-4-phenyl]benzenesulfonamide

[0059] At room temperature, sulfinylphenylimine (0.24 mmol, 1.2 equivalent) was added to a stirred mixture of compound (I) N-(4-hydroxy-4-phenylcyclohexane-2,5-diene-1-yl)-4-methylbenzenesulfonamide (0.2 mmol), triethylamine (0.4 mmol, 2.0 equivalent), and anhydrous DMF (2 mL). After stirring for 2 h (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give meta-aminoaniline compound (III) 4-methyl-N-[2-(phenylamino)-[1,1'-biphenyl]-4-yl]benzenesulfonamide 63 mg, 76% yield (based on 0.2 mmol scale).

[0060] 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.25 (s, 1H), 7.68 (d, J = 8.3 Hz, 2H),7.49–7.31 (m, 6H), 7.29–7.23 (m, 1H), 7.18–7.09 (m, 5H), 6.84 (dd, J= 8.3, 2.2Hz, 1H), 6.77–6.73 (m, 3H), 2.36 (s, 3H); 13 C NMR (101 MHz, DMSO- d 6 ): δ 144.5,143.3, 140.4, 138.8, 137.7, 136.8, 131.7, 129.7, 129.1, 128.9, 128.7, 128.4,126.8, 126.7, 119.1, 116.1, 114.1, 112.0, 21.0; HRMS (ESI) m / z calcd for[C 25 H 23 N2O2S] + [M+H] + : 415.1475, found: 415.1466. Example 5: N-[3-([2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-phenyl]amino)-4-methylphenyl]-4-methylbenzenesulfonamide

[0061] At room temperature, 3-(1-oxo-4-((oxo-λ4-thiosulfonyl)amino)isoindololin-2-yl)piperidine-2,6-dione (0.24 mmol, 1.2 equivalent) was added to a stirred mixture of compound (I) N-(4-hydroxy-4-methylcyclohexyl-2,5-diene-1-yl)-4-methylbenzenesulfonamide (0.2 mmol), triethylamine (0.4 mmol, 2.0 equivalent), and anhydrous DMF (2 mL). After stirring for 2 h (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give meta-aminoaniline compound (III) N-[3-([2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-phenyl]amino)-4-methylphenyl]-4-methylbenzenesulfonamide 103 mg, 99% yield (based on 0.2 mmol scale).

[0062] 1 H NMR (500 MHz, DMSO- d 6 ): δ 11.03 (s, 1H), 10.02 (s, 1H), 7.59 (d, J=7.9 Hz, 2H), 7.32 (dt, J = 9.5, 5.7 Hz, 4H), 7.25 (d, J = 7.4 Hz, 1H), 7.06 (d, J =8.2 Hz, 1H), 6.78 – 6.67 (m, 3H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.27 (q, J =17.3 Hz, 2H), 2.92 (ddd, J = 18.0, 13.5, 5.4 Hz, 1H), 2.61 (dt, J = 17.1, 3.4 Hz,1H), 2.33 (s, 4H), 2.07 (s, 4H); 13 C NMR (126 MHz, DMSO- d 6 ): δ 172.9, 171.2,168.4, 143.2, 141.2, 140.0, 136.7, 136.3, 133.0, 131.4, 130.5, 129.6, 129.0,126.7, 125.7, 118.8, 114.8, 114.5, 112.9, 51.6, 46.1, 31.3, 22.7, 21.0, 17.3;HRMS (ESI) m / z calcd for [C 27 H 27 N4O5S] + [M+H] + : 519.1697, found: 519.1698. Example 6: 4-[(2-methyl-5-((4-methylphenyl)sulfonamido)phenyl)amino]benzoic acid-2-(diethylamino)ethyl ester

[0063] At room temperature, 2-(diethylamino)ethyl-4-((oxo-λ4-thiosulfonyl)amino)benzoate (0.24 mmol, 1.2 equivalents) was added to a stirred mixture of compound (I) N-(4-hydroxy-4-methyl-2,5-cyclohexadien-1-yl)-4-methylbenzenesulfonamide (0.2 mmol), triethylamine (0.4 mmol, 2.0 equivalents), and anhydrous DMF (2 mL). After stirring for 2 h (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with sodium chloride and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give 69 mg of meta-aminoaniline compound (III) 4-[(2-methyl-5-((4-methylphenyl)sulfonamido)phenyl)amino]benzoic acid-2-(diethylamino)ethyl ester, 70% yield (based on 0.2 mmol scale).

[0064] 1 H NMR (500 MHz, DMSO- d 6 ): δ 10.06 (s, 1H), 8.13 (s, 1H), 7.75–7.68 (m, 2H), 7.64 –7.58 (m, 2H), 7.35 (d, J = 7.9 Hz, 2H), 7.10 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.81 (dd, J = 8.2, 2.2 Hz, 1H), 6.68–6.61 (m, 2H), 4.28(t, J = 5.9 Hz, 2H), 2.83 (s, 2H), 2.62 (s, 4H), 2.36 (s, 3H), 2.07 (s, 3H),1.00 (t, J = 7.1 Hz, 6H); 13 C NMR (126 MHz, DMSO- d 6): δ 165.5, 149.7, 143.1,139.5, 136.6, 136.1, 131.5, 130.9, 129.7, 127.3, 126.7, 118.6, 116.7, 114.9,113.4, 61.9, 50.7, 47.1, 21.0, 17.2, 11.6; HRMS (ESI) m / z calcd for[C 27 H 34 N3O4S] + [M+H] + : 496.2265, found: 496.2266. Example 7: 5-Chloro-N-[2-(diethylamino)ethyl]-2-methoxy-4-[(2-methyl-5-((4-methylphenyl)sulfonamido)phenyl)amino]benzamide

[0065] At room temperature, 5-chloro-N-(2-(diethylamino)ethyl)-2-methoxy-4-((oxo-λ4-thiosulfonyl)amino)benzamide (0.24 mmol, 1.2 equivalents) was added to a stirred mixture of compound (I) N-(4-hydroxy-4-methyl-2,5-cyclohexadiene-1-yl)-4-methylbenzenesulfonamide (0.2 mmol), triethylamine (0.4 mmol, 2.0 equivalents), and anhydrous DMF (2 mL). After stirring for 2 hours (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give meta-aminoaniline compound (III) 5-chloro-N-[2-(diethylamino)ethyl]-2-methoxy-4-[(2-methyl-5-((4-methylphenyl)sulfonamido)phenyl)amino]benzamide 89 mg, 80% yield (based on 0.2 mmol scale).

[0066] 1 H NMR (500 MHz, DMSO- d 6 ): δ 10.28 (s, 1H), 8.35 (s, 1H), 7.84 (s,1H), 7.66–7.60 (m, 2H), 7.54 (s, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.15 (d, J= 8.3Hz, 1H), 6.99 (d, J = 2.2 Hz, 1H), 6.90 (dd, J = 8.2, 2.3 Hz, 1H), 6.08 (s, 1H), 3.63 (s, 3H), 3.55 (s, 2H), 2.98 (s, 6H), 2.32 (s, 3H), 2.06 (s, 3H), 1.15(s, 6H); 13 C NMR (126 MHz, DMSO- d 6 ): δ 163.8, 157.4, 145.4, 143.2, 139.1,136.8, 136.4, 132.0, 131.5, 129.6, 128.8, 126.7, 117.1, 116.8, 112.1, 111.1,97.1, 55.7, 50.3, 48.6, 46.9, 20.9, 17.0; HRMS (ESI) m / z calcd for[C 28 H 36 ClN4O4S] + [M+H] + : 559.2140, found: 559.2140. Example 8: 4-Methyl-3-(quinoline-5-ylamino)phenol

[0067] At room temperature, sulfinyl 5-quinolinylimine (1.2 mmol, 1.2 equivalent) was added to a stirred mixture of compound (IV) 4-hydroxy-4-methylcyclohexane-2,5-dien-1-one (1.0 mmol), tetramethylguanidine (2.0 mmol, 2.0 equivalent), and anhydrous DMF (10 mL). After stirring for 2 h (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give meta-aminophenol compound (V) 4-methyl-3-(quinolin-5-ylamino)phenol 163 mg, 65% yield (based on 1.0 mmol scale).

[0068] 1 H NMR (500 MHz, DMSO- d 6): δ 9.24 (s, 1H), 9.12 (s, 1H), 8.46 (d, J =6.0 Hz, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.76 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.45 (dd, J = 8.2, 2.5 Hz, 1H), 6.41 (d, J = 2.5 Hz, 1H), 2.06 (s, 3H); 13 C NMR (126MHz, DMSO- d 6 ): δ 156.2, 152.3, 142.0, 141.7, 140.8, 131.4, 129.4, 128.0,127.6, 121.1, 118.3, 115.8, 114.3, 110.6, 109.6, 17.0; HRMS (ESI) m / z calcdfor [C 16 H 15 N2O] + [M+H] + : 251.1179, found: 251.1180. Example 9: 7-(phenylamino)-2,3-dihydro-1H-inden-5-ol

[0069] At room temperature, sulfinylphenylimine (1.2 mmol, 1.2 equivalents) was added to a stirred mixture of compound (IV) 7a-hydroxy-1,2,3,7a-tetrahydro-5H-inden-5-one (1.0 mmol), tetramethylguanidine (2.0 mmol, 2.0 equivalents), and anhydrous DMF (10 mL). After stirring for 2 h (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give meta-aminophenol compound (V) 7-(phenylamino)-2,3-dihydro-1H-inden-5-ol 102 mg, 45% yield (based on 1.0 mmol scale).

[0070] 1 H NMR (500 MHz, CDCl3): δ 7.28–7.24 (m, 2H), 7.07–7.04 (m, 2H), 6.94(tt, J = 7.3, 1.2 Hz, 1H), 6.53 (d, J = 2.1 Hz, 1H), 6.31 (d, J = 2.2 Hz, 1H), 5.41(s, 1H), 4.66 (s, 1H), 2.87 (t, J = 7.5 Hz, 2H), 2.69 (t, J = 7.3 Hz, 2H), 2.10(p, J = 7.4 Hz, 2H); 13 C NMR (126 MHz, CDCl3): δ 155.5, 147.2, 142.7, 140.3,129.4, 124.4, 121.5, 119.0, 104.1, 100.7, 33.6, 29.4, 25.1; HRMS (ESI) m / zcalcd for [C 15 H 16 NO] + [M+H] + : 226.1226, found: 226.1245. Example 10: 4-hydroxy-2-(phenylamino)phenylethyl 2-(2-fluoro-[1,1'-biphenyl]-4-phenyl)propionic acid

[0071] At room temperature, sulfinylphenylimine (0.24 mmol, 1.2 equivalent) was added to a stirred mixture of compound (IV) 2-(1-hydroxy-4-oxo-2,5-cyclohexadien-1-phenyl)ethyl 2-(2-fluoro-[1,1'-biphenyl]-4-phenyl)propionate (0.2 mmol), tetramethylguanidine (0.4 mmol, 2.0 equivalent), and anhydrous DMF (2 mL). After stirring for 2 h (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give 77 mg of meta-aminophenol compound (V) 2-(2-fluoro-[1,1'-biphenyl]-4-phenyl)propionic acid 4-hydroxy-2-(phenylamino)phenethyl ester, 85% yield (based on 0.2 mmol scale).

[0072] 1 H NMR (500 MHz, CDCl3): δ 7.52 (dt, J = 8.0, 1.5 Hz, 2H), 7.45–7.42 (m,2H), 7.38–7.34 (m, 2H), 7.26–7.22 (m, 2H), 7.10–7.05 (m, 2H), 7.00–6.98 (m,2H), 6.94 (d, J = 8.2 Hz, 1H), 6.91 (tt, J = 7.3, 1.1 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 6.36 (dd, J = 8.2, 2.5 Hz, 1H), 5.99 (s, 1H), 4.86 (s, 1H), 4.25 (ddt, J =10.8, 7.5, 3.7 Hz, 2H), 3.73 (q, J = 7.2 Hz, 1H), 2.84–2.81 (m, 2H), 1.51 (d, J =7.2 Hz, 3H); 13 C NMR (126 MHz, CDCl3): δ 174.6, 159.8 (d, J = 248.4 Hz), 155.4,143.6, 142.9, 141.7 (d, J= 7.6 Hz), 135.6, 131.7, 131.0 (d, J = 3.9 Hz), 129.5,129.1 (d, J = 2.9 Hz), 128.6, 128.0 (d, J = 13.5 Hz), 127.8, 123.6 (d, J = 3.5 Hz),121.0, 119.4, 118.1, 115.4 (d, J = 23.8 Hz), 108.8, 106.0, 65.1, 45.2, 30.3,18.5; 19 F NMR (471 MHz, CDCl3): δ -117.32 (s); HRMS (ESI) m / z calcd for[C 29 H 27 FNO3] + [M+H] + : 456.1969, found: 456.1984。

Claims

1. A method for meta-amination of aromatic amines and phenols, characterized in that, This method uses quinone alcohol compounds or iminoquinone alcohol compounds as substrates, and... N -sulfinylimide or N -The sulfinyl chloride electrophilic reagent reaction achieves the meta-amination of aromatic amines and phenols.

2. The method for meta-amination of aromatic amines and phenols according to claim 1, characterized in that, The meta-amine reaction is carried out in an alkaline and solvent environment; preferably, the alkaline is selected from sodium carbonate, potassium carbonate, potassium bicarbonate, pyridine, DMAP, triethylamine, tetramethylguanidine, DBN, LiHMDS, sodium methoxide or DBU, and the solvent is DMF, MeCN, 1,4-dioxane, DCM, CHCl3, toluene, Et2O or THF.

3. The method for meta-amination of aromatic amines and phenols according to claim 1 or 2, characterized in that, The meta-amine reaction temperature is -78 ℃ ~ 150 ℃, preferably 0 ℃ ~ 25 ℃.

4. A method for synthesizing a meta-aminoaniline compound, comprising the following steps: In an air atmosphere, compound (I) and a base were added to a solvent, followed by the addition of compound (II) to react. After the reaction was completed, the meta-aminoaniline compound (III) was obtained by purification. ； in, R is one of alkyl, aryl, heteroaryl, halogen, ester, alkoxy, silyl, sulfonyl, sulfinyl, and phosphoryl groups. 1 It is one of methanesulfonyl, p-toluenesulfonyl, and tert-butoxycarbonyl; R 2 It is one of alkyl, alkoxy, aryl, and heteroaryl; R 3 R 4 [N] is one of the following: substituted or unsubstituted aryl, heteroaryl, alkyl, allyl, or hydrogen atom; .

5. A method for synthesizing a meta-aminophenol compound, comprising the following steps: In an air atmosphere, compound (IV) and a base were added to a solvent, followed by the addition of compound (II) to react. After the reaction was completed, the mixture was purified to obtain meta-aminophenol compound (V). ； in, R is one of alkyl, aryl, heteroaryl, halogen, ester, alkoxy, silyl, sulfonyl, sulfinyl, and phosphoryl groups. 2 It is one of alkyl, alkoxy, aryl, and heteroaryl; R 3 R 4 [N] is one of the following: substituted or unsubstituted aryl, heteroaryl, alkyl, allyl, or hydrogen atom; .

6. The method for synthesizing the meta-aminoaniline compound according to claim 4, or the method for synthesizing the meta-aminophenol compound according to claim 5, characterized in that, The purification method is as follows: After the reaction is completed, the reaction mixture is concentrated, and the crude product is purified and separated by column chromatography. The eluent for column chromatography is petroleum ether: ethyl acetate = 10:1 (volume ratio) to obtain the target compound (III) or (V).

7. The method for synthesizing the meta-aminoaniline compound according to claim 4, or the method for synthesizing the meta-aminophenol compound according to claim 5, characterized in that, The molar ratio of compound (I) to compound (II) is 1:1 to 1:2, and the molar ratio of compound (IV) to compound (II) is 1:1 to 1:

2.

8. The method for synthesizing the meta-aminoaniline compound according to claim 4, or the method for synthesizing the meta-aminophenol compound according to claim 5, characterized in that, The base is selected from sodium carbonate, potassium carbonate, potassium bicarbonate, pyridine, DMAP, triethylamine, tetramethylguanidine, DBN, LiHMDS, sodium methoxide, or DBU; Preferably, the molar ratio of compound (I) to base is 1:1 to 1:3, and the molar ratio of compound (IV) to base is 1:1 to 1:3; Preferably, the solvent is DMF, MeCN, 1,4-dioxane, DCM, CHCl3, toluene, Et2O or THF.

9. The method for synthesizing the meta-aminoaniline compound according to claim 4, characterized in that, The meta-aminoaniline compound is at least one of the following compounds having the following structure: 。 10. The method for synthesizing the meta-aminophenol compound according to claim 5, characterized in that, The meta-aminophenol compound is at least one of the following compounds having the following structure: 。

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