Process for the synthesis of ortho-aminophenylsulfoxide compounds

Abstract

The present application relates to a synthesis method of ortho-aminophenylsulfoxide compounds, which realizes efficient and high regioselective synthesis of ortho-aminophenylsulfoxide by [2,3]-sigma-rearrangement reaction of aryl hydroxylamine compounds and aryl / alkyl thio-phthalimide participation under transition metal-free catalytic conditions. The present application has wide substrate range, good functional group compatibility, and successfully realizes ortho-sulfoxide modification of arylamine containing fluorine compounds, which has important significance for further development and application of the compounds in the fields of functional materials, life and medical science, etc.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic chemical synthesis, and relates to a synthesis method of an ortho-amino aryl sulfoxide compound. BACKGROUND

[0002] The sulfoxide structure is a widely used synthetic intermediate in organic chemistry and a very valuable skeleton, because of its unique structure, it has a wide application in many chiral ligands, biologically active drugs and functional materials. Sulfoxides have unique sulfinyl functional groups and have various biological activities, which are of great significance to the industrial production of medicines and pesticides. In particular, aryl sulfoxide compounds have various pharmacological properties and are used to treat various diseases due to their unique anti-inflammatory and antibacterial activities. In addition, sulfoxides are also widely used as multifunctional directing groups or key intermediates for various organic transformations, such as directed C-H functionalization reactions, Pummerer reactions and related rearrangement reactions.

[0003] There are many synthesis methods for sulfoxides at present. The commonly used strategy is to use oxidizing agents or peroxidizing agents to directly oxidize sulfides into sulfoxides. However, this synthesis method is complex, has poor stability, is easily over-oxidized into sulfone compounds and is not environmentally friendly, and the type of oxidizing agent and oxidation conditions need to be considered when used. The most common oxidizing agent is hydrogen peroxide, for example: CN107722042A uses a Ce(OTf)4 / H2O2 oxidation system to selectively oxidize S atoms into sulfoxides. However, high-concentration hydrogen peroxide is a strong explosive oxidizing agent, which is dangerous to use.

[0004] Sulfides can also be oxidized into sulfoxides by using strong acids such as nitric acid, but this method is uncontrollable and the range of substrates is limited. Currently, the ammonium cerium nitrate prepared by using nitric acid is a commonly used nitrate sulfide oxidizing agent, but it is only suitable for diaryl sulfides.

[0005] Transition metal catalysis can effectively construct sulfoxide units. First, a precursor compound capable of generating a sulfinic acid anion intermediate is constructed, and then the sulfinic acid anion is cross-coupled with various halides, triflate, iodonium salt or boron to form a sulfoxide compound under the catalysis of palladium. Although this strategy widens the range of sulfoxide compounds, it has the disadvantages of expensive catalysts and difficulty in synthesis.

[0006] There are few reports on the synthesis of sulfoxides by using visible light catalysis, mainly because of the lack of photoinduced agents for the synthesis of sulfoxides. Recently, Wu and Kuang recorded a free radical route from sulfinic acid and four kinds of substituted Hantzsch esters to sulfoxides in the presence of N-heterocyclic carbene and a photocatalyst.

[0007] The sulfoxide moiety can also be prepared from organometallic reagents and DABSO in the presence of trimethylsilyl chloride.

[0008] The above methods have made some progress, but there is still a high demand for a more efficient, environmentally friendly and simple operation scheme for synthesizing structurally diverse sulfoxide compounds from readily available materials.

[0009] In addition, aryl hydroxylamine is also a kind of widely used organic molecules and drug precursors, widely used in organic synthesis and biological medicine and other fields. Aryl hydroxylamine molecules all contain a relatively low bond energy of N-O bond (about 53 kcal mol -1 ), the low bond energy of N-O bond is caused by the mutual repulsion of the lone pair electrons on the nitrogen atom and the oxygen atom, the weak N-O bond is easy to break in the reaction process, and the strong new bond is easy to form, so the rearrangement of the compounds is easy to occur. Therefore, the rearrangement of hydroxylamine and its derivatives is a common method for preparing different heterocyclic compounds, biaryl compounds and functionalized aryl amines.

[0010] Therefore, based on the rearrangement reaction of aryl hydroxylamine and the demand for sulfoxide compounds, it is of great significance to develop an environmentally friendly and widely applicable preparation strategy for ortho-aminophenyl sulfoxide compounds. SUMMARY

[0011] In view of the above prior art, especially the defects of the existing sulfoxide preparation strategy, such as complex reaction, high preparation cost, and narrow substrate application range, the inventors of the present application have conducted in-depth and extensive research on the synthesis of sulfoxide compounds in order to obtain a preparation strategy for ortho-aminophenyl sulfoxide compounds which is free of transition metal catalysts, does not use oxidation strategy, has a wide substrate application range, and is environmentally friendly. The inventors of the present application have found that under the condition of no transition metal catalyst, the [2,3]-sigma-rearrangement reaction of aryl hydroxylamine compounds and aryl / alkyl thio-phthalimide can realize the efficient and highly regioselective synthesis of ortho-aminophenyl sulfoxide. The present application is based on the foregoing discovery.

[0012] Therefore, the purpose of the present application is to provide a synthesis method of ortho-aminophenyl sulfoxide compounds. Compared with the existing preparation strategy using oxidants and transition metal catalysts, the present application uses cheap and easily prepared aryl / alkyl N-thio-phthalimide to react with aryl hydroxylamine compounds, realizes the efficient synthesis of ortho-aminophenyl sulfoxide under the condition of no transition metal catalyst and no oxidant, and the reaction environment is friendly.

[0013] The technical solutions for achieving the above purposes of the present application can be summarized as follows:

[0014] A synthesis method of ortho-aminophenyl sulfoxide compounds, the compound has the structure shown in formula (III):

[0015]

[0016] In formula (III), Ar is substituted or unsubstituted aryl, heteroaryl or biaryl, R 1 is one of benzoyl, acetyl, pivaloyl, ester, t-butyloxycarbonyl, benzyloxycarbonyl, trifluoroacetyl, 9-fluorenylmethyloxycarbonyl; R 2 is one of substituted or unsubstituted aryl, heteroaryl or alkyl;

[0017] The method comprises the following steps:

[0018] In an air atmosphere, compound (I) and compound (II) are added to a solvent, and the mixture is reacted in the presence of a base. After the reaction is completed, purification is performed to obtain an ortho-amine aryl sulfoxide compound (III).

[0019]

[0020] According to the present application, preferably, Ar is R 3 is one or more of fluorine, chlorine, bromine, iodine, alkyl, ester, alkoxy, aryl, heteroaryl, oxo-trifluoromethyl, silicon.

[0021] According to the present application, preferably, R 2 is cyclohexyl, phenethyl, decyl, wherein R 4 is one or more of fluorine, chlorine, bromine, methyl, methoxy, nitro, heteroaryl.

[0022] According to the present application, preferably, the ortho-amine aryl sulfoxide compound has the following structure:

[0023]

[0024] According to the present application, during the reaction, the reaction progress can be tracked by TLC.

[0025] According to the present application, preferably, the purification method is as follows:

[0026] 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 = 5:1, and the target compound (III) is obtained.

[0027] According to the present application, preferably, the molar ratio of compound (I) to compound (II) is 1:(1-2), further preferably 1:(1.1-1.5); most preferably, the molar ratio of compound (I) to compound (II) is 1:1.2.

[0028] According to the present application, preferably, the base is sodium carbonate, potassium phosphate, sodium bicarbonate, pyridine, DMAP, triethylamine, DBN, potassium tert-butoxide, sodium tert-butoxide or DBU; most preferably, the base is potassium tert-butoxide.

[0029] According to the present application, preferably, the molar ratio of compound (I) to base is 0.5:(1-3), further preferably 0.5:(1.1-1.5); most preferably, the molar ratio of compound (I) to base is 1:1.

[0030] According to the present application, preferably, the solvent is DME (dimethoxyethane), MeCN (acetonitrile), DCE (dichloroethane), DCM (dichloromethane), CHCl3(trichloromethane), toluene, Et20 (diethyl ether) or THF (tetrahydrofuran); most preferably, the solvent A is DME.

[0031] According to the present application, preferably, the reaction temperature is -78°C to 25°C, further preferably -70°C to -20°C, most preferably -60°C.

[0032] According to the present application, the compound (I) has the following structure:

[0033]

[0034] Compound (I) can be prepared according to the existing technical route, the preparation route as follows:

[0035]

[0036] The synthesis steps are as follows: the nitro compound (1.0 equivalent) and 5% Rh / C (0.30 mol% Rh) are protected by inert gas (such as nitrogen), dissolved in THF (0.5 M), then the reaction system is cooled to 0°C, and hydrazine hydrate (1.2 equivalents) is slowly dropped; the reaction mixture needs to be stirred at 0°C for 1 hour, then slowly warmed to room temperature, and stirred at room temperature for 2 hours, the reaction progress can be detected by TLC, after the reaction is completed, the reaction mixture is filtered through diatomite, concentrated by rotary evaporation, and the obtained crude product hydroxylamine is directly used for the next step;

[0037] To the above crude product hydroxylamine, add an ethyl ether (0.5 M) solution, then add saturated NaHCO3aqueous solution, then cool the solution to 0°C, add the corresponding acyl chloride (1.1 equivalent) to the solution, after the dropwise addition is completed, stir at 0°C for 5 minutes, then quench the reaction with saturated NH4Cl aqueous solution, extract the reaction mixture with dichloromethane, wash the organic layer with saturated brine and dry it with anhydrous sodium sulfate, after removing the solvent in vacuum, the crude product is subjected to column chromatography (eluent dichloromethane: ethyl acetate = 50:1) or recrystallization to obtain compound (I).

[0038] According to the present application, the compound (II) N-thio-phthalimide has the following structure:

[0039]

[0040] The compound (II) can be prepared according to the existing technical route, the preparation route is as follows:

[0041] Method 1:

[0042] Method 2:

[0043] The synthesis steps are as follows:

[0044] Method 1: At 0°C, add sulfuryl chloride (1.0 equivalent, 5M in CH2Cl2) dropwise to a solution of thiol (5 mmol; 1M in CH2Cl2) and Et3N (0.01 mL) via a dropping funnel. After stirring for 15 minutes, the mixture is allowed to warm to room temperature and stirred for 30 minutes before cooling to 0°C. The resulting solution is transferred dropwise via a cannula to a solution of phthalimide (1.0 equivalent; ~1M in CH2Cl2) and Et3N (1.3 equivalents) at 0°C, then the mixture is allowed to warm to room temperature over 1 hour. Dilute the solution with H2O, extract with CH2Cl2 (3x), then dry over Na2SO4, then concentrate to give the crude product, which is purified using recrystallization. For samples where a large amount of phthalimide is present, dissolve the crude product in CH2Cl2, dilute with 1M NaOH, extract with CH2Cl2 (3x), then dry over Na2SO4, then concentrate, then purify by recrystallization to give the N-thio-phthalimide compound (II).

[0045] Method 2: Into a dry and argon-flushed round bottom flask equipped with a magnetic stir bar and septum, add N-chlorophthalimide (908 mg, 5.0 mmol, 1.0 equivalent), dry MeCN (2.6 mL), and pyridine (2.1 mL). Add the thiol (5.0 mmol, 1.0 equivalent) in dry MeCN (2.6 mL) and dry pyridine (2.1 mL) dropwise over 30 minutes at 0°C, and stir the resulting mixture for an additional 30 minutes. After removing most of the MeCN in vacuo, add water (20 mL) dropwise over 10 minutes at 0°C and stir for an additional 10 minutes. Filter the resulting suspension and wash the filtrate with ice-cold MeOH (3x 5 mL) to give the corresponding N-thio-phthalimide compound (II).

[0046] According to the present application, the by-product phthalimide at the end of the reaction can be recovered by 85-95% for the re-preparation of compound (II).

[0047] According to the application, the ortho-aminophenylsulfoxide compounds are widely concerned and have good application prospects in organic synthetic chemistry, material chemistry, pharmaceutical chemistry, chemical biology, especially in the modification of pharmaceutical intermediates and natural medicines. The compounds can exist stably in a neutral buffer for months and in a phosphate buffer with a pH value of 10 for two weeks. They are compatible with most functional groups on natural products, are important synthetic intermediates in synthetic chemistry, and have great research value and application prospects.

[0048] The technical route of the application is as follows:

[0049]

[0050] The [2,3]-sigma-rearrangement reaction mechanism involved in the application is as follows:

[0051]

[0052] The application has the following beneficial effects:

[0053] 1. The application reports a transition metal-free synthesis strategy of ortho-aminophenylsulfoxide. The reaction of cheap and easily prepared N-thio-phthalimide and aryl hydroxylamine compound is carried out under transition metal-free conditions to realize the efficient synthesis of ortho-aminophenylsulfoxide. The strategy has wide substrate range, good functional group compatibility, and successfully realizes the modification of fluorine-containing compound arylamine ortho-sulfoxide, which has important significance for the further development and application in the fields of functional materials, life and medical science, etc.

[0054] 2. The application is not limited to the synthesis of a single arylsulfoxide compound. The application synthesizes a wide range of ortho-aminophenylsulfoxide compounds. One side of the sulfoxide structure can be an unsubstituted or substituted aryl group, and the other side is not limited to various aryl groups, but also can be a chain alkane, a cyclic alkane or a heteroatom-containing aliphatic group.

[0055] 3. The application is simple to operate, has wide substrate adaptability, and is free of transition metal catalysis. The application has good universality. Various aryl hydroxylamines including natural product molecules can effectively realize ortho-carbon hydrogen bond sulfoxidation to prepare ortho-aminophenylsulfoxide compounds with excellent regioselectivity and diverse structures.

[0056] 4. The raw material aryl hydroxylamine and N-thio-phthalimide of the application are easy to prepare. The valence of the sulfur atom in N-thio-phthalimide is divalent, the valence state is low, and the electrophilicity is weak. The raw material can exist stably at room temperature, is convenient to store, and is conducive to large-scale preparation and transportation.

[0057] 5、The base used in the application is also a common commercial reagent, which is very stable, has the characteristics of low cost, high yield, simple process and less pollution. The post-treatment of the application is simple, can be recycled and has a wide application prospect.

[0058] 6、The o-aminophenylsulfoxide compound synthesized by the application has a chiral sulfur atom, which has the potential to be split into a single chiral compound. The o-aminophenylsulfoxide compound contains nitrogen atoms, sulfur atoms and oxygen atoms which are easy to coordinate with metals, so that the asymmetric o-aminophenyl compound can be used as a ligand or raw material for asymmetric catalytic synthesis. BRIEF DESCRIPTION OF DRAWINGS

[0059] Figure 1 The H-NMR spectrum of N-(2-(p-tolylsulfinyl)phenyl)benzamide prepared in Example 1 is shown in Figure 1. 1 H-NMR spectrum;

[0060] Figure 2 The C-NMR spectrum of N-(2-(p-tolylsulfinyl)phenyl)benzamide prepared in Example 1 is shown in Figure 2. 13 C-NMR spectrum;

[0061] Figure 3 The H-NMR spectrum of N-(2'-fluoro-3-(p-tolylsulfinyl)-[1,1'-biphenyl]-2-yl)benzamide prepared in Example 2 is shown in Figure 3. 1 H-NMR spectrum;

[0062] Figure 4 The C-NMR spectrum of N-(2'-fluoro-3-(p-tolylsulfinyl)-[1,1'-biphenyl]-2-yl)benzamide prepared in Example 2 is shown in Figure 4. 13 C-NMR spectrum;

[0063] Figure 5 The F-NMR spectrum of N-(2'-fluoro-3-(p-tolylsulfinyl)-[1,1'-biphenyl]-2-yl)benzamide prepared in Example 2 is shown in Figure 5. 19 F-NMR spectrum;

[0064] Figure 6 The H-NMR spectrum of N-(2-bromo-3-methoxy-6-(p-tolylsulfinyl)phenyl)benzamide prepared in Example 3 is shown in Figure 6. 1 H-NMR spectrum;

[0065] Figure 7 The C-NMR spectrum of N-(2-bromo-3-methoxy-6-(p-tolylsulfinyl)phenyl)benzamide prepared in Example 3 is shown in Figure 7. 13 C-NMR spectrum;

[0066] Figure 8N-(2-((4-fluorophenyl)sulfinyl)phenyl)benzamide prepared in Example 5 1 H-NMR spectrum;

[0067] Figure 9 N-(2-((4-fluorophenyl)sulfinyl)phenyl)benzamide prepared in Example 5 13 C-NMR spectrum;

[0068] Figure 10 N-(2-((4-fluorophenyl)sulfinyl)phenyl)benzamide prepared in Example 5 1 H-NMR spectrum;

[0069] Figure 11 N-(2-((4-fluorophenyl)sulfinyl)phenyl)benzamide prepared in Example 5 13 C-NMR spectrum;

[0070] Figure 12 N-(2-((4-fluorophenyl)sulfinyl)phenyl)benzamide prepared in Example 5 19 F-NMR spectrum;

[0071] Figure 13 N-(2-((4-fluorophenyl)sulfinyl)phenyl)benzamide prepared in Example 5 1 H-NMR spectrum;

[0072] Figure 14 N-(2-((4-fluorophenyl)sulfinyl)phenyl)benzamide prepared in Example 5 13 C-NMR spectrum; DETAILED DESCRIPTION

[0073] According to the object of the present application, a method for synthesizing an o- aminophenylsulfoxide compound having the following formula (III) is provided:

[0074]

[0075] In formula (III), Ar is a substituted or unsubstituted aryl group, heteroaryl group or biaryl group, R 1 is one of benzoyl, acetyl, pivaloyl, ester group, t-butyloxycarbonyl, benzyloxycarbonyl, trifluoroacetyl and 9-fluorenylmethyloxycarbonyl; R 2 is one of a substituted or unsubstituted aryl group, heteroaryl group or alkyl group;

[0076] The method comprises the steps of:

[0077] The compound (I) and the compound (II) are added to a solvent under an air atmosphere, and the mixture is reacted in the presence of a base. After the reaction is completed, purification is performed to obtain the o-aminophenylsulfoxide compound (III).

[0078]

[0079] According to the present application, the compound (I) has the following structure in the following embodiments:

[0080]

[0081] The compound (I) is prepared according to the existing technical route, and the preparation route is as follows:

[0082]

[0083] The synthesis steps are as follows: the nitro compound (1.0 equivalent) and 5% Rh / C (0.30 mol% Rh) are subjected to inert gas protection (such as nitrogen), dissolved in THF (0.5 M), and then the reaction system is cooled to 0°C, and hydrazine hydrate (1.2 equivalents) is slowly added dropwise; the reaction mixture needs to be stirred at 0°C for 1 hour, and then slowly warmed to room temperature and stirred at room temperature for 2 hours, and the reaction progress can be detected by TLC; after the reaction is completed, the reaction mixture is filtered through diatomite, concentrated by rotary evaporation, and the obtained crude product hydroxylamine is directly used in the next step;

[0084] To the above-mentioned crude product hydroxylamine, an ethyl ether (0.5 M) solution is added, and then saturated NaHCO3 aqueous solution is added, and then the solution is cooled to 0°C, and the corresponding acyl chloride (1.1 equivalent) is added to the solution, and after the dropwise addition is completed, the reaction is quenched with saturated NH4Cl aqueous solution after stirring at 0°C for 5 minutes, and the reaction mixture is extracted with dichloromethane, and the organic layer is washed with saturated brine and dried over anhydrous sodium sulfate; after the solvent is removed under vacuum, the crude product is subjected to column chromatography (eluent dichloromethane: ethyl acetate = 50:1) or recrystallization to obtain the compound (I).

[0085] According to the present application, the compound (II) N-thiophthalimide has the following structure in the following embodiments:

[0086]

[0087] The compound (II) is prepared according to the existing method 2 technical route, and the preparation route is as follows:

[0088] Method 2:

[0089] The synthesis steps are as follows:

[0090] Method 2: Into a dry and argon-purged round-bottom flask equipped with a magnetic stir bar and a septum was added N-chlorophthalimide (908 mg, 5.0 mmol, 1.0 equiv), dry MeCN (2.6 mL) and pyridine (2.1 mL). Thiol (5.0 mmol, 1.0 equiv) in dry MeCN (2.6 mL) and dry pyridine (2.1 mL) was added dropwise at 0 °C over 30 min and the resulting mixture was stirred for another 30 min. After removal of most of the MeCN in vacuo, water (20 mL) was added dropwise at 0 °C over 10 min and stirred for another 10 min. The resulting suspension was filtered and the filtrate was washed with ice-cold MeOH (3 x 5 mL) to give the corresponding N-thiophthalimide compound (II).

[0091] According to the present application, compound (I) is aryl hydroxylamine, which contains a relatively low-energy nitrogen-oxygen bond (about 53 kcal mol -1 The low bond energy of the nitrogen-oxygen bond is caused by the mutual repulsion of the lone pair of electrons on the nitrogen atom and the oxygen atom. During the reaction, the weak nitrogen-oxygen bond is easily broken, and the new bond with a stronger bond energy is easily formed, so that the rearrangement reaction of the compound is easy to occur. The aryl hydroxylamine is easy to prepare, and the functional group compatibility is good. Using it as a substrate can widen the group types of the ortho-aminophenyl sulfoxide compound, which is more conducive to industrial production and application.

[0092] Compound (II) is aryl / alkyl N-thiophthalimide, in which the mercapto group can undergo a [2,3]-sigma-rearrangement reaction. The rearrangement reaction of aryl hydroxylamine is in series, which realizes the smooth synthesis of the sulfoxide compound without the need for transition metal catalysis and oxidants. At the same time, aryl / alkyl N-thiophthalimide is also easy to prepare, and the functional group compatibility is good. Using it as a substrate further widens the group types of the ortho-aminophenyl sulfoxide compound, which is very conducive to industrial production and application. The by-product phthalimide at the end of the reaction of compound (I) and compound (II) can be recycled at 85-95%, which can be used to prepare compound (II) again, further reducing the production cost.

[0093] According to the present application, in the ortho-aminophenyl sulfoxide compound (III), Ar, R 1 from compound (I), R 2 from compound (II), since the functional group compatibility of compound (I) and compound (II) is good, Ar, R 1 , R 2 are suitable for the present application.

[0094] In one or more preferred embodiments, the ortho-aminophenyl sulfoxide compound (III) is a substituted phenyl compound

[0095]

[0096] R 3 is one or more of fluorine, chlorine, bromine, iodine, alkyl, ester, alkoxy, aryl, heteroaryl, oxo trifluoromethyl, silicon.

[0097] In one or more preferred embodiments, the ortho-aminophenyl sulfoxide compound is a substituted phenyl compound (III)

[0098]

[0099] R 4 is one or more of fluorine, chlorine, bromine, methyl, methoxy, nitro, heteroaryl.

[0100] In one or more preferred embodiments, the ortho-aminophenyl sulfoxide compound (III) is a substituted phenyl compound,

[0101]

[0102] R 5 is one or more of cyclohexyl, phenethyl, decyl.

[0103] In one or more preferred embodiments, the ortho-aminophenyl sulfoxide compound (III) has the following structure:

[0104]

[0105] According to the present application, the reaction process can be tracked by TLC.

[0106] In one or more preferred embodiments, the purification method is as follows:

[0107] After the reaction is completed, the reaction mixture is concentrated, and the crude product is purified and separated by column chromatography. The eluent of column chromatography is petroleum ether: ethyl acetate = 5: 1, and the target compound (III) is obtained.

[0108] According to the present application, the molar ratio of compound (I) and compound (II) is theoretically 1:1. In order to make full use of aryl hydroxylamine, compound (II) is appropriately excessive. After the reaction is completed, the by-product phthalimide can be recycled by 85-95%, which can be used to prepare compound (II) again, further reducing the production cost. Therefore, in one or more preferred embodiments, the molar ratio of compound (I) and compound (II) is 1:(1-2), further preferably 1:(1.1-1.5); most preferably, the molar ratio of compound (I) and compound (II) is 1:1.2.

[0109] According to the present application, the tandem rearrangement reaction is carried out under basic conditions, and different basic environments have important influence on the yield of the target compound (III). In one or more preferred embodiments, the base is sodium carbonate, potassium phosphate, sodium bicarbonate, pyridine, DMAP, triethylamine, DBN, potassium tert-butoxide, sodium tert-butoxide or DBU; most preferably, the base is potassium tert-butoxide or DBN.

[0110] In one or more preferred embodiments, the molar ratio of compound (I) to base is 0.5: (1-3), further preferably 0.5: (1.1-1.5); most preferably, the molar ratio of compound (I) to base is 1:1.

[0111] According to the present application, the reaction solvent also has important influence on the yield of the target compound (III), and in one or more preferred embodiments, the solvent is DME (ethylene glycol dimethyl ether), MeCN (acetonitrile), DCE (dichloroethane), DCM (dichloromethane), CHCl3(trichloromethane), toluene, Et20 (diethyl ether) or THF (tetrahydrofuran); most preferably, the solvent is DME.

[0112] According to the present application, the reaction temperature also has important influence on the yield of the target compound (III), and the tandem rearrangement reaction of the present application is more conducive to improving the reaction yield at low temperature. In one or more preferred embodiments, the reaction temperature is -78°C to 25°C, further preferably -70°C to -20°C, and most preferably -60°C.

[0113] The present application is further illustrated by the following specific examples, but is not limited thereto.

[0114] Example 1, N-(2-(p-tolylsulfinyl)phenyl)benzamide

[0115]

[0116] In a 20 mL reaction tube, N-hydroxy-N-phenylbenzamide (0.2 mmol, 43 mg), 2-(p-tolylsulfinyl)isoindole-1,3-dione (1.2 equiv, 65 mg) and ethylene glycol dimethyl ether (2 mL) were added, and after cooling to -60°C, potassium tert-butoxide (1.0 equiv, 22.5 mg) was added while stirring at -60°C. After stirring at -60°C for 12 hours, the reaction progress was tracked by TLC, and after the reaction was completed, the reaction mixture was subjected to solvent removal by a rotary evaporator. The crude product was subjected to column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain pure N-(2-(p-tolylsulfinyl)phenyl)benzamide in the form of white powder, with a yield of 82%.

[0117] 1H NMR (500 MHz, CDC13) δ 11.24 (s, 1H), 8.62 (dd, J = 8.3, 1.2 Hz, 1H), 8.07 - 7.96 (m, 2H), 7.64 - 7.46 (m, 5H), 7.40 - 7.34 (m, 2H), 7.19 (td, J = 7.6, 1.2 Hz, 1H), 7.12 (d, J = 8.1 Hz, 2H), 2.28 (s, 3H);

[0118] 13 C NMR (126 MHz, CDC13) δ 165.43, 141.82, 141.06, 139.91, 134.33, 133.35, 132.39, 130.36, 129.10, 128.42, 128.04, 127.74, 124.78, 123.66, 123.36, 21.59.

[0119] Example 2, N-(2'-fluoro-3-(p-tolylsulfinyl)-[l,l'-biphenyl]-2-yl)benzamide

[0120]

[0121] In a 20 mL reaction tube, N-hydroxy-N-(2'-fluoro-[l,l'-biphenyl]-2-yl)benzamide (0.2 mmol, 62 mg), 2-(p-tolylthio)isoindole-l,3-dione (1.2 equiv, 65 mg) and ethylene glycol dimethyl ether (2 mL) were added, cooled to -60 °C, then potassium tert-butoxide (1.0 equiv, 22.5 mg) was added with stirring at -60 °C, stirred at -60 °C for 12 hours, the reaction progress was tracked by TLC, after the reaction was completed, the reaction mixture was removed by rotary evaporator, the crude product was purified by column chromatography (eluent petroleum ether: ethyl acetate = 5: 1) to obtain white powder pure N-(2'-fluoro-3-(p-tolylsulfinyl)-[l,l'-biphenyl]-2-yl)benzamide, the yield was 70%.

[0122] 1 H NMR (500 MHz, Chloroform-d) δ 9.01 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.5 Hz, 3H), 7.52 - 7.44 (m, 2H), 7.38 (t, J = 7.6 Hz, 3H), 7.32 (d, J = 8.0 Hz, 2H), 7.22 (td, J = 5.6, 2.8 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.05 (dd, J = 14.6, 8.3 Hz, 3H), 2.30 (s, 3H).

[0123] 13 C NMR (126 MHz, CDC13) δ 164.99, 160.08, 158.11, 141.24, 139.47, 135.66, 135.07, 133.72, 131.95, 131.17, 129.95, 129.92, 129.85, 128.58, 127.69, 127.38, 127.15, 124.96, 124.49, 115.88, 115.70, 21.43;

[0124] 19 F NMR (471 MHz, Chloroform-d) δ -115.42.

[0125] Example 3, N-(2-bromo-3-methoxy-6-(p-tolylsulfinyl)phenyl)benzamide

[0126]

[0127] In a 20 mL reaction tube, N-(2-bromo-3-methoxyphenyl)-N-hydroxybenzamide (0.2 mmol, 64 mg), 2-(p-tolylthio)isoindole-1,3-dione (1.2 equiv, 65 mg) and ethylene glycol dimethyl ether (2 mL) were added, and after cooling to -60 °C, potassium tert-butoxide (1.0 equiv, 22.5 mg) was added while stirring at -60 °C. After stirring at -60 °C for 12 hours, the reaction progress was tracked by TLC, and after the reaction was completed, the reaction mixture was removed by a rotary evaporator to remove the solvent, and the crude product was subjected to column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain pure N-(2-bromo-3-methoxy-6-(p-tolylsulfinyl)phenyl)benzamide as a white powder, with a yield of 70%.

[0128] 1 H NMR (500 MHz, Chloroform-d) δ 9.23 (s, 1H), 7.91 (d, J = 7.5 Hz, 2H), 7.56 (t, J = 7.8 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.8 Hz, 1H), 3.92 (s, 3H), 2.32 (s, 3H);

[0129] 13C NMR (126 MHz, Chloroform-d) δ 165.54, 159.49, 141.10, 139.86, 137.36, 133.90, 133.24, 132.25, 129.79, 128.59, 127.88, 127.83, 124.95, 113.46, 110.15, 56.73, 21.36.

[0130] Example 4, N-(l-(p-tolylsulfinyl)naphthalen-2-yl)benzamide

[0131]

[0132] In a 20 mL reaction tube, N-hydroxy-N-(naphthalen-2-yl)benzamide (0.2 mmol, 53 mg), 2-(p-tolylthio)isoindole-l,3-dione (1.2 equiv, 65 mg) and ethylene glycol dimethyl ether (2 mL) were added, after cooling to -60 °C, potassium tert-butoxide (1.0 equiv, 22.5 mg) was added while stirring at -60 °C, and stirring was continued at -60 °C for 12 hours. The reaction progress was tracked by TLC. After the reaction was completed, the solvent was removed from the reaction mixture by a rotary evaporator, and the crude product was subjected to column chromatography (eluent: petroleum ether: ethyl acetate = 5: 1) to obtain colorless transparent viscous liquid N-(l-(p-tolylsulfinyl)naphthalen-2-yl)benzamide at a yield of 65%.

[0133] 1 H NMR (500 MHz, Chloroform-d) δ 11.91 (s, 1H), 8.71 (d, J = 9.1 Hz, 1H), 8.41 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 7.2 Hz, 2H), 8.01 (d, J = 9.1 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.65 - 7.60 (m, 1H), 7.57 (t, J = 7.3 Hz, 1H), 7.54 - 7.49 (m, 3H), 7.32 (d, J = 8.3 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 2.24 (s, 3H);

[0134] 13 C NMR (126 MHz, Chloroform-d) δ 165.32, 141.40, 141.33, 139.27, 134.06, 133.13, 132.20, 131.67, 130.11, 130.06, 128.93, 128.83, 128.30, 127.63, 125.56, 124.46, 122.22, 122.01, 121.29, 21.31.

[0135] Example 5, N-(2-((4-fluorophenyl)sulfinyl)phenyl)benzamide

[0136]

[0137] In a 20 mL reaction tube, N-hydroxy-N-phenylbenzamide (0.2 mmol, 43 mg), 2-(p- fluorophenylsulfinyl)isoindole-1,3-dione (1.2 equiv, 66 mg) and ethylene glycol dimethyl ether (2 mL) were added, after cooling to -60 °C, potassium tert-butoxide (1.0 equiv, 22.5 mg) was added while stirring at -60 °C, and stirred at -60 °C for 12 hours. The reaction progress was tracked by TLC. After the reaction was completed, the solvent of the reaction mixture was removed by a rotary evaporator, and the crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain white pure N-(2-((4-fluorophenyl)sulfinyl)phenyl)benzamide with a yield of 68%.

[0138] 1 H NMR (500 MHz, DMSO-d6) δ 11.35 (s, 1H), 10.78 (s, 1H), 7.98 (d, J = 7.3 Hz, 1H), 7.80 (s, 4H), 7.75 (dd, J = 8.0, 1.5 Hz, 1H), 7.71 - 7.65 (m, 2H), 7.65 - 7.60 (m, 1H), 7.60 - 7.55 (m, 2H), 7.45 (td, J = 7.6, 1.2 Hz, 1H), 7.33 (t, J = 8.8 Hz, 1H);

[0139] 13 C NMR (126 MHz, DMSO-d6) δ 169.27, 165.60, 163.50 (d, J = 248.6 Hz), 140.37 (d, J = 2.8 Hz), 138.55, 136.58, 134.29, 133.43, 132.63, 132.37, 132.22, 128.75, 127.53, 127.31 (d, J = 9.1 Hz), 126.82, 126.15 (d, J = 6.5 Hz), 122.93, 116.65, 116.47; C-F = 248.6 Hz), 140.37 (d, J = 2.8 Hz), 138.55, 136.58, 134.29, 133.43, 132.63, 132.37, 132.22, 128.75, 127.53, 127.31 (d, J = 9.1 Hz), 126.82, 126.15 (d, J = 6.5 Hz), 122.93, 116.65, 116.47; C-F = 248.6 Hz), 140.37 (d, J = 2.8 Hz), 138.55, 136.58, 134.29, 133.43, 132.63, 132.37, 132.22, 128.75, 127.53, 127.31 (d, J = 9.1 Hz), 126.82, 126.15 (d, J = 6.5 Hz), 122.93, 116.65, 116.47; C-F = 248.6 Hz), 140.37 (d, J = 2.8 Hz), 138.55, 136.58, 134.29, 133.43, 132.63, 132.37, 132.22, 128.75, 127.53, 127.31 (d, J = 9.1 Hz), 126.82, 126.15 (d, J = 6.5 Hz), 122.93, 116.65, 116.47; C-F = 248.6 Hz), 140.37 (d, J = 2.8 Hz), 138.55, 136.58, 134.29, 133.43, 132.63, 132.37, 132.22, 128.75, 127.53, 127.31 (d, J = 9.1 Hz), 126.82, 126.15 (d, J = 6.5 Hz), 122.93, 116.65, 116.47;

[0140] 19 F NMR (471 MHz, DMSO-d6) δ -109.42.

[0141] Example 6, N-(2-(phenethylsulfinyl)phenyl)benzamide

[0142]

[0143] In a 20 mL reaction tube, N-hydroxy-N-phenylbenzamide (0.2 mmol, 43 mg), 2- (phenethylthio)isoindole-1,3-dione (1.2 equiv, 66 mg) and ethylene glycol dimethyl ether (2 mL) were added, cooled to -60 °C, then potassium tert-butoxide (1.0 equiv, 22.5 mg) was added with stirring at -60 °C, stirred at -60 °C for 12 h, the reaction progress was tracked by TLC, after the reaction was completed, the solvent of the reaction mixture was removed by rotary evaporator, the crude product was purified by column chromatography (eluent petroleum ether: ethyl acetate = 5:1) to obtain white pure N-(2- (phenethylsulfinyl)phenyl)benzamide with a yield of 76%.

[0144] 1 H NMR (500 MHz, Chloroform-d) δ 11.61 (s, 1H), 8.75 (d, J = 8.4 Hz, 1H), 8.15 - 7.99 (m, 2H), 7.56 (d, J = 7.4 Hz, 2H), 7.51 (t, J = 7.5 Hz, 2H), 7.27 - 7.23 (m, 3H), 7.21 (d, J = 7.1 Hz, 1H), 7.17 - 7.08 (m, 3H), 3.51 (dt, J = 12.9, 7.3 Hz, 1H), 3.21 (dt, J = 12.9, 8.2 Hz, 1H), 3.00 (t, J = 7.8 Hz, 2H);

[0145] 13 C NMR (126 MHz, Chloroform-d) δ 165.39, 141.40, 137.94, 133.98, 132.87, 132.26, 128.94, 128.92, 128.57, 127.57, 127.03, 126.57, 125.65, 123.45, 123.05, 55.76, 29.29.

[0146] Test Example 1

[0147] With N-hydroxy-N-phenylbenzamide and N-thio-phthalimide as raw materials, ethylene glycol dimethyl ether as solvent, the amount of solvent was A = 2 mL, the amount of base was 1.0 equivalent, the reaction temperature was -40 °C, and the reaction was carried out in air atmosphere for 6 h. The effect of base on the reaction was explored, as shown in Table 1.

[0148] Table 1 Effect of base on reaction

[0149]

[0150] From the experimental results of Table 1, it can be seen that, t BuOK is the best base for the reaction.

[0151] Test Example 2

[0152] Using N-hydroxy-N-phenylbenzamide and N-thio-phthalimide as raw materials, potassium tert-butoxide as a base, the amount of base used was 1.0 equivalent, the amount of solvent used was A = 2 mL, the reaction temperature was -40℃, and the reaction was carried out under air atmosphere for 6h. The effect of the type of solvent on the reaction was investigated, and the amount of base used was 1.0 equivalent, as shown in Table 2.

[0153] Table 2 Effect of solvent on reaction

[0154]

[0155]

[0156] From the experimental results of Table 2, it can be seen that DME is the best solvent for the reaction.

[0157] Test Example 3

[0158] Using N-hydroxy-N-phenylbenzamide and N-thio-phthalimide as raw materials, potassium tert-butoxide as a base, the amount of base used was 1.0 equivalent, and the reaction was carried out under air atmosphere for 5min-12h. The effect of temperature and concentration on the reaction was investigated, as shown in Table 3.

[0159] Table 3 Effect of temperature and concentration on reaction

[0160]

[0161] From the experimental results of Table 3, it can be seen that the reaction was carried out at -60℃, and the solvent A = DME (2mL) was the best temperature and concentration for the reaction.

Claims

1. A method for synthesizing an ortho-aminophenylsulfoxide compound having the structure shown in formula (III): comprising the steps of: adding compound (I) and compound (II) into a solvent under an air atmosphere, reacting the mixture in the presence of a base, and purifying the reaction mixture after the reaction is completed to obtain the ortho-aminophenylsulfoxide compound (III). ； In formula (III), Ar is a substituted or unsubstituted aryl, heteroaryl or biaryl group, R 1 is one of benzoyl, acetyl, pivaloyl, ester, t-butyloxycarbonyl, benzyloxycarbonyl, trifluoroacetyl, 9-fluorenylmethyloxycarbonyl; R 2 is one of a substituted or unsubstituted aryl, heteroaryl or alkyl group; The base is sodium carbonate, potassium phosphate, sodium bicarbonate, pyridine, DMAP, triethylamine, DBN, potassium tert-butoxide, sodium tert-butoxide, or DBU, and the reaction temperature is -78 ℃ to 25 ℃. The ortho-aminophenylsulfoxide compound has the following structure: ； The purification method is as follows:

2. The method for synthesizing the o-aminoaryl sulfoxide compound according to claim 1, characterized in that, Ar is , R 3 is one or more of fluorine, chlorine, bromine, iodine, alkyl, ester, alkoxy, aryl, heteroaryl, oxo trifluoromethyl, silicon.

3. The method for synthesizing the o-aminoaryl sulfoxide compound according to claim 1, characterized in that, R 2 is , cyclohexyl, phenethyl, decyl, wherein R 4 is one or more of fluorine, chlorine, bromine, methyl, methoxy, nitro, heteroaryl.

4. The method for synthesizing the o-aminoaryl sulfoxide compound according to claim 1, characterized in that, After the reaction is completed, the reaction mixture is concentrated, and the crude product is subjected to column chromatography, and the eluent for the column chromatography is petroleum ether: ethyl acetate = 5:1, to obtain the target compound (III). 。 5. The method for synthesizing the o-aminoaryl sulfoxide compound according to claim 1, characterized in that, The molar ratio of compound (I) to compound (II) is 1: (1-2). The molar ratio of compound (I) to the base is 0.5: (1-3).

6. The method for synthesizing the o-aminoaryl sulfoxide compound according to claim 1, characterized in that, The solvent is ethylene glycol dimethyl ether, acetonitrile, dichloroethane, dichloromethane, trichloromethane, toluene, diethyl ether, or tetrahydrofuran.

7. The method for synthesizing the o-aminoaryl sulfoxide compound according to claim 1, characterized in that, ​ 8. The method for synthesizing the o-aminoaryl sulfoxide compound according to claim 1, characterized in that, ​

Images