CN116239508B - Preparation method of aryl thioimine compound - Google Patents

Abstract

The present invention relates to a method for preparing an arylsulfilimine compound. The method comprises: dissolving a sulfonamide compound and a diaryl iodonium salt compound in a solvent under alkaline conditions, heating at 0 to 40°C, and extracting the arylsulfilimine compound to obtain the arylsulfilimine compound; wherein _R1 is selected from an alkyl group or an aryl group; _R2 is selected from an acyl group, a sulfonyl group or a benzyloxycarbonyl group; Ar is an aryl group; and Lg is a leaving group. The method does not require the addition of an oxidant, has rapid reaction, is green and environmentally friendly, has a high yield, mild conditions, and is easy to operate.

Description

A method for preparing arylsulfilimine compounds

Technical Field

The present invention belongs to the technical field of chemical synthesis and more specifically relates to a method for preparing an arylsulfilimine compound.

Background technique

Sulfilimine compounds and their derivatives, sulfoximine compounds, as a very important intermediate of sulfone compounds, have special biological activity. Especially in the fields of medicine, pesticides and biology, they have very important research value, such as anti-cancer, anti-inflammatory, and antiviral. Therefore, this type of sulfoneamine compounds has attracted widespread attention. Finding efficient, green and economical synthesis methods is not only an important research content in organic synthesis methodology, but also has extraordinary significance for the development of the medical and pharmaceutical fields.

As an analogue of sulfoxide, sulfilimine is a very important structural motif. It is widely present in biologically active natural products, dyes, chemicals and various pharmaceutical intermediates. As an important analogue intermediate for the synthesis of sulfonamide drugs, it has always attracted much attention in the scientific research community.

However, the synthesis of such compounds is currently limited to the nitrene transfer amination reaction of thioether compounds. Such reactions have some limitations, such as: 1. It is often necessary to add oxidants such as trivalent iodine to mediate the reaction; 2. Thioether substrates must be synthesized in advance, which is not applicable in the later modification of natural products or drug molecules; 3. Metal catalysts are often required to ensure the smooth progress of the reaction. Therefore, there is no mature non-oxidative method for constructing such compounds at this stage. Therefore, the development of an efficient and universal method for constructing tetravalent sulfilimines plays a vital role in promoting the development of medicine.

Summary of the invention

In view of the above-mentioned prior art problems, the primary purpose of the present invention is to provide a method for preparing an arylsulfilimine compound. The present invention adopts a "one-pot method" to use sulfonamide compounds and diaryliodonium compounds as substrates. Under alkaline conditions, the sulfonamide compounds react with a base to generate a highly active intermediate, which then reacts with the diaryliodonium compounds to construct a skeleton-rich sulfilimine. The method does not require the addition of an oxidant, has a rapid reaction, is green and environmentally friendly, has a high yield, mild conditions, and is easy to operate.

The above purpose of the present invention is achieved through the following technical solutions:

A method for preparing an arylsulfilimine compound comprises dissolving a sulfenamide compound (I) and a diaryliodonium salt compound (II) in a solvent under alkaline conditions, heating at 0 to 40° C., and extracting the arylsulfilimine compound (III). The reaction formula is as follows:

Wherein, _R1 is selected from alkyl or aryl; _R2 is selected from acyl, sulfonyl or benzyloxycarbonyl; Ar is aryl; Lg is a leaving group.

Preferably, _R1 is selected from an alkyl group or an aryl group having 1 to 12 carbon atoms, wherein the aryl group is unsubstituted or substituted by one or more alkyl groups having 1 to 6 carbon atoms or alkoxy groups having 1 to 6 carbon atoms; _R2 is selected from an acyl group having 1 to 12 carbon atoms, a sulfonyl group having 1 to 12 carbon atoms or a benzyloxycarbonyl group; the aryl group in Ar is unsubstituted or substituted by one or more alkyl groups having 1 to 6 carbon atoms or halogens; Lg is selected from trifluoromethanesulfonate, tetrafluoroborate or p-toluenesulfonyloxy.

Preferably, _R1 is selected from an alkyl group having 1 to 12 carbon atoms or a phenyl group, wherein the phenyl group is unsubstituted or substituted by one or more alkyl groups having 1 to 3 carbon atoms or alkoxy groups having 1 to 3 carbon atoms; _R2 is selected from an acyl group having 1 to 12 carbon atoms, a sulfonyl group having 1 to 12 carbon atoms or a benzyloxycarbonyl group; the aryl group in Ar is unsubstituted or substituted by one or more fluorine, chlorine, bromine or iodine; Lg is selected from trifluoromethanesulfonate, tetrafluoroborate or p-toluenesulfonyloxy.

Preferably, _R1 is selected from n-hexyl, cyclohexyl, p-tolyl or p-methoxyphenyl; _R2 is selected from tert-butylcarbonyl, adamantanecarbonyl, p-benzoyl, p-toluenesulfonyl, nitrobenzenesulfonyl, methanesulfonyl or benzyloxycarbonyl; Ar is phenyl, p-chlorophenyl or o-fluorophenyl; Lg is selected from trifluoromethanesulfonate, tetrafluoroborate or p-toluenesulfonyloxy.

Preferably, the molar ratio of the sulfonamide compound to the diaryliodonium salt compound is 1:(1-1.5).

Preferably, the alkaline condition is achieved by adding an alkali auxiliary, and the alkali auxiliary is selected from one or more of LDA, NaH, MeONa or tBuONa.

Preferably, the molar ratio of the sulfenamide compound to the alkali auxiliary agent is 1:(1-1.5).

Preferably, the solvent is selected from one or more of 1,4-dioxane, acetonitrile, tetrahydrofuran, toluene or ethyl acetate.

Further preferably, the solvent is toluene. The inventors found that when toluene is used as the solvent in the system, the product has an extremely high yield.

More preferably, the heating is performed at 25-40°C; most preferably, the heating is performed at 25°C.

Preferably, the heating time is 1 to 6 hours.

Preferably, the extraction treatment is: after heating, adding saturated NH ₄ Cl solution to the reaction system, extracting with ethyl acetate, washing, drying, and concentrating under reduced pressure to obtain a crude product; then eluting with a mixed solvent of dichloromethane and methanol, removing the solvent, and obtaining the arylsulfilimine compound.

As a specific embodiment of the present invention, the extraction treatment is: after heating, adding a saturated NH ₄ Cl solution to the reaction system, stirring for 1 to 5 minutes, extracting with ethyl acetate for 1 to 3 times, washing with saturated brine for 1 to 3 times, drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a crude product; then eluting with a mixed solvent of petroleum ether and ethyl acetate, collecting the target product, and removing the solvent to obtain the arylsulfilimine compound.

Preferably, the volume ratio of petroleum ether to ethyl acetate is 1 to 10:1; most preferably, the volume ratio of petroleum ether to ethyl acetate is 4:1.

Compared with the prior art, the present invention has the following beneficial effects: the present invention adopts a "one-pot method" to use sulfonamide compounds and diaryl iodide compounds as substrates. Under alkaline conditions, the sulfonamide compounds react with a base to generate a highly active intermediate, which then reacts with the diaryl iodide compounds to construct a skeleton-rich sulfilimine. The method does not require the addition of an oxidant, has rapid reaction, is green and environmentally friendly, has high yield, mild conditions, and is easy to operate. The preparation method of the present invention has high reaction conversion rate and yield, short process flow, easy to expand reaction scale, simple product separation, and is suitable for industrial production.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 1.

FIG. 2 is the carbon NMR spectrum of the target product obtained in Example 1.

FIG. 3 is a hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 2.

FIG. 4 is a hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 3.

FIG5 is a hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 4.

FIG6 is a hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 5.

FIG. 7 is a hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 6.

FIG8 is a hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 7.

FIG. 9 is a hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 8.

FIG. 10 is a hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 9.

Detailed ways

The present invention is further described below in conjunction with the accompanying drawings and specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

Example 1 Preparation of arylsulfilimine compounds

(1) In a 25 ml single-necked bottle, N-(p-toluenethio)pivalamide (I) (0.15 mmol, 33.5 mg), sodium tert-butoxide (0.3 mmol, 28.8 mg), and 3 mL of toluene were added, stirred for 2 minutes, and finally diphenyltrifluoromethanesulfonic acid iodide (II) (Ph ₂ IOTf) (1.1 equiv, 70.9 mg) was added, and the mixture was heated at 25°C for 2 h.

(2) Add saturated NH ₄ Cl solution to the reaction system of step (1), stir for 2 minutes, and extract once with ethyl acetate in a separatory funnel. Then wash the ethyl acetate solution with saturated brine and water, dry the organic phase over anhydrous sodium sulfate, filter and concentrate the organic phase under reduced pressure to remove the solvent to obtain a crude product. The crude product is separated by a silica gel column, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1. Collect the target product arylsulfilimine compound (III), and concentrate the organic phase under reduced pressure to remove the solvent to obtain a white solid, and the isolation yield is 97%. The reaction formula of the above preparation method is as follows:

In the formula, R ₁ = p-tolyl, Lg = trifluoromethanesulfonate (OTf), R ₂ = tert-butylformyl, and Ar = phenyl.

Example 2 Preparation of arylsulfilimine compounds

(1) In a 25 ml single-necked bottle, N-(p-toluenethio)pivalamide (I) (0.15 mmol, 33.5 mg), sodium tert-butoxide (0.4 mmol, 38.4 mg), and 3 mL of toluene were added, stirred for 2 minutes, and finally diphenyl tetrafluoroborate iodine (II) (Ph ₂ IBF ₄ ) (1.1 equiv, 60.7 mg) was added, and the mixture was heated at 25° C. for 2 h.

(2) Add saturated NH ₄ Cl solution to the reaction system of step (1), stir for 2 minutes, and extract once with ethyl acetate in a separatory funnel. Then wash the ethyl acetate solution with saturated brine and water, dry the organic phase over anhydrous sodium sulfate, filter and concentrate the organic phase under reduced pressure to remove the solvent to obtain a crude product. The crude product is separated by a silica gel column, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1. Collect the target product arylsulfilimine compound (III), and concentrate the organic phase under reduced pressure to remove the solvent to obtain a white solid, and the isolation yield is 98%. The reaction formula of the above preparation method is as follows:

In the formula, R ₁ = p-tolyl, Lg = tetrafluoroborate (BF ₄ ^- ), R ₂ = tert-butylformyl, and Ar = phenyl.

Example 3 Preparation of arylsulfilimine compounds

(1) In a 25 ml single-necked bottle, N-(p-toluenethio)pivalamide (I) (0.15 mmol, 33.5 mg), sodium tert-butoxide (0.4 mmol, 38.4 mg), and 3 mL of toluene were added, stirred for 2 minutes, and finally (p-ClPh) ₂ IOTf (1.1 equiv, 82.3 mg) was added, and the mixture was heated at 25°C for 3 h.

(2) Add saturated NH ₄ Cl solution to the reaction system of step (1), stir for 2 minutes, and extract once with ethyl acetate in a separatory funnel. Then wash the ethyl acetate solution with saturated brine and water, dry the organic phase over anhydrous sodium sulfate, filter and concentrate the organic phase under reduced pressure to remove the solvent to obtain a crude product. The crude product is separated by a silica gel column, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1. Collect the target product arylsulfilimine compound (III), and concentrate the organic phase under reduced pressure to remove the solvent to obtain a white solid, and the isolation yield is 95%. The reaction formula of the above preparation method is as follows:

In the formula, R ₁ = p-tolyl, Lg = trifluoromethanesulfonate (OTf), R ₂ = tert-butylformyl, Ar = p-chlorophenyl.

Example 4 Preparation of Arylsulfilimine Compounds

(1) In a 25 ml single-necked bottle, N-(p-toluenethio)adamantane-1-carboxamide (I) (0.15 mmol, 45.2 mg), sodium tert-butoxide (0.4 mmol, 38.4 mg), and 3 mL of toluene were added and stirred for 2 minutes. Finally, diphenyltrifluoromethanesulfonic acid iodide (II) (Ph ₂ IOTf) (1.1 equiv, 70.9 mg) was added and heated at 25°C for 2.5 h.

(2) Add saturated NH ₄ Cl solution to the reaction system of step (1), stir for 2 minutes, and extract once with ethyl acetate in a separatory funnel. Then wash the ethyl acetate solution with saturated brine and water, dry the organic phase over anhydrous sodium sulfate, filter and concentrate the organic phase under reduced pressure to remove the solvent to obtain a crude product. The crude product is separated by a silica gel column, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1. Collect the target product arylsulfimine compound (III), and concentrate the organic phase under reduced pressure to remove the solvent to obtain a white solid, and the isolation yield is 93%. The reaction formula of the above preparation method is as follows:

In the formula, R ₁ = p-tolyl, Lg = trifluoromethanesulfonate (OTf), R ₂ = adamantanecarbonyl, and Ar = phenyl.

Example 5 Preparation of Arylsulfilimine Compounds

(1) In a 25 ml single-necked bottle, 4-methyl-N-(p-tolylthio)benzamide (I) (0.15 mmol, 38.6 mg), sodium tert-butoxide (0.4 mmol, 38.4 mg), and 3 mL of toluene were added. The mixture was stirred for 2 minutes. Finally, diphenyltrifluoromethanesulfonic acid iodide (II) (Ph ₂ IOTf) (1.1 equiv, 70.9 mg) was added. The mixture was heated at 25°C for 2.5 h.

(2) Add saturated NH ₄ Cl solution to the reaction system of step (1), stir for 2 minutes, and extract once with ethyl acetate in a separatory funnel. Then wash the ethyl acetate solution with saturated brine and water, dry the organic phase over anhydrous sodium sulfate, filter and concentrate the organic phase under reduced pressure to remove the solvent to obtain a crude product. The crude product is separated by a silica gel column, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1. Collect the target product arylsulfilimine compound (III), and concentrate the organic phase under reduced pressure to remove the solvent to obtain a white solid, and the isolation yield is 92%. The reaction formula of the above preparation method is as follows:

In the formula, R ₁ = p-tolyl, Lg = trifluoromethanesulfonate (OTf), R ₂ = p-toluoyl, and Ar = phenyl.

Example 6 Preparation of Arylsulfilimine Compounds

(1) In a 25 ml single-necked bottle, add N-(p-methoxyphenylthio)pivalamide (I) (0.15 mmol, 35.9 mg), sodium tert-butoxide (0.4 mmol, 38.4 mg), and 3 mL of toluene. Stir for 2 minutes, and finally add diphenyltrifluoromethanesulfonic acid iodide (II) (Ph ₂ IOTf) (1.1 equiv, 70.9 mg). Heat the reaction at 25°C for 2 h.

(2) Add saturated NH ₄ Cl solution to the reaction system of step (1), stir for 2 minutes, and extract once with ethyl acetate in a separatory funnel. Then wash the ethyl acetate solution with saturated brine and water, dry the organic phase over anhydrous sodium sulfate, filter and concentrate the organic phase under reduced pressure to remove the solvent to obtain a crude product. The crude product is separated by a silica gel column, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1. Collect the target product arylsulfilimine compound (III), and concentrate the organic phase under reduced pressure to remove the solvent to obtain a white solid, and the isolation yield is 96%. The reaction formula of the above preparation method is as follows:

In the formula, R ₁ = p-methoxyphenyl, Lg = trifluoromethanesulfonate (OTf), R ₂ = tert-butylformyl, and Ar = phenyl.

Example 7 Preparation of Arylsulfilimine Compounds

(1) In a 25 ml single-necked bottle, N-(p-toluenethio)pivalamide (I) (0.15 mmol, 33.5 mg), sodium tert-butoxide (0.4 mmol, 38.4 mg), and 3 mL of toluene were added, stirred for 2 minutes, and finally (oF-Ph) ₂ IOTs (1.1 equiv, 80.6 mg) was added, and the mixture was heated at 25°C for 2 h.

(2) Add saturated NH ₄ Cl solution to the reaction system of step (1), stir for 2 minutes, and extract once with ethyl acetate in a separatory funnel. Then wash the ethyl acetate solution with saturated brine and water, dry the organic phase over anhydrous sodium sulfate, filter and concentrate the organic phase under reduced pressure to remove the solvent to obtain a crude product. The crude product is separated by a silica gel column, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1. Collect the target product sulfilimine compound (III), and concentrate the organic phase under reduced pressure to remove the solvent to obtain a white solid, and the isolation yield is 96%. The reaction formula of the above preparation method is as follows:

In the formula, R ₁ = p-tolyl, Lg = p-toluenesulfonyloxy (OTs), R ₂ = tert-butylformyl, and Ar = o-fluorophenyl.

Example 8 Preparation of Arylsulfilimine Compounds

(1) In a 25 ml single-necked bottle, benzyl (hexylthio) carbamate (I) (0.15 mmol, 40.1 mg), sodium tert-butoxide (0.4 mmol, 38.4 mg), and 3 mL of toluene were added, stirred for 2 minutes, and finally diphenyl trifluoromethanesulfonic acid iodide (II) (Ph ₂ IOTf) (1.1 equiv, 70.9 mg) was added, and the mixture was heated at 25°C for 1 h.

(2) Add saturated NH ₄ Cl solution to the reaction system of step (1), stir for 2 minutes, and extract once with ethyl acetate in a separatory funnel. Then wash the ethyl acetate solution with saturated brine and water, dry the organic phase over anhydrous sodium sulfate, filter and concentrate the organic phase under reduced pressure to remove the solvent to obtain a crude product. The crude product is separated by a silica gel column, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1. Collect the target product arylsulfilimine compound (III), and concentrate the organic phase under reduced pressure to remove the solvent to obtain a white solid, and the isolation yield is 96%. The reaction formula of the above preparation method is as follows:

In the formula, R ₁ = n-hexyl, Lg = trifluoromethanesulfonate (OTf), R ₂ = benzyloxycarbonyl, and Ar = phenyl.

Example 9 Preparation of Arylsulfilimine Compounds

(1) In a 25 ml single-necked bottle, N-(hexylthio)pivalamide (I) (0.15 mmol, 32.3 mg), sodium tert-butoxide (0.4 mmol, 38.4 mg), and 3 mL of toluene were added, stirred for 2 minutes, and finally diphenyltrifluoromethanesulfonic acid iodide (II) (Ph ₂ IOTf) (1.1 equiv, 70.9 mg) was added, and the mixture was heated at 25° C. for 3 h.

(2) Add saturated NH ₄ Cl solution to the reaction system of step (1), stir for 2 minutes, and extract once with ethyl acetate in a separatory funnel. Then wash the ethyl acetate solution with saturated brine and water, dry the organic phase over anhydrous sodium sulfate, filter and concentrate the organic phase under reduced pressure to remove the solvent to obtain a crude product. The crude product is separated by a silica gel column, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1. Collect the target product arylsulfilimine compound (III), and concentrate the organic phase under reduced pressure to remove the solvent to obtain a white solid, and the isolation yield is 96%. The reaction formula of the above preparation method is as follows:

In the formula, R ₁ = cyclohexyl, Lg = trifluoromethanesulfonate (OTf), R ₂ = tert-butylformyl, and Ar = phenyl.

The substances used and yields of the above examples are shown in Table 1.

Table 1

The target products obtained in the above examples were detected by hydrogen nuclear magnetic resonance spectrum and/or carbon nuclear magnetic resonance spectrum. As shown in Figures 1 and 2, Example 1 synthesized the target product arylsulfimine compound. As shown in Figures 3 to 10, Examples 2 to 9 synthesized the target product arylsulfimine compound. The hydrogen nuclear magnetic resonance spectrum and/or carbon nuclear magnetic resonance spectrum data of the target products obtained in other examples are shown in Table 2.

Table 2

The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims (7)

1. A method for preparing an arylsulfilimine compound, characterized in that, under alkaline conditions, a sulfenamide compound (I) and a diaryliodonium salt compound (II) are dissolved in a solvent, heated at 25 to 40° C., and subjected to extraction treatment to obtain the arylsulfilimine compound (III), wherein the reaction formula is as follows: wherein _R1 is selected from an alkyl group having 1 to 12 carbon atoms or a phenyl group, wherein the phenyl group is unsubstituted or substituted with one or more alkyl groups having 1 to 3 carbon atoms or alkoxy groups having 1 to 3 carbon atoms; _R2 is selected from an acyl group having 1 to 12 carbon atoms, a sulfonyl group having 1 to 12 carbon atoms or a benzyloxycarbonyl group; the aryl group in Ar is unsubstituted or substituted with one or more fluorine, chlorine, bromine or iodine; The molar ratio of the sulfonamide compound to the diaryliodonium salt compound is 1:1-1.5. 2. The method according to claim 1, characterized in that R ₁ is selected from n-hexyl, cyclohexyl, p-tolyl or p-methoxyphenyl; R ₂ is selected from tert-butylcarbonyl, adamantanecarbonyl, p-benzoyl, p-toluenesulfonyl, nitrobenzenesulfonyl, methylsulfonyl or benzyloxycarbonyl; Ar is phenyl, p-chlorophenyl or o-fluorophenyl. 3. The method according to claim 1 or 2, characterized in that the alkaline condition is achieved by adding an alkali auxiliary agent, and the alkali auxiliary agent is selected from one or more of LDA, NaH, MeONa or tBuONa. 4. The method according to claim 1, characterized in that the molar ratio of the sulfenamide compound to the alkali auxiliary agent is 1:1 to 1.5. 5. The method according to claim 1, characterized in that the solvent is selected from one or more of 1,4-dioxane, acetonitrile, tetrahydrofuran, toluene or ethyl acetate. 6. The method according to claim 5, characterized in that the solvent is toluene. 7. The method according to claim 1, characterized in that the extraction treatment comprises: adding a saturated _NH4Cl solution to the reaction system, extracting, washing, drying, and concentrating under reduced pressure to remove the solvent to obtain a crude product; then eluting with a mixed solvent of petroleum ether and ethyl acetate to remove the solvent to obtain the arylsulfilimine compound.