Multi-component preparation method of N-sulfonyl fluoride compound

Abstract

The invention discloses a multi-component preparation method of an N-sulfonyl fluoride compound, and relates to the field of organic synthesis. The preparation method comprises the following steps: reacting an amine compound with a chlorine source in a solvent to generate an intermediate, then continuously adding a sulfur dioxide source and a fluorine source for reaction, and purifying after one-pot reaction to obtain the N-sulfonyl fluoride compound, the structural general formula of the amine compound is shown in the specification, the structural general formula of the N-sulfonyl fluoride compound is shown in the specification. The reaction general formula is shown in the specification. The method has the advantages of cheap and easily available raw materials, simple operation, mild conditions, safety, environmental protection, short reaction time, good yield and wide substrate range, can be applied to various types of amine substrates, including primary (alkyl / aromatic) amine, secondary (alkyl / aromatic) amine, amide, nitrogen-containing heteroaromatic ring and the like, and has wide application prospects. Wide application prospects are realized in the fields of medicinal chemistry, synthetic chemistry, material science and the like.

Description

Technical Field

[0001] This application relates to the field of organic synthesis, and in particular to a multi-component method for preparing N-sulfonyl fluoride compounds. Background Technology

[0002] N-sulfonyl fluoride compounds are used in SuFEx click chemistry ( Angew.·Chem. Int.·Ed 2014, 54 The unique reactivity and broad application potential of N-sulfonyl fluorides (9430.) have attracted much attention in organic synthesis, medicinal chemistry, and chemical biology. N-sulfonyl fluorides are stable in air at room temperature and react efficiently with a variety of nucleophiles. These compounds exhibit potential biological activity in medicinal chemistry and are also important intermediates in the synthesis of complex molecules.

[0003] Currently, the synthetic methods for N-sulfonyl fluoride compounds include: 1. Substitution reaction between fluoride anions and N-sulfonyl chlorides; 2. Substitution reaction between amine compounds and highly toxic gaseous sulfuryl fluoride; 3. Substitution reaction between amine compounds and pre-prepared aniline disulfonyl fluoride (AISF). Org. Lett. 2018, 20 , 812.) undergo substitution reactions; 4. Amine compounds react with pre-prepared sulfonylfluoroimidazole salts ( Angew. Chem. Int. Ed. 2017, 57 , 2605.) undergo substitution reactions, etc.; 5. Fluorosulfonyl N-pyridine salt (FSAPor PNSF, Angew. Chem. Int. Ed. 2024, 63 , e202405944; ACS Catal. 2024, 14 , 12082; Org. Lett. 2024, 26 The free radical fluorosulfonamide reaction of , 6714.

[0004] However, methods 1 and 2 suffer from low reaction efficiency, difficulty in operation, and high risk. Methods 3–5 have a limited substrate range, and the synthesis of reagents still requires the use of highly toxic gaseous sulfuryl fluoride or fluorine gas. Due to regulatory reasons, sulfuryl fluoride gas is difficult to obtain in many countries and regions worldwide, and the use of fluorine gas is extremely dangerous. In short, the synthesis of N-sulfonyl fluoride compounds still faces problems such as low reaction efficiency, difficulty in obtaining raw materials, operational difficulties, and high risk. Summary of the Invention

[0005] In view of the shortcomings of the aforementioned related technologies, this application provides a multi-component preparation method for N-sulfonyl fluoride compounds. The raw materials used in this application are inexpensive and readily available, the operation is simple, the conditions are mild, it is safe and environmentally friendly, the reaction time is short, the yield is good, and the substrate range is broad. It can be applied to various types of amine substrates, including primary (alkyl / aromatic) amines, secondary (alkyl / aromatic) amines, amides, nitrogen-containing heteroaromatic rings, etc., and has broad application prospects in medicinal chemistry, synthetic chemistry, and materials science.

[0006] Firstly, the multi-component preparation method for N-sulfonyl fluoride compounds provided in this application adopts the following technical solution: A multi-component preparation method for N-sulfonyl fluoride compounds includes the following steps: reacting an amine compound with a chlorine source in a solvent to generate an intermediate, then adding a sulfur dioxide source and a fluorine source to react, and purifying the N-sulfonyl fluoride compound after a one-pot reaction; The general structural formula of the amine compounds is: The general structural formula of the N-sulfonyl fluoride compound is as follows: Wherein, R1 and R2 may be the same or different. When R1 and R2 are not cyclic, R1 includes one of substituted or unsubstituted alkyl, aryl, and aromatic heterocyclic compounds; R2 includes one of substituted or unsubstituted alkyl, aryl, aromatic heterocyclic compounds, carbonyl, and hydrogen. When R1 and R2 are cyclic, they form nitrogen heterocyclic compounds, which include one of saturated nitrogen heterocyclic compounds, imidazole, benzimidazole, pyrazole, benzopyrazole, and carbazole. Its general reaction formula is as follows: .

[0007] Preferably, the amine compound has a structural formula including one of the following: .

[0008] Preferably, the chlorine source includes one or more of N-chlorosuccinimide, trichloroisocyanuric acid, sodium hypochlorite, and tert-butyl hypochlorite.

[0009] Preferably, the chlorine source is one or more of N-chlorosuccinimide, sodium hypochlorite, and tert-butyl hypochlorite.

[0010] Preferably, the chlorine source is N-chlorosuccinimide.

[0011] Preferably, the sulfur dioxide source includes 1,4-diazabicyclo[2.2.2]octane-1,4-dionthium-1,4-disulfinic acid (DABSO).

[0012] Preferably, the sulfur dioxide source is 1,4-diazabicyclo[2.2.2]octane-1,4-dionthium-1,4-disulfinic acid (DABSO).

[0013] Preferably, the fluorine source includes one or more of potassium fluoride, silver fluoride, cesium fluoride, and triethylamine trifluoride.

[0014] Preferably, the fluorine source is cesium fluoride.

[0015] Preferably, the solvent includes one or more of acetonitrile, dichloromethane, dimethyl sulfoxide, and N,N-dimethylformamide.

[0016] Preferably, the solvent is acetonitrile.

[0017] Preferably, the molar ratio of the amine compound, the chlorine source, the sulfur dioxide source and the fluorine source is 1:0.9-2.1:1:0.9-2.1.

[0018] Preferably, the molar ratio of the amine compound, the chlorine source, the sulfur dioxide source, and the fluorine source is 1:1:1:2.

[0019] Preferably, the molar ratio of the amine compound, the chlorine source, the sulfur dioxide source, and the fluorine source is 1:2:1:2.

[0020] Preferably, the reaction temperature for reacting the amine compound with the chlorine source in a solvent to generate the intermediate is -2°C to 27°C, and the reaction time is 0.8-1.5 h.

[0021] Preferably, the reaction temperature for reacting the amine compound with the chlorine source in a solvent to generate the intermediate is 25 °C, and the reaction time is 1 h.

[0022] Preferably, the reaction between the sulfur dioxide source and the fluorine source includes a heating reaction or a light-induced reaction.

[0023] Preferably, the heating reaction includes controlling the temperature conditions at 45-55 °C and the reaction time at 5.5-6.5 h.

[0024] Preferably, the heating reaction includes controlling the temperature at 50 °C and the reaction time at 6 h.

[0025] Preferably, the photoreaction includes controlling the temperature conditions to be between -2°C and 10°C, adding a photocatalyst, and reacting with light of 427 nm wavelength at a power of 30-50 W for 10-20 h.

[0026] Preferably, the photoreaction includes controlling the temperature to 0 °C, adding a photocatalyst, and reacting for 12 h with light at a wavelength of 427 nm and a power of 40 W.

[0027] Preferably, the photocatalyst comprises 9-phenylacridine ( ), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (4CzIPN), fac -tris(2-phenylpyridine)iridium( fac One or more of the following: -Ir(ppy)3), bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium hexafluorophosphate (Ir(dF(CF3)ppy)2(dtbbpy)PF6), and terpyridine ruthenium chloride hexahydrate (Ru(bpy)3Cl·6H2O).

[0028] Preferably, the photocatalyst is 9-phenylacridine.

[0029] Secondly, this application provides an N-sulfonyl fluoride compound prepared by the above-described preparation method.

[0030] An N-sulfonyl fluoride compound having one of the following structural formulas: .

[0031] In summary, this application includes the following beneficial technical effects: 1. This application generates an intermediate by reacting an amine compound with a chlorine source, and then adds a sulfur dioxide source and a fluorine source in a one-pot reaction without separating the intermediate to generate N-sulfonyl fluoride compounds. This simplifies the preparation steps of N-sulfonyl fluoride compounds and reduces the difficulty of preparing them. 2. This application creatively utilizes the nitrogen-chlorine reactive intermediate generated by the reaction of amine compounds with a chlorine source for sulfonyl fluorination reaction. The reaction efficiency of amines with chlorine sources is high, and the applicable substrate types are diverse. Therefore, this method can be applied to more types of amine substrates, including primary (alkyl / aromatic) amines, secondary (alkyl / aromatic) amines, amides, nitrogen-containing heteroaromatic rings, etc. 3. The nitrogen-chlorine intermediate generated by the reaction of amine compounds with a chlorine source in this application exhibits high reactivity. Under heating conditions, it can undergo homolytic cleavage to generate nitrogen and chlorine radicals, or under photocatalytic conditions, it can undergo single-electron reduction cleavage to generate nitrogen radicals and chloride anions. The nitrogen radicals are highly reactive and can be captured by the sulfur dioxide source in the reaction system, then combine with chlorine radicals or undergo photocatalytic oxidation to form highly reactive sulfonyl chloride or sulfonyl DABCO cationic intermediates. Subsequently, fluoride ions undergo nucleophilic substitution to generate the corresponding sulfonyl fluoride target product. The nitrogen-chlorine intermediate does not need to be separated, mainly because the efficient reaction of amine compounds with the chlorine source reduces the residue of amine compounds and minimizes their impact on subsequent reactions. Detailed Implementation

[0032] The present application will be further described in detail below with reference to the embodiments. The following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions in the following embodiments were performed under conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, the methods used are conventional methods known in the art, and the consumables and reagents used are commercially available. Unless otherwise stated, the technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods or materials similar to or equivalent to those described herein may also be applied to the present invention.

[0033] The raw materials used in the examples and comparative examples are all commercially available.

[0034] Example 1 Example 1 of this application provides an N-sulfonyl fluoride compound, which is prepared by the following steps: A solution of 32.2 mg of an amino compound was prepared by dissolving it in 1 mL of acetonitrile at room temperature. 26.7 mg of N-chlorosuccinimide (NCS) was added to the solution. After stirring in a reactor at 25 °C for 1 h, 48.1 mg of 1,4-diazabicyclo[2.2.2]octane-1,4-dionium-1,4-disulfinic acid (DABSO) and 60.8 mg of cesium fluoride (CsF) were added to the reactor in a single batch. The reaction was carried out at 50 °C under argon protection for 6 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1, product Rf = 0.6). After the reaction was complete, the product was purified by column chromatography (silica gel 300-400 mesh, petroleum ether:ethyl acetate = 30:1) to obtain an N-sulfonyl fluoride compound (colorless liquid).

[0035] The structural formula of the amine compound in this embodiment is: The structural formula of the target product, an N-sulfonyl fluoride compound, is: .

[0036] Example 2 Example 2 of this application provides an N-sulfonyl fluoride compound. The difference between Example 2 and Example 1 is that the structural formula of the amine compound used in Example 2 is: The amount of amine compound used was 48.1 mg, and the structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0037] Example 3 Example 3 of this application provides an N-sulfonyl fluoride compound. The difference between Example 3 and Example 1 is that the structural formula of the amine compound used in Example 3 is: The amount of amine compound used was 32.8 mg, and the structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0038] Example 4 Example 4 of this application provides an N-sulfonyl fluoride compound. The difference between Example 4 and Example 1 is that the structural formula of the amine compound used in Example 4 is: The amount of amine compound used was 32.6 mg, and the structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0039] Example 5 Example 5 of this application provides an N-sulfonyl fluoride compound. The difference between Example 5 and Example 1 is that the structural formula of the amine compound used in Example 5 is: The amount of amine compound used was 64.3 mg, and the structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0040] Example 6 Example 6 of this application provides an N-sulfonyl fluoride compound. The difference between Example 6 and Example 1 is that the structural formula of the amine compound used in Example 6 is: The amount of amine compound used was 33.4 mg, and the structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0041] Example 7 Example 7 of this application provides an N-sulfonyl fluoride compound. The difference between Example 7 and Example 1 is that the structural formula of the amine compound used in Example 7 is: The amount of amine compound used was 41.4 mg, and the structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0042] Example 8 Example 8 of this application provides an N-sulfonyl fluoride compound. The difference between Example 8 and Example 1 is that the structural formula of the amine compound used in Example 8 is: The amount of amine compound used was 61.9 mg, and the structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0043] Example 9 Example 9 of this application provides an N-sulfonyl fluoride compound. The difference between Example 9 and Example 1 is that the structural formula of the amine compound used in Example 9 is: The amount of amine compound used was 31.8 mg, and the structural formula of the target product, the N-sulfonyl fluoride compound, is as follows: .

[0044] Example 10 Example 10 of this application provides an N-sulfonyl fluoride compound. The difference between Example 10 and Example 1 is that the structural formula of the amine compound used in Example 10 is: The amount of amine compound used was 29.4 mg, and the structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0045] Example 11 Example 11 of this application provides an N-sulfonyl fluoride compound. The difference between Example 11 and Example 1 is that the structural formula of the amine compound used in Example 11 is: The amount of amine compound used was 37.5 mg, and the structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0046] Example 12 Example 12 of this application provides an N-sulfonyl fluoride compound. The difference between Example 12 and Example 1 is that the structural formula of the amine compound used in Example 12 is: The amount of amine compound used was 19.8 mg, and the structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0047] Example 13 Example 13 of this application provides an N-sulfonyl fluoride compound. The difference between Example 13 and Example 1 is that the structural formula of the amine compound used in Example 13 is: The amount of amine compound used was 28.6 mg, and the structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0048] Example 14 Example 14 of this application provides an N-sulfonyl fluoride compound. The difference between Example 14 and Example 1 is that the structural formula of the amine compound used in Example 14 is: The amount of amine compound used was 29.4 mg, and 43.4 mg of tert-butyl hypochlorite was used to replace N-chlorosuccinimide (NCS). The structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0049] Example 15 Example 15 of this application provides an N-sulfonyl fluoride compound. The difference between Example 15 and Example 1 is that the structural formula of the amine compound used in Example 15 is: The amount of amine compound used was 62.2 mg, and the structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0050] Example 16 Example 16 of this application provides an N-sulfonyl fluoride compound. The difference between Example 16 and Example 1 is that the structural formula of the amine compound used in Example 16 is: The amount of amine compound used was 65.9 mg, and the structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0051] Example 17 Example 17 of this application provides an N-sulfonyl fluoride compound. The difference between Example 17 and Example 1 is that the structural formula of the amine compound used in Example 17 is: The N-chlorosuccinimide (NCS) was replaced with 26.4 mg of an 0.22 mL solution of 10% sodium hypochlorite. The structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0052] Example 18 Example 18 of this application provides an N-sulfonyl fluoride compound. The difference between Example 18 and Example 17 is that the structural formula of the amine compound used in Example 18 is: The amount of amine compound used was 43.3 mg, and the structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0053] Example 19 Example 19 of this application provides an N-sulfonyl fluoride compound, which is prepared by the following steps: A solution of 39.5 mg of an amino compound was prepared by dissolving it in 2 mL of dichloromethane at room temperature. 53.4 mg of N-chlorosuccinimide (NCS) was added to the solution. The mixture was stirred in a reactor at 0 °C for 1 h, and then the dichloromethane was removed under reduced pressure. 48.1 mg of 1,4-diazabicyclo[2.2.2]octane-1,4-dionium-1,4-disulfinic acid (DABSO), 2.6 mg of 9-phenylacridine, and 60.8 mg of cesium fluoride (CsF) were added to the reactor in a single step, along with 2 mL of acetonitrile. The reaction was carried out at 0 °C under argon protection using a 40 W catalytic light source (Kessil lamp) at a wavelength of 427 nm. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1, product Rf = 0.4). After the reaction was complete, the product was purified by column chromatography (300-400 mesh silica gel, petroleum ether: ethyl acetate = 5:1) to obtain N-sulfonyl fluoride compounds.

[0054] The structural formula of the amine compound in this embodiment is: The structural formula of the target product, an N-sulfonyl fluoride compound, is: .

[0055] Example 20 Example 20 of this application provides an N-sulfonyl fluoride compound. The difference between Example 20 and Example 19 is that the structural formula of the amine compound used in Example 20 is: The amount of amine compound used was 29.8 mg, and the structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0056] Example 21 Example 21 of this application provides an N-sulfonyl fluoride compound. The difference between Example 21 and Example 19 is that the structural formula of the amine compound used in Example 21 is: The amount of amine compound used was 67.9 mg, and the structural formula of the target product, an N-sulfonyl fluoride compound, is as follows: .

[0057] Testing and Inspection (1) The target products of Examples 1-21 1 HNMR, 13 CNMR and yield are shown in Table 1 below.

[0058] Table 1:

[0059] Results Analysis The following detailed description of this application is based on the experimental results provided in Table 1.

[0060] According to Table 1 1 H NMR and 13 C18 NMR results confirm that the N-sulfonyl fluoride compounds obtained in Examples 1-21 of this application are the corresponding target products. This demonstrates that the preparation method of this application avoids the use of traditional, cumbersome, and toxic synthetic steps through a one-pot reaction, successfully synthesizing N-sulfonyl fluoride compounds as high-value SuFEx (sulfur-fluorine exchange) hubs for click chemical linkages or precisely controlled polymerization of bioactive molecular fragments.

[0061] Referring to Table 1, the yields of N-sulfonyl fluoride compounds in Examples 1, 4-7, 11-12, 14-18, and 21 were all higher than 60%. This is attributed to the rapid binding rate of nitrogen free radicals to sulfur dioxide during the preparation process, which minimizes the likelihood of other side reactions. In contrast, the yields of N-sulfonyl fluoride compounds in Examples 2, 3, 8, 9, 10, 13, 19, and 20 were lower than 60%. This is attributed to the tendency of the corresponding nitrogen free radicals to undergo partial hydrogen atom transfer reactions, generating amine compounds as the reactant.

[0062] Referring to Table 1, Examples 1-18 are applicable to heating conditions, and reactions can also occur under light conditions. Examples 19-21 use light-induced reactions to minimize the occurrence of side reactions due to instability of the nitrogen-chlorine intermediates of the corresponding primary alkylamines in the raw materials under heating conditions.

[0063] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A multi-component preparation method for N-sulfonyl fluoride compounds, characterized in that: Includes the following steps: The amine compound was reacted with a chlorine source in a solvent to generate an intermediate. Then, a sulfur dioxide source and a fluorine source were added to react. After a one-pot reaction, the N-sulfonyl fluoride compound was obtained by purification. The general structural formula of the amine compounds is: The general structural formula of the N-sulfonyl fluoride compound is as follows: Wherein, R1 and R2 may be the same or different. When R1 and R2 are not cyclic, R1 includes one of substituted or unsubstituted alkyl, aryl, and aromatic heterocyclic groups, and R2 includes one of substituted or unsubstituted alkyl, aryl, aromatic heterocyclic groups, carbonyl, and hydrogen. When R1 and R2 are cyclic, they form nitrogen heterocyclic compounds, which include one of saturated nitrogen heterocyclic groups, imidazole, benzimidazole, pyrazole, benzopyrazole, and carbazole. Its general reaction formula is as follows: 。 2. The multi-component preparation method of an N-sulfonyl fluoride compound according to claim 1, characterized in that: The structural formula of the amine compound includes one of the following structural formulas: 。 3. The multi-component preparation method of an N-sulfonyl fluoride compound according to claim 1, characterized in that: The chlorine source includes one or more of N-chlorosuccinimide, trichloroisocyanuric acid, sodium hypochlorite, and tert-butyl hypochlorite.

4. The multi-component preparation method of an N-sulfonyl fluoride compound according to claim 1, characterized in that: The fluorine source includes one or more of potassium fluoride, silver fluoride, cesium fluoride, triethylamine, and hydrogen trifluoride.

5. The multi-component preparation method of an N-sulfonyl fluoride compound according to claim 1, characterized in that: The solvent includes one or more of acetonitrile, dichloromethane, dimethyl sulfoxide, and N,N-dimethylformamide.

6. The multi-component preparation method of an N-sulfonyl fluoride compound according to claim 1, characterized in that: The molar ratio of the amine compound, the chlorine source, the sulfur dioxide source, and the fluorine source is 1:0.9-2.1:1:0.9-2.

1.

7. The multi-component preparation method of an N-sulfonyl fluoride compound according to claim 1, characterized in that: The reaction between the sulfur dioxide source and the fluorine source includes a heating reaction or a light-induced reaction.

8. The multi-component preparation method of an N-sulfonyl fluoride compound according to claim 7, characterized in that: The heating reaction includes controlling the temperature conditions at 45-55 ℃ and the reaction time at 5.5-6.5 h.

9. A multi-component preparation method for an N-sulfonyl fluoride compound according to claim 7, characterized in that: The photo-reaction involves controlling the temperature to -2°C to 10°C, adding a photocatalyst, and reacting with 427 nm wavelength light at a power of 30-50 W for 10-20 h.

10. An N-sulfonyl fluoride compound prepared by the multi-component preparation method of any one of claims 1-9, characterized in that: Its structural formula includes one of the following structural formulas: 。

Images