A method of sulfonylation of a halogenated quinoline with an arylsulfonyl hydrazide

Abstract

The application discloses a method for sulfonylating halogenated quinoline and aryl sulfonohydrazide, wherein the halogenated quinoline compound and the aryl sulfonohydrazide are subjected to a sulfonylating reaction in a solvent to obtain a target compound. The application provides a simple method for forming a sulfonyl quinoline without adding any catalyst and additive, and the method is green and environment-friendly, and the reaction condition is simple and mild, and the method has the characteristics of simple post-treatment, green step, low pollution, high economic benefit and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to a sulfonylation method of haloquinoline and arylsulfonylhydrazine. Background Technology

[0002] Arylsulfonyl compounds are among the most important compounds in medicinal chemistry. Various synthetic methods for preparing organosulfonyl compounds have been developed and are widely used in organic synthesis. A common arylsulfonation method involves the reaction of arylsulfonating reagents with CH-activated compounds via coupling or addition reactions. However, these methods have some drawbacks, such as requiring harsh conditions and robust substrates, which limits the range of substrates that can be synthesized. To address these issues, it is therefore crucial to explore new, more environmentally friendly methods for synthesizing arylsulfonyl compounds with milder reaction conditions. Summary of the Invention

[0003] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0004] In view of the problems existing in the above and / or prior art, the present invention is proposed.

[0005] One objective of this invention is to provide a sulfonation method for halogenated quinolines and arylsulfonyl hydrazides, which has mild reaction conditions and features simple post-processing, green steps, low pollution, and high economic benefits.

[0006] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a sulfonation method for halogenated quinoline and arylsulfonyl hydrazine, comprising sulfonating the halogenated quinoline compound represented by Formula I and the arylsulfonyl hydrazine represented by Formula II in a solvent to obtain the compound represented by Formula III;

[0007]

[0008]

[0009] Wherein, R includes one of halogen, ester group, methyl, methoxy, hydroxy, tert-butyldimethylsiloxy, quinoxalinyl, pyridinyl, benzothiazolyl, and isoquinoxalinyl;

[0010] X includes one of fluorine, chlorine, bromine, and iodine;

[0011] R' includes one of the following: phenyl, methyl, methoxy, halogen, trifluoromethyl, cyano, nitro, ester, naphthyl, dansamido, benzofuranyl, 3,5-dimethylisoxazolyl, thiophene, and propenyl.

[0012] As a preferred embodiment of the sulfonation method of haloquinolines and arylsulfonyl hydrazides of the present invention, the haloquinoline compound includes one of 2-chloroquinoline, 2-bromoquinoline, methyl 2-chloro-3-quinoline carboxylate, 2-chloro-3-methylquinoline, 2,4-dichloroquinoline, 2-chloro-4-methylquinoline, 2,6-dichloroquinoline, 2-chloro-6-bromoquinoline, 2-chloro-6-methylquinoline, 2-chloro-6-methoxyquinoline, 2-chloro-6-hydroxyquinoline, 2-chloro-6-tert-butyldimethylsiloxyquinoline, 2-chloro-8-bromoquinoline, 2-chloroquinoxaline, 2-fluoropyridine, 2-chloropyridine, 2-bromopyridine, 2-iodopyridine, 2-chlorobenzothiazole, and 1-chloroisoquinoline.

[0013] As a preferred embodiment of the sulfonation method of haloquinoline and arylsulfonyl hydrazine of the present invention, wherein the arylsulfonyl hydrazine compound includes one of benzenesulfonyl hydrazine, 4-toluenesulfonyl hydrazine, 4-methoxybenzenesulfonyl hydrazine, 4-fluorobenzenesulfonyl hydrazine, 4-chlorobenzenesulfonyl hydrazine, 4-(trifluoromethyl)-benzenesulfonyl hydrazine, 4-cyanobenzenesulfonyl hydrazine, 4-nitrobenzenesulfonyl hydrazine, 4-methyl carbamate benzenesulfonyl hydrazine, 2-naphthalenesulfonyl hydrazine, dansyl hydrazine, 2,3-dihydrobenzofuran-5-sulfonyl hydrazine, 3,5-dimethylisozol-4-sulfonyl hydrazine, 2-thiophenesulfonyl hydrazine, and propylsulfonyl hydrazine.

[0014] As a preferred embodiment of the sulfonation method of haloquinoline and arylsulfonyl hydrazine of the present invention, wherein the molar ratio of the haloquinoline compound and the arylsulfonyl hydrazine is 1:1.

[0015] As a preferred embodiment of the sulfonation method of the present invention of halogenated quinoline and aryl sulfonyl hydrazine, wherein: the sulfonation reaction is carried out at a reaction temperature of 25-110°C; preferably at 100°C.

[0016] In a preferred embodiment of the sulfonation method of the present invention involving haloquinolines and arylsulfonyl hydrazides, the sulfonation reaction is carried out for 6–12 hours; preferably, for 6 hours.

[0017] As a preferred embodiment of the sulfonation method of haloquinoline and arylsulfonylhydrazine of the present invention, the solvent includes one of water, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, methanol, and ethanol; preferably, the solvent is water.

[0018] As a preferred embodiment of the sulfonation method of haloquinoline and arylsulfonyl hydrazine of the present invention, the method further includes a step of purifying the obtained target compound.

[0019] In summary, the chemical equation for the optimal reaction conditions of this invention is as follows:

[0020]

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] This invention provides a novel method for the sulfonation reaction of haloquinolines with arylsulfonylhydrazides, offering a simple approach to the formation of sulfonylquinolines without the addition of any catalysts or additives. Furthermore, this method is environmentally friendly, with simpler and milder reaction conditions, demonstrating significant innovation. The preparation method of this invention features mild reaction conditions, simple post-processing, green procedures, low pollution, and high economic benefits. Attached Figure Description

[0023] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Wherein:

[0024] Figure 1 The 1H NMR spectrum of 2-(benzenesulfonyl)quinoline, the target product of Example 1 of this invention;

[0025] Figure 2 The carbon spectrum of 2-(benzenesulfonyl)quinoline, the target product of Example 1 of the present invention.

[0026] Figure 3 The 1H NMR spectrum of 2-((4-methoxyphenyl)sulfonyl)quinoline, the target product of Example 2 of this invention;

[0027] Figure 4 The carbon spectrum of 2-((4-methoxyphenyl)sulfonyl)quinoline, the target product of Example 2 of the present invention.

[0028] Figure 5 The 1H NMR spectrum of 2-((4-fluorophenyl)sulfonyl)quinoline, the target product of Example 3 of this invention;

[0029] Figure 6 The carbon spectrum of 2-((4-fluorophenyl)sulfonyl)quinoline, the target product of Example 3 of the present invention.

[0030] Figure 7The fluorine spectrum of 2-((4-fluorophenyl)sulfonyl)quinoline, the target product of Example 3 of the present invention. Detailed Implementation

[0031] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0032] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0033] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0034] Unless otherwise specified, all raw materials used in the examples are commercially available.

[0035] The arylsulfonyl hydrazine (Formula II) used in the examples was prepared according to the following literature:

[0036] [1] Zhang, G.; Fan, Q.; Wang, H.; Zhao, Y.; Ding, C.NaHSO3-Mediated DirectSynthesis of Sulfinic Esters from Sulfonyl Hydrazides under Transition-Metal-Free Conditions. Adv.Synth.Catal.2021,363,833-837.

[0037] Example 1

[0038] (1) Add 2-chloroquinoline (81.8 mg, 0.5 mmol, 1.0 equiv.), benzenesulfonyl hydrazine (86.1 mg, 0.5 mmol, 1 equiv.), and H2O (2 mL) to a sealed tube equipped with a magnetic stir bar. Stir the reaction mixture at 100 °C for 6 hours.

[0039] (2) The reaction was then cooled to room temperature and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then removed by rotary evaporation. The crude product was purified by silica gel column chromatography under the following conditions: 300-400 mesh silica gel powder as the stationary phase and petroleum ether / ethyl acetate at a ratio of 10:1 as the mobile phase. 108.1 mg of the target product, 2-(benzenesulfonyl)quinoline, was finally obtained. The structural formula of this compound is:

[0040]

[0041] The above-mentioned 2-(benzenesulfonyl)quinoline was characterized as follows: Figure 1 and 2 As shown, the result is: a yellow solid; 1 H NMR (400MHz, CDCl3): δ8.38(d,J=8.5Hz,1H),8.25–8.09(m,4H),7.87(d,J=8.2Hz,1H),7.81–7.75(m,1H),7.68–7.56(m,2H),7.53(t,J=7.6Hz,2H)ppm. 13 C NMR (100MHz, CDCl3): δ157.9,147.3,139.0,138.7,133.7,131.0,130.3,129.2,129.0,12 8.9,128.7,127.7,117.7ppm.IR(KBr):ν=3057,2924,1322,756,722,684,641,613,568cm -1 .HRMS(m / z):calcdfor C 15 H 12 NO2S + [M+H] + 270.0583, found: 270.0581.

[0042] Characterization data showed that the obtained reaction product was 2-(benzenesulfonyl)quinoline (purity > 98%); the product yield was calculated to be 80%.

[0043] The target product 2-(benzenesulfonyl)quinoline synthesized in Example 1 can be further synthesized into 2-phenylquinoline, a pharmaceutical intermediate, optoelectronic material intermediate, and synthetic material intermediate, via nickel-catalyzed intramolecular desulfurization coupling. The reaction formula is as follows:

[0044]

[0045] For specific reaction conditions, please refer to reference [2] Takahashi, F.; Nogi, K.; Yorimitsu, H. Intramolecular Desulfitative Coupling: Nickel-Catalyzed Transformation of Diaryl Sulfones into Biaryls via Extrusion of SO2. Org. Lett. 2018, 20, 6601-6605.

[0046] Example 2

[0047] (1) Add 2-chloroquinoline (81.8 mg, 0.5 mmol, 1.0 equiv.), 4-methoxybenzenesulfonyl hydrazine (101.1 mg, 0.5 mmol, 1 equiv.), and H2O (2 mL) to a sealed tube equipped with a magnetic stir bar. Stir the reaction mixture at 100 °C for 6 hours.

[0048] (2) The reaction was then cooled to room temperature and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then removed by rotary evaporation. The crude product was purified by silica gel column chromatography under the following conditions: 300-400 mesh silica gel powder as the stationary phase and petroleum ether / ethyl acetate at a ratio of 10:1 as the mobile phase. 120.3 mg of the target product, 2-((4-methoxyphenyl)sulfonyl)quinoline, was finally obtained. The structural formula of this compound is:

[0049]

[0050] The above-mentioned 2-((4-methoxyphenyl)sulfonyl)quinoline was characterized as follows: Figure 3 and 4 As shown, the result is: a yellow solid; 1 H NMR (400MHz, CDCl3): δ8.30(d,J=8.5Hz,1H),8.14–8.06(m,2H),8.03(d,J=8.8Hz,2H),7.78( d,J=8.2Hz,1H),7.73–7.65(m,1H),7.60–7.51(m,1H),6.93(d,J=7.7Hz,2H),3.76(s,3H)ppm. 13C NMR (100MHz, CDCl3): δ163.7,158.3,147.1,138.6,131.0,130.8,130.2,129.9,128.9,128. 5,127.5,117.3,114.2,55.5ppm.IR(KBr):ν=3734,3046,2922,1595,1498,1163,756,559cm -1 .HRMS(m / z):calcd for C 16 H 14 NO3S + [M+H] + 300.0689, found: 300.0683.

[0051] Characterization data showed that the obtained reaction product was 2-((4-methoxyphenyl)sulfonyl)quinoline (purity > 98%); the product yield was calculated to be 80%.

[0052] Example 3

[0053] (1) Add 2-chloroquinoline (81.8 mg, 0.5 mmol, 1.0 equiv.), 4-fluorobenzenesulfonyl hydrazine (95.1 mg, 0.5 mmol, 1 equiv.), and H2O (2 mL) to a sealed tube equipped with a magnetic stir bar. Stir the reaction mixture at 100 °C for 6 hours.

[0054] (2) The reaction was then cooled to room temperature and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then removed by rotary evaporation. The crude product was purified by silica gel column chromatography under the following conditions: 300-400 mesh silica gel powder as the stationary phase and petroleum ether / ethyl acetate at a ratio of 10:1 as the mobile phase. 120.3 mg of the target product, 2-((4-fluorophenyl)sulfonyl)quinoline, was finally obtained. The structural formula of this compound is:

[0055]

[0056] The above-mentioned 2-((4-fluorophenyl)sulfonyl)quinoline was characterized as follows: Figure 5 , 6 As shown in Figure 7, the result is: a yellow solid; 1H NMR (400MHz, CDCl3): δ8.37(d,J=7.8Hz,1H),8.20–8.10(m,4H),7.85(d,J=6.8Hz,1H),7. 76(ddd,J=8.5,6.9,1.5Hz,1H),7.63(ddd,J=8.1,6.9,1.2Hz,1H),7.22–7.15(m,2H)ppm. 13 C NMR (100MHz, CDCl3): δ165.8(d,J C-F =257.8Hz),157.8,147.3,138.8,134.9(d,J C-F =3.2Hz), 131.9(d,J C-F =9.8Hz),131.0,130.1,129.2,128.7,127.7,117.4,116.3(d,J C-F =22.7Hz)ppm. 19 F NMR(376MHz, CDCl3): δ-103.14–-103.23(m,1F)ppm.IR(KBr):ν=3059,1586,1493,1328,845,756,686,652,552cm -1 .HRMS(m / z):calcd for C 15 H 11 FNO2S + [M+H] + 288.0489, found: 288.0493.

[0057] Characterization data showed that the obtained reaction product was 2-((4-fluorophenyl)sulfonyl)quinoline (purity > 98%); the product yield was calculated to be 82%.

[0058] Example 4

[0059] Example 4 is basically the same as Example 1, except that the temperature in step (1) is different, as shown in Table 1 below:

[0060] Table 1

[0061] temperature Yield (%) rt <5 60℃ 57 80℃ 80 90℃ 83 100℃ 85 110℃ 86

[0062] As can be seen from Table 1, under the same reaction conditions, the synthesis can be successfully carried out at different temperatures, such as room temperature, 60℃, 80℃, 90℃, 100℃ and 110℃. 100℃ was selected as the optimal reaction temperature with a yield of 85%.

[0063] Example 5

[0064] Example 5 is basically the same as Example 1, except that the time in step (1) is different, as shown in Table 2 below:

[0065] Table 2

[0066] time Yield (%) 4h 80 6h 85 12h 85

[0067] As can be seen from Table 2, under the same reaction conditions, different times, such as 4h, 6h and 12h, can be successfully synthesized. 6h is selected as the optimal reaction time with a yield of 85%.

[0068] Example 6

[0069] Example 6 is basically the same as Example 1, except that the solvent in step (1) is different, as shown in Table 3 below:

[0070] Table 3

[0071]

[0072]

[0073] As can be seen from Table 3, under the same reaction conditions, different solvents, such as toluene, dimethyl sulfoxide, acetonitrile, methanol, ethanol, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, and water, can all be successfully used to synthesize the product. The best results are achieved when water is used as the solvent, with the highest yield of 85%.

[0074] Example 7

[0075] Example 7 is basically the same as Example 1, except that in step (1), the arylsulfonyl hydrazide and haloquinoline are different, as shown in Table 4 below:

[0076] Table 4

[0077]

[0078]

[0079]

[0080] This invention provides a novel method for the sulfonation reaction of haloquinolines with arylsulfonylhydrazides, offering a simple approach to the formation of sulfonylquinolines without the addition of any catalysts or additives. Furthermore, this method is environmentally friendly, with simpler and milder reaction conditions, demonstrating significant innovation. The preparation method of this invention features mild reaction conditions, simple post-processing, green procedures, low pollution, and high economic benefits.

[0081] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for preparing the compound of formula III by sulfonation reaction, characterized in that: include, The compound shown in Formula I and the compound shown in Formula II were subjected to sulfonation in a solvent to obtain the compound shown in Formula III; (Formula I); (Formula II); (Formula III); in, The compound represented by Formula I is selected from one of the following: 2-chloroquinoline, 2-bromoquinoline, methyl 2-chloro-3-quinoline carboxylate, 2-chloro-3-methylquinoline, 2,4-dichloroquinoline, 2-chloro-4-methylquinoline, 2,6-dichloroquinoline, 2-chloro-6-bromoquinoline, 2-chloro-6-methylquinoline, 2-chloro-6-methoxyquinoline, 2-chloro-6-hydroxyquinoline, 2-chloro-6-tert-butyldimethylsiloxyquinoline, 2-chloro-8-bromoquinoline, 2-chloroquinoxaline, 2-fluoropyridine, 2-chloropyridine, 2-bromopyridine, 2-iodopyridine, 2-chlorobenzothiazole, and 1-chloroisoquinoline. The compound represented by Formula II is selected from one of the following: benzenesulfonyl hydrazide, 4-toluenesulfonyl hydrazide, 4-methoxybenzenesulfonyl hydrazide, 4-fluorobenzenesulfonyl hydrazide, 4-chlorobenzenesulfonyl hydrazide, 4-(trifluoromethyl)-benzenesulfonyl hydrazide, 4-cyanobenzenesulfonyl hydrazide, 4-nitrobenzenesulfonyl hydrazide, 4-methyl carbamate benzenesulfonyl hydrazide, 2-naphthalenesulfonyl hydrazide, dansyl hydrazide, 2,3-dihydrobenzofuran-5-sulfonyl hydrazide, 3,5-dimethylisozol-4-sulfonyl hydrazide, 2-thiophenesulfonyl hydrazide, and propylsulfonyl hydrazide. The solvent is water; The reaction is carried out at a temperature of 60~110 ℃.

2. The method as described in claim 1, characterized in that: The molar ratio of the compound represented by Formula I to the compound represented by Formula II is 1:

1.

3. The method as described in claim 1, characterized in that: The reaction temperature is 110 °C.

4. The method according to any one of claims 1 to 3, characterized in that: The reaction takes 6 to 12 hours.

5. The method according to any one of claims 1 to 3, characterized in that: It also includes a step of purifying the obtained target compound.

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