Sulfonylation method of halogenated quinoline and aryl sulfonyl hydrazide

Abstract

The invention discloses a sulfonylation method of halogenated quinoline and aryl sulfonyl hydrazide, which is characterized in that a halogenated quinoline compound and aryl sulfonyl hydrazide are subjected to sulfonylation reaction in a solvent to obtain a target compound. The invention provides a simple method for the composition of the sulfonylquinoline without adding any catalyst and additive, and the method is green and environment-friendly, the reaction conditions are simpler and milder, and the method has the characteristics of simple post-treatment, green steps, low pollution, high economic benefit and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and specifically relates to a sulfonylation method of halogenated quinoline and arylsulfonyl hydrazide. Background Art

[0002] Arylsulfonyl compounds are among the most important compounds in medicinal chemistry. Various synthetic methods for preparing organic sulfonyl compounds have been developed and widely used in organic synthesis. The common arylsulfonylation method is the reaction of arylsulfonylating agents with CH-activated compounds through coupling or addition reactions. However, these methods have some disadvantages, such as the need for harsh conditions and strong substrates, which leads to a limited substrate range. In order to solve these problems, it is more meaningful to explore a new method for synthesizing arylsulfonyl compounds that is greener and has milder reaction conditions. Summary of the invention

[0003] The purpose of this section is to summarize some aspects of embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the specification abstract and the invention title of this application to avoid blurring the purpose of this section, the specification abstract and the invention title, and such simplifications or omissions cannot be used to limit the scope of the present invention.

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

[0005] One of the purposes of the present invention is to provide a method for sulfonylation of halogenated quinoline with arylsulfonylhydrazide, which has mild reaction conditions, simple post-treatment, green steps, low pollution, high economic benefits and the like.

[0006] In order to solve the above technical problems, the present invention provides the following technical solutions: a method for sulfonylation of a halogenated quinoline with an arylsulfonylhydrazide, comprising: subjecting a halogenated quinoline compound represented by formula I and an arylsulfonylhydrazide represented by formula II to a sulfonylation reaction in a solvent to obtain a compound represented by formula III;

[0007]

[0008]

[0009] Wherein, R includes one of halogen, ester, methyl, methoxy, hydroxyl, tert-butyldimethylsiloxy, quinoxaline, pyridyl, benzothiazolyl, and isoquinolyl;

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

[0011] R' includes one of phenyl, methyl, methoxy, halogen, trifluoromethyl, cyano, nitro, ester, naphthyl, dansyl, benzofuranyl, 3,5-dimethylisoxazolyl, thienyl, and propenyl.

[0012] As a preferred embodiment of the sulfonylation method of halogenated quinoline with arylsulfonyl hydrazide of the present invention, the halogenated quinoline compound comprises one of 2-chloroquinoline, 2-bromoquinoline, 2-chloro-3-quinolinecarboxylic acid methyl ester, 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-butyldimethylsilyloxyquinoline, 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 sulfonylation method of halogenated quinoline with aryl sulfonyl hydrazide of the present invention, the aryl sulfonyl hydrazide compound comprises one of benzenesulfonyl hydrazide, 4-toluenesulfonyl hydrazide, 4-methoxybenzenesulfonyl hydrazide, 4-fluorobenzenesulfonyl hydrazide, 4-chlorobenzenesulfonyl hydrazide, 4-(trifluoromethyl)-benzenesulfonic acid hydrazide, 4-cyanobenzenesulfonyl hydrazide, 4-nitrobenzenesulfonyl hydrazide, 4-methyl formate benzenesulfonyl hydrazide, 2-naphthalenesulfonyl hydrazide, dansyl hydrazide, 2,3-dihydrobenzofuran-5-sulfonyl hydrazide, 3,5-dimethylisoxazole-4-sulfonyl hydrazide, 2-thiophenesulfonyl hydrazide and propylsulfonyl hydrazide.

[0014] As a preferred embodiment of the sulfonylation method of the present invention with a haloquinoline and an arylsulfonylhydrazide, the molar ratio of the haloquinoline compound to the arylsulfonylhydrazide is 1:1.

[0015] As a preferred embodiment of the sulfonylation method of the present invention with halogenated quinoline and arylsulfonylhydrazide, the sulfonylation reaction is carried out at a temperature of 25 to 110°C, preferably 100°C.

[0016] As a preferred embodiment of the sulfonylation method of the present invention with halogenated quinoline and arylsulfonylhydrazide, the sulfonylation reaction is carried out for 6 to 12 hours, preferably 6 hours.

[0017] As a preferred embodiment of the sulfonylation method of the present invention with halogenated quinoline and arylsulfonyl hydrazide, the solvent comprises one of water, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, methanol and ethanol; the preferred solvent is water.

[0018] As a preferred embodiment of the sulfonylation method of the present invention with halogenated quinoline and arylsulfonylhydrazide, it further comprises a step of purifying the obtained target compound.

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

[0020]

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

[0022] The invention provides a novel method for the sulfonylation reaction of a halogenated quinoline and an arylsulfonylhydrazine, and provides a simple method for the formation of sulfonylquinoline without adding any catalyst or additive. In addition, the method is green and environmentally friendly, and the reaction conditions are simpler and milder, and the method has good innovation. The preparation method of the invention has mild reaction conditions, simple post-treatment, green steps, low pollution, high economic benefits, and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative labor. Among them:

[0024] Figure 1 This is the hydrogen spectrum of the target product 2-(phenylsulfonyl)quinoline of Example 1 of the present invention;

[0025] Figure 2 This is the carbon spectrum of the target product 2-(phenylsulfonyl)quinoline of Example 1 of the present invention.

[0026] Figure 3 This is the hydrogen spectrum of the target product 2-((4-methoxyphenyl)sulfonyl)quinoline of Example 2 of the present invention;

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

[0028] Figure 5 This is the hydrogen spectrum of the target product 2-((4-fluorophenyl)sulfonyl)quinoline of Example 3 of the present invention;

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

[0030] Figure 7This is the fluorine spectrum of the target product 2-((4-fluorophenyl)sulfonyl)quinoline of Example 3 of the present invention. DETAILED DESCRIPTION

[0031] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0032] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present 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 term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0034] Unless otherwise specified, the raw materials used in the examples were purchased commercially.

[0035] The raw material arylsulfonylhydrazide (Formula II) used in the example was prepared with reference 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) 2-Chloroquinoline (81.8 mg, 0.5 mmol, 1.0 equiv.), benzenesulfonyl hydrazide (86.1 mg, 0.5 mmol, 1 equiv.) and H2O (2 mL) were added in one portion to a sealed tube equipped with a magnetic stirring bar. The reaction mixture was stirred at 100°C for 6 hours.

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

[0040]

[0041] The above 2-(phenylsulfonyl)quinoline is characterized, as Figure 1 and 2 As shown, the result is: 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] According to the characterization data, the obtained reaction product is 2-(phenylsulfonyl)quinoline (purity>98%); the product yield is calculated and the result is 80%.

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

[0044]

[0045] For specific reaction conditions, please refer to the literature [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) 2-Chloroquinoline (81.8 mg, 0.5 mmol, 1.0 equiv.), 4-methoxybenzenesulfonyl hydrazide (101.1 mg, 0.5 mmol, 1 equiv.) and H2O (2 mL) were added in one portion to a sealed tube equipped with a magnetic stirring bar. The reaction mixture was stirred at 100°C for 6 hours.

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

[0049]

[0050] The above 2-((4-methoxyphenyl)sulfonyl)quinoline was characterized, as shown in Figure 3 and 4 As shown, the result is: 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] According to the characterization data, the obtained reaction product is 2-((4-methoxyphenyl)sulfonyl)quinoline (purity>98%); the product yield is calculated and the result is 80%.

[0052] Example 3

[0053] (1) 2-Chloroquinoline (81.8 mg, 0.5 mmol, 1.0 equiv.), 4-fluorobenzenesulfonyl hydrazide (95.1 mg, 0.5 mmol, 1 equiv.) and H2O (2 mL) were added in one portion to a sealed tube equipped with a magnetic stirring bar. The reaction mixture was stirred at 100°C for 6 hours.

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

[0055]

[0056] The above 2-((4-fluorophenyl)sulfonyl)quinoline was characterized, as shown in Figure 5 , 6 , 7, the result is: 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] According to the characterization data, the obtained reaction product is 2-((4-fluorophenyl)sulfonyl)quinoline (purity>98%); the product yield is 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] It can be seen from Table 1 that under the same reaction conditions, different temperatures, such as room temperature, 60°C, 80°C, 90°C, 100°C, and 110°C, can all be successfully synthesized. 100°C 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] It can be seen from Table 2 that under the same reaction conditions, different reaction times, such as 4 h, 6 h, and 12 h, can all be successfully synthesized, and 6 h 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] It can be seen from Table 3 that 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 synthesized. The best effect is 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 the halogenated quinoline are different, as shown in Table 4 below:

[0076] Table 4

[0077]

[0078]

[0079]

[0080] The invention provides a novel method for the sulfonylation reaction of a halogenated quinoline and an arylsulfonylhydrazine, and provides a simple method for the formation of sulfonylquinoline without adding any catalyst or additive. In addition, the method is green and environmentally friendly, and the reaction conditions are simpler and milder, and the method has good innovation. The preparation method of the invention has mild reaction conditions, simple post-treatment, green steps, low pollution, high economic benefits, and the like.

[0081] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for sulfonylation of haloquinoline with arylsulfonylhydrazide, characterized in that: include, The halogenated quinoline compound represented by formula I and the arylsulfonylhydrazide represented by formula II are subjected to sulfonylation reaction in a solvent to obtain a compound represented by formula III; Wherein, R includes one of halogen, ester, methyl, methoxy, hydroxyl, tert-butyldimethylsiloxy, quinoxaline, pyridyl, benzothiazolyl, and isoquinolyl; X includes one of fluorine, chlorine, bromine and iodine; R' includes one of phenyl, methyl, methoxy, halogen, trifluoromethyl, cyano, nitro, ester, naphthyl, dansyl, benzofuranyl, 3,5-dimethylisoxazolyl, thienyl, and propenyl.

2. The sulfonylation method of haloquinoline and arylsulfonylhydrazide as claimed in claim 1, characterized in that: The molar ratio of the halogenated quinoline compound to the arylsulfonyl hydrazide is 1:

1.

3. The sulfonylation method of haloquinoline and arylsulfonylhydrazide as claimed in claim 1 or 2, characterized in that: The halogenated quinoline compound is selected from 2-chloroquinoline, 2-bromoquinoline, 2-chloro-3-quinolinecarboxylic acid methyl ester, 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-butyldimethylsilyloxyquinoline, 2-chloro-8-bromoquinoline, 2-chloroquinoxaline, 2-fluoropyridine, 2-chloropyridine, 2-bromopyridine, 2-iodopyridine, 2-chlorobenzothiazole, and 1-chloroisoquinoline.

4. The sulfonylation method of haloquinoline and arylsulfonylhydrazide as claimed in claim 3, characterized in that: The aryl sulfonyl hydrazide compound is selected from one of benzenesulfonyl hydrazide, 4-toluenesulfonyl hydrazide, 4-methoxybenzenesulfonyl hydrazide, 4-fluorobenzenesulfonyl hydrazide, 4-chlorobenzenesulfonyl hydrazide, 4-(trifluoromethyl)-benzenesulfonic acid hydrazide, 4-cyanobenzenesulfonyl hydrazide, 4-nitrobenzenesulfonyl hydrazide, 4-methyl formate benzenesulfonyl hydrazide, 2-naphthalenesulfonyl hydrazide, dansyl sulfonyl hydrazide, 2,3-dihydrobenzofuran-5-sulfonyl hydrazide, 3,5-dimethylisoxazole-4-sulfonyl hydrazide, 2-thiophenesulfonyl hydrazide and propylsulfonyl hydrazide.

5. The sulfonylation method of the halogenated quinoline and arylsulfonyl hydrazide as described in any one of claims 1, 2 and 4, characterized in that: The sulfonylation reaction is carried out at a temperature of 25 to 110°C.

6. The sulfonylation method of haloquinoline with arylsulfonylhydrazide as claimed in claim 5, characterized in that: The sulfonylation reaction is carried out at a temperature of 110°C.

7. The sulfonylation method of halogenated quinoline and arylsulfonyl hydrazide as described in any one of claims 1, 2, 4, and 6, characterized in that: The sulfonylation reaction has a reaction time of 6 to 12 hours.

8. The sulfonylation method of the halogenated quinoline and arylsulfonyl hydrazide as described in any one of claims 1, 2, 4, and 6, characterized in that: The solvent includes one of water, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, methanol and ethanol.

9. The sulfonylation method of haloquinoline and arylsulfonylhydrazide as claimed in claim 8, characterized in that: The solvent is water.

10. The sulfonylation method of any one of claims 1, 2, 4, 6, and 9 with a halogenated quinoline and an arylsulfonyl hydrazide, characterized in that: The method also includes a step of purifying the obtained target compound.

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