CN117658750A - Synthesis process of sulfonyl fluoride compound - Google Patents

Synthesis process of sulfonyl fluoride compound Download PDF

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CN117658750A
CN117658750A CN202311645669.1A CN202311645669A CN117658750A CN 117658750 A CN117658750 A CN 117658750A CN 202311645669 A CN202311645669 A CN 202311645669A CN 117658750 A CN117658750 A CN 117658750A
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sulfonyl fluoride
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fluoride
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谢兰贵
赵健琳
董博
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Nanjing Normal University
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Nanjing Normal University
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Abstract

The invention discloses a synthesis process of sulfonyl fluoride compounds; under the protection of nitrogen, the sulfhydryl-containing compound and the dimethyl sulfonium bromide are subjected to oxidative fluorination reaction under the action of alkali, an oxidizing reagent and a fluorinating reagent to generate sulfonyl fluoride compounds; wherein, the alkali is 2,4, 6-trimethylpyridine, the oxidant is sodium chlorite, the fluorinating agent is potassium bifluoride, the sulfhydryl compound is aliphatic mercaptan or thiophenol containing aromatic ring or heterocycle; the method has the advantages of mild conditions, simple and easily obtained raw materials, simple operation and higher application value.

Description

Synthesis process of sulfonyl fluoride compound
Technical Field
The invention relates to the field of synthesis of organic intermediates, in particular to a synthesis process of sulfonyl fluoride compounds.
Background
Sulfonyl fluoride compounds are very important components in many fields of synthetic chemistry, pharmaceutical chemistry, fine chemicals, industrial applications, etc. Sulfonyl fluorides are also used in chemical biology as covalent protein modulators, strong protease inhibitors and active probes. Because of the unique structure and nature of the S-F bonds in sulfonyl fluoride compounds, they can be used not only as important functional groups for the synthesis of natural products, but also as intermediates commonly existing in the industry for preparing fine chemical products such as fluorine-containing pesticides, dyes and the like, and specific synthesis methods have been reported:
the method comprises the following steps: synthesizing sulfonyl fluoride by using methanol and water as solvents at the temperature of 0 ℃.
The reaction has the defects of high toxicity, extremely high risk coefficient and severe requirements on experimental conditions and experimental equipment because of the requirement of using highly toxic gas chlorine with strong pungent smell.
The second method is as follows: the aromatic hydrocarbon sulfonyl fluoride is synthesized from aryl bromide by a one-pot method by taking palladium as a catalyst.
The reaction has the defects that noble metal palladium is required to be used as a catalyst, more byproducts are generated, the post-treatment of the experiment is greatly influenced, the economy of reaction atoms is low, and the cost of the reaction is high.
And a third method: DMF is taken as solvent, SOF 2 The reaction is carried out for 1h at 130 ℃ to obtain the corresponding sulfonyl fluoride compound.
The reaction has the defects that boron trifluoride diethyl etherate is needed to be used, is sensitive to moisture, can react violently to emit toxic fluorine-containing gas when meeting water, is extremely harmful to human bodies, needs to use anhydrous reagent, and also needs to react under high temperature condition, and has high requirements on reaction conditions and equipment, so that the reaction cost is greatly increased.
The method four: by CH 3 CN and H 2 O is solvent, KF is fluorine source electrochemical condition, and thiol or thiophenol is converted into sulfonyl fluoride.
The reaction has the defects that flammable and explosive hydrogen can be generated, the danger coefficient is high after the amplification reaction, the requirement on experimental equipment is high, and the reaction time is long.
Disclosure of Invention
Aiming at the problems, the invention aims to provide a synthesis process of sulfonyl fluoride compounds, which has the advantages of low cost, simple operation, no participation of heavy metals, mild reaction conditions and easy popularization in industrial production.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: the synthesis process of sulfonyl fluoride compound is characterized by comprising the following steps:
wherein R is a substituent selected from C 6 ～C 15 Aliphatic, C 6 ～C 15 Or a 5-to 10-membered heteroaryl group containing 1-5O, N, S heteroatoms; the organic sulfonium reagent is dimethyl sulfonium bromide; the oxidant is sodium chlorite, NBS, DDQ or H 2 O 2 One of the following; the alkali is one of tertiary amine, pyridine, cyclohexylmethyl amine and 2,4, 6-trimethylpyridine.
The substituent R in the process of the invention is preferably C 6 ～C 15 Aliphatic or C of (2) 6 ～C 15 Is an aromatic compound.
The reaction mechanism of the invention is as follows:
in the process method of the invention, when the molar ratio of the dimethyl sulfonium bromide to the R-SH is 1:2-3, and the preferable molar ratio is 1:3, the yield of the final product is highest.
In the process method, when the molar ratio of the dimethyl sulfonium bromide to the alkali is 1:1-2, and the preferable molar ratio is 1:1.5, the yield of the final product is highest; the alkali is 2,4, 6-trimethyl pyridine.
In the process method of the invention, the dimethyl sulfonium bromide and KHF are brominated 2 The final product yield is highest when the molar ratio of (2) to (3) is 1:2, preferably 1:3.
In the synthesis method, when the molar ratio of the dimethyl sulfonium bromide to the oxidant is 1:3-4 and the preferred molar ratio is 1:4, the yield of the final product is highest; the oxidant is sodium chlorite.
The reaction solvent in the process method is acetonitrile; from the viewpoints of reaction yield and simplicity of operation, no other organic solvent is added, namely a single organic solvent is used as a reaction solvent; the molar concentration of R-SH in the reaction solvent is 0.2mmol/mL; KHF (KHF) 2 The molar concentration in the reaction solvent was 0.3mmol/mL.
The reaction temperature in the process method is-20 ℃ to 20 ℃, preferably 0 ℃; the reaction time is 10 to 48 hours, preferably 14 hours; the reaction temperature and the reaction time of the invention can be determined by technicians according to different sulfhydryl compounds and actual needs.
After the reaction of the present invention is completed, the reaction solution is washed with saturated saline solution and extracted three times with ethyl acetate, and the refined sulfonyl fluoride product is obtained by column chromatography separation.
The invention has the advantages that: the sulfonyl fluoride compound is synthesized simply and efficiently under the condition of nitrogen by taking a simple and easily obtained fluorine compound and a sulfhydryl compound as reaction substrates, taking commercially available dimethyl sulfonium bromide which is simple to prepare and insensitive to air as a reaction reagent, taking cheap and easily obtained 2,4, 6-trimethyl pyridine as alkali, and naturally recovering to room temperature after feeding at the temperature of 0 ℃. Compared with other methods for synthesizing sulfonyl fluoride compounds, the method has the characteristics of low cost, environment friendliness, safe operation and convenience in industrial popularization, and the used reaction raw materials (including a fluorination reagent, dimethyl sulfonium bromide and alkali) are cheap and easy to obtain, and dangerous strong alkali and corrosive acid are not needed to be used.
The method of the invention has good compatibility with aliphatic, aromatic and heterocyclic raw materials. Therefore, there is practically no particular strict limitation on the substituents in the mercapto compounds and derivatives thereof.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of benzo [ d ] thiazole-2-sulfonyl fluoride described in example 1;
FIG. 2 is a nuclear magnetic resonance spectrum of benzo [ d ] thiazole-2-sulfonyl fluoride described in example 1;
FIG. 3 is a nuclear magnetic resonance fluorine spectrum of benzo [ d ] thiazole-2-sulfonyl fluoride described in example 1;
FIG. 4 is a nuclear magnetic resonance spectrum of 4-chlorobenzenesulfonyl fluoride described in example 2;
FIG. 5 is a nuclear magnetic resonance spectrum of 4-chlorobenzenesulfonyl fluoride described in example 2;
FIG. 6 is a nuclear magnetic resonance spectrum of 4-chlorobenzenesulfonyl fluoride described in example 2;
FIG. 7 is a nuclear magnetic resonance spectrum of 4- (tert-butyl) benzenesulfonyl fluoride described in example 3;
FIG. 8 is a nuclear magnetic resonance hydrogen spectrum of 2-methoxybenzenesulfonyl fluoride described in example 4;
FIG. 9 is a nuclear magnetic resonance hydrogen spectrum of 2, 6-dimethylbenzenesulfonyl fluoride described in example 5;
FIG. 10 is a nuclear magnetic resonance hydrogen spectrum of 3, 4-dimethoxybenzenesulfonyl fluoride described in example 6;
FIG. 11 is a nuclear magnetic resonance spectrum of 4-fluorobenzenesulfonyl fluoride described in example 7;
FIG. 12 is a nuclear magnetic resonance spectrum of benzylsulfonyl fluoride described in example 8.
FIG. 13 is a nuclear magnetic resonance hydrogen spectrum of 4- (tert-butyl) benzylsulfonyl fluoride described in example 9.
FIG. 14 is a nuclear magnetic resonance spectrum of methyl 2- (fluorosulfonyl) benzoate as described in example 10.
FIG. 15 is a nuclear magnetic resonance hydrogen spectrum of 4-methoxybenzenesulfonyl fluoride described in example 11.
FIG. 16 is a nuclear magnetic resonance hydrogen spectrum of pyridine-2-sulfonyl fluoride according to example 12.
FIG. 17 is a nuclear magnetic resonance hydrogen spectrum of naphthalene-2-sulfonyl fluoride described in example 13.
Detailed Description
The invention is described in further detail below with reference to the accompanying drawings and detailed description.
The starting materials used in the following examples are commercially available, and each reagent is purified, if necessary, by means well known in the art and used.
In the present invention, the "mercapto compound" has the meaning generally understood by those skilled in the art, that is, a compound containing a mercapto group (-SH), such as 2-mercaptobenzoxazole, 2-mercaptobenzothiazole, and various derivatives thereof.
In the present invention, the "sulfonyl fluoride-based compound" has a meaning generally understood by those skilled in the art, that is, a compound having a sulfur atom bonded to an oxygen atom, such as S- (benzo [ d ] thiazol-2-yl) -N-benzylsulfonyl and various derivatives thereof.
The starting materials used in the following examples are commercially available, and each reagent is purified, if necessary, by means well known in the art and used.
1 H NMR 13 C NMR was measured using a Bruker Avance 400spectrometer instrument. The test temperature was room temperature and the solvent was deuterated chloroform, and the reference was selected: 1 H NMR:CHCl 3 7.260ppm; 13 C NMR:CHCl 3 77.000ppm.
Example 1: synthesis of benzo [ d ] thiazole-2-sulfonyl fluoride
Into a nitrogen-protected Schlenk reaction tube equipped with a magnetic stirrer was charged dimethyl sulfonium bromide (110.9 mg,0.5mmol,1 equiv), meCN (5 mL) was added at 0deg.C (ice water bath) and dissolved to form a mixed solution, and the mixed solution was stirred for 5min, 2,4, 6-trimethylpyridine (95 mg,0.75mmol,1.5 equiv) was added and reacted for a while, and benzo [ d ] thiazole-2-thiol (167 mg,1mmol,2 equiv) was added. After stirring for 5 minutes, potassium fluorohydride (117 mg,1.5mmol,3 equiv) and sodium chlorite (226 mg,2mmol,4 equiv) were sequentially added, the reaction was naturally restored to room temperature, the reaction was continued for 14 hours, after the completion of the reaction, the reaction solution was washed with water and extracted three times with ethyl acetate, 10mL each time, the organic phases were combined, concentrated by rotary evaporation and then subjected to column chromatography to give 103mg of benzo [ d ] thiazole-2-sulfonyl fluoride in 95% yield.
Product benzo [ d ]]Thiazole-2-sulfonyl fluoride: 1 H NMR(400MHz,Chloroform-d)δ8.31–8.26(m,1H),8.07–8.03(m,1H),7.73–7.66(m,2H). 13 C NMR(101MHz,Chloroform-d)δ155.9(d,J＝38.2Hz),151.8(d,J＝2.6Hz).137.0,129.4,128.4,126.1,122.2. 19 F NMR(376MHz,Chloroform-d)δ64.15.
example 2: synthesis of 4-chlorobenzenesulfonyl fluoride
Into a nitrogen-protected Schlenk reaction tube equipped with a magnetic stirrer was added dimethyl sulfonium bromide (110.9 mg,0.5mmol,1 equiv), meCN (5 mL) was added at 0deg.C (ice water bath) and dissolved to form a mixed solution, and the mixed solution was stirred for 5min, 2,4, 6-trimethylpyridine (95 mg,0.75mmol,1.5 equiv) was added and reacted for a while, and 4-chlorophenylthiol (145 mg,1mmol,2 equiv) was added. After stirring for 5 minutes, potassium fluorohydride (117 mg,1.5mmol,3 equiv) and sodium chlorite (226 mg,2mmol,4 equiv) were sequentially added, the reaction was naturally restored to room temperature, the reaction was continued for 14 hours, after the completion of the reaction, the reaction solution was washed with water and extracted three times with ethyl acetate, 10mL each time, the organic phases were combined, concentrated by rotary evaporation and then subjected to column chromatography to give 60mg of 4-chlorobenzenesulfonyl fluoride in 62% yield.
The product 4-chlorobenzenesulfonyl fluoride: 1 H NMR(400MHz,Chloroform-d)δ7.98–7.93(m,2H),7.63–7.59(m,2H). 13 C NMR(101MHz,Chloroform-d)δ142.6,131.3(d,J＝25.7Hz),130.1,129.8. 19 F NMR(376MHz,CDCl 3 )δ66.50.
EXAMPLE 3 Synthesis of 4- (tert-butyl) benzenesulfonyl fluoride
Into a nitrogen-protected Schlenk reaction tube equipped with a magnetic stirrer was added dimethyl sulfonium bromide (110.9 mg,0.5mmol,1 equiv), meCN (5 mL) was added at 0deg.C (ice water bath) and dissolved to form a mixed solution, and the mixed solution was stirred for 5min, and after adding 2,4, 6-trimethylpyridine (95 mg,0.75mmol,1.5 equiv), the reaction was continued for a while, and 4- (tert-butyl) thiophenol (166 mg,1mmol,2 equiv) was added. After stirring for 5 minutes, potassium fluorohydride (117 mg,1.5mmol,3 equiv) and sodium chlorite (226 mg,2mmol,4 equiv) were sequentially added, the reaction was naturally restored to room temperature, the reaction was continued for 14 hours, after the completion of the reaction, the reaction solution was washed with water and extracted three times with ethyl acetate, 10mL each time, the organic phases were combined, concentrated by rotary evaporation and then subjected to column chromatography to give 87mg of 4- (tert-butyl) benzenethiol in 77% yield.
Product 4- (tert-butyl) benzenesulfonyl fluoride: 1 H NMR(400MHz,Chloroform-d)δ7.54–7.45(m,1H),7.44–7.36(m,1H),7.36–7.30(m,1H),7.30–7.24(m,1H),1.45–1.01(m,9H). 13 C NMR(101MHz,CDCl 3 )δ157.5,155.0,140.2,136.3,127.4,126.4,125.7,124.6,35.2,34.9,31.1,31.0. 19 F NMR(376MHz,CDCl 3 )δ66.24.
EXAMPLE 4 Synthesis of 2-methoxybenzenesulfonyl fluoride
Into a nitrogen-protected Schlenk reaction tube equipped with a magnetic stirrer was added dimethyl sulfonium bromide (110.9 mg,0.5mmol,1 equiv), meCN (5 mL) was added at 0deg.C (ice water bath) and dissolved to form a mixed solution, and the mixed solution was stirred for 5min, 2,4, 6-trimethylpyridine (95 mg,0.75mmol,1.5 equiv) was added and reacted for a while, followed by addition of 2-methoxyphenylthiophenol (140 mg,1mmol,2 equiv). After stirring for 5 minutes, potassium fluorohydride (117 mg,1.5mmol,3 equiv) and sodium chlorite (226 mg,2mmol,4 equiv) were sequentially added, the reaction was naturally restored to room temperature, the reaction was continued for 14 hours, after the completion of the reaction, the reaction solution was washed with water and extracted three times with ethyl acetate, 10mL each time, the organic phases were combined, concentrated by rotary evaporation and then subjected to column chromatography to give 71mg of 2-methoxybenzenesulfonyl fluoride in 75% yield.
The product 2-methoxybenzenesulfonyl fluoride: 1 H NMR(400MHz,Chloroform-d)δ7.95–7.92(m,1H),7.72–7.68(m,1H),7.1–7.09(m,2H),4.01(s,2H). 13 C NMR(101MHz,CDCl 3 )δ158.07,137.37,131.23,131.21,120.49,112.74,56.54. 19 F NMR(376MHz,CDCl 3 )δ58.57.
EXAMPLE 5 Synthesis of 2, 6-dimethylbenzenesulfonyl fluoride
Into a nitrogen-protected Schlenk reaction tube equipped with a magnetic stirrer was charged dimethyl sulfonium bromide (110.9 mg,0.5mmol,1 equiv), meCN (5 mL) was added at 0deg.C (ice water bath) and dissolved to form a mixed solution, and the mixed solution was stirred for 5min, 2,4, 6-trimethylpyridine (95 mg,0.75mmol,1.5 equiv) was added and reacted for a while, and 2, 6-dimethylbenzene (138 mg,1mmol,2 equiv) was added. After stirring for 5 minutes, potassium fluorohydride (117 mg,1.5mmol,3 equiv) and sodium chlorite (226 mg,2mmol,4 equiv) were sequentially added, the reaction was naturally restored to room temperature, the reaction was continued for 14 hours, after the completion of the reaction, the reaction solution was washed with water and extracted three times with ethyl acetate, 10mL each time, the organic phases were combined, concentrated by rotary evaporation and then subjected to column chromatography to give 56mg of 2, 6-dimethylbenzenesulfonyl fluoride in 61% yield.
Product 2, 6-dimethylbenzenesulfonyl fluoride: 1 H NMR(400MHz,Chloroform-d)δ7.45–7.41(m,1H),7.24–7.22(m,2H),2.69(s,6H). 13 C NMR(101MHz,Chloroform-d)δ140.1,134.0,132.05(d,J＝20.1Hz),131.10(d,J＝1.4Hz),22.44(d,J＝2.1Hz). 19 F NMR(376MHz,CDCl 3 )δ67.84.
example 6: synthesis of 3, 4-dimethoxy benzenesulfonyl fluoride
Into a nitrogen-protected Schlenk reaction tube equipped with a magnetic stirrer was added dimethyl sulfonium bromide (110.9 mg,0.5mmol,1 equiv), meCN (5 mL) was added at 0deg.C (ice water bath) and dissolved to form a mixed solution, and the mixed solution was stirred for 5min, 2,4, 6-trimethylpyridine (95 mg,0.75mmol,1.5 equiv) was added and reacted for a while, and 3, 4-dimethoxythiophenol (170 mg,1mmol,2 equiv) was added. After stirring for 5 minutes, potassium fluorohydride (117 mg,1.5mmol,3 equiv) and sodium chlorite (226 mg,2mmol,4 equiv) were sequentially added, the reaction was naturally restored to room temperature, the reaction was continued for 14 hours, after the completion of the reaction, the reaction solution was washed with water and extracted three times with ethyl acetate, 10mL each time, the organic phases were combined, concentrated by rotary evaporation and then subjected to column chromatography to give 80mg of 3, 4-dimethoxybenzenesulfonyl fluoride in 73% yield.
The product 3, 4-dimethoxy benzenesulfonyl fluoride: 1 H NMR(400MHz,Chloroform-d)δ7.66–7.64(m,1H),7.39–7.38(m,1H),7.01(d,J＝8.5Hz,1H),3.98(s,3H),3.95(s,3H). 13 C NMR(101MHz,Chloroform-d)δ154.9,149.5,123.92(d,J＝24.6Hz),123.2,110.8,110.1,56.4,56.3. 19 F NMR(376MHz,Chloroform-d)δ67.22.
example 7: synthesis of 4-fluorobenzenesulfonyl fluoride
Into a nitrogen-protected Schlenk reaction tube equipped with a magnetic stirrer was added dimethyl sulfonium bromide (110.9 mg,0.5mmol,1 equiv), meCN (5 mL) was added at 0deg.C (ice water bath) and dissolved to form a mixed solution, and the mixed solution was stirred for 5min, 2,4, 6-trimethylpyridine (95 mg,0.75mmol,1.5 equiv) was added and reacted for a while, followed by 4-fluorobenzene thiophenol (128 mg,1mmol,2 equiv). After stirring for 5 minutes, potassium fluorohydride (117 mg,1.5mmol,3 equiv) and sodium chlorite (226 mg,2mmol,4 equiv) were sequentially added, the reaction was naturally restored to room temperature, the reaction was continued for 14 hours, after the completion of the reaction, the reaction solution was washed with water and extracted three times with ethyl acetate, 10mL each time, the organic phases were combined, concentrated by rotary evaporation and then subjected to column chromatography to give 69mg of 4-fluorobenzenesulfonyl fluoride in 77% yield.
The product 4-fluorobenzenesulfonyl fluoride: 1 H NMR(400MHz,Chloroform-d)δ8.08–8.04(m,2H),7.34–7.30(m,2H). 13 C NMR(101MHz,CDCl 3 )δ168.1,165.6,131.6,131.5,117.3,117.1. 19 F NMR(376MHz,CDCl 3 )δ66.82,-99.27.
example 8: synthesis of benzylsulfonyl fluorides
Into a nitrogen-protected Schlenk reaction tube equipped with a magnetic stirrer was added dimethyl sulfonium bromide (110.9 mg,0.5mmol,1 equiv), meCN (5 mL) was added at 0deg.C (ice water bath) and dissolved to form a mixed solution, and the mixed solution was stirred for 5min, 2,4, 6-trimethylpyridine (95 mg,0.75mmol,1.5 equiv) was added and reacted for a while, and benzyl mercaptan (124 mg,1mmol,2 equiv) was added. After stirring for 5 minutes, potassium fluorohydride (117 mg,1.5mmol,3 equiv) and sodium chlorite (226 mg,2mmol,4 equiv) were sequentially added, the reaction was naturally restored to room temperature, the reaction was continued for 14 hours, after the completion of the reaction, the reaction solution was washed with water and extracted three times with ethyl acetate, 10mL each time, the organic phases were combined, concentrated by rotary evaporation and then subjected to column chromatography to give 76mg of benzylsulfonyl fluoride in 88% yield.
The product benzylsulfonyl fluoride: 1 H NMR(400MHz,Chloroform-d)δ7.49–7.42(m,5H),4.60(d,J＝3.3Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ130.6,129.9,129.3,125.4,56.8(d,J＝17.6Hz). 19 FNMR(376MHz,CDCl 3 )δ51.38.
EXAMPLE 9 Synthesis of 4- (tert-butyl) benzylsulfonyl fluoride
Into a nitrogen-protected Schlenk reaction tube equipped with a magnetic stirrer was added dimethyl sulfonium bromide (110.9 mg,0.5mmol,1 equiv), meCN (5 mL) was added at 0deg.C (ice water bath) and dissolved to form a mixed solution, and the mixed solution was stirred for 5min, and after adding 2,4, 6-trimethylpyridine (95 mg,0.75mmol,1.5 equiv), the reaction was continued for a while, 4- (t-butyl) benzyl mercaptan (180 mg,1mmol,2 equiv) was added. After stirring for 5 minutes, potassium fluorohydride (117 mg,1.5mmol,3 equiv) and sodium chlorite (226 mg,2mmol,4 equiv) were sequentially added, the reaction was naturally restored to room temperature, the reaction was continued for 14 hours, after the completion of the reaction, the reaction solution was washed with water and extracted three times with ethyl acetate, 10mL each time, the organic phases were combined, concentrated by rotary evaporation and then subjected to column chromatography to give 82mg of 4- (tert-butyl) benzenesulfonyl fluoride in 71% yield.
Product 4- (tert-butyl) benzylsulfonyl fluoride: 1 H NMR(400MHz,Chloroform-d)δ7.48–7.46(m,2H),7.38–7.36(m,2H),4.58(s,2H),1.34(s,9H). 13 C NMR(101MHz,CDCl 3 )δ153.1,130.3,126.3,122.3,56.50,56.3,34.7,31.1. 19 F NMR(376MHz,CDCl 3 )δ51.12.
EXAMPLE 10 Synthesis of methyl 2- (fluorosulfonyl) benzoate
Into a nitrogen-protected Schlenk reaction tube equipped with a magnetic stirrer was added dimethyl sulfonium bromide (110.9 mg,0.5mmol,1 equiv), meCN (5 mL) was added at 0deg.C (ice water bath) and dissolved to form a mixed solution, and the mixed solution was stirred for 5min, and after adding 2,4, 6-trimethylpyridine (95 mg,0.75mmol,1.5 equiv), the reaction was continued for a while, and methyl 2-mercaptobenzoate (168 mg,1mmol,2 equiv) was added. After stirring for 5 minutes, potassium fluorohydride (117 mg,1.5mmol,3 equiv) and sodium chlorite (226 mg,2mmol,4 equiv) were sequentially added, the reaction was naturally restored to room temperature, the reaction was continued for 14 hours, after the completion of the reaction, the reaction solution was washed with water and extracted three times with ethyl acetate, 10mL each time, the organic phases were combined, concentrated by rotary evaporation and then subjected to column chromatography to give 93mg of methyl 2- (fluorosulfonyl) benzoate in 82% yield.
Product methyl 2- (fluorosulfonyl) benzoate: 1 H NMR(400MHz,Chloroform-d)δ8.18–8.13(m,1H),7.90–7.85(m,1H),7.85–7.80(m,1H),7.76–7.71(m,1H),3.99(s,2H). 13 C NMR(101MHz,CDCl 3 )δ165.7,135.2,133.0,132.0,131.6,130.7,130.5,,53.50. 19 F NMR(376MHz,CDCl 3 )δ64.48.
EXAMPLE 11 Synthesis of 4-methoxybenzenesulfonyl fluoride
Into a nitrogen-protected Schlenk reaction tube equipped with a magnetic stirrer was added dimethyl sulfonium bromide (110.9 mg,0.5mmol,1 equiv), meCN (5 mL) was added at 0deg.C (ice water bath) and dissolved to form a mixed solution, and the mixed solution was stirred for 5min, 2,4, 6-trimethylpyridine (95 mg,0.75mmol,1.5 equiv) was added and reacted for a while, followed by 4-methoxyphenylthiophenol (140 mg,1mmol,2 equiv). After stirring for 5 minutes, potassium fluorohydride (117 mg,1.5mmol,3 equiv) and sodium chlorite (226 mg,2mmol,4 equiv) were sequentially added, the reaction was naturally restored to room temperature, the reaction was continued for 14 hours, after the completion of the reaction, the reaction solution was washed with water and extracted three times with ethyl acetate, 10mL each time, the organic phases were combined, concentrated by rotary evaporation and then subjected to column chromatography to give 46mg of 4-methoxybenzenesulfonyl fluoride in 86% yield.
The product 4-methoxybenzenesulfonyl fluoride: 1 H NMR(400MHz,Chloroform-d)δ7.94–7.89(m,2H),7.07–7.03(m,2H),3.90(s,3H). 13 C NMR(101MHz,CDCl 3 )δ165.2,130.8,123.9(d,J＝24.6Hz),55.8. 19 FNMR(376MHz,CDCl 3 )δ67.31.
example 12: synthesis of pyridine-2-sulfonyl fluoride
Into a nitrogen-protected Schlenk reaction tube equipped with a magnetic stirrer was added dimethyl sulfonium bromide (110.9 mg,0.5mmol,1 equiv), meCN (5 mL) was added at 0deg.C (ice water bath) and dissolved to form a mixed solution, and the mixed solution was stirred for 5min, 2,4, 6-trimethylpyridine (95 mg,0.75mmol,1.5 equiv) was added and reacted for a while, and pyridine-2-thiol (111 mg,1mmol,2 equiv) was added. After stirring for 5 minutes, potassium fluorohydride (117 mg,1.5mmol,3 equiv) and sodium chlorite (226 mg,2mmol,4 equiv) were sequentially added, the reaction was naturally restored to room temperature, the reaction was continued for 14 hours, after the completion of the reaction, the reaction solution was washed with water and extracted three times with ethyl acetate, 10mL each time, the organic phases were combined, concentrated by rotary evaporation and then subjected to column chromatography to give 97mg of pyridine-2-sulfonyl fluoride in 61% yield.
The product pyridine-2-sulfonyl fluoride: 1 H NMR(400MHz,Chloroform-d)δ8.8–8.83(m,1H),8.14–8.12(m,1H),8.08–8.04(m,1H),7.73–7.70(m,1H). 13 C NMR(101MHz,CDCl 3 )δ151.3,151.0,138.7,129.2,124.. 19 F NMR(376MHz,CDCl 3 )δ55.84.
example 13: synthesis of naphthalene-2-sulfonyl fluoride
Into a nitrogen-protected Schlenk reaction tube equipped with a magnetic stirrer was added dimethyl sulfonium bromide (110.9 mg,0.5mmol,1 equiv), meCN (5 mL) was added at 0deg.C (ice water bath) and dissolved to form a mixed solution, and the mixed solution was stirred for 5min, 2,4, 6-trimethylpyridine (95 mg,0.75mmol,1.5 equiv) was added and reacted for a while, and naphthalene-2-thiol (160 mg,1mmol,2 equiv) was added. After stirring for 5 minutes, potassium fluorohydride (117 mg,1.5mmol,3 equiv) and sodium chlorite (226 mg,2mmol,4 equiv) were sequentially added, the reaction was naturally restored to room temperature, the reaction was continued for 14 hours, after the completion of the reaction, the reaction solution was washed with water and extracted three times with ethyl acetate, 10mL each time, the organic phases were combined, concentrated by rotary evaporation and then subjected to column chromatography to give 208mg of naphthalene-2-sulfonyl fluoride in 99% yield.
The product naphthalene-2-sulfonyl fluoride: 1 H NMR(400MHz,Chloroform-d)δ8.58(d,J＝2.0Hz,1H),8.07–7.90(m,4H),7.76–7.72(m,1H),7.69–7.65(m,1H). 13 C NMR(101MHz,Chloroform-d)δ135.9,131.7,130.8(d,J＝1.1Hz),130.3,130.0,129.7,129.5,128.2,128.0,122.0. 19 F NMR(376MHz,CDCl 3 )δ66.39.
it should be noted that the foregoing is merely a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and any combination or equivalent transformation made on the basis of the foregoing embodiment falls within the scope of the present invention.

Claims (9)

1. The synthesis process of sulfonyl fluoride compound is characterized by comprising the following steps:
wherein R is a substituent selected from C 6 ～C 15 Aliphatic, C 6 ～C 15 Or a 5-to 10-membered heteroaryl group containing 1-5O, N, S heteroatoms;
the organic sulfonium reagent is dimethyl sulfonium bromide;
the oxidant is sodium chlorite, NBS, DDQ or H 2 O 2 One of the following;
the alkali is one of tertiary amine, pyridine, cyclohexylmethyl amine and 2,4, 6-trimethylpyridine.
2. The process for synthesizing sulfonyl fluoride compound according to claim 1, wherein the substituent R is preferably C 6 ～C 15 Aliphatic or C of (2) 6 ～C 15 Is an aromatic compound.
3. The process for synthesizing sulfonyl fluoride according to claim 1, wherein the molar ratio of dimethyl sulfonium bromide to R-SH in the process is 1:2-3, preferably 1:3.
4. The synthesis process of sulfonyl fluoride compound according to claim 1, wherein the molar ratio of dimethyl sulfonium bromide to alkali in the process is 1:1-2, preferably 1:1.5; the alkali is 2,4, 6-trimethyl pyridine.
5. The synthesis process of sulfonyl fluoride compound according to claim 1, wherein the process comprises brominating dimethyl sulfonium bromide and KHF 2 The molar ratio of (2) is 1:2-3, preferably 1:3.
6. The synthesis process of sulfonyl fluoride compound according to claim 1, wherein the molar ratio of dimethyl sulfonium bromide to oxidizing agent in the synthesis method is 1:3-4, preferably 1:4; the oxidant is sodium chlorite.
7. The synthesis process of sulfonyl fluoride compound according to claim 1, wherein the reaction solvent in the process is acetonitrile; the molar concentration of R-SH in the reaction solvent is 0.2mmol/mL; KHF (KHF) 2 The molar concentration in the reaction solvent was 0.3mmol/mL.
8. The synthesis process of sulfonyl fluoride compound according to claim 1, wherein the reaction temperature in the process is-20 ℃ to 20 ℃, preferably 0 ℃; the reaction time is 10 to 48 hours, preferably 14 hours.
9. The process according to claim 1, wherein the reaction mixture is washed with a saturated brine and extracted three times with ethyl acetate, and the purified sulfonyl fluoride is obtained by column chromatography.
CN202311645669.1A 2023-12-04 2023-12-04 Synthesis process of sulfonyl fluoride compound Pending CN117658750A (en)

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