阅读说明：本技术 一种制备烷基磺酰氟的方法 (Method for preparing alkyl sulfonyl fluoride ) 是由 刘超 马占虎 马晓玉 胡晓钧 庞婉 吴晶晶 于 2021-08-27 设计创作，主要内容包括：本发明涉及一种制备烷基磺酰氟的方法,以烷基羧酸转化的还原活性酯为原料,二氧化硫替代试剂为二氧化硫源,亲电氟化试剂为氟源,在还原性金属还原及惰性气体保护条件下反应得到目标产物烷基磺酰氟。与现有技术相比,本发明合成方法简单,具有原位引入磺酰氟基团的选择性及较高产率,易于实现规模化生产。(The invention relates to a method for preparing alkyl sulfonyl fluoride, which takes reduction active ester converted from alkyl carboxylic acid as a raw material, a sulfur dioxide substitute reagent as a sulfur dioxide source and an electrophilic fluorinating reagent as a fluorine source, and reacts under the conditions of reducing metal reduction and inert gas protection to obtain a target product of alkyl sulfonyl fluoride. Compared with the prior art, the synthesis method is simple, has selectivity of in-situ introduction of the sulfonyl fluoride group and higher yield, and is easy to realize large-scale production.)

1. A method for preparing alkyl sulfonyl fluoride is characterized in that reduction active ester converted from alkyl carboxylic acid is used as a raw material, a sulfur dioxide substitute reagent is used as a sulfur dioxide source, an electrophilic fluorinating reagent is used as a fluorine source, and the reaction is carried out under the conditions of reducing metal reduction and inert gas protection to obtain a target product of alkyl sulfonyl fluoride.

2. The process for preparing alkylsulfonyl fluorides of claim 1, characterized in that said reductive active ester converted from alkylcarboxylic acid is a compound having the following general structural formula:

wherein R is alkyl, cycloalkyl or arylmethyl.

3. The method of claim 2, wherein R is arylmethyl, and wherein R is a compound having the following general structural formula:

wherein R is₁Is at least one of phenyl, substituted phenyl, aromatic heterocycle or aromatic heterocycle containing derivative groups, condensed ring aryl and substituted condensed ring aryl; r₂Including alkyl groups.

4. The method of claim 1, wherein the sulfur dioxide replacement reagent is any one of 1, 4-diazabicyclo [2.2.2] octane-1, 4-diimmonium-1, 4-disulfinic acid, sodium hydrosulfite, potassium metabisulfite, sodium metabisulfite, 4-dimethylaminopyridine complex sulfur dioxide, sodium formaldehyde sulfoxylate, sodium sulfite, and sodium trifluoromethanesulfonate.

5. The method for preparing alkylsulfonyl fluoride according to claim 1, wherein said electrophilic fluorinating reagent is any one of 1-chloromethyl-4-fluoro-1, 4-diazacyclo [2.2.2] octane tetrafluoroborate, 1-fluoro-4-methyl-1, 4-diazacyclo [2.2.2] octane trifluoromethanesulfonate, 1-fluoro-1, 4-diazacyclo [2.2.2] octane fluoroborate, N-fluoropyridine trifluoromethanesulfonate, N-fluoro-2, 4, 6-trimethylpyridine trifluoromethanesulfonate and N-fluorobisbenzenesulfonamide.

6. The method of claim 1, wherein the reducing metal is any one of zinc powder, copper powder, iron powder, and manganese powder.

7. The method according to claim 1, wherein the inert gas is any one of nitrogen and argon.

8. The method of claim 1, wherein the molar ratio of the reducing active ester converted from the alkyl carboxylic acid, the reducing metal, the electrophilic fluorinating reagent and the sulfur dioxide substitute reagent is 1 (1-3): 1-4: 0.5-3.

9. The method for preparing alkylsulfonyl fluoride according to claim 1, wherein said reaction process is performed in a solvent, and said solvent is one or a mixture of several of N, N-dimethylformamide, N-dimethylacetamide, N-dimethylpropionamide, N-methylpyrrolidone, tetrahydrofuran, dimethylsulfoxide, acetonitrile, acetone, chloroform, ethyl acetate, and water.

10. The method of claim 1, wherein the reaction process comprises the steps of:

(1) under the conditions of reducing metal and inert gas protection, carrying out a first-step reaction on reducing active ester converted from alkyl carboxylic acid and a sulfur dioxide substitute reagent at the reaction temperature of 40-120 ℃ for 2-24 h;

(2) cooling to room temperature, adding electrophilic fluorinating reagent, and carrying out the second step reaction at room temperature for 2-12 h.

Technical Field

The invention relates to the technical field of synthetic chemistry, in particular to a method for preparing alkyl sulfonyl fluoride.

Background

Fluorosulfonyl (SO)₂F) Is a unique fluorine-containing sulfur-containing functional group, and because fluorine atoms have super-strong electron-withdrawing capability, the S-F bond is difficult to break by means of homolytic cleavage. In particular, it is a proton (H) when it undergoes nucleophilic substitution⁺) Or silicon ion (R)₃Si⁺) Can stabilize the leaving fluorinion, so that the reaction has the advantages of large driving force, water resistance, good specificity and controllability and the like. In addition to this, it has hydrolytic stability, resistance to reduction and chemoselective reactivity with sulphur centres, compared with other S (VI) -X bonds. Due to this, sulfonyl fluoride is widely used in the fields of chemistry, surface chemistry, biochemistry, and organic synthesis of polymer materials.

The concept of Click chemistry (Click chemistry) proposed by professor k.barry sharp of norprize has been keen through the development of recent 20 years, and chemists rapidly discover new molecules with specific functions and properties through simple and easy modular synthesis. The most representative reactions in click chemistry, one is the monovalent copper catalyzed cycloaddition reaction of terminal alkynes with azides (CuAAC) reported in 2002, and the other is the high-valent sulfur-fluorine exchange reaction (SuFEx) reported in 2014 (angelw. chem. int.ed.2014,53,9430.), which is considered as a new generation of click reaction, can rapidly obtain the target product with extremely high yield, and is substantially orthogonal to other reactions, providing a practical and efficient new scheme for molecular fragment linking, thus also drawing great attention and extensive research.

Containing C-SO₂The F bond sulfonyl fluoride compound is constructed according to two aspects that the target product mainly comprises an aromatic hydrocarbon sulfonyl fluoride compound and an aliphatic hydrocarbon sulfonyl fluoride compound: mono, aromatic hydrocarbon sulfonyl fluoride compound (Ar-SO)₂F) The construction of (A) can be further divided into: (a) by oxidative fluorination or fluorine-chlorine exchange of the corresponding sulfur-containing precursor compounds, the reaction not involving C-SO₂Construction of F-bonds, the sulfur-containing precursor substrates used tend to be not readily available or difficult to prepare (j.org.chem.2013,78,11262 Tetrahedron 2014,70,2464-2471 Green chem.2016,18,1224 Tetrahedron 2017,58,2244 j.am.chem.soc.2019,141,11832 eur.j.org.chem.2020,17,2497.); (b) obtaining a non-sulfur-containing aromatic group compound precursor and then adding SO₂Source re-fluorination involves a free radical or metal catalyzed coupling process (chem.sci.2017,8,3249.j.org.chem.2017,82,2294.org.lett.2020,22,3072.org.lett.2020,22,2281.). In recent years, the conversion of aliphatic hydrocarbon sulfonyl fluoride compounds into vinyl sulfonyl fluoride blocks, which is mainly represented by the Qinheli group, university of Wuhan Engineers, generally produces alkenyl sulfonyl fluorides or alkyl sulfonyl fluorides having two or more carbons (J.org.chem.2016,81,11360.Synthesis 2020,52,673.Nat Communn 2019,10, 3752). In addition, there is a new free radical trifluoromethylating agent, silver fluorosulfonyl difluoroacetate (Ag (O)₂CCF₂SO₂F) Reaction with non-activated unsaturated hydrocarbons (Angew. chem. int. Ed.2017,56,15432.).

For alkylsulfonyl fluorides, the current synthetic methods are few and limited to alkyl halides, ESF blocks.

Disclosure of Invention

The invention aims to provide a method for preparing alkyl sulfonyl fluoride, which has simple synthesis method, selectivity of introducing sulfonyl fluoride groups in situ and higher yield.

The purpose of the invention can be realized by the following technical scheme: a method for preparing alkyl sulfonyl fluoride comprises the steps of taking reduction active ester converted from alkyl carboxylic acid as a raw material, taking a sulfur dioxide substitute reagent as a sulfur dioxide source, taking an electrophilic fluorination reagent as a fluorine source, and reacting under the conditions of reducing metal and inert gas protection to obtain a target product, namely alkyl sulfonyl fluoride.

The invention provides a method for preparing alkyl sulfonyl fluoride from alkyl carboxylic acid compounds through sulfur dioxide insertion fluorination. The reaction general formula of the invention is as follows: the general reaction formula is as follows:

preferably, the alkyl carboxylic acid converted reduction active ester is a compound having the following structural formula:

wherein R is alkyl, cycloalkyl or arylmethyl.

The alkyl carboxylic acid converted reduction active ester can be prepared by the following method:

taking dichloromethane as a solvent, R-group formic acid and N-hydroxyphthalimide as reactants, and N, N' -diisopropyl carbodiimide (DIC) and 4-Dimethylaminopyridine (DMAP) as catalysts, reacting at room temperature, filtering, washing and purifying to obtain the reduction active ester converted from the alkyl carboxylic acid.

Further preferably, when R is arylmethyl, the compound comprises a compound having the following structural formula:

wherein R is₁Is at least one of phenyl, substituted phenyl, aromatic heterocycle or aromatic heterocycle containing derivative groups, condensed ring aryl and substituted condensed ring aryl; r₂Including alkyl groups. When R is₂When the alkyl is alkyl, the alpha-position of the alkyl comprises a long chain of C1-C18 with primary carbon, or an alkyl compound containing a derivative group on the chain.

When R is alkyl, the long chain of C1-C18 comprises various groups of which the primary, secondary and tertiary carbons contain branched chains.

When R is cycloalkyl, it includes cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantane and the like, and derivatives containing hetero atoms such as alkyl branches, aryl group branches or N, O, S on the ring.

Preferably, the sulfur dioxide-replacing reagent is 1, 4-diazabicyclo [2.2.2]Octane-1, 4-diimmonium-1, 4-Disulfonic Acid (DABSO), sodium hydrosulfite (Na)₂S₂O₄) Potassium metabisulfite (K)₂S₂O₅) Sodium metabisulfite (Na)₂S₂O₅) 4-dimethylaminopyridine complexed sulfur dioxide (DMAP-SO)₂) Sodium formaldehyde sulfoxylate (Rongalite), sodium sulfite (Na)₂SO₃) Sodium trifluoromethanesulfonate (CF)₃SO₂Na). The sulfur dioxide-replacing reagent is preferably 1, 4-diazabicyclo [2.2.2]Octane-1, 4-diimmonium-1, 4-Disulfonic Acid (DABSO).

Preferably, the electrophilic fluorinating reagent is any one of 1-chloromethyl-4-fluoro-1, 4-diazacyclo [2.2.2] octane tetrafluoroborate, 1-fluoro-4-methyl-1, 4-diazacyclo [2.2.2] octane trifluoromethylsulfonate, 1-fluoro-1, 4-diazacyclo [2.2.2] octane fluoroborate, N-fluoropyridine trifluoromethylsulfonate, N-fluoro-2, 4, 6-trimethylpyridine trifluoromethylsulfonate and N-fluorobisbenzenesulfonamide. The electrophilic fluorinating reagent is preferably N-fluorobisbenzenesulfonamide (NFSI).

Preferably, the reducing metal is any one of zinc powder, copper powder, iron powder and manganese powder. The reducing metal is preferably zinc powder.

Preferably, the inert gas is any one of nitrogen and argon. The inert gas is preferably argon.

Preferably, the molar ratio of the reduction active ester converted from the alkyl carboxylic acid, the reducing metal, the electrophilic fluorinating reagent and the sulfur dioxide substitute reagent is 1 (1-3): 1-4: (0.5-3). The molar ratio is more preferably 1:2:3: 1.5.

Preferably, the reaction process is carried out in a solvent, and the solvent is any one or a mixture of several of N, N-dimethylformamide, N-dimethylacetamide, N-dimethylpropionamide, N-methylpyrrolidone, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, acetone, chloroform, ethyl acetate and water.

Further preferably, the solvent is a mixed system of N, N-dimethylpropionamide and water.

Still more preferably, the volume ratio of the N, N-dimethylpropionamide to water is 5: 1. I.e. V_DMPr:V_{Water (W)}＝5:1。

Or the reaction system contains an organic solvent and an additive, wherein the organic solvent is one of N, N-dimethylformamide, N-dimethylacetamide, N-dimethylpropionamide, N-methylpyrrolidone, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, acetone, chloroform and ethyl acetate; the additive is water.

Preferably, the solvent is N, N-dimethylpropionamide, and the volume ratio of the N, N-dimethylpropionamide to the water is 5: 1.

Preferably, the reaction process adopts a 'one-pot' two-step reaction, and comprises the following steps:

(1) under the conditions of reducing metal and inert gas protection, carrying out a first-step reaction on reducing active ester converted from alkyl carboxylic acid and a sulfur dioxide substitute reagent at the reaction temperature of 40-120 ℃ for 2-24 h;

(2) cooling to room temperature, adding electrophilic fluorinating reagent, and carrying out the second step reaction at room temperature for 2-12 h.

Further preferably, the first-step reaction temperature is preferably 80 ℃, and the reaction time is 9 h; the second reaction time is preferably 4 hours.

Still further preferably, the reaction process comprises the steps of: adding reducing active ester converted from alkyl carboxylic acid, a sulfur dioxide substitute reagent and reducing metal into a reaction vessel, adding N, N-dimethylpropionamide and water under the protection of inert gas, heating to 80 ℃ under stirring for reaction for 9h, cooling to room temperature, and adding an electrophilic fluorination reagent for reaction for 4 h. Preferably, the volume ratio of the N, N-dimethylpropionamide to the water is 5: 1.

Compared with the prior art, the invention has the following advantages:

1. the invention takes cheap and easily obtained alkyl carboxylic acid compounds as raw materials to directly remove groups in situ to generate sulfonyl fluoride, introduces sulfonyl fluoride groups in situ directionally, fully expands the compound library of alkyl sulfonyl fluoride and provides a new method for constructing fluorine-containing sulfonyl drug molecules;

2. the synthetic method is simple, and has selectivity of in-situ introduction of sulfonyl fluoride groups and higher yield;

3. the invention is easy to realize large-scale production, and experimental results show that the fluorine spectrum yield of the obtained alkyl sulfonyl fluoride compound can reach 50-90 percent;

4. the invention takes the reduction active ester converted from alkyl carboxylic acid as raw material, and the raw material is rapidly decarboxylated under the action of reducing metal to generate alkyl free radical which is converted from SO₂"capture of SO in Source₂And combining with a fluorinating reagent to generate the alkyl sulfonyl fluoride.

Drawings

FIG. 1 is a nuclear magnetic resonance fluorine spectrum of a nonanyl-1-sulfonyl fluoride compound in example 6 of the present invention;

FIG. 2 is a NMR spectrum of a nonanyl-1-sulfonyl fluoride compound in example 6 according to the invention;

FIG. 3 is a carbon NMR spectrum of a nonanyl-1-sulfonyl fluoride compound in example 6 according to the invention;

FIG. 4 is a nuclear magnetic resonance fluorine spectrum of a 1- (4-isobutylphenyl) ethanesulfonyl fluoride compound according to example 11 of the present invention;

FIG. 5 is a NMR spectrum of a 1- (4-isobutylphenyl) ethanesulfonyl fluoride compound according to example 11 of the present invention;

FIG. 6 is a NMR carbon spectrum of a 1- (4-isobutylphenyl) ethanesulfonyl fluoride compound according to example 11 of the present invention;

FIG. 7 is a NMR spectrum of a 1-methylcyclohexane-1-sulfonyl fluoride compound in example 13 of the present invention;

FIG. 8 is a NMR spectrum of a 1-methylcyclohexane-1-sulfonyl fluoride compound in example 13 of the present invention;

FIG. 9 is a NMR carbon spectrum of a 1-methylcyclohexane-1-sulfonyl fluoride compound in example 13 of the present invention.

Detailed Description

The invention is described in detail below with reference to the figures and specific embodiments. The following examples are carried out on the premise of the technical scheme of the invention, and detailed embodiments and specific operation processes are given, but the scope of the invention is not limited to the following examples.

In the following examples, unless otherwise specified, all the conventional commercially available raw materials or conventional processing techniques in the art are indicated.

The preparation method of the reductive active ester converted from the alkyl carboxylic acid comprises the following steps:

for example, when R is cyclohexyl, 1.28g (10mmol) of cyclohexanecarboxylic acid, 1.63g (10mmol) of N-hydroxyphthalimide and 0.12g (1mmol) of DMAP are placed in a round-bottomed flask, 100mL of dichloromethane is added as a solvent, and the mixture is vigorously stirred. Then, 1.7mL (10mmol) of DIC was added, and the mixture was stirred at room temperature for 3 to 5 hours. The mixture was filtered through a thin layer of celite or silica gel and then rinsed with dichloromethane. The filtrate was collected and the solvent was removed under reduced pressure. Purifying by column chromatography or crystallization to obtain the required carboxylic acid reduction active ester raw material.

All carboxylic acid reducing active ester starting materials of the present invention are prepared according to this method.

Example 1

Synthesis of Cyclohexylsulfonyl fluoride Using the reductive active ester of Cyclohexylcarboxylic acid as template substrate, Na₂S₂O₄NFSI as a fluorine source and DMF as a solvent are used as sulfur dioxide sources and reacted under the protection of inert gases and heating to generate sulfonyl fluoride. The reaction formula and the specific implementation content are as follows:

a10 mL sealed tube was placed in a magneton, and 54.9mg (0.2mmol) of a reduction-active ester of cyclohexylcarboxylic acid and 52.3mg (0.3mmol) of Na were weighed₂S₂O₄Adding into the mixture, pumping and changing argon for three times, adding 2mL of N, N-Dimethylformamide (DMF) as a solvent under the protection of argon, heating to 80 ℃ under stirring for reaction for 9 hours, cooling to room temperature, adding 189.2mg (0.6 mmo)l) post reaction for 4 hours with NFSI. After the reaction is finished, 4-methoxy trifluoromethoxybenzene is added as an internal standard, and the yield of the fluorine spectrum is 0% through nuclear magnetic analysis.

Example 2

Synthesis of Cyclohexylsulfonyl fluoride Using the reductive active ester of Cyclohexylcarboxylic acid as template substrate, Na₂S₂O₄NFSI as a source of sulfur dioxide, DMF as a solvent, and water as an additive. The reaction formula is shown as follows:

a10 mL sealed tube was placed in a magneton, and 54.9mg (0.2mmol) of a reduction-active ester of cyclohexylcarboxylic acid and 52.3mg (0.3mmol) of Na were weighed₂S₂O₄Adding into the mixture, pumping and changing argon for three times, and adding N, N-Dimethylformamide (DMF) and water (V) under the protection of argon_DMF:V_{Water (W)}2:0.4, mL) as solvent and additive, heated to 80 ℃ with stirring for 9 hours, cooled to room temperature, added 189.2mg (0.6mmol) of NFSI and reacted for 4 hours. After the reaction is finished, 4-methoxy trifluoromethoxybenzene is added as an internal standard, and the yield of the fluorine spectrum is 22% through nuclear magnetic analysis.

Example 3

Synthesis of Cyclohexylsulfonyl fluoride Using the reductive active ester of Cyclohexylcarboxylic acid as template substrate, Na₂S₂O₄NFSI is used as a sulfur dioxide source, NFSI is used as a fluorine source, zinc powder is used as a reducing agent, DMF is used as a solvent, and water is used as an additive. The reaction formula is shown as follows:

a10 mL sealed tube was placed in a magneton, and 54.9mg (0.2mmol) of a reduction-active ester of cyclohexylcarboxylic acid and 52.3mg (0.3mmol) of Na were weighed₂S₂O₄And 26.0mg (0.4mmol) of zinc powder are added, argon is pumped three times, and N, N-dimethylformamide is added under the protection of argon(DMF) and water (V)_DMF:V_{Water (W)}2:0.4, mL), heated to 80 ℃ with stirring, reacted for 9 hours, cooled to room temperature, added 189.2mg (0.6mmol) of NFSI, and reacted for 4 hours. After the reaction is finished, 4-methoxy trifluoromethoxybenzene is added as an internal standard, and the yield of the fluorine spectrum obtained by nuclear magnetic analysis is 40%.

Example 4

In addition to example 3 (zinc powder was added and water was added to the solvent), conditions such as the type of organic solvent and the temperature were selected.

Through the screening of the conditions, the obtained preferable conditions are as follows: substrate (0.2mmol,1.0equiv.), Na₂S₂O₄(0.3mmol,1.5equiv.), NFSI (0.6mmol,3equiv.), Zinc powder (0.4mmol,2.0equiv.), N, N-dimethylpropionamide (DMPr), and Water (V)_DMPr:V_{Water (W)}2:0.4, mL) under an argon atmosphere. The reaction formula is shown as follows:

example 5

Synthesis of Cyclohexylsulfonyl fluoride Using the reductive active ester of Cyclohexylcarboxylic acid as template substrate, Na₂S₂O₄As a sulfur dioxide source, NFSI is a fluorine source, zinc powder is a reducing agent, and the solvent is a mixture of DMPr and water (V)_DMPr:V_{Water (W)}2:0.4, mL), the reaction produced sulfonyl fluoride. The reaction formula is shown as follows:

the environment of the reaction system is changed from 'reaction under the atmosphere of inert gas and argon gas' to 'reaction under the environment of direct air', and other conditions are not changed.

A10 mL sealed tube was placed in a magneton, and 54.9mg (0.2mmol) of a reduction-active ester of cyclohexylcarboxylic acid and 52.3mg (0.3mmol) of Na were weighed₂S₂O₄And 26.0mg (0.4mmol) of zinc powder were added thereto, and N, N-dimethylpropionamide (DMPr) and water (V) were added_DMPr:V_{Water (W)}2:0.4, mL), heated to 80 ℃ with stirring, reacted for 9 hours, cooled to room temperature, added 189.2mg (0.6mmol) of NFSI, and reacted for 4 hours. After the reaction is finished, 4-methoxy trifluoromethoxybenzene is added as an internal standard, and the yield of the fluorine spectrum is 28% through nuclear magnetic analysis.

The experimental results show that the sulfonyl fluoride compound can still be obtained by using the method in an air atmosphere, but the yield is low, which indicates that oxygen in the air has an influence on the reaction. Thus, the optimal conditions were determined to be: substrate (0.2mmol,1.0equiv.), Na₂S₂O₄(0.3mmol,1.5equiv.), NFSI (0.6mmol,3equiv.), zinc powder (0.4mmol,2.0equiv.), N, N-dimethylpropionamide (DMPr) and water in a volume ratio of 5:1, under an argon atmosphere, were subjected to a "one-pot" reaction. The reaction comprises two steps, the first step: the reaction temperature is 80 ℃, and the reaction time is 9 h. The second step is that: cooling to room temperature, adding NFSI, reacting at room temperature for 4 h.

Example 6

The synthesis of nonanyl-1-sulfonyl fluoride has the following reaction formula:

a10 mL sealed tube was placed in a magneton, and 126.8mg (0.4mmol) of a reductive active ester of nonane-1-carboxylic acid and 104.5mg (0.6mmol) of Na were weighed₂S₂O₄And 52.0mg (0.8mmol) of zinc powder are added thereto, argon is evacuated three times, and N, N-dimethylpropionamide (DMPr) and water (V) are added under the protection of argon_DMPr:V_{Water (W)}4:0.8, mL), heated to 80 ℃ with stirring, reacted for 9 hours, cooled to room temperature, added with 378.4mg (1.2mmol) of NFSI, and reacted for 4 hours. Inverse directionAfter the reaction, a proper amount of water was added to the reaction system, dichloromethane was used as an extractant, extraction was performed 3 times, washing was performed 2 times with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried, and finally separated by column chromatography to obtain the objective product (61% fluorine spectrum yield; 48.5mg, 58% isolation yield).¹⁹F NMR(376MHz,Chloroform-d)δ53.15.¹H NMR(400MHz,Chloroform-d)δ3.41–3.29(m,2H),1.94(p,J＝7.7Hz,2H),1.47(p,J＝7.2Hz,2H),1.40–1.17(m,10H),0.88(t,J＝6.8Hz,3H).¹³C NMR(101MHz,Chloroform-d)δ50.95,31.89,28.94,27.99,23.52,22.75,14.20.HRMS(EI)m/z:[M]⁺Calcd for C₉H₁₉O₂FS210.1084；Found 210.1083.

Example 7

The synthesis of phenylmethanesulfonyl fluoride has the following reaction formula:

a10 mL sealed tube was placed in a magneton, and 112mg (0.4mmol) of a reducing active ester of benzylcarboxylic acid and 104.5mg (0.6mmol) of Na were weighed₂S₂O₄And 52.0mg (0.8mmol) of zinc powder are added thereto, argon is evacuated three times, and N, N-dimethylpropionamide (DMPr) and water (V) are added under the protection of argon_DMPr:V_{Water (W)}4:0.8, mL), heated to 80 ℃ with stirring, reacted for 9 hours, cooled to room temperature, added with 378.4mg (1.2mmol) of NFSI, and reacted for 4 hours. After the reaction, a proper amount of water is added into the reaction system, dichloromethane is used as an extracting agent for extraction for 3 times, saturated saline solution is used for washing for 2 times, organic phases are combined, anhydrous sodium sulfate is dried, filtration and spin-drying are carried out, and finally, a target product (71% fluorine spectrum yield; 43.8mg, 68% separation yield) is obtained through column chromatography separation.¹⁹F NMR(376MHz,Chloroform-d)δ51.31(t,J＝3.4Hz).¹H NMR(400MHz,Chloroform-d)δ7.45(d,J＝3.8Hz,5H),4.60(d,J＝3.2Hz,2H).¹³C NMR(101MHz,Chloroform-d)δ130.69,129.93,129.33,125.51,56.92,56.75.HRMS(EI)m/z:[M]⁺Calcd for C₇H₇O₂FS 174.0145；Found 174.0150.

Example 8

Synthesis of 4-phenylbutane-1-sulfonyl fluoride, the reaction scheme is shown below:

a10 mL sealed tube was placed in a magneton, and 129.2mg (0.4mmol) of a reductive active ester of 4-phenylbutylcarboxylic acid and 104.5mg (0.6mmol) of Na were weighed₂S₂O₄And 52.0mg (0.8mmol) of zinc powder are added thereto, argon is evacuated three times, and N, N-dimethylpropionamide (DMPr) and water (V) are added under the protection of argon_DMPr:V_{Water (W)}4:0.8, mL), heated to 80 ℃ with stirring, reacted for 9 hours, cooled to room temperature, added with 378.4mg (1.2mmol) of NFSI, and reacted for 4 hours. After the reaction, a proper amount of water is added into the reaction system, dichloromethane is used as an extracting agent for extraction for 3 times, saturated saline solution is used for washing for 2 times, organic phases are combined, anhydrous sodium sulfate is dried, filtration and spin-drying are carried out, and finally, a target product (66% fluorine spectrum yield; 54.5mg, 63% separation yield) is obtained through column chromatography separation.¹⁹F NMR(376MHz,Chloroform-d)δ53.54(t,J＝4.3Hz).¹H NMR(400MHz,Chloroform-d)δ7.32(t,J＝7.3Hz,2H),7.23(t,J＝7.4Hz,1H),7.19(d,J＝6.9Hz,2H),3.41–3.32(m,2H),2.69(t,J＝7.5Hz,2H),2.04–1.93(m,2H),1.83(p,J＝7.6Hz,2H).¹³C NMR(101MHz,Chloroform-d)δ140.84,128.70,126.39,50.76,35.15,29.59,23.06.HRMS(EI)m/z:[M]⁺Calcd for C₁₀H₁₃O₂FS 216.0615；Found216.0612.

Example 9

Synthesis of 2- (3, 4-dimethoxyphenyl) ethanesulfonyl fluoride, the reaction formula is shown below:

a10 mL sealed tube was placed in a magneton, and 135.8mg (0.4mmol) of a reducing active ester of 2- (3, 4-dimethoxyphenyl) acetic acid and 104.5mg (0.6mmol) of Na were weighed₂S₂O₄And 52.0mg (0.8mmol) of zinc powder are added thereto, argon is evacuated three times, and N, N-dimethylpropionamide (DMPr) and water (V) are added under the protection of argon_DMPr:V_{Water (W)}4:0.8, mL), heated to 80 ℃ with stirring, reacted for 9 hours, cooled to room temperature, added with 378.4mg (1.2mmol) of NFSI, and reacted for 4 hours. After the reaction, a proper amount of water was added to the reaction system, dichloromethane was used as an extractant, extraction was performed 3 times, washing was performed 2 times with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried, and finally separated by column chromatography to obtain the objective product (52% fluorine spectrum yield; 46.0mg, 50% isolation yield).¹⁹F NMR(376MHz,Chloroform-d)δ53.31(t,J＝4.3Hz).¹H NMR(400MHz,Chloroform-d)δ6.83(d,J＝8.2Hz,1H),6.77(dd,J＝8.2,2.0Hz,1H),6.72(d,J＝1.9Hz,1H),3.88(d,J＝5.5Hz,6H),3.65–3.55(m,2H),3.23–3.14(m,2H).¹³C NMR(101MHz,Chloroform-d)δ149.49,148.62,128.51,120.57,111.73,111.60,56.08,29.42.HRMS(EI)m/z:[M]⁺Calcd for C₁₀H₁₃O₂FS248.0513；Found 248.0520.

Example 10

Synthesis of cyclohexyl sulfonyl fluoride, the reaction is shown as follows:

a10 mL sealed tube was placed in a magneton, and 109.2mg (0.4mmol) of a reduction-active ester of cyclohexylcarboxylic acid and 104.5mg (0.6mmol) of Na were weighed₂S₂O₄And 52.0mg (0.8mmol) of zinc powder are added thereto, argon is evacuated three times, and N, N-dimethylpropionamide (DMPr) and water (V) are added under the protection of argon_DMPr:V_{Water (W)}4:0.8, mL), heated to 80 ℃ with stirring, reacted for 9 hours, cooled to room temperature, added with 378.4mg (1.2mmol) of NFSI, and reacted for 4 hours. After the reaction is finished, adding a proper amount of water into the reaction system, extracting for 3 times by using dichloromethane as an extracting agent, washing for 2 times by using saturated saline solution, combining organic phases, drying by using anhydrous sodium sulfate, filtering, spin-drying, and finally separating by using column chromatography to obtain a target product (78% fluorine)The spectral yield; 43.8mg, 66% isolated yield).¹⁹F NMR(376MHz,Chloroform-d)δ40.77.¹H NMR(400MHz,Chloroform-d)δ3.30(t,J＝12.6Hz,1H),2.29(d,J＝12.7Hz,2H),1.95(d,J＝13.0Hz,2H),1.69(ddd,J＝24.9,16.1,12.4Hz,3H),1.32(td,J＝23.1,20.5,10.7Hz,3H).¹³C NMR(101MHz,Chloroform-d)δ61.17,61.05,53.57,26.61,24.81.HRMS(EI)m/z:[M]⁺Calcd for C₆H₁₂O₂FS 167.0537；Found 167.0535.

Example 11

Synthesis of 1- (4-isobutylphenyl) ethanesulfonyl fluoride, the reaction scheme is as follows:

a10 mL sealed tube was placed in a magneton, and 140.4mg (0.4mmol) of ibuprofen reductively active ester and 104.5mg (0.6mmol) of Na were weighed₂S₂O₄And 52.0mg (0.8mmol) of zinc powder are added thereto, argon is evacuated three times, and N, N-dimethylpropionamide (DMPr) and water (V) are added under the protection of argon_DMPr:V_{Water (W)}4:0.8, mL), heated to 80 ℃ with stirring, reacted for 9 hours, cooled to room temperature, added with 378.4mg (1.2mmol) of NFSI, and reacted for 4 hours. After the reaction is finished, adding a proper amount of water into the reaction system, using dichloromethane as an extracting agent, extracting for 3 times, washing for 2 times by using saturated saline solution, combining organic phases, drying by anhydrous sodium sulfate, filtering, spin-drying, and finally separating by column chromatography to obtain the target product (90% fluorine spectrum yield; 80.1mg, 82% separation yield).¹⁹F NMR(376MHz,Chloroform-d)δ42.21.¹H NMR(400MHz,Chloroform-d)δ7.36(d,J＝8.2Hz,2H),7.21(d,J＝8.2Hz,2H),4.63(q,J＝7.2Hz,1H),2.50(d,J＝7.2Hz,2H),1.93(d,J＝7.2Hz,3H),1.86(dt,J＝13.7,6.8Hz,1H),0.92(d,J＝6.6Hz,6H).¹³C NMR(101MHz,Chloroform-d)δ143.89,129.97,128.65,63.11,62.97,45.17,30.99,30.21,22.44,16.08.HRMS(EI)m/z:[M]⁺Calcd for C₁₂H₁₇O₂FS 244.0928；Found 244.0926.

Example 12

The synthesis of adamantane-1-sulfonyl fluoride, the reaction formula is as follows:

a10 mL sealed tube was placed in a magneton, and 130.0mg (0.4mmol) of a reductive active ester of adamantane-1-carboxylic acid and 104.5mg (0.6mmol) of Na were weighed₂S₂O₄And 52.0mg (0.8mmol) of zinc powder are added thereto, argon is evacuated three times, and N, N-dimethylpropionamide (DMPr) and water (V) are added under the protection of argon_DMPr:V_{Water (W)}4:0.8, mL), heated to 80 ℃ with stirring, reacted for 9 hours, cooled to room temperature, added with 378.4mg (1.2mmol) of NFSI, and reacted for 4 hours. After the reaction, a proper amount of water is added into the reaction system, dichloromethane is used as an extracting agent for extraction for 3 times, saturated saline solution is used for washing for 2 times, organic phases are combined, anhydrous sodium sulfate is dried, filtration and spin-drying are carried out, and finally, the target product (50% fluorine spectrum yield; 34.8mg, 45% separation yield) is obtained through column chromatography separation.¹⁹F NMR(376MHz,Chloroform-d)δ26.44.¹H NMR(400MHz,Chloroform-d)δ2.22(s,3H),2.18(s,6H),1.83–1.69(m,6H).¹³C NMR(101MHz,Chloroform-d)δ36.10,35.54,28.02.HRMS(EI)m/z:[M]⁺Calcd for C₁₀H₁₆O₂FS 217.0693；Found217.0690.

Example 13

The synthesis of 1-methylcyclohexane-1-sulfonyl fluoride has the following reaction formula:

a10 mL sealed tube was placed in a magneton, and 114.9mg (0.4mmol) of a reductive active ester of 1-methylcyclohexane-1-carboxylic acid and 104.5mg (0.6mmol) of Na were weighed₂S₂O₄And 52.0mg (0.8mmol) of zinc powder are added thereto, argon is evacuated three times, and N, N-dimethylpropionamide (DMPr) and water (V) are added under the protection of argon_DMPr:V_{Water (W)}4:0.8, mL), heated to 80 ℃ with stirring, reacted for 9 hours, cooledAfter addition of 378.4mg (1.2mmol) of NFSI at room temperature, the reaction was continued for 4 hours. After the reaction, a proper amount of water is added into the reaction system, dichloromethane is used as an extracting agent for extraction for 3 times, saturated saline solution is used for washing for 2 times, organic phases are combined, anhydrous sodium sulfate is dried, filtration and spin-drying are carried out, and finally, a target product (68% fluorine spectrum yield; 39.6mg, 55% separation yield) is obtained through column chromatography separation.¹⁹F NMR(376MHz,Chloroform-d)δ29.02.¹H NMR(400MHz,Chloroform-d)δ2.02(td,J＝12.8,4.1Hz,2H),1.89(d,J＝13.0Hz,2H),1.79(dt,J＝13.1,3.7Hz,2H),1.70(dt,J＝13.1,3.7Hz,1H),1.58(s,3H),1.54–1.40(m,2H),1.29(dddd,J＝16.4,12.4,8.0,3.8Hz,1H).¹³C NMR(101MHz,Chloroform-d)δ65.11,65.02,53.56,31.31,24.83,21.18,18.63.HRMS(EI)m/z:[M]⁺Calcd for C₇H₁₄O₂FS181.0693；Found 181.0697.

The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.